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How Malaria Has Affected the Human Genome and What Human Genetics Can Teach Us about Malaria
Abstract
Malaria is a major killer of children worldwide and the strongest known force for evolutionary selection in the recent history of the human genome. The past decade has seen growing evidence of ethnic differences in susceptibility to malaria and of the diverse genetic adaptations to malaria that have arisen in different populations: epidemiological confirmation of the hypotheses that G6PD deficiency, alpha+ thalassemia, and hemoglobin C protect against malaria mortality; the application of novel haplotype-based techniques demonstrating that malaria-protective genes have been subject to recent positive selection; the first genetic linkage maps of resistance to malaria in experimental murine models; and a growing number of reported associations with resistance and susceptibility to human malaria, particularly in genes involved in immunity, inflammation, and cell adhesion. The challenge for the next decade is to build the global epidemiological infrastructure required for statistically robust genomewide association analysis, as a way of discovering novel mechanisms of protective immunity that can be used in the development of an effective malaria vaccine.
... Malaria, the strongest evolutionary selective force in the recent history of the human genome [6], leads to human adaptations that comprise some of the most common Mendelian diseases of mankind [7]. These adaptative traits have evolved independently in different malaria-endemic populations [8,9], such as hemoglobin S (HbS) and Hemoglobin C (HbC), which have risen to a high frequency despite the fatal consequences for homozygote carriers [8]. ...
... Malaria, the strongest evolutionary selective force in the recent history of the human genome [6], leads to human adaptations that comprise some of the most common Mendelian diseases of mankind [7]. These adaptative traits have evolved independently in different malaria-endemic populations [8,9], such as hemoglobin S (HbS) and Hemoglobin C (HbC), which have risen to a high frequency despite the fatal consequences for homozygote carriers [8]. ...
... In this review, we aim to outline host genetic factors that may influence human resistance and susceptibility to malaria in order to demonstrate how the co-evolution of the malaria parasite and the human host has led to the selection of human genetic factors and how these genetic changes have been shown to limit malaria disease and mortality [8,[10][11][12][13]]. ...
Introduction: Malaria is one of the strongest known forces of evolutionary selection in the recent history of the human genome, having had important implications in human adaptation and in the response to its infections. The objective of this systematic review was to provide an update on human genetics that have been described as affecting the human susceptibility to malaria around the world and particularly in Africa. Methods: Through world wide web research vectors and using PubMed and Google Scholar, we reviewed relevant original articles, review papers, short reports, and peer-reviewed papers on human genetics factors described as related to human susceptibility to malaria. Here, we reviewed the literature on human genetic polymorphisms associated with protection from Plasmodium infections and/or disease. Results: After reviewing and summarizing 140 manuscripts, we found that several factors appeared to hamper an effective control of malaria, including the complex biology of Plasmodium parasites, parasite genetic diversity, environmental factors, resistance to antimalarial drugs, and the lack of a highly effective vaccine for public health use. Although the cellular and molecular regulatory mechanisms underlying the pathogenesis of disease are still not fully understood, it is well-established that genetic determinants of the host play an important role in the outcome of infection and the severity of the disease. Conclusions: The interaction between malaria parasites and humans has led to the selection of several inherited traits conferring protection against malaria, such as hemoglobinopathies, enzymopathies, and immunogenetic variation, whilst others’ polymorphism describes susceptibility to the infection.
... Pimenoff et al., 2018;Van Blerkom, 2003;Wolfe et al., 2007). The deep-time frame of the shared human-disease coevolutionary relationship in Africa strongly suggests that disease will have acted as a strong selective pressure, and the role of disease acting as a constraint on host-populations has been widely recorded in Sub-Saharan hunter-gatherer populations (Ferwerda et al., 2007;Kwiatkowski, 2005;Linz et al., 2007;Tallavaara et al., 2018;Tanabe, Mita, Jombart, et al., 2010). This selective pressure not only constrained populations but also influenced patterns of dispersal out of, and within Africa, but without ancient DNA or skeletal lesions, remains a largely invisible force (Linz et al., 2007;Tanabe, Mita, & Balloux, 2010;Wolfe et al., 2007). ...
... Malaria (particularly malaria caused by P. falciparum) is a significant selection pressure in Africa (Kwiatkowski, 2005), because most of the burden of mortality is experienced by children, and serious childhood infections have implications for the development of an effective adult immune system and may lead to lifelong health consequences, for example reduced growth (Halcrow et al., 2020). It may even be the most significant selection pressure humans experienced during our evolution (Kwiatkowski, 2005). ...
... Malaria (particularly malaria caused by P. falciparum) is a significant selection pressure in Africa (Kwiatkowski, 2005), because most of the burden of mortality is experienced by children, and serious childhood infections have implications for the development of an effective adult immune system and may lead to lifelong health consequences, for example reduced growth (Halcrow et al., 2020). It may even be the most significant selection pressure humans experienced during our evolution (Kwiatkowski, 2005). Comparing the frequencies of human genetic mutations which are protective against malaria in different African groups points towards a Pleistocene origin for the most famous host genetic response to malaria: the sickle cell trait. ...
The impact of endemic and epidemic disease on humans has traditionally been seen as a comparatively recent historical phenomenon associated with the Neolithisation of human groups, an increase in population size led by sedentarism, and increasing contact with domesticated animals as well as species occupying opportunistic symbiotic and ectosymbiotic relationships with humans. The orthodox approach is that Neolithisation created the conditions for increasing population size able to support a reservoir of infectious disease sufficient to act as selective pressure. This orthodoxy is the result of an overly simplistic reliance on skeletal data assuming that no skeletal lesions equated to a healthy individual, underpinned by the assumption that hunter‐gatherer groups were inherently healthy while agricultural groups acted as infectious disease reservoirs. The work of van Blerkom, Am. J. Phys. Anthropol., vol. suppl 37 (2003), Wolfe et al., Nature, vol. 447 (2007) and Houldcroft and Underdown, Am. J. Phys. Anthropol., vol. 160, (2016) has changed this landscape by arguing that humans and pathogens have long been fellow travelers. The package of infectious diseases experienced by our ancient ancestors may not be as dissimilar to modern infectious diseases as was once believed. The importance of DNA, from ancient and modern sources, to the study of the antiquity of infectious disease, and its role as a selective pressure cannot be overstated. Here we consider evidence of ancient epidemic and endemic infectious diseases with inferences from modern and ancient human and hominin DNA, and from circulating and extinct pathogen genomes. We argue that the pandemics of the past are a vital tool to unlock the weapons needed to fight pandemics of the future.
... The most clinically significant agent of malaria in Africa, Plasmodium falciparum, has infected humans for nearly 10,000 years [1]. Over this time, the high mortality of severe falciparum malaria has imposed strong selective pressure on the human genome [2]. As such, specific erythrocyte polymorphisms that may otherwise be detrimental to the host (e.g., HbS mutation responsible for sickle cell disease) have been maintained in malaria-endemic populations as that these mutations confer malaria resistance by rendering the erythrocyte less hospitable for the invading parasite [3][4][5]. ...
... In contrast to severe malaria, host genetic polymorphisms that associate with resistance to uncomplicated malaria have primarily involved erythrocyte gene variants [2,5]. Whereas several non-erythrocyte genes have been associated with protection against severe malaria [6,7,9], only a handful of genes involved in the inflammatory response, namely NOS2 and TNF, have been specifically associated with differential risk of uncomplicated or mild malaria [2,[35][36][37][38]. ...
... In contrast to severe malaria, host genetic polymorphisms that associate with resistance to uncomplicated malaria have primarily involved erythrocyte gene variants [2,5]. Whereas several non-erythrocyte genes have been associated with protection against severe malaria [6,7,9], only a handful of genes involved in the inflammatory response, namely NOS2 and TNF, have been specifically associated with differential risk of uncomplicated or mild malaria [2,[35][36][37][38]. ...
Background
TP53 has been shown to play a role in inflammatory processes including malaria. We previously found that p53 attenuates parasite-induced inflammation and predicts clinical protection to Plasmodium falciparum infection in Malian children. Here, we investigated whether p53 codon 47 and 72 polymorphisms are associated with differential risk of P. falciparum infection and uncomplicated malaria in a prospective cohort study of malaria immunity.
Methods
P53 codon 47 and 72 polymorphisms were determined by sequencing exon 4 of TP53 in 631 Malian children and adults enrolled in the Kalifabougou cohort study. The effects of these polymorphisms on the prospective risk of febrile malaria, incident parasitemia, and time-to-fever after PCR-detectable parasitemia over 6 months of intense malaria transmission were assessed by Cox proportional hazards models.
Results
Confounders of malaria risk, including age and hemoglobin S or C, were similar between individuals with and without p53 S47 and R72 polymorphisms. Relative to their respective common variants, neither S47 nor R72 was associated with differences in prospective risk of febrile malaria, incident parasitemia, or febrile malaria once parasitemic.
Conclusions
These findings indicate that p53 codon 47 and 72 polymorphisms are not associated with protection against incident P. falciparum parasitemia or uncomplicated febrile malaria.
... Because of the enormous impact on human health, it is not at all surprising that malaria has served as an important selective force throughout our history and in fact, the disease is thought to have been the strongest source of natural selection on human evolution at least in recent times (Kwiatkowski, 2005). Two prominent examples are often discussed, sickle cell anemia and Duffy coat receptors. ...
... In human populations native to sub-Saharan Africa, there has been an almost complete fixation of a mutation that causes red blood cells to not express a protein that is necessary for the merozoite stage of Plasmodium vivax parasites to invade them (Kwiatkowski, 2005). This is known as the Duffy blood group-negative phenotype and makes those who have it essentially immune from P. vivax and P. knowlesicaused forms of malaria. ...
... Beyond its current health impact, malaria has profoundly influenced human evolution, exerting one of the strongest identified selective pressures on the human genome. Congenital haematological conditions, including sickle-cell disease, G6PD deficiency and thalassaemia, have persisted because they confer partial resistance to malaria, indicating a long-term relationship between the pathogen and human populations 6 . ...
... Together with the near-fixation of the Duffy-negative allele in many human groups in sub-Saharan Africa, this provides strong support for an African origin for P. vivax 1 . The Duffy antigen, encoded by the FY locus, facilitates P. vivax erythrocyte invasion, and individuals homozygous for the Duffy-negative allele were once considered completely immune to P. vivax malaria 1,6 . Accumulating evidence demonstrates that populations with high rates of Duffy negativity can maintain low levels of P. vivax transmission, and the phenotype seems to reduce the efficiency of erythrocyte invasion and provide protection against blood-stage infection 16 . ...
Malaria-causing protozoa of the genus Plasmodium have exerted one of the strongest selective pressures on the human genome, and resistance alleles provide biomolecular footprints that outline the historical reach of these species¹. Nevertheless, debate persists over when and how malaria parasites emerged as human pathogens and spread around the globe1,2. To address these questions, we generated high-coverage ancient mitochondrial and nuclear genome-wide data from P. falciparum, P. vivax and P. malariae from 16 countries spanning around 5,500 years of human history. We identified P. vivax and P. falciparum across geographically disparate regions of Eurasia from as early as the fourth and first millennia bce, respectively; for P. vivax, this evidence pre-dates textual references by several millennia³. Genomic analysis supports distinct disease histories for P. falciparum and P. vivax in the Americas: similarities between now-eliminated European and peri-contact South American strains indicate that European colonizers were the source of American P. vivax, whereas the trans-Atlantic slave trade probably introduced P. falciparum into the Americas. Our data underscore the role of cross-cultural contacts in the dissemination of malaria, laying the biomolecular foundation for future palaeo-epidemiological research into the impact of Plasmodium parasites on human history. Finally, our unexpected discovery of P. falciparum in the high-altitude Himalayas provides a rare case study in which individual mobility can be inferred from infection status, adding to our knowledge of cross-cultural connectivity in the region nearly three millennia ago.
... However, we observed convincing replication of this association in 32 previously reported mild malaria 19 cases from Mali, for which RNA-seq data has previously been reported [32]. Excluding 5 samples which 20 appeared to have mixed bases in RNA reads at this locus (requiring < 5% or > 95% of reads at the locus 21 to support expression of the T allele), we found strong evidence for replication: 11 of 14 (79%) ...
... It is made available under a preprint (which was not certified by peer review) is the author/funder, who has granted bioRxiv a license to display the preprint in The copyright holder for this this version posted September 14, 2023. ; https://doi.org/10.1101/2023.09.14.557461 doi: bioRxiv preprint samples that total read counts (reflecting expression levels) were associated with b S status or with the Ghanaian cases from this study, and Malian cases from [32]. Text indicates the 2-sided P-value for 9 each point. ...
Heterozygosity for sickle haemoglobin (HbS) confers protection against severe malaria caused by the parasite Plasmodium falciparum. Recent work suggests that this protective effect can depend on the parasite genotype. Here, we performed a genome-wide association analysis of P. falciparum against human beta-globin genotypes in a sample of 1,368 people with mild malaria in northern Ghana. We replicated the previously identified associations with HbS at two parasite loci. However, a newly identified locus within the serine/threonine kinase FIKK4.2, which we term Pfsa4, was also associated with HbS; this finding replicated in a published sample from Mali. The Pfsa1-4 mutations vary widely in frequencies across Africa, are absent from Asia, and are highly correlated with each-other across multiple populations. We found no strong associations with haemoglobin C. These findings add new complexity to the emerging picture of association between human and co-evolving malaria parasite genomes, suggesting new avenues for functional exploration.
... are especially susceptible to severe malaria as maternal immunity begins to wane and adaptive immunity starts to develop with repeated episodes of malaria [38]. Since childhood immunity to malaria gradually develops across successive episodes [39], the impact of genetic variants of malaria and SMA is best captured in longitudinal studies during the development of naturally-acquired malarial immunity [40]. To the best of our knowledge, we report the first study on the longitudinal risk of clinical malaria and SMA in carriers of rs2736191 and rs11575837, and their haplotypes. ...
... There is mounting evidence that natural selection influences the frequencies of diseaseassociated genetic variants in different populations [50]. For example, malaria exerts a strong evolutionary force on risk-associated alleles [7,40] and may, at least in part, explain findings presented here on the allelic distribution. ...
Background:
Plasmodium falciparum malaria is a leading cause of pediatric morbidity and mortality in holoendemic transmission areas. Severe malarial anemia [SMA, hemoglobin (Hb) < 5.0 g/dL in children] is the most common clinical manifestation of severe malaria in such regions. Although innate immune response genes are known to influence the development of SMA, the role of natural killer (NK) cells in malaria pathogenesis remains largely undefined. As such, we examined the impact of genetic variation in the gene encoding a primary NK cell receptor, natural cytotoxicity-triggering receptor 3 (NCR3), on the occurrence of malaria and SMA episodes over time.
Methods:
Susceptibility to malaria, SMA, and all-cause mortality was determined in carriers of NCR3 genetic variants (i.e., rs2736191:C > G and rs11575837:C > T) and their haplotypes. The prospective observational study was conducted over a 36 mos. follow-up period in a cohort of children (n = 1,515, aged 1.9-40 mos.) residing in a holoendemic P. falciparum transmission region, Siaya, Kenya.
Results:
Poisson regression modeling, controlling for anemia-promoting covariates, revealed a significantly increased risk of malaria in carriers of the homozygous mutant allele genotype (TT) for rs11575837 after multiple test correction [Incidence rate ratio (IRR) = 1.540, 95% CI = 1.114-2.129, P = 0.009]. Increased risk of SMA was observed for rs2736191 in children who inherited the CG genotype (IRR = 1.269, 95% CI = 1.009-1.597, P = 0.041) and in the additive model (presence of 1 or 2 copies) (IRR = 1.198, 95% CI = 1.030-1.393, P = 0.019), but was not significant after multiple test correction. Modeling of the haplotypes revealed that the CC haplotype had a significant additive effect for protection against SMA (i.e., reduced risk for development of SMA) after multiple test correction (IRR = 0.823, 95% CI = 0.711-0.952, P = 0.009). Although increased susceptibility to SMA was present in carriers of the GC haplotype (IRR = 1.276, 95% CI = 1.030-1.581, P = 0.026) with an additive effect (IRR = 1.182, 95% CI = 1.018-1.372, P = 0.029), the results did not remain significant after multiple test correction. None of the NCR3 genotypes or haplotypes were associated with all-cause mortality.
Conclusions:
Variation in NCR3 alters susceptibility to malaria and SMA during the acquisition of naturally-acquired malarial immunity. These results highlight the importance of NK cells in the innate immune response to malaria.
... Malaria parasites have exerted the strongest known selective pressure on the human genome over the last 10,000 years [1]. Polymorphisms in red blood cell (RBC) genes that confer a protective role against Plasmodium falciparum malaria have been maintained in the human population and their highest frequencies have been found in sub-Saharan Africa [1,2]. ...
... Malaria parasites have exerted the strongest known selective pressure on the human genome over the last 10,000 years [1]. Polymorphisms in red blood cell (RBC) genes that confer a protective role against Plasmodium falciparum malaria have been maintained in the human population and their highest frequencies have been found in sub-Saharan Africa [1,2]. Sickle cell disease (SCD) is among the most common monogenic disorders worldwide. ...
Background
Sickle cell trait (SCT) refers to the carriage of one abnormal copy of the β-globin gene, the HbS allele. SCT offers protection against malaria, controlling parasite density and preventing progression to symptomatic malaria. However, it remains unclear whether SCT also affects transmission stages and mosquito infection parameters. Deciphering the impact of the SCT on human to mosquito malaria transmission is key to understanding mechanisms that maintain the trait in malaria endemic areas.
Methods
The study was conducted from June to July 2017 among asymptomatic children living in the locality of Mfou, Cameroon. Blood samples were collected from asymptomatic children to perform malaria diagnosis by microscopy, Plasmodium species by PCR and hemoglobin typing by RFLP. Infectiousness of gametocytes to mosquitoes was assessed by membrane feeding assays using blood from gametocyte carriers of HbAA and HbAS genotypes. A zero-inflated model was fitted to predict distribution of oocysts in mosquitoes according to hemoglobin genotype of the gametocyte source.
Results
Among the 1557 children enrolled in the study, 314 (20.16%) were of the HbAS genotype. The prevalence of children with P. falciparum gametocytes was 18.47% in HbAS individuals and 13.57% in HbAA, and the difference is significant (χ² = 4.61, P = 0.032). Multiplicity of infection was lower in HbAS gametocyte carriers (median = 2 genotypes/carrier in HbAS versus 3.5 genotypes/carrier in HbAA, Wilcoxon sum rank test = 188, P = 0.032). Gametocyte densities in the blood donor significantly influenced mosquito infection prevalence in both HbAS and HbAA individuals. The HbAS genotype had no significant effect on mosquito infection outcomes when using immune or naïve serum in feeding assays. In AB replacement feeding experiments, the odds ratio of mosquito infection for HbAA blood as compared to HbAS was 0.56 (95% CI 0.29–1.10), indicating a twice higher risk of infection in mosquitoes fed on gametocyte-containing blood of HbAS genotype.
Conclusion
Plasmodium transmission stages were more prevalent in SCT individuals. This may reflect the parasite’s enhanced investment in the sexual stage to increase their survival rate when asexual replication is impeded. The public health impact of our results points the need for intensive malaria control interventions in areas with high prevalence of HbAS. The similar infection parameters in feeding experiments where mosquitoes received the original serum from the blood donor indicated that immune responses to gametocyte surface proteins occur in both HbAS and HbAA individuals. The higher risk of infection in mosquitoes fed on HbAS blood depleted of immune factors suggests that changes in the membrane properties in HbAS erythrocytes may impact on the maturation process of gametocytes within circulating red blood cells.
... Although natural immunity is acquired following repeated infections with P. falciparum [9][10][11] , innate immunity is particularly important for influencing disease severity in young, malaria-naïve children. Our previous longitudinal studies in Kenyan children using a combination of candidate-gene approaches, genome-wide association studies, high-throughput genotyping, and array-based whole transcriptional profiling revealed that the development of SMA is mediated, partially by innate immune response genes 7,[12][13][14][15] . Our targeted transcriptome analyses also revealed that differentially expressed genes (DEGs) in host ubiquitination processes are a central feature of SMA pathogenesis 16 . ...
This study on severe malarial anemia (SMA: Hb < 6.0 g/dL), a leading global cause of childhood morbidity and mortality, compares the entire expressed whole blood host transcriptome between Kenyan children (3-48 mos.) with non-SMA (Hb ≥ 6.0 g/dL, n = 39) and SMA (n = 18). Differential expression analyses reveal 1403 up-regulated and 279 down-regulated transcripts in SMA, signifying impairments in host inflammasome activation, cell death, and innate immune and cellular stress responses. Immune cell profiling shows decreased memory responses, antigen presentation, and immediate pathogen clearance, suggesting an immature/improperly regulated immune response in SMA. Module repertoire analysis of blood-specific gene signatures identifies up-regulation of erythroid genes, enhanced neutrophil activation, and impaired inflammatory responses in SMA. Enrichment analyses converge on disruptions in cellular homeostasis and regulatory pathways for the ubiquitin-proteasome system, autophagy, and heme metabolism. Pathway analyses highlight activation in response to hypoxic conditions [Hypoxia Inducible Factor (HIF)−1 target and Reactive Oxygen Species (ROS) signaling] as a central theme in SMA. These signaling pathways are also top-ranking in protein abundance measures and a Ugandan SMA cohort with available transcriptomic data. Targeted RNA-Seq validation shows strong concordance with our entire expressed transcriptome data. These findings identify key molecular themes in SMA pathogenesis, offering potential targets for new malaria therapies.
... Malaria is one of the most significant infectious diseases in the world. Available statistics suggest that 2 to 5% of all human deaths in the 20th Century were attributed to the disease (Carter et al., 2002), and increasing evidence identifies malaria as the most significant recent selective pressure on the human genome (Kwiatkowski, 2005). In 2000, 20% of all deaths of children under 5 years in Sub-Saharan Africa were attributable to malaria (Black et al., 2003;WHO, 2006). ...
An entomological survey was conducted to determine the malaria vectors density and their distribution. The study was aimed at identifying the distribution and feeding behaviour of major malaria vectors. Mosquitoes were sampled using Pyrethroid Spray Collection (PSC) and CDC light trap methods to collect indoors and outdoors resting mosquitoes for a period of three months (April, May and June) and were identified morphologically. A total of 462(100%) mosquitoes were collected in the study areas, 238(51.5%) were collected in Gitata and 224(48.5%) were collected in Panda. Of the 462 (100%) mosquitoes collected, 433(93.7%) were Anopheline while 29(6.3%) were Culicine. Statistically, there was a statistical difference (p<0.05) in the distribution of malaria vectors encountered in the study areas. Out of the 433(100%) Anopheles mosquitoes collected, 279(64.4%) feed indoor while 154(35.6%) feed outdoor. The indoor resting density of the mosquitoes were also calculated, the result showed that Panda had the highest indoor resting density of 7.5 than Gitata 7.0. The human biting rate (HBR) of mosquitoes collected in each month at the study areas were also determine and the result showed a high biting rate of 2.515 in Panda compared to 2.321 in Gitata. The parity rate (PR) of the mosquitoes collected in Gitata and Panda for the three months were also analyzed, and the result showed that, out of the 433 Anopheles mosquitoes collected, 146(100%) were dissected, 85(58.2%) were parous and 61(41.8%) were nulliparous. This study therefore, will be used as a baseline data to help in designing strategies for the control of malaria vector diseases in Karu Local Government of Nasarawa State and its environs.
... Indeed, this will need to consider the type of subpopulation, given the observed differences, noting there might be an overestimation of GCF in AFR and SAS Arabs due to their low sample size. High consanguinity would be a main driver for the high GCF observed in the cohort, with other cases may be attributable to balancing selection, as illustrated by HBB and CFTR in which variants are known to confer resistance against Malaria and Cholera, respectively [75,76]. ...
Background
Genome sequencing of large biobanks from under-represented ancestries provides a valuable resource for the interrogation of Mendelian disease burden at world population level, complementing small-scale familial studies.
Methods
Here, we interrogate 6045 whole genomes from Qatar—a Middle Eastern population with high consanguinity and understudied mutational burden—enrolled at the national Biobank and phenotyped for 58 clinically-relevant quantitative traits. We examine a curated set of 2648 Mendelian genes from 20 panels, annotating known and novel pathogenic variants and assessing their penetrance and impact on the measured traits.
Results
We find that 62.5% of participants are carriers of at least 1 known pathogenic variant relating to recessive conditions, with homozygosity observed in 1 in 150 subjects (0.6%) for which Peninsular Arabs are particularly enriched versus other ancestries (5.8-fold). On average, 52.3 loss-of-function variants were found per genome, 6.5 of which affect a known Mendelian gene. Several variants annotated in ClinVar/HGMD as pathogenic appeared at intermediate frequencies in this cohort (1–3%), highlighting Arab founder effect, while others have exceedingly high frequencies (> 5%) prompting reconsideration as benign. Furthermore, cumulative gene burden analysis revealed 56 genes having gene carrier frequency > 1/50, including 5 ACMG Tier 3 panel genes which would be candidates for adding to newborn screening in the country. Additionally, leveraging 58 biobank traits, we systematically assess the impact of novel/rare variants on phenotypes and discover 39 candidate large-effect variants associating with extreme quantitative traits. Furthermore, through rare variant burden testing, we discover 13 genes with high mutational load, including 5 with impact on traits relevant to disease conditions, including metabolic disorder and type 2 diabetes, consistent with the high prevalence of these conditions in the region.
Conclusions
This study on the first phase of the growing Qatar Genome Program cohort provides a comprehensive resource from a Middle Eastern population to understand the global mutational burden in Mendelian genes and their impact on traits in seemingly healthy individuals in high consanguinity settings.
Supplementary Information
The online version contains supplementary material available at 10.1186/s13073-024-01307-6.
... As such, it has exerted the strongest known selective pressure on the human genome and has resulted in the selection of various polymorphisms that confer Plasmodium tolerance or resistance. Among the most prominent examples are haemoglobin S (Hbs; sickle cell trait) [8] and alphathalassemia variants [9], both of which are common in malaria endemic regions despite causing disease in the homozygous state [7]. The HbS polymorphism in the heterozygous state confers the greatest protection (effect size > 80%; [7,10]). ...
Background
'Benign ethnic neutropenia' (BEN) is a heritable condition characterized by lower neutrophil counts, predominantly observed in individuals of African ancestry, and the genetic basis of BEN remains a subject of extensive research. In this study, we aimed to dissect the genetic architecture underlying neutrophil count variation through a linear-mixed model genome-wide association study (GWAS) in a population of African ancestry (N = 5976). Malaria caused by P. falciparum imposes a tremendous public health burden on people living in sub-Saharan Africa. Individuals living in malaria endemic regions often have a reduced circulating neutrophil count due to BEN, raising the possibility that reduced neutrophil counts modulate severity of malaria in susceptible populations. As a follow-up, we tested this hypothesis by conducting a Mendelian randomization (MR) analysis of neutrophil counts on severe malaria (MalariaGEN, N = 17,056).
Results
We carried out a GWAS of neutrophil count in individuals associated to an African continental ancestry group within UK Biobank, identifying 73 loci (r² = 0.1) and 10 index SNPs (GCTA-COJO loci) associated with neutrophil count, including previously unknown rare loci regulating neutrophil count in a non-European population. BOLT-LMM was reliable when conducted in a non-European population, and additional covariates added to the model did not largely alter the results of the top loci or index SNPs. The two-sample bi-directional MR analysis between neutrophil count and severe malaria showed the greatest evidence for an effect between neutrophil count and severe anaemia, although the confidence intervals crossed the null.
Conclusion
Our GWAS of neutrophil count revealed unique loci present in individuals of African ancestry. We note that a small sample-size reduced our power to identify variants with low allele frequencies and/or low effect sizes in our GWAS. Our work highlights the need for conducting large-scale biobank studies in Africa and for further exploring the link between neutrophils and severe malaria.
... Malaria is a life-threatening disease with a significant impact on the human genome as evidenced by the positive selection of protective genetic traits such as sickle cell trait and beta-thalassaemia. 1,2 The disease recorded an alarming number of 241 million cases leading to 627 000 deaths in 2021. 3 Drugs that have been used against this disease over the years include aryl amino alcohol compounds, antifolates, artemisinin and its derivatives, and artemisinin combination therapies. ...
6-Pyruvoyl tetrahydropterin synthase (6-PTPS) is a lyase involved in the synthesis of tetrahydrobiopterin. In Plasmodium species where dihydroneopterin aldolase (DHNA) is absent, it acts in the folate biosynthetic pathway necessary for the growth and survival of the parasite. The 6-pyruvoyl tetrahydropterin synthase of Plasmodium falciparum (PfPTPS) has been identified as a potential antimalarial drug target. This study identified potential inhibitors of PfPTPS using molecular docking techniques. Molecular docking and virtual screening of 62 compounds including the control to the deposited Protein Data Bank (PDB) structure was carried out using AutoDock Vina in PyRx. Five of the compounds, N,N-dimethyl-N’-[4-oxo-6-(2,2,5-trimethyl-1,3-dioxolan-4-yl)-3H-pteridin-2-yl]methanimidamide (140296439), 2-amino-6-[(1R)-3-cyclohexyl-1-hydroxypropyl]-3H-pteridin-4-one (140296495), 2-(2,3-dihydroxypropyl)-8,9-dihydro-6H-pyrimido[2,1-b]pteridine-7,11-dione (144380406), 2-(dimethylamino)-6-[(2,2-dimethyl-1,3-dioxolan-4-yl)-hydroxymethyl]-3H-pteridin-4-one (135573878), and [1-acetyloxy-1-(2-methyl-4-oxo-3H-pteridin-6-yl)propan-2-yl] acetate (136075207), showed better binding affinity than the control ligand, biopterin (135449517), and were selected and screened. Three conformers of 140296439 with the binding energy of −7.2, −7.1, and −7.0 kcal/mol along with 140296495 were better than the control at −5.7 kcal/mol. In silico absorption, distribution, metabolism, excretion, and toxicity (ADMET) studies predicted good pharmacokinetic properties of all the compounds while reporting a high risk of irritant toxicity in 140296439 and 144380406. The study highlights the five compounds, 140296439, 140296495, 144380406, 135573878 and 136075207, as potential inhibitors of PfPTPS and possible compounds for antimalarial drug development.
... These contribute to susceptibility to disease, from very rare highly penetrant germline sequence variants causing monogenic primary immunodeficiencies (PIDs), to more common variants contributing to polygenic traits such as seen in autoimmunity or infectious diseases (Figure 1). Malaria and other pathogens have been a major selective pressure on human genetic architecture, with specific alleles driven to high frequency or fixation in some populations (Kwiatkowski, 2005;Kwok et al., 2021). While this may serve to protect individuals in high exposure environments, there may be a cost in terms of autoimmune risk such as seen with some human leukocyte antigen (HLA) alleles (Dendrou et al., 2018). ...
The interplay between genetic and environmental factors plays a significant role in interindividual variation in immune and inflammatory responses. The availability of high-throughput low-cost genotyping and next-generation sequencing has revolutionized our ability to identify human genetic variation and understand how this varies within and between populations, and the relationship with disease. In this review, we explore the potential of genomics for patient benefit, specifically in the diagnosis, prognosis and treatment of inflammatory and immune-related diseases. We summarize the knowledge arising from genetic and functional genomic approaches, and the opportunity for personalized medicine. The review covers applications in infectious diseases, rare immunodeficiencies and autoimmune diseases, illustrating advances in diagnosis and understanding risk including use of polygenic risk scores. We further explore the application for patient stratification and drug target prioritization. The review highlights a key challenge to the field arising from the lack of sufficient representation of genetically diverse populations in genomic studies. This currently limits the clinical utility of genetic-based diagnostic and risk-based applications in non-Caucasian populations. We highlight current genome projects, initiatives and biobanks from diverse populations and how this is being used to improve healthcare globally by improving our understanding of genetic susceptibility to diseases and regional pathogens such as malaria and tuberculosis. Future directions and opportunities for personalized medicine and wider application of genomics in health care are described, for the benefit of individual patients and populations worldwide.
... As a result, these individuals are resistant to P. vivax infection, although recent reports indicate P. vivax infections among Duffy-negative individuals. This suggests that there has been extensive exposure to P. vivax, but genetic changes in the human population have significantly reduced the prevalence of this particular parasite in Africa compared to P. falciparum (Kwiatkowski 2005). ...
... 1 In the EEA, infectious diseases were variable in space and time, with different timescales requiring different kinds of adaptations -from the genetic to the high-cognition level. On one extreme, stably inhabiting a given area -a malarial region, for example (Kwiatkowski, 2005) -would favor the selection of some genes working against the infections that were characteristic of that area ("hardware" solution) (Barreiro and Quintana-Murci, 2010). On the other extreme, frequently moving to a different location would rely on the high-level cognitive skills necessary to quickly find and adopt new and safer practices ("software" solution). ...
Attachment is the evolutionarily-established process through which humans create bonds with others to receive care from them. The phenomenon is as essential to our physical survival as it is to our psychological development. An increasing number of studies demonstrates that in sensitive periods during the early years of life, our brain circuitry is programmed in the interactions with our caregivers, with the imprinting of information over multiple attachment dimensions. Adopting a basic brain-computer analogy, we can think of this knowledge as the psycho-social firmware of our mind. According to a recently proposed extension of the classical three-dimensional view, one attachment dimension – somaticity – concerns the caregiver’s task of reflecting and confirming the child’s (internal) states – such as sensations, emotions, and representations – to support the child’s ability to identify and define those entities autonomously. Relying on multidisciplinary evidence – from neuroscientific, developmental, evolutionary, and clinical sources – we suggest that somaticity (H1) has the adaptive function to modulate our tendency to comply and affiliate with a reference group but also (H2) increases the vulnerability to developing Social Anxiety (SA) and Eating Disorders (EDs). We evaluate H1-H2, (1) indicating the evolutionary role of somaticity in modulating our affiliation tendency to optimize the ancestral threat-opportunity balance coming from infectious diseases and (2) showing the deep connection between SA-EDs and the features most closely related to somaticity – interoception and parenting style. Finally, we discuss three relevant implications of H1-H2: (A) Bringing into research focus the adaptive role of our firmware knowledge system versus the hardware (neural substrate) and software (higher cognition) ones. (B) Complementing the well-grounded Objectification and Allocentric Lock Theories, allowing us to integrate multiple levels of explanation on the etiology of psychopathology. (C) Suggesting the design of new psychological treatments. While not aiming to prove H1-H2, our analysis supports them and encourages their direct testing.
... With the advent of highthroughput genotyping technology and analytical methodologies, dozens of genetic loci have been linked to the natural selection (Benton et al. 2021). These loci reflect adaptations to various challenges such as high-altitude (Yang et al. 2017), novel pathogens (Kwiatkowski 2005), changes of food sources (Mathieson and Mathieson 2018), etc. Detection of positive selection for each local population not only greatly enhances our understanding of the adaptive evolution, but also has important medical implications (Vasseur and Quintana-Murci 2013). ...
Natural selection signatures across Japanese subpopulations are under-explored. Here we conducted genome-wide selection scans with 622,926 single nucleotide polymorphisms for 20,366 Japanese individuals, who were recruited from the main-islands of Japanese Archipelago (Hondo) and the Ryukyu Archipelago (Ryukyu), representing two major Japanese subpopulations. The integrated haplotype score (iHS) analysis identified several signals in one or both subpopulations. We found a novel candidate locus at IKZF2, especially in Ryukyu. Significant signals were observed in the major histocompatibility complex region in both subpopulations. The lead variants differed and demonstrated substantial allele frequency differences between Hondo and Ryukyu. The lead variant in Hondo tags HLA-A*33:03-C*14:03-B*44:03-DRB1*13:02-DQB1*06:04-DPB1*04:01, a haplotype specific to Japanese and Korean. While in Ryukyu, the lead variant tags DRB1*15:01-DQB1*06:02, which had been recognized as a genetic risk factor for narcolepsy. In contrast, it is reported to confer protective effects against type 1 diabetes and human T lymphotropic virus type 1-associated myelopathy/tropical spastic paraparesis. The FastSMC analysis identified 8 loci potentially affected by selection within the past 20–150 generations, including 2 novel candidate loci. The analysis also showed differences in selection patterns of ALDH2 between Hondo and Ryukyu, a gene recognized to be specifically targeted by selection in East Asian. In summary, our study provided insights into the selection signatures within the Japanese and nominated potential sources of selection pressure.
... Repeated exposures of children to Pf and other pathogens allow individuals in endemic African regions to gradually develop immunity against clinical malaria. The high mortality rate associated with malarial infection has exerted strong selective pressure, shaping the human genome in endemic regions throughout recent history [2]. Several studies have for varying susceptibility to infectious or autoimmune diseases in different geographic regions [31,40]. ...
Antibodies play a crucial role in activating protective immunity against malaria by interacting with Fc-gamma receptors (FcγRs). Genetic variations in genes encoding FcγRs can affect immune cell responses to the parasite. In this study, our aim was to investigate whether non-coding variants that regulate FcγR expression could influence the prevalence of Plasmodium falciparum infection. Through bioinformatics approaches, we selected expression quantitative trait loci (eQTL) for FCGR2A, FCGR2B, FCGR2C, FCGR3A, and FCGR3B genes encoding FcγRs (FCGR),in whole blood. We prioritized two regulatory variants, rs2099684 and rs1771575, located in open genomic regions. These variants were identified using RegVar, ImmuNexUT, and transcription factor annotations specific to immune cells. In addition to these, we genotyped the coding variants FCGR2A/rs1801274 and FCGR2B/rs1050501 in 234 individuals from a malaria-endemic area in Burkina Faso. We conducted age and family-based analyses to evaluate associations with the prevalence of malarial infection in both children and adults. The analysis revealed that the regulatory rs1771575-CC genotype was predicted to influence FCGR2B/FCGR2C/FCGR3A transcripts in immune cells and was the sole variant associated with a higher prevalence of malarial infection in children. In conclusion, this study identifies the rs1771575 cis-regulatory variant affecting several FcγRs in myeloid and neutrophil cells and associates it with the inter-individual capacity of children living in Burkina Faso to control malarial infection.
... In particular, convergent adaptation occurs when distantly related species/populations, which live in distinct geographical areas or epochs, occupy comparable ecological settings and are subjected to the same selective pressures, thus being similarly targeted by natural selection (Stern, 2013). Several cases of convergent evolution have been described so far in a number of animal and plant taxa (Scott & Spielman, 2006;Stern, 2013;Chemes et al., 2015;Wen et al., 2020), with fewer examples (e.g., skin pigmentation, malaria resistance, lactose tolerance, and metabolic adaptations to cold climates) being instead reported in the human species when comparing adaptive traits among populations of different ancestry (Kwiatkowski, 2005;Edwards et al., 2010;Balentine & Bolnick, 2022). Nevertheless, experimental approaches to accurately characterize genomic variability within and between species/populations, as well as inferential statistical methods suitable to investigate how far phenotypic convergence is achieved by means of genetic convergence, have been only recently conceived. ...
Convergent adaptations represent paradigmatic examples of the capacity of natural selection to influence organisms biology. However, the possibility to investigate genetic determinants underpinning convergent complex adaptive traits has been offered only recently by methods for inferring polygenic adaptations from genomic data. Relying on this approach, we demonstrate how high-altitude Andean human groups experienced pervasive selective events at angiogenic pathways, which resemble those previously attested for Himalayan populations despite partial convergence at the single-gene level was observed. This provides unprecedented evidence for the drivers of convergent evolution of enhanced blood perfusion in populations exposed to hypobaric hypoxia for thousands of years.
... It is transmitted to humans through the bites of infected female Anopheles mosquitoes [16]. Globally malaria poses a significant threat primarily to children and has exerted considerable evolutionary pressure on the human genome, making it one of the most impactful factors in recent evolutionary history [17]. Malaria remains a significant public health concern in NE India ( Figure 1). ...
North East India, with its unique geographical and cultural characteristics, bears a significant burden of infectious diseases. This mini review provides an overview of the prevalent infectious diseases in the region, highlighting the highest disease burden and the most endemic diseases. Malaria emerges as a major public health concern, with frequent outbreaks and substantial morbidity and mortality. Dengue fever, tuberculosis, Japanese encephalitis, Chikungunya, rickettsia diseases, waterborne enteric infections, hepatitis, and HIV/AIDS are also prevalent in the region. Challenges such as rugged terrain, limited transportation infrastructure, limited healthcare infrastructure, inadequate diagnostics, socio-economic factors and sharing of international border with four neighboring countries etc hinder disease control efforts. Strengthening vector control, improving diagnostics, expanding healthcare access, and raising community awareness are crucial strategies for reducing the burden of infectious diseases. Surveillance and research efforts are needed to enhance understanding and control of these diseases. Febrile illness like Scrub typhus stands out as the most endemic disease in the hilly regions, characterized by high prevalence, associated morbidity and mortality, and a lack of knowledge about its epidemiology and impact. Active surveillance is crucial to better understand the burden and distribution of the disease and address the challenges in the region.
... Moreover, lactase persistence-associated alleles in the Tunisian population show close affinity to South European and Mediterranean groups and thus possibly result from relatively recent gene flow during the settlement of the Roman Empire in NA 38 . Malaria has also been recognized as a strong selective pressure in those geographic areas where the disease is endemic, leading to many adaptive alleles in distinct genes and WEA populations, including HBA, HBB, SLC4A1, G6PD, FY, GYPA, GYPB, GYPC, CD36, and ICAM1, among others 39 . Skin pigmentation is another phenotypical trait subjected to strong selection in humans in response to differential UV exposure. ...
Because of its location, North Africa (NA) has witnessed continuous demographic movements with an impact on the genomes of present-day human populations. Genomic data describe a complex scenario with varying proportions of at least four main ancestry components: Maghrebi, Middle Eastern-, European-, and West-and-East-African-like. However, the footprint of positive selection in NA has not been studied. Here, we compile genome-wide genotyping data from 190 North Africans and individuals from surrounding populations, investigate for signatures of positive selection using allele frequencies and linkage disequilibrium-based methods and infer ancestry proportions to discern adaptive admixture from post-admixture selection events. Our results show private candidate genes for selection in NA involved in insulin processing (KIF5A), immune function (KIF5A, IL1RN, TLR3), and haemoglobin phenotypes (BCL11A). We also detect signatures of positive selection related to skin pigmentation (SLC24A5, KITLG), and immunity function (IL1R1, CD44, JAK1) shared with European populations and candidate genes associated with haemoglobin phenotypes (HPSE2, HBE1, HBG2), other immune-related (DOCK2) traits, and insulin processing (GLIS3) traits shared with West and East African populations. Finally, the SLC8A1 gene, which codifies for a sodium-calcium exchanger, was the only candidate identified under post-admixture selection in Western NA.
... Also, due to the substantial mortality and morbidity caused by P. falciparum, the human genome has been exposed to tremendous selection pressure. Consequently, several genetic factors, such as sickle cell trait, thalassaemia features, glucose-6-phosphate dehydrogenase deficiency, and the absence of Duffy antigens, provide partial resistance to Plasmodium infection [12]. Eridani (2011) reviewed the evidence that sickle-cell disease is related to a decreased incidence of malaria infections [13]. ...
Plasmodium vivax and Plasmodium falciparum are southern Africa’s most prevalent human malaria parasites. Although several control measures have been focused on lowering malaria incidence and fatalities in the region, as malaria diagnostics improve, there is more evidence that P.vivax and P.falciparum constitute significant health challenges in the region. Furthermore, P.vivax can lie dormant in the liver and is resistant to the combination treatment with artemisinin. It also infects Duffy-negative people who were thought to be immune to it. This review focuses on the prevalence of P.vivax and P.falciparum in southern Africa, examines the Duffy susceptibility to P.vivax and P.falciparum and reviews their epidemiology. In addition, challenges in malaria treatment, control and diagnostic approaches are discussed. This review concludes with the status of malaria eradication strategies and future malaria research areas.
... However, the antiquity of malaria in human populations is poorly understood and has previously focussed on human remains from ancient Egypt, including mummies and non-mummy samples such as bones and teeth [6][7][8][9][10][11][12][13][14][15][16]. Studies have also been carried out in Italy [17][18][19][20][21] using molecular detection assays, including immunoenzymatic, polymerase chain reaction (PCR), next generation sequencing (NGS) and indirect immunofluorescence assays. The aim of this study was to evaluate the use of rapid diagnostic tests (RDT) to detect Plasmodium antigens in dental pulp from teeth collected from human remains. ...
Background
Paleomicrobiological data have clarified that Plasmodium spp. was circulating in the past in southern European populations, which are now devoid of malaria. The aim of this study was to evaluate the efficacy of immunodetection and, more particularly, rapid diagnostic tests (RDT), in order to further assess Plasmodium infections in ancient northern European populations.
Methods
A commercially available RDT, PALUTOP® + 4 OPTIMA, which is routinely used to detect malaria, was used to detect Plasmodium antigens from proteins recovered from ancient specimens extracted from 39 dental pulp samples. These samples were collected from 39 individuals who were buried in the sixth century, near the site of the current Palace of Versailles in France. Positive and negative controls were also used. Antigens detected were quantified using chemiluminescence imaging system analysis.
Results
Plasmodium antigens were detected in 14/39 (35.9%) individuals, including Plasmodium vivax antigens in 11 individuals and Plasmodium falciparum antigens co-detected in two individuals, while Pan-Plasmodium antigens were detected in three individuals. Controls all yielded expected results.
Conclusions
The data reported here showed that RDTs are a suitable tool for detecting Plasmodium spp. antigens in ancient dental pulp samples, and demonstrated the existence of malaria in Versailles, France, in the sixth century. Plasmodium vivax, which is regarded as being responsible for an attenuated form of malaria and less deadly forms, was the most prevalent species. This illustrates, for the first time in ancient populations, co-infection with P. falciparum, bringing into question the climate-driven ecosystems prevailing at that time in the Versailles area.
... The HbS allele, or sickle-cell variant, is often credited with providing Africans and their descendants protection from malaria; however, mutations of this gene (and others) are present in southeast Asians and their descendants as well. This is not a "racial" adaptation, but rather one in response to an ecosystem with a high prevalence of malaria [34]. Similarly, it is intended that "ancestral" skeletal traits can be assessed to identify their (continental) region of geographic origin, thus providing an "ancestry" estimate, but this doesn't necessarily reflect culturally constructed race categories. ...
... Untreated Plasmodium infection can lead to devastating hypoxic injuries in the various organs throughout the body (Park et al., 2019). Extraordinary evolutionary pressure has given way to a multitude of red blood cell pathologies including sickle cell, beta thalassemia, glucose-6phosphate dehydrogenase deficiency, and other red blood cell defects (Kwiatkowski, 2005). These phenotypic polymorphisms have afforded some protection against malaria, but they have also resulted in red blood cell related disorders. ...
Since its inception, cellular plasticity has undergone many iterations. Today we define it as the ability of mature, terminally differentiated cells to change their identity, meaning lineage change of the cells by transdifferentiation, dedifferentiation and reprogramming. This process does not involve a single DNA sequence change or a mutation. We now know that the behavior of a cell is profoundly affected by the surrounding environment. There is a perpetual pressure placed on the genetic expression of the cells. The external environment and specifically the microenvironment of the cells greatly influences the genotype. There is a never-ending dynamic interplay between the genotype and the phenotype. Incremental phenotypic adjustments are continuously occurring to yield improved cell survival. These changes are beneficial to the cells at a given moment. As the environmental condition declines, then more extensive phenotypic transformation (via transdifferentiation and dedifferentiation) can follow. When the cellular environment further deteriorates, cellular plasticity can trigger a pathologic sequence that eventually leads to cancers/diseases. These modifications are all part of an adaptive process that enhances the survival of the cells. They can offer short term advantages, but they can also lead to diseases. Oxygen level plays a pivotal role in the development of chronic diseases. Cellular response to hypoxia is mediated through hypoxia inducible factor (HIF). HIF is an oxygen sensor that is closely involved in the pathophysiologic adaptation to hypoxia. Our hypothesis centers on hypoxia as the major stressor initiating cellular plasticity and restoring normoxia is an essential step in the healing process. This theory could be tested using chronic pathological processes in animal models whereby achieving an adequate cellular oxygen level could improve or halt both plastic change and diseases.
... That is, while genetic and epigenetic heritable changes occur at each generation, largeeffect, easily observable ones that are particularly relevant to resisting the new environmental pressure often may take multiple generations to arise via evolutionary honing in and mutational replacement (although sometimes they may appear immediately and give the appearance of Lamarckism; 5 Hull et al. 2017). Therefore, whereas previous studies looked for an immediate, directed mutational response to an environmental challenge (Luria and Delbrück 1943;Cairns et al. 1988), IBE led us to compare the HbS mutation rate between populations that had been subject to different malarial selection pressures for an estimated 10,000 years (Kwiatkowski 2005). Consistently, results showed that the rate was higher both in the gene (comparing 20A→ T in HBB and HBD) and in the population where HbS is of adaptive significance . ...
Recent results have shown that the human malaria-resistant hemoglobin S mutation originates de novo more frequently in the gene and in the population where it is of adaptive significance, namely, in the hemoglobin subunit beta gene compared to the nonresistant but otherwise identical 20A[Formula: see text]T mutation in the hemoglobin subunit delta gene, and in sub-Saharan Africans, who have been subject to intense malarial pressure for many generations, compared to northern Europeans, who have not. This finding raises a fundamental challenge to the traditional notion of accidental mutation. Here, we address this finding with the replacement hypothesis, according to which preexisting genetic interactions can lead directly and mechanistically to mutations that simplify and replace them. Thus, an evolutionary process under selection can gradually hone in on interactions of importance for the currently evolving adaptations, from which large-effect mutations follow that are relevant to these adaptations. We exemplify this hypothesis using multiple types of mutation, including gene fusion mutations, gene duplication mutations, A[Formula: see text]G mutations in RNA-edited sites and transcription-associated mutations, and place it in the broader context of a system-level view of mutation origination called interaction-based evolution. Potential consequences include that similarity of mutation pressures may contribute to parallel evolution in genetically related species, that the evolution of genome organization may be driven by mutational mechanisms, that transposable element movements may also be explained by replacement, and that long-term directed mutational responses to specific environmental pressures are possible. Such mutational phenomena need to be further tested by future studies in natural and artificial settings.
... Moreover, Africa is home to a large array of biomes and terrains, and indigenous Africans continue to practice diverse cultural and subsistence strategies. Together, these environmental pressures have driven genetic adaptations to infectious disease [16], diet [17], and climate [10,18], sometimes in a population-specific manner. These adaptive variants can have important implications for human health in Africa, and elsewhere [19], and inclusion of African populations is therefore vital for our understanding of human evolutionary history and health. ...
Background
Mapping of quantitative trait loci (QTL) associated with molecular phenotypes is a powerful approach for identifying the genes and molecular mechanisms underlying human traits and diseases, though most studies have focused on individuals of European descent. While important progress has been made to study a greater diversity of human populations, many groups remain unstudied, particularly among indigenous populations within Africa. To better understand the genetics of gene regulation in East Africans, we perform expression and splicing QTL mapping in whole blood from a cohort of 162 diverse Africans from Ethiopia and Tanzania. We assess replication of these QTLs in cohorts of predominantly European ancestry and identify candidate genes under selection in human populations.
Results
We find the gene regulatory architecture of African and non-African populations is broadly shared, though there is a considerable amount of variation at individual loci across populations. Comparing our analyses to an equivalently sized cohort of European Americans, we find that QTL mapping in Africans improves the detection of expression QTLs and fine-mapping of causal variation. Integrating our QTL scans with signatures of natural selection, we find several genes related to immunity and metabolism that are highly differentiated between Africans and non-Africans, as well as a gene associated with pigmentation.
Conclusion
Extending QTL mapping studies beyond European ancestry, particularly to diverse indigenous populations, is vital for a complete understanding of the genetic architecture of human traits and can reveal novel functional variation underlying human traits and disease.
Background
Antibodies against blood group antigens play a key role in the pathophysiology of haemolytic transfusion reactions (HTRs) and haemolytic disease of the fetus and newborn (HDFN). This study aimed to determine the frequencies of alleles, genotypes, and risk of alloimmunisation of clinically significant blood group systems in ethnic northeastern Thais.
Methods
In total, 345 unrelated, healthy, ethnic northeastern Thais were tested using the in‐house PCR‐sequence specific primers (PCR‐SSP) method for simultaneously genotyping of RHCE, Kell, Duffy, Kidd, Diego and MNS glycophorin hybrids and results confirmed by Sanger sequencing.
Results
In this cohort, the alleles RHCE*C (81.0%) and RHCE*e (84.8%) were more prevalent than RHCE*c (19.0%) and RHCE*E (15.2%). The most common predicted haplotype combinations of the RHCE alleles were C+c‐E−e+(R 1 R 1 ) (59.4%) followed by the C+c+E+e+ (R 1 R 2 ) (20.6%) and C+c+E−e+ (R 1 r) (11.3%). The KEL*01 allele was not found in this study. The frequencies of FY*01 and FY*02 were 88.3% and 11.7%, respectively. The genotype FY*02/02 was found in four samples (1.2%). The frequencies of JK*01 and JK*02 were 52.5% and 47.5%, respectively. Homozygous JK*02/02 was found in 81 samples (23.5%). The frequencies of DI*01 and DI*02 were 0.6% and 99.4%, respectively. In total, 64 samples (18.6%) were found to carry the MNS glycophorin hybrids.
Conclusions
Our results indicated a possible high risk of c, E, Fy b , Jk a , Jk b and Mi a alloimmunisation in these populations. Moreover, methods established for genotyping clinically significant blood groups in this study can now be utilised in routine clinical application.
Both cancer and cardio-metabolic disease disparities exist among specific populations in the US. For example, African Americans experience the highest rates of breast and prostate cancer mortality and the highest incidence of obesity. Native and Hispanic Americans experience the highest rates of liver cancer mortality. At the same time, Pacific Islanders have the highest death rate attributed to type 2 diabetes (T2D), and Asian Americans experience the highest incidence of non-alcoholic fatty liver disease (NAFLD) and cancers induced by infectious agents. Notably, the pathologic progression of both cancer and cardio-metabolic diseases involves innate immunity and mechanisms of inflammation. Innate immunity in individuals is established through genetic inheritance and external stimuli to respond to environmental threats and stresses such as pathogen exposure. Further, individual genomes contain characteristic genetic markers associated with one or more geographic ancestries (ethnic groups), including protective innate immune genetic programming optimized for survival in their corresponding ancestral environment(s). This perspective explores evidence related to our working hypothesis that genetic variations in innate immune genes, particularly those that are commonly found but unevenly distributed between populations, are associated with disparities between populations in both cancer and cardio-metabolic diseases. Identifying conventional and unconventional innate immune genes that fit this profile may provide critical insights into the underlying mechanisms that connect these two families of complex diseases and offer novel targets for precision-based treatment of cancer and/or cardio-metabolic disease.
There is evidence linking genes for thalassaemia, sickle cell diseases, and glucose-6-phosphate dehydrogenase (G6PD) deficiency to a high prevalence of malaria infection. Haemoglobinopathies are hereditary conditions that mostly results in thalassaemia and sickle-cell anaemia. The current global haemoglobin gene carrier population (i.e., healthy individuals who have acquired only one mutant gene from one parent) is between 1 and 5%. Some haemoglobinopathy genes (alpha-thal, beta-thal and HbS) cause alpha-thalassaemia, beta-thalassaemia and sickle-cell anaemia, respectively. Nigerians have a prevalence of 25–30% for sickle cell anaemia (SCA), G6PD, but both alpha thalassaemia and beta thalassaemia are at the lower limit. Thalassaemia and SCA have comparable clinical manifestations. which is quite prevalent in Nigeria? This could lead to underdiagnosis of thalassaemia, which accompany hypochromia and microcytosis, that could be mistaken for iron deficiency anaemia. Depending on the levels of foetal haemoglobin and haemoglobin A2, thalassemia, iron deficiency anaemia, and sickle cell disease continue to be the most common chronic types of anaemia. This review provides details information on the prevalence of thalassaemia in Nigeria and molecular mechanisms in the expression of thalassaemia genes. The authors also suggest various possible way to minimize the occurrences of thalassaemia in Nigeria
The cardiovascular system provides blood supply throughout the body and as such is perpetually applying mechanical forces to cells and tissues. Thus, this system is primed with mechanosensory structures that respond and adapt to changes in mechanical stimuli. Since their discovery in 2010, PIEZO ion channels have dominated the field of mechanobiology. These have been proposed as the long-sought-after mechanosensitive excitatory channels involved in touch and proprioception in mammals. However, more and more pieces of evidence point to the importance of PIEZO channels in cardiovascular activities and disease development. PIEZO channel-related cardiac functions include transducing hemodynamic forces in endothelial and vascular cells, red blood cell homeostasis, platelet aggregation, and arterial blood pressure regulation, among others. PIEZO channels contribute to pathological conditions including cardiac hypertrophy and pulmonary hypertension and congenital syndromes such as generalized lymphatic dysplasia and xerocytosis. In this review, we highlight recent advances in understanding the role of PIEZO channels in cardiovascular functions and diseases. Achievements in this quickly expanding field should open a new road for efficient control of PIEZO-related diseases in cardiovascular functions.
Population disparities in health and disease have been observed and amply documented. While often attributable to genetic underpinnings, such disparities extend beyond population genetic predisposition to include environmental and geographic determinants, most pronouncedly the division between rural and urban lifestyles. Under such influences, genes and gene products may become affected by epigenetic factors, microbial modifiers including infections, and the body microbiome that ultimately shapes the outcome of a complex milieu of protein networks. Retrospective, demographic, genotype, and expression data from two rural populations in eastern Sudan were analysed for genotype, allele frequency distribution, Hardy-Weinberg equilibrium, and expression profiles using an array panel of Th1, Th2, and Th3 genes in a subset of the rural population sample against matched urban controls. Differences between urban and rural samples were observed in the departure from HWE, with an excess of heterozygosity in the rural sample. In the Th1, Th2, and Th3 array, cytokines were consistently overexpressed in the rural cohort compared to the urban cohort and were replicated in 7 selected genes that are associated with chronic diseases amongst urban dwellers in contrast to rural village inhabitants. IgE levels, as a feature of parasitic infections, are another difference to include in that dichotomy. Gene expression appears to be more exposed to the overall outcome of genetic variations, including the interaction with environmental influences within and outside the body. Here, it may be gathered from the contrast in the expression patterns between the rural and urban samples. The presence of signals of natural selection in genes that are key to certain biological functions, such as CD40L and FasL, and the sharp contrast between urban and rural populations in gene variants distribution and expression patterns, may provide important clues towards understanding the disparity between human communities in non-communicable diseases of lifestyle as well as some of the emerging infectious diseases.
Background
Though Plasmodium vivax is the second most common malaria species to infect humans, it has not traditionally been considered a major human health concern in central Africa given the high prevalence of the human Duffy-negative phenotype that is believed to prevent infection. Increasing reports of asymptomatic and symptomatic infections in Duffy-negative individuals throughout Africa raise the possibility that P. vivax is evolving to evade host resistance, but there are few parasite samples with genomic data available from this part of the world.
Methods
Whole genome sequencing of one new P. vivax isolate from the Democratic Republic of the Congo (DRC) was performed and used in population genomics analyses to assess how this central African isolate fits into the global context of this species.
Results
Plasmodium vivax from DRC is similar to other African populations and is not closely related to the non-human primate parasite P. vivax-like. Evidence is found for a duplication of the gene PvDBP and a single copy of PvDBP2.
Conclusion
These results suggest an endemic P. vivax population is present in central Africa. Intentional sampling of P. vivax across Africa would further contextualize this sample within African P. vivax diversity and shed light on the mechanisms of infection in Duffy negative individuals. These results are limited by the uncertainty of how representative this single sample is of the larger population of P. vivax in central Africa.
Individuals of European descent have historically been the focus of genetic studies and possess relatively homogenous genomes. As a result, analytical methods have been developed and optimized with such genomes in mind. African‐descent and Latino individuals generally possess genomes of greater architectural complexity due to mosaic genomic ancestry, which can extensively and intricately impact phenotypic expression. As such, genetic analyses of admixed individuals require that genetic admixture be quantified to accurately model the impact of genetic variation on phenotypic expression. In this overview, we explore how fundamental genetic concepts such as linkage disequilibrium and differential allele frequency interact with genetic admixture to uniquely influence phenotypes in admixed individuals. © 2023 The Authors. Current Protocols published by Wiley Periodicals LLC.
Malaria, the most prevalent mosquito-borne infectious disease worldwide, has accompanied humanity for millennia and remains an important public health issue despite advances in its prevention and treatment. Most infections are asymptomatic, but a small percentage of individuals with a heavy parasite burden develop severe malaria, a group of clinical syndromes attributable to organ dysfunction. Cerebral malaria is an infrequent but life-threatening complication of severe malaria that presents as an acute cerebrovascular encephalopathy characterized by unarousable coma. Despite effective antiparasite drug treatment, 20% of patients with cerebral malaria die from this disease, and many survivors of cerebral malaria have neurocognitive impairment. Thus, an important unmet clinical need is to rapidly identify people with malaria who are at risk of developing cerebral malaria and to develop preventive, adjunctive and neuroprotective treatments for cerebral malaria. This Review describes important advances in the understanding of cerebral malaria over the past two decades and discusses how these mechanistic insights could be translated into new therapies.
During pregnancy, women have an increased relative risk of exposure to infectious diseases. This study was designed to assess the prevalence of the co-occurrence of glucose-6-phosphate dehydrogenase deficiency (G6PDd) and sickle cell trait (SCT) and the impact on anemia outcomes among pregnant women exposed to frequent infectious diseases. Over a six-year period (March 2013 to October 2019), 8473 pregnant women attending antenatal clinics (ANCs) at major referral hospitals in Northern Ghana were recruited and diagnosed for common infectious diseases (malaria, syphilis, hepatitis B, and HIV), G6PDd, and SCT. The prevalence of all the infections and anemia did not differ between women with and without G6PDd (χ2 < 3.6, p > 0.05 for all comparisons). Regression analysis revealed a significantly higher proportion of SCT in pregnant women with G6PDd than those without G6PDd (AOR = 1.58; p < 0.011). The interaction between malaria and SCT was observed to be associated with anemia outcomes among the G6PDd women (F-statistic = 10.9, p < 0.001). Our findings show that anemia is a common condition among G6PDd women attending ANCs in northern Ghana, and its outcome is impacted by malaria and SCT. This warrants further studies to understand the impact of antimalarial treatment and the blood transfusion outcomes in G6PDd/SCT pregnant women.
Malaria has exhibited the strongest known selective pressure on the human genome in recent history and is the evolutionary driving force behind genetic conditions, such as sickle-cell disease, glucose-6-phosphatase deficiency, and some other erythrocyte defects. Genomic studies (e.g., The 1000 Genomes project) have provided an invaluable baseline for human genetics, but with an estimated two thousand ethno-linguistic groups thought to exist across the African continent, our understanding of the genetic differences between indigenous populations and their implications on disease is still limited. Low-cost sequencing-based approaches make it possible to target specific molecular markers and genes of interest, leading to potential insights into genetic diversity. Here we demonstrate the versatility of custom dual-indexing technology and Illumina next generation sequencing to generate a genetic profile of human polymorphisms associated with malaria pathology. For 100 individuals diagnosed with severe malaria in Northeast Tanzania, variants were successfully characterised on the haemoglobin subunit beta (HBB), glucose-6-phosphate dehydrogenase (G6PD), atypical chemokine receptor 1 (ACKR1) genes, and the intergenic Dantu genetic blood variant, then validated using pre-existing genotyping data. High sequencing coverage was observed across all amplicon targets in HBB, G6PD, ACKR1, and the Dantu blood group, with variants identified at frequencies previously observed within this region of Tanzania. Sequencing data exhibited high concordance rates to pre-existing genotyping data (> 99.5%). Our work demonstrates the potential utility of amplicon sequencing for applications in human genetics, including to personalise medicine and understand the genetic diversity of loci linked to important host phenotypes, such as malaria susceptibility.
This study on severe malarial anemia (SMA: Hb < 6.0 g/dL), a leading global cause of childhood morbidity and mortality, analyzed the entire expressed transcriptome in whole blood from children with non-SMA (Hb ≥ 6.0 g/dL, n = 41) and SMA (n = 25). Analyses revealed 3,420 up-regulated and 3,442 down-regulated transcripts, signifying impairments in host inflammasome activation, cell death, innate immune responses, and cellular stress responses in SMA. Immune cell profiling showed a decreased antigenic and immune priming response in children with SMA, favoring polarization toward cellular proliferation and repair. Enrichment analysis further identified altered neutrophil and autophagy-related processes, consistent with neutrophil degranulation and altered ubiquitination and proteasome degradation. Pathway analyses highlighted SMA-related alterations in cellular homeostasis, signaling, response to environmental cues, and cellular and immune stress responses. Validation with a qRT-PCR array showed strong concordance with the sequencing data. These findings identify key molecular themes in SMA pathogenesis, providing potential targets for new malaria therapies.
APOBEC3s are powerful human anti-viral proteins that inhibit viral replication and proliferation by inducing mutations in viral genomes. We found that in the regulatory region of the APOBEC3 cluster on human chromosome 22, there exist three distinct haplogroups that began to have diverged nearly 1 million years ago and have since been maintained in both African and non-African populations today. Despite the long persistence time of the haplogroups, one of which is shared by archaic hominins, we also found that the nucleotide diversity within each haplogroup is extremely low. With a simulation-based method, the observed low diversity within haplogroups and large divergence between haplogroups suggested that these haplogroups have been maintained by special forms of positive Darwinian selection. Repeated occurrence of such selection entails the enhanced substitution rate in this regulatory region in both the human and chimpanzee lineages. The causal events of such positive selection, which are most likely viral epidemics, are shown to have occurred at least three times in the modern human population: one before the Out-of-Africa migration and another two in the common ancestors of non-Africans.
Vaccine efficacy determined within the controlled environment of a clinical trial is usually substantially greater than real-world vaccine effectiveness. Typically, this results from reduced protection of immunologically vulnerable populations, such as children, elderly individuals and people with chronic comorbidities. Consequently, these high-risk groups are frequently recommended tailored immunisation schedules to boost responses. In addition, diverse groups of healthy adults may also be variably protected by the same vaccine regimen. Current population-based vaccination strategies that consider basic clinical parameters offer a glimpse into what may be achievable if more nuanced aspects of the immune response are considered in vaccine design. To date, vaccine development has been largely empirical. However, next-generation approaches require more rational strategies. We foresee a generation of precision vaccines that consider the mechanistic basis of vaccine response variations associated with both immunogenetic and baseline health differences. Recent efforts have highlighted the importance of balanced and diverse extra-neutralising antibody functions for vaccine-induced protection. However, in immunologically vulnerable populations, significant modulation of polyfunctional antibody responses that mediate both neutralisation and effector functions has been observed. Here, we review the current understanding of key genetic and inflammatory modulators of antibody polyfunctionality that affect vaccination outcomes and consider how this knowledge may be harnessed to tailor vaccine design for improved public health.
SARS-CoV-2 (severe acute respiratory syndrome coronavirus 2) infection is silent or benign in most infected individuals, but causes hypoxemic COVID-19 pneumonia in about 10% of cases. We review studies of the human genetics of life-threatening COVID-19 pneumonia, focusing on both rare and common variants. Large-scale genome-wide association studies have identified more than 20 common loci robustly associated with COVID-19 pneumonia with modest effect sizes, some implicating genes expressed in the lungs or leukocytes. The most robust association, on chromosome 3, concerns a haplotype inherited from Neanderthals. Sequencing studies focusing on rare variants with a strong effect have been particularly successful, identifying inborn errors of type I interferon (IFN) immunity in 1–5% of unvaccinated patients with critical pneumonia, and their autoimmune phenocopy, autoantibodies against type I IFN, in another 15–20% of cases. Our growing understanding of the impact of human genetic variation on immunity to SARS-CoV-2 is enabling health systems to improve protection for individuals and populations.
Expected final online publication date for the Annual Review of Biomedical Data Science, Volume 6 is August 2023. Please see http://www.annualreviews.org/page/journal/pubdates for revised estimates.
The acute innate immune response to infection and tissue trauma is affected and regulated through the release of a large number of inducible proteins known as cytokines. Normally present in the circulation at very low levels, cytokine expression and release are induced in response to danger signals detected by pattern recognition receptors on innate immune cells. The dynamic nature of the cytokine response and the ease with which it can be shown to impact survival in animal models of acute inflammation have made these mediators attractive candidates for the targeted therapy of sepsis. The results of their manipulation in critical illness have been disappointing, though many have emerged as promising treatments for chronic inflammatory disorders such as rheumatoid arthritis. This chapter reviews the biology of the cytokine response and its potential as a therapeutic target. Building on insights derived from studies of cytokine manipulation in COVID-19, it discusses the reasons for an apparent lack of efficacy in sepsis and identifies priorities to overcome these.
The malaria hypothesis proposes a survival advantage for individuals with hemoglobin variants in areas of endemicPlasmodium falciparum malaria. Hemoglobin C (HbC) is a possible example in West Africa, where this hemoglobin has a centric distribution with high frequencies among certain populations including the Dogon ethnic group. To test whether HbC is associated with protection from malaria, we performed a case-control study in the Dogon of Bandiagara, Mali. HbC was present in 68 of 391 (17.4%) of uncomplicated malaria control cases, whereas it was detected in only 3 of 67 cases (4.5%) of severe malaria (odds ratio [OR], 0.22;P = .01). Further, HbC was present in only 1 of 34 cases (2.9%) with cerebral manifestations, the most common presentation of severe malaria in this population (OR, 0.14; P = .03). Episodes of uncomplicated malaria and parasitemias (4800-205 050/μL) were identified in cases of homozygous HbC (HbCC), which indicates thatP falciparum parasites are able to efficiently replicate within HbCC erythrocytes in vivo. These findings suggest that HbC does not protect against infection or uncomplicated malaria but can protect against severe malaria in the Dogon population of Bandiagara, Mali. The data also suggest that the protective effect associated with HbC may be greater than that of HbS in this population.
The malarial parasite Plasmodium falciparum has acted as a potent selective force on the human ge-nome. The particular virulence of this organism is thought to be due to the adherence of parasitised red blood cells to small vessel endothelium through several receptors, including CD36, thrombospondin and intercellular adhesion molecule 1 (ICAM-1, CD54), and parasite isolates differ in their ability to bind to each. Immunohistochemical studies have implicated ICAM-1 as of potential importance in the pathogenesis of cer-ebral malaria, leading us to reason that if any single receptor were involved in the development of cerebral malaria, then in view of the high mortality of that complication , natural selection should have produced variants with reduced binding capacity. We therefore sequenced the N-terminal domain of ICAM-1 from a number of Africans and discovered a single mutation present at high frequency. Genotypes at this locus from samples from a case–control study indicated an association of the polymorphism with the severity of clinical malaria such that individuals homozygous for the mutation have increased susceptibility to cerebral malaria with a relative risk of two. These counter-intuitive results have implications for the mechanism of malaria pathogenesis, resistance to other infectious agents and transplantation immunology.
We developed an F 11 AIL population from an F 1 cross of A/J (susceptible) and C57BL/6J (resistant) mouse strains. One thousand F 11 mice were challenged with P.c. chabaudi 54X, and 340 mice selected from the phenotypic extremes for susceptibility and resistance were genotyped for microsatellite markers on Chromosomes (Chrs) 5, 8, and 17. QTL originally detected in backcross and F 2 populations were confirmed on the three chromosomes within narrower genomic regions, by maximum likelihood and regression analyses. Each of the previously mapped QTL on Chrs 5 and 17 resolved into two linked QTLs. The distal and proximal QTLs on Chrs 5 and 17, respectively, map to the previously reported QTL.
Host-parasite coevolution has been likened to a molecular arms race, with particular parasite genes evolving to evade specific
host defenses. Study of the variants of an antigenic epitope ofPlasmodium falciparum that induces a cytotoxic T cell response supports this view. In African children with malaria, the variants present are influenced
by the presence of a human leukocyte antigen (HLA) type that restricts the immune response to this epitope. The distribution
of parasite variants may be further influenced by the ability of cohabiting parasite strains to facilitate each other's survival
by down-regulating cellular immune responses, using altered peptide ligand antagonism.
We compared malaria indicators among sympatric groups to study human heterogeneities in the response
to Plasmodium falciparum malaria infection. Four cross-sectional surveys and two longitudinal surveys in two sympatric
ethnic groups (Dogon and Fulani) in Mali were carried out from 1998 to 2000. Spleen and parasite rates were evaluated
during the cross-sectional surveys and disease incidence was assessed during longitudinal surveys. In spite of similar
sociocultural factors and entomologic inoculation rates between ethnic groups, the Fulani had a significantly higher
spleen enlargement rate, lower parasite rate, and were less affected by the disease than the Dogon group, whose
frequency of hemoglobin C was higher than that recorded among the Fulani group. The Fulani group had significantly
higher levels of IgG and IgE against crude malaria antigen than the Dogon group, suggesting a role of anti-malaria
antibodies in the immune protection seen in this group.
The humoral immune response against synthetic peptides of two Plasmodium falciparum blood-stage antigens, Pf155/ring-infected erythrocyte surface antigen (RESA) (EENV)6 and Pf332 (SVTEEIAEEDK)2, in individuals belonging to three sympatric ethnic groups (Mossi, Rimaibe, and Fulani) living in the same conditions of hyperendemic transmission in a Sudan savanna area northeast of Ouagadougou, Burkina Faso were examined. The Mossi and Rimaibe are Sudanese Negroid populations with a long tradition of sedentary farming, while the Fulani are nomadic pastoralists partly settled and characterized by non-Negroid features of possible Caucasoid origin. A total of 764 subjects (311 Mossi, 273 Rimaibe, and 180 Fulani) were tested. A lower P. falciparum prevalence was observed in the Fulani of all age groups. The serologic results clearly indicate the existence of interethnic differences in the capacity to respond to these two P. falciparum antigens. The Mossi and Rimaibe showed similar responses, whereas the Fulani displayed consistently higher prevalences and levels of antibodies against both epitopes tested. The anti-(EENV)6 and anti-(SVTEEIAEEDK)2 seroprevalences were 29.9% and 38.9% in Mossi, 29.7% and 39.2% in Rimaibe, 86.1% and 76.1% in Fulani (all P values of Fulani-Mossi and Fulani-Rimaibe comparisons < 0.001). Anti-RESA and anti-Pf332 antibody levels were approximately 65% (P < 0.001) and 45% (P < 0.001), respectively, higher in seropositive Fulani than in seropositive Mossi and Rimaibe, who showed very similar values. The observed differences cannot be explained in terms of interethnic heterogeneity of malaria exposure since these communities have lived in the same area for more than 30 years and the P. falciparum inoculation rate, measured during two consecutive years, was substantially uniform for the three ethnic groups. The possibility of remarkable heterogeneities in the capacity to mount immune responses against P. falciparum antigens among populations with different genetic backgrounds must be taken into account in the development of anti-malaria vaccines.
Explaining the causes of variation in the severity of malarial disease remains a major challenge in the treatment and control of malaria. Many factors are known to contribute to this variation, including parasite genetics, host genetics, acquired immunity, and exposure levels. However, the relative importance of each of these to the overall burden of malarial disease in human populations has not been assessed. Here, we have partitioned variation in the incidence of malarial infection and the clinical intensity of malarial disease in a rural population in Sri Lanka into its component causes by pedigree analysis of longitudinal data. We found that human genetics, housing, and predisposing systematic effects (e.g., sex, age, occupation, history of infections, village) each explained approximately 15% of the variation in the frequency of malarial infection. For clinical intensity of illness, 20% of the variation was explained by repeatable differences between patients, about half of which was attributable to host genetics. The other half was attributable to semipermanent differences among patients, most of which could be explained by known predisposing factors. Three percent of variation in clinical intensity was explained by housing, and an additional 7% was explained by current influences relating to infection status (e.g., parasitemia, parasite species). Genetic control of Plasmodium falciparum infections appeared to modulate the frequency and intensity of infections, whereas genetic control of Plasmodium vivax infections appeared to confer absolute susceptibility or refractoriness but not intensity of disease. Overall, the data show consistent, repeatable differences among hosts in their susceptibility to clinical disease, about half of which are attributable to host genes.
Plasmodium falciparum malaria parasites invade human erythrocytes by means of a parasite receptor for erythrocytes, the 175-kD erythrocyte binding antigen (EBA-175). Similar to invasion efficiency, binding requires N-acetylneuraminic acid (Neu5Ac) on human erythrocytes, specifically the glycophorins. EBA-175 bound to erythrocytes with receptor-like specificity and was saturable. The specificity of EBA-175 binding was studied to determine if its binding is influenced either by simple electrostatic interaction with the negatively charged Neu5Ac (on the erythrocyte surface); or if Neu5Ac indirectly affected the conformation of an unknown ligand, or if Neu5Ac itself in specific linkage and carbohydrate composition was the primary ligand for EBA-175 as demonstrated for hemagglutinins of influenza viruses. Most Neu5Ac on human erythrocytes is linked to galactose by alpha 2-3 and alpha 2-6 linkages on glycophorin A. Soluble Neu5Ac by itself in solution did not competitively inhibit the binding of EBA-175 to erythrocytes, suggesting that linkage to an underlying sugar is required for binding in contrast to charge alone. Binding was competitively inhibited only by Neu5Ac(alpha 2-3)Gal-containing oligosaccharides. Similar oligosaccharides containing Neu5Ac(alpha 2-6)Gal-linkages had only slight inhibitory effects. Binding inhibition assays with modified sialic acids and other saccharides confirmed that oligosaccharide composition and linkage were primary factors for efficient binding. EBA-175 bound tightly enough to glycophorin A that the complex could be precipitated with an anti-glycophorin A monoclonal antibody. Selective cleavage of O-linked tetrasaccharides clustered at the NH2 terminus of glycophorin A markedly reduced binding in inhibition studies. We conclude that the Neu5Ac(a2,3)-Gal- determinant on O-linked tetrasaccharides of glycophorin A appear to be the preferential erythrocyte ligand for EBA-175.
The sickle cell mutation (beta s) arose as at least three independent events in Africa and once in Asia, being termed the Senegal, Benin, Bantu and Indian types respectively. An investigation in Cameroon was carried out to determine whether the atypical sickle genes observed in the neighboring countries are the result of recombination or the presence of a sickle cell mutation of a different genetic origin. It was conducted on 40 homozygous SS patients followed at the Blood Transfusion Center in the capital city of Yaoundé. On 80 beta s chromosomes, 13 exhibited a novel polymorphic pattern that was observed three times in the homozygous state. This chromosome contains an A gamma T gene. The restriction fragment length polymorphism haplotype is different from all the other beta s chromosomes in both the 5' and 3' regions, but has previously been reported in sporadic cases. The (AT)8(T)5 sequence in the -500 region of the beta gene is specific and different from that of the Senegal, Benin, Bantu or Indian beta s genes. All the carriers of this specific chromosome belong to the Eton ethnic group and originate from the Sanaga river valley. This observation strongly argues for yet another independent origin of the sickle cell mutation in Africa, here referred to as the "Cameroon type". The Benin haplotype and a Benin/Bantu recombinant haplotype have been observed in the other studied populations: Ewondo, Bamiléké, Bassa, Yambassa and Boulou.
Adhesion of parasitized erythrocytes to post-capillary venular endothelium or uninfected red cells is strongly implicated in the pathogenesis of severe Plasmodium falciparum malaria. Neoantigens at the infected red-cell surface adhere to a variety of host receptors, demonstrate serological diversity in field isolates and may also be a target of the host-protective immune response. Here we use sequential cloning of P. falciparum by micromanipulation to investigate the ability of a parasite to switch antigenic and cytoadherence phenotypes. Our data show that antigens at the parasitized cell surface undergo clonal variation in vitro in the absence of immune pressure at the rate of 2% per generation with concomitant modulations of the adhesive phenotype. A clone has the potential to switch at high frequency to a variety of antigenic and adhesive phenotypes, including a new type of cytoadherence behaviour, 'auto-agglutination' of infected erythrocytes. This rapid appearance of antigenic and functional heterogeneity has important implications for pathogenesis and acquired immunity.
The polymorphic frequency of the gene for beta s-globin involved in the generation of sickle trait and sickle cell anemia in the human population is caused by the enhanced resistance of sickle trait individuals to Plasmodium falciparum malaria, as supported by epidemiologic and in vitro studies. However, the mechanism for the protective effect of sickle hemoglobin in vivo has not been fully defined. The generation of transgenic mice expressing high levels of human beta s- and alpha-chains has allowed us to study this phenomenon in vivo in an experimental model. We infected the transgenic beta s mice with two species of rodent malaria and found a diminished and delayed increase in parasitemia as compared with controls. This is in contrast to our previous studies involving the introduction of a beta A transgene, which does not alter the infection. The use of this model allowed us to address the question of the mechanism of protection against malaria in mice expressing sickle hemoglobin. We find that splenectomy of transgenic mice completely reverses the protection against Plasmodium chabaudi adami infection. The results reported have shown a relationship between the presence of the beta s gene product and partial resistance to malaria in an experimental model in vivo and shows that the spleen plays an important role in this protection.
We examined the extent to which the intracellular polymerization of sickle hemoglobin (HbS) can account for the severity of anemia and of vaso-occlusive manifestations in the various sickling syndromes. Polymer formation in sickle cell disease depends principally on the intraerythrocytic hemoglobin composition and concentration. In our studies, the polymer fraction in sickle red cells was determined from reported mean values for hemoglobin composition and mean corpuscular hemoglobin concentration (MCHC) in 12 groups of patients with sickle hemoglobinopathies (homozygotes for HbS, with and without coexistent alpha-thalassemia or various forms of the hereditary persistence of fetal hemoglobin [HPFH], beta+-, beta 0-, and delta beta-thalassemia, and heterozygotes for HbS with HbA). The calculated HbS polymer fractions at full deoxygenation and at physiologic oxygen saturation values were closely correlated with mean blood hemoglobin concentrations. In addition, polymer fraction correlated with the ranking of the sickling syndromes by vaso-occlusive severity. We find that polymer fraction accounts for about 80% of the variability in hemolytic and clinical severity. The method of analysis presented here provides a quantitative and systematic means of assessing the role of polymer formation in the pathophysiologic manifestations of the sickling syndromes. Our results support the hypothesis that the intracellular polymerization of HbS is the primary determinant of the severity of both anemia and clinical symptomatology in the sickle hemoglobinopathies.
Background A potential problem for malaria vaccine development and testing is between-host variation in antibody responses to specific malaria antigens. Previous work in adults in an area highly endemic for Plasmodium falciparum in Papua New Guinea found that genetic regulation partly explained heterogeneity in responsiveness. We have now assessed the relative contributions of environmental and genetic factors in total IgG responses to specific malaria antigens in children, and quantified temporal variation within individuals of total IgG responses.
Methods Total IgG responses against schizont extract, merozoite surface protein-1, merozoite surface protein-2, ring-infected erythrocyte surface antigen, and SPf66 were measured by ELISA. Variance component analysis was used to estimate the variation explained by genetic and environmental factors in these antibody responses. Intra- and inter-class correlations of antibody responses within relative pairs were estimated. We adjusted for age, P. falciparum density, sex and village differences either within or prior to the analysis.
Results For all malaria antigens, temporal variation in the total IgG response was the predominant source of variation. There was substantial familial aggregation of all IgG responses, but it remained unclear how much this clustering was attributable to genetic factors and how much to a common environment in the household. The remaining variance, which could not be explained by either of the above, was very small for most of the antigens.
Conclusions Temporal variation and clustering of immune responses to specific malaria antigens need to be taken into account when planning, conducting and interpreting immuno-epidemiological and vaccine studies.
Malaria continues to claim the lives of more children worldwide than any other infectious disease, and improved understanding of disease immunology is a priority for the development of new therapeutic and vaccination strategies. FcgammaRIIa (CD32) contains a polymorphic variant (H/R131) that has been associated with variability in susceptibility to both bacterial diseases and Plasmodium falciparum parasitemia. We investigated the role of this polymorphism in West Africans with mild and severe malarial disease. The HH131 genotype was significantly associated with susceptibility to severe malaria (P = 0.03, odds ratio = 1.40, 95% confidence interval = 1.02-1.91). In contrast to studies of parasitemia, the presence of the R131 allele, rather than the RR131 genotype, appeared to be the important factor in protection from disease. This is the first evidence for an association between CD32 polymorphism and severe malaria and provides an example of balancing selective pressures from different infectious diseases operating at the same genetic locus.
Until recently, little light had been shed on the murky origins of human malaria. Did Plasmodium falciparum, the most virulent malaria parasite, emerge as a common pathogen only in the past few thousand years, as suggested by some analyses of its nucleotide sequence diversity? Or, was it an ancient scourge of early humans >100000 years ago, as suggested by others? A recent study, using complete mitochondrial DNA sequence polymorphism data and new analytical methods, points to an intermediate date of origin and expansion out of Africa. Subsequent population growth in each continent is less well resolved.
Sheral S. Patel, Rajeev K. Mehlotra, William Kastens, Charles S. Mgone, James W. Kazura, and PeterA. ZimmermanErythrocyte polymorphisms, includingovalocytosis, have been associated withprotection against malaria. This study inthe Wosera, a malaria holoendemic re-gion of Papua New Guinea, examined thegeneticbasisofovalocytosisanditsinflu-ence on susceptibility to malaria infec-tion. Whereas previous studies showedsignificant associations between South-east Asian ovalocytosis (caused by a 27–base pair deletion in the anion exchanger1 protein gene) and protection from cere-bral malaria, this mutation was observedinonly1of1019individualsintheWosera.Polymerasechainreactionstrategiesweredeveloped to genotype individuals for theglycophorin C exon 3 deletion associatedwith Melanesian Gerbich negativity(GPCDex3).Thispolymorphismwascom-monly observed in the study population(GPCDex3 frequency 5 0.465, n 5 742).Although GPCDex3 was significantly as-sociated with increased ovalocytosis, itwas not associated with differences ineither Plasmodium falciparumor P vivaxinfection measured over the 7-monthstudy period. Future case-control studieswill determine if GPCDex3 reduces sus-ceptibility to malaria morbidity. (Blood.2001;98:3489-3491)
Cerebral malaria (CM) causes death in children and nonimmune adults. TNF-α has been thought to play a key role in the development of CM. In contrast, the role of the related cyto-kine lymphotoxin α (LTα) in CM has been overlooked. Here we show that LTα, not TNFα, is the principal mediator of murine CM. Mice deficient in TNFα (B6.TNFα−/−) were as susceptible to CM caused by Plasmodium berghei (ANKA) as C57BL/6 mice, and died 6 to 8 d after infection after developing neurological signs of CM, associated with perivascular brain hemorrhage. Significantly, the development of CM in B6.TNFα−/− mice was not associated with increased intracellular adhesion molecule (ICAM)-1 expression on cerebral vasculature and the intraluminal accumulation of complement receptor 3 (CR3)-positive leukocytes was moderate. In contrast, mice deficient in LTα (B6.LTα−/−) were completely resistant to CM and died 11 to 14 d after infection with severe anemia and hyperparasitemia. No difference in blood parasite burden was found between C57BL/6, B6.TNFα−/−, and B6.LTα−/− mice at the onset of CM symptoms in the two susceptible strains. In addition, studies in bone marrow (BM) chimeric mice showed the persistence of cerebral LTα mRNA after irradiation and engraftment of LTα-deficient BM, indicating that LTα originated from a radiation-resistant cell population.
Plasmodium falciparum malaria parasites invade human erythrocytes by means of a parasite receptor for erythrocytes, the 175-kD erythrocyte binding antigen (EBA-175). Similar to invasion efficiency, binding requires N-acetylneuraminic acid (Neu5Ac) on human erythrocytes, specifically the glycophorins. EBA-175 bound to erythrocytes with receptor-like specificity and was saturable. The specificity of EBA-175 binding was studied to determine if its binding is influenced either by simple electrostatic interaction with the negatively charged Neu5Ac (on the erythrocyte surface); or if Neu5Ac indirectly affected the conformation of an unknown ligand, or if Neu5Ac itself in specific linkage and carbohydrate composition was the primary ligand for EBA-175 as demonstrated for hemagglutinins of influenza viruses. Most Neu5Ac on human erythrocytes is linked to galactose by alpha 2-3 and alpha 2-6 linkages on glycophorin A. Soluble Neu5Ac by itself in solution did not competitively inhibit the binding of EBA-175 to erythrocytes, suggesting that linkage to an underlying sugar is required for binding in contrast to charge alone. Binding was competitively inhibited only by Neu5Ac(alpha 2-3)Gal-containing oligosaccharides. Similar oligosaccharides containing Neu5Ac(alpha 2-6)Gal-linkages had only slight inhibitory effects. Binding inhibition assays with modified sialic acids and other saccharides confirmed that oligosaccharide composition and linkage were primary factors for efficient binding. EBA-175 bound tightly enough to glycophorin A that the complex could be precipitated with an anti-glycophorin A monoclonal antibody. Selective cleavage of O-linked tetrasaccharides clustered at the NH2 terminus of glycophorin A markedly reduced binding in inhibition studies. We conclude that the Neu5Ac(a2,3)-Gal- determinant on O-linked tetrasaccharides of glycophorin A appear to be the preferential erythrocyte ligand for EBA-175.
The haptoglobin phenotypes of Sudanese patients with complicated and uncomplicated falciparum malaria, and those of uninfected randomly selected individuals, were determined by electrophoresis of sera on polyacrylamide gels followed by benzidine staining of the gels. Among 273 malaria patients, the proportions with haptoglobin phenotypes (1-1), (2-1) and (2-2) were 60·8%, 29·7% and 9·5%, respectively, and in 72 cerebral malaria patients the proportions were 63·9%, 29·2% and 6·9%. The distribution among 208 control individuals was 26·0%, 55·8% and 18·3%, respectively. The difference between patients and controls was highly significant (P < 0·001). The distribution of the different haptoglobin phenotypes among the randomly selected group of 208 Sudanese individuals was comparable to that in many other populations. The results suggest that the haptoglobin phenotype (1-1) is associated with susceptibility to falciparum malaria and the development of severe complications; alternatively, the other phenotypes may confer resistance.
In Papua New Guinea (PNG), numerous blood group polymorphisms and hemoglobinopathies characterize the human population. Human genetic polymorphisms of this nature are common in malarious regions, and all four human malaria parasites are holoendemic below 1500 meters in PNG. At this elevation, a prominent condition characterizing Melanesians is α⁺-thalassemia. Interestingly, recent epidemiological surveys have demonstrated that α⁺-thalassemia is associated with increased susceptibility to uncomplicated malaria among young children. It is further proposed that α⁺-thalassemia may facilitate so-called “benign” Plasmodium vivax infection to act later in life as a “natural vaccine” against severe Plasmodium falciparum malaria. Here, in a P. vivax-endemic region of PNG where the resident Abelam-speaking population is characterized by a frequency of α⁺-thalassemia ≥0.98, we have discovered the mutation responsible for erythrocyte Duffy antigen-negativity (Fy[a−b−]) on the FY*A allele. In this study population there were 23 heterozygous and no homozygous individuals bearing this new allele (allele frequency, 23/1062 = 0.022). Flow cytometric analysis illustrated a 2-fold difference in erythroid-specific Fy-antigen expression between heterozygous (FY*A/FY*Anull) and homozygous (FY*A/FY*A) individuals, suggesting a gene-dosage effect. In further comparisons, we observed a higher prevalence of P. vivax infection in FY*A/FY*A (83/508 = 0.163) compared with FY*A/FY*Anull (2/23 = 0.087) individuals (odds ratio = 2.05, 95% confidence interval = 0.47–8.91). Emergence of FY*Anull in this population suggests that P. vivax is involved in selection of this erythroid polymorphism. This mutation would ultimately compromise α⁺-thalassemia/P. vivax-mediated protection against severe P. falciparum malaria.
A critical step in infection by Plasmodium falciparum, the microorganism
that causes the most severe form of malaria, is the adhesion of parasitized
red blood cells to capillary endothelium. The human protein CD36 is a major
receptor for P. falciparum-infected red blood cells1, 2
and may contribute to the disease by sequestering infected red blood cells1, 2 and inhibiting the immune response to the parasite3.
We have found that African populations contain an exceptionally high frequency
of mutations in CD36. Unexpectedly, these mutations that cause CD36 deficiency
are associated with susceptibility to severe malaria, suggesting that the
presence of distinct CD36 mutations in Africans and Asians4, 5, 6
is due to some selection pressure other than malaria.
The α thalassaemias are the commonest known human genetic disorders. Although they have almost certainly risen to their current frequencies through natural selection by malaria, the precise mechanism of malaria protection remains unknown. We have investigated the characteristics of red blood cells (RBCs) from individuals heterozygous for α0thalassaemia (–/αα) from a range of perspectives. On the basis of the hypothesis that defects in membrane transport could be relevant to the mechanism of malaria protection, we investigated sodium and potassium transport and the activity of the Plamodium falciparum-induced choline channel but found no significant differences in –/αα RBCs. Using flow cytometry, we found that thalassaemic P. falciparum-infected RBCs (IRBCs) bound 44% more antibody from immune plasma than control IRBCs. This excess binding was abrogated by predigestion of IRBCs with trypsin but was not directed at the variant surface molecule PfEMP1. Furthermore, we found no evidence for altered cytoadhesion of α-thalassaemic IRBCs to the endothelial receptors intercellular adhesion molecule-1 (ICAM-1), CD36 or thrombospondin. We hypothesize that altered red-cell membrane band 3 protein may be a target for enhanced antibody binding to α-thalassaemic IRBCs and could be involved in the mechanism of malaria protection.
We have investigated the association between alleles of the genes for tumour necrosis factor-alpha (TNF-) and TNF-β and severity of disease during malarial (Plasmodium falciparum) and other infections in the Sri Lankan population. Patients were categorized as having either (i) uncomplicated malaria, (ii) severe and complicated malaria, or (iii) severe and complicated infection in which a diagnosis of malaria had been excluded. For all the patients, as well as for a group of matched healthy controls, TNF- and TNF-β allelic types were identified using the polymerase chain reaction (PCR) and allele-specific oligonucleotide probes and restriction enzyme digestion. The odds in favour of carrying the TNF*2 allele, mainly of the heterozygous genotype (TNF*1,*2), were two to three times greater among individuals with severe disease, of either malarial or other infectious origin, relative to healthy controls or to those with uncomplicated malarial infections. No significant risk was associated with either of the alleles of TNF-β.
The haemoglobinopathies are the commonest single gene disorders known, and are so common in some regions of the world that the majority of the population carries at least one genetic abnormality affecting the structure or synthesis of the haemoglobin molecule. The prevalence of the common haemoglobinopathies (the α- and β-thalassaemias, HbS, HbC and HbE) is almost certainly a result of the protection they provide against malaria, as the epidemiological evidence reviewed in this chapter shows. World-wide, the distributions of malaria and the common haemoglobinopathies largely overlap, and micro-epidemiological surveys have confirmed the close relationship between the disorders.However, there are complications to this picture which appear to undermine the malaria hypothesis. First, in some areas, malaria and haemoglobinopathies are not coincident. Second, the malaria hypothesis does not easily explain why no two regions of the world have the same haemoglobinopathy or combination of haemoglobinopathies. The majority of mutations have arisen only once and are regionally specific.By using molecular characterization of mutations and the analysis of haplotypes on haemoglobinopathy-bearing chromosomes it is possible to show how a combination of selection by malaria, genetic drift and population movements can explain the first complication.In order to explain the second, we have argued that malaria selection has operated relatively recently on human populations (within the last 5000 years). The present distribution is then seen as the result of selection elevating sporadic mutations in local populations. In the absence of sufficient gene flow to spread all mutations to all populations, the consequence is a patchwork distribution of haemoglobinopathies. Given time, we would expect the mutations that protect and do not compromise the health of their carriers to become widely disseminated, but it is likely that human intervention will alter this process of natural selection.
Human cerebral malaria (CM) during acute Plasmodium falciparum infection is a serious neurological complication that leads to coma and death. P. berghei ANKA infection of CBA mice is a useful experimental model of CM. To identify host susceptibility loci, we performed chromosomal mapping in crossbred populations of both CM-susceptible CBA and CM-resistant DBA/2 mice. One significant region for a CM-susceptible locus in CBA mice was mapped to H2 region on Chromosome 17, tentatively designated cmsc. cmsc was mapped to a different chromosomal region from that previously reported in the C57BL/6 mouse model of CM. It is possible that different loci contribute to CM in CBA and C57BL/6 mouse strains. Comparison of the function of CM susceptibility loci between CBA and C57BL/6 mice could have important implications for the study of the complex pathogenesis of CM in humans.
In 700 children of both sexes from a rural area of holo-endemic malaria (P. falciparum), who presented to hospital because of an acute febrile illness, we have determined the parasite rate, the parasite density, and the genotype for the red-cell enzyme, glucose-6-phosphate dehydrogenase. In males, there was no evidence that enzyme-deficient subjects have any greater resistance against malaria than normal subjects. However, amongst non-deficient male subjects, those with the electrophoretic variant A of glucose-6-phosphate dehydrogenase have significantly lower parasite counts than those with the B variant of the enzyme. In females, homozygous deficient subjects again show no evidence of protection. However, subjects heterozygous for glucose-6-phosphate-dehydrogenase deficiency (specifically, those with the GdA-/GdB genotype) have significantly lower parasite counts than any other group of females or males. We conclude that the high frequency of the gene for the non-deficient variant A in the population studied is probably maintained by the advantage against malaria selection of hemizygous males (and perhaps of homozygous females). The high frequency of the glucose-6-phosphate-dehydrogenase deficiency gene is maintained mainly, and perhaps entirely, by the advantage against malaria of heterozygous females.
RELATIVE protection against Plasmodium falciparum malaria afforded to heterozygous carriers of the sickle-cell gene is now the accepted mechanism for the high frequency of the gene in areas where malaria is (or was) common1-3. However, the cellular mechanisms whereby Hb S protects the red cell against the malarial parasite are still not fully understood. We have compared the rates of invasion and growth of P. falciparum in normal red cells and in those of individuals with the sickling disorders, in both aerobic conditions and conditions of reduced oxygen tension. As a result of these studies, we suggest a possible mechanism for the protection of sickle-cell heterozygotes against P. falciparum malaria.
Duffy-blood-group-negative human erythrocytes, FyFy, are resistant to invasion in vitro by Plasmodium knowlesi. The FyFy genotype is found predominantly in African and American blacks, who are the only groups completely resistant to infection by P. vivax. To determine if the FyFy genotype is the vivax resistance factor, we performed blood typing on 11 black and six white volunteers who had been exposed to the bites of P. vivax-infected mosquitoes. Only the five FyFy blacks were resistant to erythrocytic infection; the remaining six blacks and all whites had the Duffy-positive determinants (Fya or Fyb or both) and had contracted malaria. We conclude that Duffy determinants (Fya or Fyb or both) on the erythrocyte surface are required for invasion of erythrocytes by vivax merozoites.
The protective association between the human leukocyte antigen HLA-B53 and severe malaria was investigated by sequencing of peptides eluted from this molecule followed by screening of candidate epitopes from pre-erythrocytic-stage antigens of Plasmodium falciparum in biochemical and cellular assays. Among malaria-immune Africans, HLA-B53-restricted cytotoxic T lymphocytes recognized a conserved nonamer peptide from liver-stage-specific antigen-1 (LSA-1), but no HLA-B53-restricted epitopes were identified in other antigens. These findings indicate a possible molecular basis for this HLA-disease association and support the candidacy of liver-stage-specific antigen-1 as a malaria vaccine component.
CBA/T6 and Balb/c mice inoculated with Plasmodium berghei ANKA strain (PbA) died from cerebral malaria 6-8 days post-inoculation. DBA/2J mice similarly inoculated developed a non-fatal cerebral malaria, with mild temporary cerebral symptoms, and died between days 15 and 22 from other malaria-related complications. When inoculated with P. berghei K173 (Pb) these mouse strains did not develop a cerebral malaria but died between days 15 and 22 from other malaria-related complications. These mouse strain/parasite strain combinations allow for detailed examination of factors critical in the pathology of murine cerebral malaria. Monastral Blue, a colloid dye, when injected intravascularly between days 0 and 2 into PbA-inoculated CBA (PbA-CBA) or Balb/c (PbA-Balb/c) mice prevented death from cerebral malaria. There was no evidence of increased vascular permeability at this stage. When Monastral Blue was injected between days 5 and 8, there was increased vascular permeability in the kidney, liver, lung, spleen and brain of PbA-CBA and PbA-Balb/c mice. Injection of Monastral Blue into these animals at this time also precipitated cerebral symptoms and death, but not in Pb-infected mice. Endothelial and mononuclear cells phagocytosed, and were coated with, the Monastral Blue particles when the dye was injected between days 5 and 8 into PbA-CBA and PbA-Balb/c mice. Control, uninfected mice did not demonstrate either of these features. Pb-infected mice only demonstrated coated mononuclear cells. Mononuclear cell attachment to the endothelium, increased vascular permeability and increased association of Monastral Blue particles with monocytes and endothelial cells were correlated with cerebral symptoms and death. Monastral Blue is thus a useful agent for studying the roles of mononuclear cells and endothelium in murine cerebral malaria.
Morbidity from Plasmodium falciparum malaria and humoral and in vitro cellular immune responses to defined malaria antigens were measured in rural Gambian children with haemoglobin phenotype
AS (HbAS) and in those with a normal haemoglobin (HbAA). In a survey undertaken during the dry season, HbAS children had a
higher parasite rate than HbAA children but a lower prevalence of parasitaemia at a level of 500/μl or greater. Malariometric
indices measured during a rainy season survey were similar in the 2 groups of children. During the rainy season, the incidence
of infection with P. falciparum did not vary with haemoglobin phenotype. However, in children aged 6 years or less, a significantly smaller proportion of
HbAS children who acquired infection developed clinical symptoms than did HbAA children. During both the dry season and rainy
season surveys, humoral and in vitro cellular immune responses to defined antigens from the sporozoite and merozoite stages of P. falciparum were similar in the 2 groups of children. Thus, despite the differences in parasite indices and morbidity from malaria between
the 2 groups of children, we found no evidence of an enhanced immune response to malaria infection amongst HbAS children compared
with normal children.
The malaria parasite rates and densities were compared in 79 ovalocytic-normocytic pairs of Malayan Aborigines matched for age, sex, proximity of residence to each other, and use of bed nets when sleeping in their jungle settlement in central Peninsular Malaysia. Malaria infection was determined from thick and thin Giemsa-stained blood films collected monthly for a period of six months. Blood films from ovalocytic individuals were found to be positive for malaria less often than in persons with normal red blood cells (P less than 0.05). Malaria infections per 100 person-months at risk were 9.7 in the ovalocytic group compared with 15.19 in the normocytic group. Among individuals parasitemic at any time, heavy infections (greater than or equal to 10,000 parasites/mm3 of blood) with Plasmodium falciparum, P. vivax, and P. malariae were encountered only in normocytic subjects, which comprised approximately 12.5% of the malaria-positive individuals in this group. In an earlier survey of 629 settlers that identified subjects for the above study, the prevalence of ovalocytosis was found to increase significantly with age. The above field observations support the view that ovalocytic individuals might have a survival advantage in the face of malaria. Consideration of the ovalocytic factor is indicated in future evaluations of malaria control measures in areas where ovalocytosis is prevalent.
Immune responses to defined antigens may differ between individuals in a population as the reflection of differences in genetic regulation. In experimental animals, variation in responsiveness to a given epitope may be due to major histocompatibility complex (HLA, in humans) class II restrictions, implying serious limitations for the development of subunit vaccines. For human populations, knowledge of the relative importance of genetic as opposed to environmental factors affecting the immune response is scarce. We have compared antibody levels after immunization through repeated infections to a major malarial antigen (Pf155/RESA) in monozygotic twins with those in dizygotic twins, siblings, or unrelated controls. Antibody responses to the intact antigen and to some of its immunodominant epitopes were found to be more concordant within monozygotic twin pairs than in dizygotic pairs or age- and sex-matched siblings living under similar environmental conditions. The results support the conclusion that the antibody responses were genetically regulated. When the responses were assessed for possible associations with different HLA class II DRB, DQA, and DQB alleles had haplotypes, no associations were found. This suggests that the regulation of the Pf155/RESA antibody responses seen in this study reflects the impact of factors encoded by genes outside the HLA class II regions.
The profound influence that the genetic makeup of the host has on resistance to malaria infection has been established in numerous animal studies. This genetic heterogeneity is one of the main causes of the difficulties in developing an effective malaria vaccine. Segregation analysis is the first step in identifying the nature of genetic factors involved in the expression of human complex diseases, as infectious diseases. To assess the role of host genes in human malaria, we performed segregation analysis of blood parasite densities in 42 Cameroonian families by using both the unified mixed model and the class D regressive model of analysis. The results provide clear evidence for the presence of a recessive major gene controlling the degree of infection in human malaria. Parameter estimates show a frequency of .44-.48 for the deleterious allele, indicating that about 21% of the population is predisposed to high levels of infection.
A large case-control study of malaria in West African children shows that a human leucocyte class I antigen (HLA-Bw53) and an HLA class II haplotype (DRB1*1302-DQB1*0501), common in West Africans but rare in other racial groups, are independently associated with protection from severe malaria. In this population they account for as great a reduction in disease incidence as the sickle-cell haemoglobin variant. These data support the hypothesis that the extraordinary polymorphism of major histocompatibility complex genes has evolved primarily through natural selection by infectious pathogens.
Pentoxifylline, a widely used methylxanthine, was tested for its capacity to prevent cerebral malaria (CM) in Plasmodium berghei ANKA-infected CBA/Ca mice. Nine of 12 control mice developed neurologic signs and died from CM ∼2 weeks after infection.
All 12 mice treated with daily intraperitoneal pentoxifylline (1 mg) for 10 days after infection did not develop CM. All surviving
mice developed high parasitemia and severe anemia and died 2 weeks later without neurologic signs. In pentoxifylline-treated
mice, serum tumor necrosis factor (TNF) bioactivity was nondetectable, whereas control mice had high TNF levels on day 6 after
infection. These findings were supported by in vitro investigations of malaria antigen-induced TNF synthesis. Northern blot
analysis ofTNF mRNA from stimulated macrophages showed that pentoxifylline inhibited TNF expression at the transcription level,
and TNF bioactivity in supernatants was strongly depressed. These findings make pentoxifylline a potential candidate for study
as a supportive agent in human CM.
We have previously reported that the Tharu people of the Terai region in southern Nepal have an incidence of malaria about sevenfold lower than that of synpatric non-Tharu people. In order to find out whether this marked resistance against malaria has a genetic basis, we have now determined in these populations the prevalence of candidate protective genes and have performed in-vitro cultures of Plasmodium falciparum in both Tharu and non-Tharu red cells. We have found significant but relatively low and variable frequencies of beta-thal, beta S, G6PD (-), and Duffy (a-b-) in different parts of the Terai region. The average in-vitro rate of invasion and of parasite multiplication did not differ significantly in red cells from Tharus versus those from non-Tharu controls. By contrast, the frequency of alpha-thalassemia is uniformly high in Tharus, with the majority of them having the homozygous alpha-/alpha-genotype and an overall alpha-thal gene (alpha-) frequency of .8. We suggest that holoendemic malaria has caused preferential survival of subjects with alpha-thal and that this genetic factor has enabled the Tharus as a population to survive for centuries in a malaria-holoendemic area. From our data we estimate that the alpha-thal homozygous state decreases morbidity from malaria by about 10-fold. This is an example of selection evolution toward fixation of an otherwise abnormal gene.
Cerebral malaria in A/J and CBA/H mice infected with Plasmodium berghei ANKA is accompanied by mononuclear cell infiltration, haemorrhage and cerebral endothelial cell damage. This damage is presumably one of the causes of the breakdown of the blood-brain barrier which was detected by measuring the movement of the dye Evans blue and radioisotope labelled albumin and erythrocytes. The density of brain tissue, measured by a Percoll gradient technique, was significantly reduced in mice exhibiting cerebral symptoms, suggesting the occurrence of cerebral oedema.