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Evolution At 2 Levels In Humans And Chimpanzees
Abstract
The comparison of human and chimpanzee macromolecules leads to several inferences: 1) Amino acid sequencing, immunological, and electrophoretic methods of protein comparison yield concordant estimates of genetic resemblance. These approaches all indicate that the average human polypeptide is more than 99 percent identical to its chimpanzee counterpart. 2) Nonrepeated DNA sequences differ more than amino acid sequences. A large proportion of the nucleotide differences between the two species may be ascribed to redundancies in the genetic code or to differences in non-transcribed regions. 3) The genetic distance between humans and chimpanzees, based on electrophoretic comparison of proteins encoded by 44 loci is very small, corresponding to the genetic distance between sibling species of fruit flies or mammals. Results obtained with other biochemical methods are consistent with this conclusion. However, the substantial anatomical and behavioral differences between humans and chimpanzees have led to their classification in separate families. This indicates that macromolecules and anatomical or behavioral features of organisms can evolve at independent rates. 4) A relatively small number of genetic changes in systems controlling the expression of genes may account for the major organismal differences between humans and chimpanzees. Some of these changes may result from the rearrangement of genes on chromosomes rather than from point mutations (53).
... Early in 1970s, Wilson et al. proposed that divergence in gene expression regulation plays a significant role in evolution [1,2]. This hypothesis was subsequently supported by a series of studies in various animals and plants, including genes related to domestication in cultivated plants and genes leading to morphological variation among varieties [3]. ...
... Compared to sequence variation in the genome, variation at the transcriptome level could change with time and space. This form of expression regulatory variation is more closely associated with phenotypic variation and is most likely to be preserved through natural and artificial selection [1,8]. Especially when plants face sudden environmental stress, changes in expression levels can respond to environmental changes quickly, providing hope for the survival of plants. ...
... Previous studies have shown that expression variation plays a crucial role in adaptive evolution and speciation processes [33,34]. For instance, King and Wilson (1975) proposed that the significant differences between humans and chimpanzees is not caused by the changes in protein-coding genes but by the alterations in gene expression regulatory mechanisms [1]. In a speciation study of two crow species (Corvus [corone] corone and Corvus [corone] cornix), there was almost no difference in 25 intron sequences examined between them, but significant differences were observed at the expression level, indicating the significant effects of expression variation on species divergence [34]. ...
Changes in gene expression patterns can lead to the variation of morphological traits. This phenomenon is particularly evident in recent evolution events such as crop domestication and responses to environmental stress, where alterations in expression levels can efficiently give rise to domesticated syndromes and adaptive phenotypes. Rice (Oryza sativa L.), one of the world’s most crucial cereal crops, comprises two morphologically distinct subspecies, Indica and Japonica. To investigate the morphological divergence between these two rice subspecies, this study planted a total of 315 landrace individuals of both Indica and Japonica under identical cultivation conditions. Out of the 16 quantitative traits measured in this study, 12 exhibited significant differences between the subspecies. To determine the genetic divergence between Indica and Japonica at the whole-genome sequence level, we constructed a phylogenetic tree using a resequencing dataset encompassing 95 rice landrace accessions. The samples formed two major groups that neatly corresponded to the two subspecies, Indica and Japonica. Furthermore, neighbor-joining (NJ) trees based on the expression quantity of effectively expressed genes (EEGs) across five different tissues categorized 12 representative samples into two major clades aligning with the two subspecies. These results imply that divergence in genome-wide expression levels undergoes stabilizing selection under non-stressful conditions, with evolutionary trends in expression levels mirroring sequence variation levels. This study further supports the pivotal role of changes in genome-wide expression regulation in the divergence of the two rice subspecies, Indica and Japonica.
... Notably, these 40 loci were significantly enriched for alternative haplotypes, like the HLA locus (permutation test n=10,000, p<0.0001) and segmental duplications (permutation test n=10,000, p<0.0357). Together, these findings demonstrate that genomic regions containing haplotypes marked by the most genetic diversity within the human population (Dilthey et al., 2015;Sudmant et al., 2010Sudmant et al., , 2015 also show marked haplotype-selective chromatin patterns, suggesting that one of the selective pressures and/or consequences of these diverse haplotypes is also at the level of altered gene regulatory patterns (King & Wilson, 1975). ...
... The copyright holder for this preprint this version posted June 16, 2024. ; Wilson, 1975), this 6 Gbp view of human gene regulation will likely markedly improve our understanding of the regulatory architectures that make us humans. ...
Most human cells contain two non-identical genomes, and differences in their regulation underlie human development and disease. We demonstrate that Fiber-seq Inferred Regulatory Elements (FIREs) enable the accurate quantification of chromatin accessibility across the 6 Gbp diploid human genome with single-molecule and single-nucleotide precision. We find that cells can harbor >1,000 regulatory elements with haplotype-selective chromatin accessibility (HSCA) and show that these elements preferentially localize to genomic loci containing the most human genetic diversity, with the human leukocyte antigen (HLA) locus showing the largest amount of HSCA genome-wide in immune cells. Furthermore, we uncover HSCA elements with sequence non-deterministic chromatin accessibility, representing likely somatic epimutations, and show that productive transcription from the inactive X chromosome is buttressed by clustered promoter-proximal elements that escape X chromosome inactivation.
... Keogh, 1982) [14] ; gene mutation is responsible for the evolution of humans from the chimpanzees (King and Wilson, 1975) [60] . But gene mutation is opposite to any kind of evolution (Ahad, 2011c(Ahad, , 2014b(Ahad, , 2022c [22,61,62] . ...
... Keogh, 1982) [14] ; gene mutation is responsible for the evolution of humans from the chimpanzees (King and Wilson, 1975) [60] . But gene mutation is opposite to any kind of evolution (Ahad, 2011c(Ahad, , 2014b(Ahad, , 2022c [22,61,62] . Thus, modern genetic research opposes the Descent of Man (human evolution) from a chimpanzee. ...
The objectives of this article are to prove that Darwin's theory of Sexual selection is opposite to the Descent of Man (Human evolution) from the lower animal like a chimpanzee. According to Darwin, humans evolved from a lower animal through sexual selection. However, literature claims that sexual selection is absent in all kinds of animals; as sexual selection is not possible in monogamous, monomorphic, polymorphic animals and about 300-500 vertebrates (hermaphrodite) species. Even 65 experiments of meta-analysis and the Mayer experiment on Giant Silk Moth, Callosamia promethea, and many other experiments opposed sexual selection. Again, sexual selection is possible in polygamous animals, and the choice of mate, and battle for mating is possible here. However, it is absent in polygamous animals. Because, sexual selection requires sense, intelligence, love, etc. But except modern man, such attributes are entirely absent in the animal kingdom, its evidence is that animals are unable to know (at mature stage/young stage) their brothers, sisters, fathers, mothers, etc.; even they mate with them, which strongly opposes sexual selection. As the progenitor of humans were animals; so, they had no sense, intelligence, love, etc. to choose a mate, and thus, humans had not evolved through sexual selection. Alfred Russel Wallace also strongly opposed sexual selection. Sexual selection has come far from the Victorian ideas. Moreover, the mechanism of the Descent of Man is based on the wrong theory of Lamarck, and the belief of Darwin. Besides, fossil evidence, modern genetics research, Mendelian genetics (DNA), common sense/logic, Handle dilemma and the existing Tupaia opposes the Descent of Man from a lower animal. Again, how did the extinct progenitor of humans produce modern humans, why did humans and other organisms evolve millions of years ago but still existing in their own respective and unmodified forms? If evolution/ Darwin's theory is valid, then humans and other living organisms should be immortal but not so happen. Hence, numerous biologists also rejected the sexual selection theory of Darwin.
... In 1975 King and Wilson compared amino acid substitutions and sequences from different proteins from humans and chimpanzees. They looked at sequences of fibrinopeptide, cytochrome c, lysozyme, hemoglobin (α, β, γ and δ subunits), myoglobin, carbonic anhydrase, transferin and serum albumin (King and Wilson 1975). In humans and monkeys revealed a 1 % difference in the amino acid sequence, and 14 % difference for haemoglobin. ...
... Approaches used by King and Wilson indicated that humans and chimps are more than 99 % identical (King and Wilson, 1975). This demonstrates that small changes to our molecular make up can give large morphological difference. ...
... Since King and Wilson ( 1975 ) concluded that variation in protein sequence alone cannot explain the phenotypic differences between human and chimpanzees, transcriptional regulation has been shown to play a fundamental role in phenotypic evolution and diversification ( Brawand et al. 2011 ;Barbosa-Morais et al. 2012 ;Merkin et al. 2012 ). However, few studies have focused on recently diverged species, where regulatory changes are hypothesised to dominate phenotypic divergence, as they can emerge more rapidly from standing genetic variation and relaxed selection than de novo protein-coding variation ( Singh et al. 2017 ;El Taher et al. 2020 ;Richards et al. 2021 ;Singh et al 2021 ;Singh and Ahi 2022 ;Carruthers et al. 2022 ). ...
... Variation in gene regulation is associated with phenotypic diversity and adaptation ( King and Wilson 1975 ) and it is more likely to be important during short evolutionary timescales because new beneficial protein-coding and structural mutations take more time to evolve and establish. While the role of gene regulation has been studied in the context of adaptation and speciation ( Mack and Nachman 2017, Singh et al. 2017, El Taher et al. 2020, Pavey et al. 2010, its developmental and ontogenetic dynamics are not well understood. ...
Developmental shifts in gene regulation underlying key innovations remain largely uncharacterised at short evolutionary timescales. Here we investigate the gene expression and alternative splicing landscape of trophic innovations in the fastest vertebrate adaptive radiation: cichlid fishes from Lake Victoria. Using whole-transcriptomes of the oral and pharyngeal jaws from two life stages of species adapted to divergent trophic niches, we show that gene and isoform expression were fine-tuned during development to generate specialised species-specific eco-morphologies in adults. This is a striking contrast to mammals where tissue-specific gene expression is conserved across species even after 90 million years of evolution and suggests that gene regulatory programs have evolved rapidly in Lake Victoria cichlids. We show that gene expression during development is highly modular and this developmental modularity may have facilitated trophic diversification. Furthermore, we discovered that retrotransposon mediated exonisation of a craniofacial development gene, KAZNB, has contributed to the evolution of a novel trophic niche. This advocates for the importance of exonisation and the splicing machinery in rapidly expanding the coding capacity of the genome <15,000 years. We also identified a major transcription factor of craniofacial remodelling in Darwins finches, ALX3, to have contributed to jaw divergence in Lake Victoria cichlids. Overall, our results suggest that developmental tinkering of gene regulation is a major facilitator of key innovations and diversification during adaptive radiation.
... We can frame this question using concepts introduced by King and Wilson almost half a century ago, who introduced a key distinction between two types of genetic variationnamed structural and regulatory variation-for exploring the molecular basis for phenotypic traits [4]. Structural variation is genetic variation that will influence gene product structure, and potentially, function, via changes in coding sequence, whereas in the case of regulatory variation, genetic variation will influence the control of gene product expression, for example, via sequence in cis-regulatory control regions, which may alter a phenotypic outcome. ...
... We have made use of the distinction between structural and regulatory genetic variation, concepts and terminology originally introduced by King and Wilson [4]. Although the presence of regulatory variation is harder to evaluate, it is likely that it will play an important role, both within and between species, in influencing variation in glycogen metabolism. ...
Nearly 50 years ago, King and Wilson introduced a key distinction between two types of genetic variation–named structural and regulatory variation–for exploring the molecular basis for phenotypic traits. Structural variation is genetic variation that will influence gene product structure via changes in coding sequence, whereas regulatory variation will influence the control of gene product expression. Here we repurpose these concepts to study the molecular basis of eco-physiological traits observed in microbial ecology, focusing on a specialized glycogen accumulating phenotype, known to be exhibited by a phylogenetically diverse group of microbes. We analyse the statistical properties of the protein sequence of the 1,4– α –glucan branching enzyme ( glgB ), a key enzyme responsible for formation of glycogen from linear glucans. We show that the glgB proteins in a subgroup of these organisms show unusual statistical properties of protein sequence length, sequence similarity and patterning of functional domains, compared to organisms that do not exhibit this phenotype. These findings suggest a role for structural genetic variation in determining this phenotype in some species. Our analysis holds implications for dissecting the genetic/genomic architecture of complex traits exhibited by microbial communities and also provides a complementary framework to presence–absence level analyses that are ubiquitous in microbial ecology.
... Meanwhile, our study highlights the evolution of the DvirARP gene at two levels, a concept initially proposed in the evolution of genes between humans and chimpanzees [83,84]: changes in the coding region as discussed above and changes in the regulatory region, in which minor Sophophora subgenus. We demonstrate that a dramatic fold change can occur in evolution, which is in contrast to the generally accepted opinion that protein spatial structures are more conserved in evolution than primary sequences [63,64]. ...
Insect host defense comprises two complementary dimensions, microbial killing-mediated resistance and microbial toxin neutralization-mediated resilience, both jointly providing protection against pathogen infections. Insect defensins are a class of effectors of innate immunity primarily responsible for resistance to Gram-positive bacteria. Here, we report a newly originated gene from an ancestral defensin via genetic deletion following gene duplication in Drosophila virilis, which confers an enhanced resilience to Gram-positive bacterial infection. This gene encodes an 18-mer arginine-rich peptide (termed DvirARP) with differences from its parent gene in its pattern of expression, structure and function. DvirARP specifically expresses in D. virilis female adults with a constitutive manner. It adopts a novel fold with a 310 helix and a two CXC motif-containing loop stabilized by two disulfide bridges. DvirARP exhibits no activity on the majority of microorganisms tested and only a weak activity against two Gram-positive bacteria. DvirARP knockout flies are viable and have no obvious defect in reproductivity but they are more susceptible to the DvirARP-resistant Staphylococcus aureus infection than the wild type files, which can be attributable to its ability in neutralization of the S. aureus secreted toxins. Phylogenetic distribution analysis reveals that DvirARP is restrictedly present in the Drosophila subgenus, but independent deletion variations also occur in defensins from the Sophophora subgenus, in support of the evolvability of this class of immune effectors. Our work illustrates for the first time how a duplicate resistance-mediated gene evolves an ability to increase the resilience of a subset of Drosophila species against bacterial infection.
... The evolution of gene expression and regulation is a major source of phenotypic diversity [46][47][48] . To explore the roles of hypoxia-adaptive genes in long-term adaptation and short-term acclimatization, we integrated gene expression data with genome sequencing data to perform a joint analysis. ...
High-altitude hypoxia acclimatization requires whole-body physiological regulation in highland immigrants, but the underlying genetic mechanism has not been clarified. Here we use sheep as an animal model for low-to-high altitude translocation. We generate multi-omics data including whole-genome sequences, time-resolved bulk RNA-Seq, ATAC-Seq and single-cell RNA-Seq from multiple tissues as well as phenotypic data from 20 bio-indicators. We characterize transcriptional changes of all genes in each tissue, and examine multi-tissue temporal dynamics and transcriptional interactions among genes. Particularly, we identify critical functional genes regulating the short response to hypoxia in each tissue (e.g., PARG in the cerebellum and HMOX1 in the colon). We further identify TAD-constrained cis-regulatory elements, which suppress the transcriptional activity of most genes under hypoxia. Phenotypic and transcriptional evidence indicate that antenatal hypoxia could improve hypoxia tolerance in offspring. Furthermore, we provide time-series expression data of candidate genes associated with human mountain sickness (e.g., BMPR2) and high-altitude adaptation (e.g., HIF1A). Our study provides valuable resources and insights for future hypoxia-related studies in mammals.
... Moreover, we showed that ISL1 coexpresses with POMC in ventral hypothalamic neurons of mice and zebrafish, and also that both ISL1 orthologs are critical for the onset of POMC expression in each of these distant vertebrate species (7). Enhancer mutations and turnover are main drivers of variation, innovation, and animal diversity during evolution (51), as has been originally suggested (52). In particular, loss of cell-specific enhancers may lead to drastic phenotypic changes, as documented in notorious examples. ...
Food intake and energy balance are tightly regulated by a group of hypothalamic arcuate neurons expressing the proopiomelanocortin ( POMC) gene. In mammals, arcuate-specific POMC expression is driven by two cis -acting transcriptional enhancers known as nPE1 and nPE2. Because mutant mice lacking these two enhancers still showed hypothalamic Pomc mRNA, we searched for additional elements contributing to arcuate Pomc expression. By combining molecular evolution with reporter gene expression in transgenic zebrafish and mice, here, we identified a mammalian arcuate-specific Pomc enhancer that we named nPE3, carrying several binding sites also present in nPE1 and nPE2 for transcription factors known to activate neuronal Pomc expression, such as ISL1, NKX2.1, and ERα. We found that nPE3 originated in the lineage leading to placental mammals and remained under purifying selection in all mammalian orders, although it was lost in Simiiformes (monkeys, apes, and humans) following a unique segmental deletion event. Interestingly, ablation of nPE3 from the mouse genome led to a drastic reduction (>70%) in hypothalamic Pomc mRNA during development and only moderate (<33%) in adult mice. Comparison between double (nPE1 and nPE2) and triple (nPE1, nPE2, and nPE3) enhancer mutants revealed the relative contribution of nPE3 to hypothalamic Pomc expression and its importance in the control of food intake and adiposity in male and female mice. Altogether, these results demonstrate that nPE3 integrates a tripartite cluster of partially redundant enhancers that originated upon a triple convergent evolutionary process in mammals and that is critical for hypothalamic Pomc expression and body weight homeostasis.
... redirect=no). Although the sequences of orthologous genes are highly conserved, functional divergence between orthologous gene products frequently occurs during evolution [42]. Doyeon Ha et al. conducted evolutionary rewiring of regulatory networks and identified 642 high-phenotype-similarity genes and 642 low-phenotype-similarity genes based on phenotype similarity (PS) scores [43]. ...
The development of an innovative drug is complex and time-consuming, and the drug target identification is one of the critical steps in drug discovery process. Effective and accurate identification of drug targets can accelerate the drug development process. According to previous research, evolutionary and genetic information of genes has been found to facilitate the identification of approved drug targets. In addition, allosteric proteins have great potential as targets due to their structural diversity. However, this information that could facilitate target identification has not been collated in existing drug target databases. Here, we construct a comprehensive drug target database named Genetic and Evolutionary features of drug Targets database (GETdb, http://zhanglab.hzau.edu.cn/GETdb/page/index.jsp). This database not only integrates and standardizes data from dozens of commonly used drug and target databases, but also innovatively includes the genetic and evolutionary information of targets. Moreover, this database features an effective allosteric protein prediction model. GETdb contains approximately 4000 targets and over 29,000 drugs, and is a user-friendly database for searching, browsing and downloading data to facilitate the development of novel targets.
... By experimentally studying ten MCL-1 homologs and their interactions with a photo-switchable ligand PUMA BH3, we gained valuable insights into the dynamics of the proteins on a broader evolutionary time scale. Using time-resolved infrared spectroscopy, we successfully recorded the kinetic footprints of the MCL-1/PUMA BH3 complex and analytically compared them-similar to bones, skulls, and footprints in the classic field of paleontology (55,56), or protein structures and genetic information in its molecular form (57)(58)(59). ...
Protein dynamics form a critical bridge between protein structure and function, yet the impact of evolution on ultrafast processes inside proteins remains enigmatic. This study delves deep into nanosecond-scale protein dynamics of a structurally and functionally conserved protein across species separated by almost a billion years, investigating ten homologs in complex with their ligand. By inducing a photo-triggered destabilization of the ligand inside the binding pocket, we resolved distinct kinetic footprints for each homolog via transient infrared spectroscopy. Strikingly, we found a cascade of rearrangements within the protein complex which manifest in time points of increased dynamic activity conserved over hundreds of millions of years within a narrow window. Among these processes, one displays a subtle temporal shift correlating with evolutionary divergence, suggesting reduced selective pressure in the past. Our study not only uncovers the impact of evolution on molecular processes in a specific case, but has also the potential to initiate a field of scientific inquiry within molecular paleontology, where species are compared and classified based on the rapid pace of protein dynamic processes; a field which connects the shortest conceivable time scale in living matter (10^−9 s) with the largest ones (10^16 s).
... Understanding the molecular mechanisms that give rise to phenotypic diversity is a major goal in evolutionary biology. Ever since King and Wilson (1975) hypothesised that changes in gene regulation may be important for species' evolution, research has explored the various ways in which regulation of gene expression may have mediated evolutionary transitions and innovations. So far, most studies have focused on changes in mRNA abundance, i.e., total gene expression. ...
... (van Noort et al. 2003)], and changes in gene expression are thought to be a major mechanism underlying organismal evolution [e.g. (King and Wilson 1975)]. However, comparisons between related species have found that cellular phenotype can be conserved despite significant changes in the underlying gene expression and regulatory networks (Barrière and Ruvinsky 2014). ...
What constraints govern the evolution of gene expression patterns across development remains a fundamental question of evolutionary biology. The advent of single-cell sequencing opens the possibility of learning these constraints by systematically profiling homologous cells across different organisms. The nematode C. elegans is a well-studied model for embryonic development, and its invariant lineage that is conserved with other Caenorhabditis species makes it an ideal model to directly compare gene expression between homologous progenitor and terminal cell types across evolution. We have measured the spatiotemporal divergence of gene expression across embryogenesis by collecting, annotating and comparing the transcriptomes of homologous embryonic progenitors and terminal cell types, using a dataset comprising >200,000 C. elegans cells and >190,000 C. briggsae cells. We find a high level of similarity in gene expression programs between the species despite tens of millions of years of evolutionary divergence, consistent with their conserved developmental lineages. Even still, thousands of genes show divergence in their cell-type specific expression patterns, and these are enriched for categories involved in environmental response and behavior. Comparing the degree of expression conservation across cell types reveals that certain cell types such as neurons, have diverged more than others such as the intestine and body wall muscle. Taken together, this work identifies likely constraints on the evolution of developmental gene expression and provides a powerful resource for addressing diverse evolutionary questions.
... This is also not a new realization. For example in 1975, it was described that protein-coding differences between humans and chimpanzees were insufficient to explain their phenotypic differences ( 76 ). A recent study substantiated this and found only 126 out of 24 374 human-specific variants that are coding missense variants ( 77 ). ...
Machine Learning-based scoring and classification of genetic variants aids the assessment of clinical findings and is employed to prioritize variants in diverse genetic studies and analyses. Combined Annotation-Dependent Depletion (CADD) is one of the first methods for the genome-wide prioritization of variants across different molecular functions and has been continuously developed and improved since its original publication. Here, we present our most recent release, CADD v1.7. We explored and integrated new annotation features, among them state-of-the-art protein language model scores (Meta ESM-1v), regulatory variant effect predictions (from sequence-based convolutional neural networks) and sequence conservation scores (Zoonomia). We evaluated the new version on data sets derived from ClinVar, ExAC/gnomAD and 1000 Genomes variants. For coding effects, we tested CADD on 31 Deep Mutational Scanning (DMS) data sets from ProteinGym and, for regulatory effect prediction, we used saturation mutagenesis reporter assay data of promoter and enhancer sequences. The inclusion of new features further improved the overall performance of CADD. As with previous releases, all data sets, genome-wide CADD v1.7 scores, scripts for on-site scoring and an easy-to-use webserver are readily provided via https://cadd.bihealth.org/ or https://cadd.gs.washington.edu/ to the community.
... Gene expression is an important molecular phenotype that associates genetic variation with organismic phenotype. The role of gene expression changes in phenotypic variation; species evolution has long been postulated, and has been supported by recent studies [41][42][43]. The advent of expression quantitative trait locus (eQTL) mapping, a powerful approach, has shed light on gene regulatory relationships. ...
Shrub willows are widely planted for landscaping, soil remediation, and biomass production, due to their rapid growth rates. Identification of regulatory genes in wood formation would provide clues for genetic engineering of willows for improved growth traits on marginal lands. Here, we conducted an expression quantitative trait locus (eQTL) analysis, using a full sibling F1 population of Salix suchowensis, to explore the genetic mechanisms underlying wood formation. Based on variants identified from simplified genome sequencing and gene expression data from RNA sequencing, 16,487 eQTL blocks controlling 5505 genes were identified, including 2148 cis-eQTLs and 16,480 trans-eQTLs. eQTL hotspots were identified, based on eQTL frequency in genomic windows, revealing one hotspot controlling genes involved in wood formation regulation. Regulatory networks were further constructed, resulting in the identification of key regulatory genes, including three transcription factors (JAZ1, HAT22, MYB36) and CLV1, BAM1, CYCB2;4, CDKB2;1, associated with the proliferation and differentiation activity of cambium cells. The enrichment of genes in plant hormone pathways indicates their critical roles in the regulation of wood formation. Our analyses provide a significant groundwork for a comprehensive understanding of the regulatory network of wood formation in S. suchowensis.
... Gene regulatory mechanisms have played a predominant role in the evolution of organismal diversity, including the origin of multicellularity (King and Wilson 1975;Carroll 2005;Wittkopp and Kalay 2011;Kianianmomeni 2015). Transcriptional and posttranscriptional processes constitute the early steps of gene expression. ...
The recognition of 5-prime splice site (5-prime ss) is one of the earliest steps of pre-mRNA splicing. To better understand the mechanism and regulation of 5-prime ss recognition, we selectively humanized components of the yeast U1 snRNP to reveal the function of these components in 5-prime ss recognition and splicing. We targeted U1C and Luc7, two proteins that interact with and stabilize the yeast U1 (yU1) snRNA and the 5-prime ss RNA duplex. We replaced the Zinc-Finger (ZnF) domain of yU1C with its human counterpart, which resulted in cold-sensitive growth phenotype and moderate splicing defects. Next, we added an auxin-inducible degron to yLuc7 protein and found that Luc7-depleted yU1 snRNP resulted in the concomitant loss of PRP40 and Snu71 (two other essential yeast U1 snRNP proteins), and further biochemical analyses suggest a model of how these three proteins interact with each other in the U1 snRNP. The loss of these proteins resulted in a significant growth retardation accompanied by a global suppression of pre-mRNA splicing. The splicing suppression led to mitochondrial dysfunction as revealed by a release of Fe2+ into the growth medium and an induction of mitochondrial reactive oxygen species. Together, these observations indicate that the human U1C ZnF can substitute that of yeast, Luc7 is essential for the incorporation of the Luc7-Prp40-Snu71 trimer into yeast U1 snRNP, and splicing plays a major role in the regulation of mitochondria function in yeast.
... Moreover, almost all living organisms have some basic identical biochemical molecules, including DNA, ATP and many other identical or nearly identical enzymes, which indicate common ancestry (Mader, 2003). It is noted from the compared figures of DNA sequences that 99% similarities are found between humans and chimpanzees (Wilson and King, 1975), which indicates that human have evolved from the chimpanzee. But literature claim that there is no single evidence of biochemical and molecular similarities at the molecular level. ...
Living organisms are greatly similar at their molecular level, which leads the concept of their common ancestry. But it is not true, as every being is definite at the molecular level of each species. So, according to the current theory, each species is unique in that its base pairs are arranged in different orders and proportions, which vary from all other species. Again, the DNA base-sequence varies as much as between individuals of the same society and also of different societies of human races. Even, each person has a unique "Genetic fingerprint" and DNA molecules which are completely different from one another. So, there are no similarities among different types of species at their molecular levels. Again, there is no evidence that a reproductively isolated species/breed/variety/race evolves either artificially or naturally, which opposes modern (contemporary) evidence. Again, once it is thought that vestigial organs are useless. But today, those are medically regarded as essential ones.
... One of the major questions in biology is the origin of the striking diversity in morphological traits across the plant and animal kingdoms. Over the past 50 years evolutionary biology has sought to uncover the genetic and developmental bases of adaptive phenotypes (Carroll, 2008;Jacob, 1977;King & Wilson, 1975), for instance in the radiation of cichlid fishes. Lake Malawi cichlids are a textbook example of adaptation, characterized by diverse craniofacial structures that are shaped by distinct feeding strategies, habitats, and biomechanical performances (reviewed in Burress, 2015;Henning & Meyer, 2014;Kocher, 2004;Konings, 2007;Powder & Albertson, 2015;Salzburger, 2018;Seehausen, 2006;Svardal et al., 2021). ...
A central question in biology is the molecular origins of phenotypic diversity. While genetic changes are key to the genotype–phenotype relationship, alterations to chromatin structure and the physical packaging of histone proteins may also be important drivers of vertebrate divergence. We investigate the impact of such an epigenetic mechanism, histone acetylation, within a textbook example of an adaptive radiation. Cichlids of Lake Malawi have adapted diverse craniofacial structures, and here we investigate how histone acetylation influences morphological variation in these fishes. Specifically, we assessed the effect of inhibiting histone deacetylation using the drug trichostatin A (TSA) on developing facial structures. We examined this during three critical developmental windows in two cichlid species with alternate adult morphologies. Exposure to TSA during neural crest cell (NCC) migration and as postmigratory NCCs proliferate in the pharyngeal arches resulted in significant changes in lateral and ventral shape in Maylandia , but not in Tropheops . This included an overall shortening of the head, widening of the lower jaw, and steeper craniofacial profile, all of which are paedomorphic morphologies. In contrast, treatment with TSA during early chondrogenesis did not result in significant morphological changes in either species. Together, these data suggest a sensitivity to epigenetic alterations that are both time‐ and species‐dependent. We find that morphologies are due to nonautonomous or potentially indirect effects on NCC development, including in part a global developmental delay. Our research bolsters the understanding that proper histone acetylation is essential for early craniofacial development and identifies a species‐specific robustness to developmental change. Overall, this study demonstrates how epigenetic regulation may play an important role in both generating and buffering morphological variation.
... Moreover, expression of the human-specific Srgap2c in mice, which originates from a gene duplication, delays synapse maturation in cortical pyramidal neurons (1,6,7). However, due to the generally high conservation of protein-coding genes, it has been suggested early on that most phenotypic differences between humans and other primates might be rather caused by changes in non-coding DNA regulating gene expression (8). Regulatory regions of the genome that evolved particularly fast in humans, such as the human accelerated regions (HAR) and human gained enhancers (HGE), represent interesting candidates in this regard (9). ...
Neural circuit development in the human cortex is considerably prolonged in comparison to non-human primates, a trait that contributes to the remarkable cognitive capacity of modern humans. Here, we explore the regulatory role of non-coding RNAs, which dramatically expanded during brain evolution, in synapse development of human-induced pluripotent stem-cell derived neurons. Inhibition of a human-specific microRNA, miR-1229-3p, results in accelerated formation of excitatory synapses and enhanced synaptic transmission. Mechanistically, miR-1229-3p controls mitochondrial homeostasis by targeting important regulators of mitochondrial autophagy and fission, such as Pink1. Stimulation of mitochondrial metabolism rescues decreased calcium buffering in miR-1229-3p depleted neurons. Our findings reveal an important function of human-specific miR-1229-3p in developmental timing of human synaptogenesis and generally implicate non-coding RNAs in the control of human connectivity and cognition.
One-Sentence Summary
A human-specific microRNA slows down the formation and maturation of neuronal synapses by reducing mitochondrial metabolism and renewal.
... Multiple top significantly enriched pathways are related to gene expression, including generic transcription (73 genes, corrected p value = 4.28 × 10 −7 ), RNA polymerase II transcription (76 genes, corrected p value = 1.93 × 10 −6 ), and transcriptional regulation by TP53 (26 genes, corrected p value = 0.0023) (Additional file 2: Table S2). This is consistent with previous studies showing that evolutionary changes in gene expression regulation played an essential role in the origin and development of Homo sapiens [7,30,31]. ...
We developed maximum likelihood method for detecting positive selection or balancing selection using multilocus or genomic polymorphism and divergence data from two species. The method is especially useful for investigating natural selection in noncoding regions. Simulations demonstrate that the method outperforms existing methods in detecting both positive and balancing selection. We apply the method to population genomic data from human and chimpanzee. The list of genes identified under selection in the noncoding regions is prominently enriched in pathways related to the brain and nervous system. Therefore, our method will serve as a useful tool for comparative population genomic analysis.
Supplementary Information
The online version contains supplementary material available at 10.1186/s13059-023-03068-8.
... By experimentally studying ten MCL-1 homologs and their interactions with a photo-switchable ligand PUMA BH3, we gained valuable insights into the dynamics of the proteins on a broader evolutionary time scale. Using time-resolved infrared spectroscopy, we successfully recorded the kinetic footprints of the MCL-1/PUMA BH3 complex and analytically compared them -similar to bones, skulls, and footprints in the classic field of paleontology 49,50 , or protein structures and genetic information in its molecular form [51][52][53] . ...
Protein dynamics form a critical bridge between protein structure and function, yet the impact of evolution on ultrafast processes inside proteins remains enigmatic.
This study delves deep into nanosecond-scale protein dynamics of a structurally and functionally conserved protein across species separated by almost a billion years, investigating ten homologs in complex with their ligand. By inducing a phototriggered destabilization of the ligand inside the binding pocket, we resolved distinct kinetic footprints for each homolog via transient infrared spectroscopy. Strikingly, we found a cascade of rearrangements within the protein complex which manifest in three discrete time points of dynamic activity, conserved over hundreds of millions of years within a narrow window. Among these processes, one displays a subtle temporal shift correlating with evolutionary divergence, suggesting reduced selective pressure in the past. Our study not only uncovers the impact of evolution on molecular processes in a specific case, but has also the potential to initiate a novel field of scientific inquiry within molecular paleontology, where species are compared and classified based on the rapid pace of protein dynamic processes; a field which connects the shortest conceivable time scale in living matter (10^−9 s) with the largest ones (10^16 s).
Genes involved in reproduction often evolve rapidly at the sequence level due to postcopulatory sexual selection (PCSS) driven by male–male competition and male–female sexual conflict, but the impact of PCSS on gene expression has been under‐explored. Further, though multiple tissues contribute to male reproductive success, most studies have focused on the testes. To explore the influence of mating system variation on reproductive tract gene expression in natural populations, we captured adult males from monogamous Peromyscus californicus and polygynandrous P . boylii and P . maniculatus . We generated RNAseq libraries, quantified gene expression in the testis, seminal vesicle, epididymis, and liver, and identified 3627 mating system‐associated differentially expressed genes (MS‐DEGs), where expression shifted in the same direction in P . maniculatus and P . boylii relative to P . californicus . Gene expression variation was most strongly associated with mating behaviour in the seminal vesicles, where 89% of differentially expressed genes were MS‐DEGs, including the key seminal fluid proteins Svs2 and Pate4 . We also used published rodent genomes to test for positive and relaxed selection on Peromyscus ‐expressed genes. Though we did not observe more overlap than expected by chance between MS‐DEGs and positively selected genes, 203 MS‐DEGs showed evidence of positive selection. Fourteen reproductive genes were under tree‐wide positive selection but convergent relaxed selection in P . californicus and Microtus ochrogaster , a distantly related monogamous species. Changes in transcript abundance and gene sequence evolution in association with mating behaviour suggest that male mice may respond to sexual selection intensity by altering aspects of sperm motility, sperm‐egg binding and copulatory plug formation.
Language is a defining characteristic of our species, but the function, or functions, that it serves has been debated for centuries. Here we bring recent evidence from neuroscience and allied disciplines to argue that in modern humans, language is a tool for communication, contrary to a prominent view that we use language for thinking. We begin by introducing the brain network that supports linguistic ability in humans. We then review evidence for a double dissociation between language and thought, and discuss several properties of language that suggest that it is optimized for communication. We conclude that although the emergence of language has unquestionably transformed human culture, language does not appear to be a prerequisite for complex thought, including symbolic thought. Instead, language is a powerful tool for the transmission of cultural knowledge; it plausibly co-evolved with our thinking and reasoning capacities, and only reflects, rather than gives rise to, the signature sophistication of human cognition.
In exploring the evolutionary trajectories of both pathogenesis and karyotype dynamics in fungi, we conducted a large-scale comparative genomic analysis spanning the Cryptococcus genus, encompassing both global human fungal pathogens and nonpathogenic species, and related species from the sister genus Kwoniella. Chromosome-level genome assemblies were generated for multiple species, covering virtually all known diversity within these genera. Although Cryptococcus and Kwoniella have comparable genome sizes (about 19.2 and 22.9 Mb) and similar gene content, hinting at preadaptive pathogenic potential, our analysis found evidence of gene gain (via horizontal gene transfer) and gene loss in pathogenic Cryptococcus species, which might represent evolutionary signatures of pathogenic development. Genome analysis also revealed a significant variation in chromosome number and structure between the 2 genera. By combining synteny analysis and experimental centromere validation, we found that most Cryptococcus species have 14 chromosomes, whereas most Kwoniella species have fewer (11, 8, 5, or even as few as 3). Reduced chromosome number in Kwoniella is associated with formation of giant chromosomes (up to 18 Mb) through repeated chromosome fusion events, each marked by a pericentric inversion and centromere loss. While similar chromosome inversion–fusion patterns were observed in all Kwoniella species with fewer than 14 chromosomes, no such pattern was detected in Cryptococcus. Instead, Cryptococcus species with less than 14 chromosomes showed reductions primarily through rearrangements associated with the loss of repeat-rich centromeres. Additionally, Cryptococcus genomes exhibited frequent interchromosomal translocations, including intercentromeric recombination facilitated by transposons shared between centromeres. Overall, our findings advance our understanding of genetic changes possibly associated with pathogenicity in Cryptococcus and provide a foundation to elucidate mechanisms of centromere loss and chromosome fusion driving distinct karyotypes in closely related fungal species, including prominent global human pathogens.
In this chapter, we look at the other side, the cases where the rules have become exceptions. The factors responsible for these changes are diverse. Let us consider, for example, those changes produced by nature itself, where certain characters, behaviors, and even interactions that were previously very common became rare or even disappeared; changes associated with climatic relics, relict species, up to major extinction events. Let us also think of the changes that humans have made in nature that are responsible for certain rules becoming exceptions, the effects of artificial selection, deforestation, species introduced into environments that are not natural, and of course the climate change in which we are major participants, to name just a few examples. Additionally, the changes from rules to exceptions can result from changes in scientific interpretations, such as biases in study approaches, biases in the choice of model species for research, and their general extrapolation of results without, in many cases, the necessary precautions, in addition to the biases in interpretations associated with the use of certain current equipment and methodologies.
The pervasiveness of gene expression variation and its contribution to phenotypic variation and evolution is well known. This gene expression variation is context dependent, with differences in regulatory architecture often associated with intrinsic and environmental factors, and is modulated by regulatory elements that can act in cis (linked) or in trans (unlinked) relative to the genes they affect. So far, little is known about how this genetic variation affects the evolution of regulatory architecture among closely related tissues during population divergence. To address this question, we analyzed gene expression in the midgut, hindgut, and Malpighian tubule as well as microbiome composition in the two gut tissues in four Drosophila melanogaster strains and their F1 hybrids from two divergent populations: one from the derived, European range and one from the ancestral, African range. In both the transcriptome and microbiome data, we detected extensive tissue- and genetic background-specific effects, including effects of genetic background on overall tissue specificity. Tissue-specific effects were typically stronger than genetic background-specific effects, although the two gut tissues were not more similar to each other than to the Malpighian tubules. An examination of allele specific expression revealed that, while both cis and trans effects were more tissue-specific in genes expressed differentially between populations than genes with conserved expression,trans effects were more tissue-specific than ciseffects. Despite there being highly variable regulatory architecture, this observation was robust across tissues and genetic backgrounds, suggesting that the expression of trans variation can be spatially fine-tuned as well as or better than cis variation during population divergence and yielding new insights into cisand trans regulatory evolution.
Regulation of gene expression is arguably the main mechanism underlying the phenotypic diversity of tissues within and between species. Here we assembled an extensive transcriptomic dataset covering 8 tissues across 20 bilaterian species and performed analyses using a symmetric phylogeny that allowed the combined and parallel investigation of gene expression evolution between vertebrates and insects. We specifically focused on widely conserved ancestral genes, identifying strong cores of pan-bilaterian tissue-specific genes and even larger groups that diverged to define vertebrate and insect tissues. Systematic inferences of tissue-specificity gains and losses show that nearly half of all ancestral genes have been recruited into tissue-specific transcriptomes. This occurred during both ancient and, especially, recent bilaterian evolution, with several gains being associated with the emergence of unique phenotypes (for example, novel cell types). Such pervasive evolution of tissue specificity was linked to gene duplication coupled with expression specialization of one of the copies, revealing an unappreciated prolonged effect of whole-genome duplications on recent vertebrate evolution.
Changes in gene regulatory elements play critical roles in human phenotypic divergence. However, identifying the base-pair changes responsible for the distinctive morphology of Homo sapiens remains challenging. Here, we report a noncoding single-nucleotide polymorphism (SNP), rs41298798, as a potential causal variant contributing to the morphology of the skull base and vertebral structures found in Homo sapiens. Screening for differentially regulated genes between Homo sapiens and extinct relatives revealed 13 candidate genes associated with basicranial development, with TBX1, implicated in DiGeorge syndrome, playing a pivotal role. Epigenetic markers and in silico analyses prioritized rs41298798 within a TBX1 intron for functional validation. CRISPR editing revealed that the 41-base-pair region surrounding rs41298798 modulates gene expression at 22q11.21. The derived allele of rs41298798 acts as an allele-specific enhancer mediated by E2F1, resulting in increased TBX1 expression levels compared to the ancestral allele. Tbx1-knockout mice exhibited skull base and vertebral abnormalities similar to those seen in DiGeorge syndrome. Phenotypic differences associated with TBX1 deficiency are observed between Homo sapiens and Neanderthals (Homo neanderthalensis). In conclusion, the regulatory divergence of TBX1 contributes to the formation of skull base and vertebral structures found in Homo sapiens.
Gene regulatory divergence between species can result from cis-acting local changes to regulatory element DNA sequences or global trans-acting changes to the regulatory environment. Understanding how these mechanisms drive regulatory evolution has been limited by challenges in identifying trans-acting changes. We present a comprehensive approach to directly identify cis- and trans-divergent regulatory elements between human and rhesus macaque lymphoblastoid cells using assay for transposase-accessible chromatin coupled to self-transcribing active regulatory region (ATAC-STARR) sequencing. In addition to thousands of cis changes, we discover an unexpected number (∼10,000) of trans changes and show that cis and trans elements exhibit distinct patterns of sequence divergence and function. We further identify differentially expressed transcription factors that underlie ∼37% of trans differences and trace how cis changes can produce cascades of trans changes. Overall, we find that most divergent elements (67%) experienced changes in both cis and trans, revealing a substantial role for trans divergence—alone and together with cis changes—in regulatory differences between species.
Vocal production learning is a convergently evolved trait in vertebrates. To identify brain genomic elements associated with mammalian vocal learning, we integrated genomic, anatomical and neurophysiological data from the Egyptian fruit-bat with analyses of the genomes of 215 placental mammals. First, we identified a set of proteins evolving more slowly in vocal learners. Then, we discovered a vocal-motor cortical region in the Egyptian fruit-bat, an emergent vocal learner, and leveraged that knowledge to identify active cis -regulatory elements in the motor cortex of vocal learners. Machine learning methods applied to motor cortex open chromatin revealed 50 enhancers robustly associated with vocal learning whose activity tended to be lower in vocal learners. Our research implicates convergent losses of motor cortex regulatory elements in mammalian vocal learning evolution.
Seminal fluid protein (Sfp) genes show, in general, a higher rate of sequence divergence than genes from other categories, which is often attributed to forms of postcopulatory sexual selection or sexual conflict. Recently, the relaxation of selective constraints has been proposed as an alternative explanation for the rapid sequence evolution of Sfps and other genes with sex-limited expression. The expression of Sfp genes is a likely target of selection, but the evolution of differences in their expression levels is less understood. Here, we explore both polymorphism and divergence in Sfp gene expression between Drosophila melanogaster and Drosophila simulans, how selection might have influenced their expression, and whether changes in expression might trigger the evolution of reproductive isolating barriers. In our analysis, Sfp genes showed higher divergence, but not higher polymorphism, in expression than the average male reproductive glands gene. Sfp genes with reproductive-tissue-specific expression were enriched for both directional and stabilizing selection, while relaxed selection was the predominant mode of evolution among Sfp genes with any other nonreproductive tissue-specific or nontissue-specific expression. The knockdown of single genes known to affect intraspecific sperm competition, and with patterns of expression divergence and polymorphism suggestive of directional selection, was not enough to break down postmating reproductive isolation barriers between species. Our results identify the expression of male-specific Sfp genes as an enriched target of selection and suggest a complex molecular relationship between postcopulatory sexual selection on a single gene’s expression and its effect on the onset of speciation.
Mutation is the ultimate source of genetic variation, the bedrock of evolution. Yet, predicting the consequences of new mutations remains a challenge in biology. Gene expression provides a potential link between a genotype and its phenotype. But the variation in gene expression created by de novo mutation and the fitness consequences of mutational changes to expression remain relatively unexplored. Here, we investigate the effects of >2600 de novo mutations on gene expression across the transcriptome of 28 mutation accumulation lines derived from two independent wild-type genotypes of the green algae Chlamydomonas reinhardtii. We observed that the amount of genetic variance in gene expression created by mutation (Vm) was similar to the variance that mutation generates in typical polygenic phenotypic traits and approximately 15-fold the variance seen in the limited species where Vm in gene expression has been estimated. Despite the clear effect of mutation on expression, we did not observe a simple additive effect of mutation on expression change, with no linear correlation between the total expression change and mutation count of individual MA lines. We therefore inferred the distribution of expression effects of new mutations to connect the number of mutations to the number of differentially expressed genes (DEGs). Our inferred DEE is highly L-shaped with 95% of mutations causing 0-1 DEG while the remaining 5% are spread over a long tail of large effect mutations that cause multiple genes to change expression. The distribution is consistent with many cis-acting mutation targets that affect the expression of only one gene and a large target of trans-acting targets that have the potential to affect tens or hundreds of genes. Further evidence for cis-acting mutations can be seen in the overabundance of mutations in or near differentially expressed genes. Supporting evidence for trans-acting mutations comes from a 15:1 ratio of DEGs to mutations and the clusters of DEGs in the co-expression network, indicative of shared regulatory architecture. Lastly, we show that there is a negative correlation with the extent of expression divergence from the ancestor and fitness, providing evidence of the deleterious effects of perturbing gene expression.
Although the primate brain contains numerous functionally distinct structures that have experienced diverse genetic changes during the course of evolution and development, these changes remain to be explored in detail. Here we utilize two classic metrics from evolutionary biology, the evolutionary rate index (ERI) and the transcriptome age index (TAI), to investigate the evolutionary alterations that have occurred in each area and developmental stage of the primate brain. We observed a higher evolutionary rate for those genes expressed in the non-cortical areas during primate evolution, particularly in human, with the highest rate of evolution being exhibited at brain developmental stages between late infancy and early childhood. Further, the transcriptome age of the non-cortical areas was lower than that of the cerebral cortex, with the youngest age apparent at brain developmental stages between late infancy and early childhood. Our exploration of the evolutionary patterns manifest in each brain area and developmental stage provides important reference points for further research into primate brain evolution.
Primate evolution has led to a remarkable diversity of behavioral specializations and pronounced brain size variation among species (Barton, 2012; DeCasien & Higham, 2019; Powell, Isler, & Barton, 2017). Gene expression provides a promising opportunity for studying the molecular basis of brain evolution, but it has been explored in very few primate species to date (e.g. Khaitovich et al., 2005; Khrameeva et al., 2020; Ma et al., 2022; Somel et al., 2009). To understand the landscape of gene expression evolution across the primate lineage, we generated and analyzed RNA-Seq data from four brain regions in an unprecedented eighteen species. Here we show a remarkable level of variation in gene expression among hominid species, including humans and chimpanzees, despite their relatively recent divergence time from other primates. We found that individual genes display a wide range of expression dynamics across evolutionary time reflective of the diverse selection pressures acting on genes within primate brain tissue. Using our samples that represents a 190-fold difference in primate brain size, we identified genes with variation in expression most correlated with brain size. Our study extensively broadens the phylogenetic context of what is known about the molecular evolution of the brain across primates and identifies novel candidate genes for study of genetic regulation of brain evolution.
Genetic variation is truly responsible for every new phenotypical appearance or silencing. In human genome, all genes were identified for their particular functions but if any variation occurs in genotype of the person was changed and resulted altered protein levels or protein dysfunction. In case of cancer, several genetic variations were reported either somatic or germline. Somatic variation or predisposition of genetic variations in healthy population occurred during daily routine life, causing several types of cancers like breast cancer, liver hepatocarcinoma, renal carcinoma, sarcoma, etc. Germline genetic variations always occurred in next generation's gene pool like BRCA1 and BRCA2 in breast cancer. Mostly common somatic genetic variation predispositions are TP53, PIK3CA, AKT1, MAP2K7, MYC, PTEN, etc. Identification of somatic-genetic variation predisposition in particular cancer might help to develop target therapy for particular cancers.
Although previous studies have identified human-specific accelerated regions as playing a key role in the recent evolution of the human brain, the characteristics and cellular functions of rapidly evolving conserved elements (RECEs) in ancestral primate lineages remain largely unexplored. Here, based on large-scale primate genome assemblies, we identify 888 RECEs that have been highly conserved in primates that exhibit significantly accelerated substitution rates in the ancestor of the Simiiformes. This primate lineage exhibits remarkable morphological innovations, including an expanded brain mass. Integrative multi-omics analyses reveal that RECEs harbor sequences with potential cis-regulatory functions that are activated in adult human brain. Importantly, genes linked to RECEs exhibit pronounced expression trajectories in adult brain relative to the fetal stage. Furthermore, we observed an increase in the chromatin accessibility of RECEs in oligodendrocytes from individuals with Alzheimer's disease (AD) compared to that of a control group, indicating that these RECEs may contribute to brain aging and AD. Our findings serve to expand our knowledge of the genetic underpinnings of brain function during primate evolution.
Evolution of gene expression mediated by cis-regulatory changes is thought to be an important contributor to organismal adaptation, but identifying adaptive cis-regulatory changes is challenging due to the difficulty in knowing the expectation under no positive selection. A new approach for detecting positive selection on transcription factor binding sites (TFBSs) was recently developed, thanks to the application of machine learning in predicting transcription factor (TF) binding affinities of DNA sequences. Given a TFBS sequence from a focal species and the corresponding inferred ancestral sequence that differs from the former at n sites, one can predict the TF binding affinities of many n-step mutational neighbors of the ancestral sequence and obtain a null distribution of the derived binding affinity, which allows testing whether the binding affinity of the real derived sequence deviates significantly from the null distribution. Applying this test genomically to all experimentally identified binding sites of three TFs in humans, a recent study reported positive selection for elevated binding affinities of TFBSs. Here we show that this genomic test suffers from an ascertainment bias because, even in the absence of positive selection for strengthened binding, the binding affinities of known human TFBSs are more likely to have increased than decreased in evolution. We demonstrate by computer simulation that this bias inflates the false positive rate of the selection test. We propose several methods to mitigate the ascertainment bias and show that almost all previously reported positive selection signals disappear when these methods are applied.
Modern comparative biology owes much to phylogenetic regression. At its conception, this technique sparked a revolution that armed biologists with phylogenetic comparative methods (PCMs) for disentangling evolutionary correlations from those arising from hierarchical phylogenetic relationships. Over the past few decades, the phylogenetic regression framework has become a paradigm of modern comparative biology that has been widely embraced as a remedy for shared ancestry. However, recent evidence has sown doubt over the efficacy of phylogenetic regression, and PCMs more generally, with the suggestion that many of these methods fail to provide an adequate defense against unreplicated evolution—the primary justification for using them in the first place. Importantly, some of the most compelling examples of biological innovation in nature result from abrupt lineage-specific evolutionary shifts, which current regression models are largely ill-equipped to deal with. Here we explore a solution to this problem by applying robust linear regression to comparative trait data. We formally introduce robust phylogenetic regression to the PCM toolkit with linear estimators that are less sensitive to model violations than the standard least-squares estimator, while still retaining high power to detect true trait associations. Our analyses also highlight an ingenuity of the original algorithm for phylogenetic regression based on independent contrasts, whereby robust estimators are particularly effective. Collectively, we find that robust estimators hold promise for improving tests of trait associations and offer a path forward in scenarios where classical approaches may fail. Our study joins recent arguments for increased vigilance against unreplicated evolution and a better understanding of evolutionary model performance in challenging–yet biologically important–settings.
Noncoding DNA is central to our understanding of human gene regulation and complex diseases1,2, and measuring the evolutionary sequence constraint can establish the functional relevance of putative regulatory elements in the human genome3–9. Identifying the genomic elements that have become constrained specifically in primates has been hampered by the faster evolution of noncoding DNA compared to protein-coding DNA¹⁰, the relatively short timescales separating primate species¹¹, and the previously limited availability of whole-genome sequences¹². Here we construct a whole-genome alignment of 239 species, representing nearly half of all extant species in the primate order. Using this resource, we identified human regulatory elements that are under selective constraint across primates and other mammals at a 5% false discovery rate. We detected 111,318 DNase I hypersensitivity sites and 267,410 transcription factor binding sites that are constrained specifically in primates but not across other placental mammals and validate their cis-regulatory effects on gene expression. These regulatory elements are enriched for human genetic variants that affect gene expression and complex traits and diseases. Our results highlight the important role of recent evolution in regulatory sequence elements differentiating primates, including humans, from other placental mammals.
Denisovans, a group of now extinct humans who lived in Eastern Eurasia in the Middle and Late Pleistocene, were first identified from DNA sequences just over a decade ago. Only ten fragmentary remains from two sites have been attributed to Denisovans based entirely on molecular information. Nevertheless, there has been great interest in using genetic data to understand Denisovans and their place in human history. From the reconstruction of a single high-quality genome, it has been possible to infer their population history, including events of admixture with other human groups. Additionally, the identification of Denisovan DNA in the genomes of present-day individuals has provided insights into the timing and routes of dispersal of ancient modern humans into Asia and Oceania, as well as the contributions of archaic DNA to the physiology of present-day people. In this Review, we synthesize more than a decade of research on Denisovans, reconcile controversies and summarize insights into their population history and phenotype. We also highlight how our growing knowledge about Denisovans has provided insights into our own evolutionary history.
Genotype-phenotype mapping (GPM) or the association of trait variation to genetic variation has been a long-lasting problem in biology. The existing approaches to this problem allowed researchers to partially understand within- and between-species variation as well as the emergence or evolution of phenotypes. However, traditional GPM methods typically ignore the transcriptome or have low statistical power due to challenges related to dataset scale. Thus, it is not clear to what extent selection modulates transcriptomes and whether cis- or trans-regulatory elements are more important. To overcome these challenges, we leveraged the cost efficiency and scalability of single-cell RNA sequencing (scRNA-seq) by collecting data from 18,233 yeast cells from 4,489 segregants of a cross between the laboratory strain BY4741 and the vineyard strain RM11-1a. More precisely, we performed eQTL mapping with the scRNA-seq data to identify single-cell eQTL (sc-eQTL) and transcriptome variation patterns associated to fitness variation inferred from the segregants' bulk fitness assay. Due to the larger scale of our dataset, we were able to recapitulate results from decades of work in GPM from yeast bulk assays while revealing new associations between phenotypic and transcriptomic variations. The multidimensionality of this dataset also allowed us to measure phenotype and expression heritability and partition the variance of cell fitness into genotype and expression components to highlight selective pressure at both levels. Altogether these results suggest that integrating large-scale scRNA-seq data into GPM improves our understanding of trait variation in the context of transcriptomic regulation.
The coding sequences of developmental genes are expected to be deeply conserved, with cis-regulatory change driving the modulation of gene function. In contrast, proteins with roles in defense are expected to evolve rapidly, in molecular arms-races with pathogens. However, some gene families include both developmental and defense genes. In these families, does the tempo and mode of evolution differ between genes with divergent functions, despite shared ancestry and structure? The leucine-rich repeat receptor-like kinase (LRR-RLKs) protein family includes members with roles in plant development and defense, thus providing an ideal system for answering this question. LRR-RLKs are receptors that traverse plasma membranes. LRR domains bind extracellular ligands, RLK domains initiate intracellular signaling cascades in response to ligand binding. In LRR-RLKs with roles in defense, LRR domains evolve faster than RLK domains. To determine whether this asymmetry extends to LRR-RLKs that function primarily in development, we assessed evolutionary rates and tested for selection acting on eleven sub-families of LRR-RLKs, using deeply sampled protein trees. To assess functional evolution, we performed heterologous complementation assays in Arabidopsis thaliana (arabidopsis). We found that the LRR domains of all tested LRR-RLK proteins evolved faster than their cognate RLK domains. All tested sub-families of LRR-RLKs had strikingly similar patterns of molecular evolution, despite divergent functions. Heterologous transformation experiments revealed that multiple mechanisms likely contribute to the evolution of LRR-RLK function, including escape from adaptive conflict. Our results indicate specific and distinct evolutionary pressures acting on LRR vs. RLK domains, despite diverse organismal roles for LRR-RLK proteins.
Self-transcribing active regulatory region sequencing (STARR-seq) and its variants have been widely used to characterize enhancers. However, it has been reported that up to 87% of STARR-seq peaks are located in repressive chromatin and are not functional in the tested cells. While some of the STARR-seq peaks in repressive chromatin might be active in other cell/tissue types, some others might be false positives. Meanwhile, many active enhancers may not be identified by the current STARR-seq methods. Although methods have been proposed to mitigate systematic errors caused by the use of plasmid vectors, the artifacts due to the intrinsic limitations of current STARR-seq methods are still prevalent and the underlying causes are not fully understood. Based on predicted cis-regulatory modules (CRMs) and non-CRMs in the human genome as well as predicted active CRMs and non-active CRMs in a few human cell lines/tissues with STARR-seq data available, we reveal prevalent false positives and false negatives in STARR-seq peaks generated by major variants of STARR-seq methods and possible underlying causes. Our results will help design strategies to improve STARR-seq methods and interpret the results.
Changes in gene expression are thought to play a major role in adaptive evolution. While it is known that gene expression is highly sensitive to the environment, very few studies have determined the influence of genetic and environmental effects on adaptive gene expression differences in natural populations. Here, we utilize allele-specific expression to characterize cis and trans gene regulatory divergence in temperate and tropical house mice in two metabolic tissues under two thermal conditions. First, we show that gene expression divergence is pervasive between populations and across thermal conditions, with roughly 5 to 10% of genes exhibiting genotype-by-environment interactions. Second, we found that most expression divergence was due to cis -regulatory changes that were stable across temperatures. In contrast, patterns of expression plasticity were largely attributable to trans -effects, which showed greater sensitivity to temperature. Nonetheless, we found a small subset of temperature-dependent cis -regulatory changes, thereby identifying loci underlying expression plasticity. Finally, we performed scans for selection in wild house mice to identify genomic signatures of rapid adaptation. Genomic outliers were enriched in genes with evidence for cis -regulatory divergence. Notably, these genes were associated with phenotypes that affected body weight and metabolism, suggesting that cis- regulatory changes are a possible mechanism for adaptive body size evolution between populations. Our results show that gene expression plasticity, largely controlled in trans , may facilitate the colonization of new environments, but that evolved changes in gene expression are largely controlled in cis , illustrating the genetic and nongenetic mechanisms underlying the establishment of populations in new environments.
Resurrection experiments provide a unique opportunity to evaluate phenotypic and molecular evolution in response to environmental challenges. To understand the evolution of urban populations of Helianthus annuus, we compared plants from 36-year-old antecedent seed collections to modern seed collections from the same area using molecular and quantitative genetic approaches. We found 200 differentially expressed transcripts between antecedent and modern groups, and transcript expression was generally higher in modern samples as compared to antecedent samples. Admixture analysis indicated gene flow from domesticated to modern populations over time. After a greenhouse refresher generation, one antecedent-modern population pair was grown under two water availability (well-watered and drought) and temperature (ambient and elevated by 2.8°C) conditions reflecting historical and contemporary climates. Overall, 78% (7 out of 9) of traits differed between the antecedent and modern populations, with modern individuals displaying some trait changes that are coherent with climate changes expectations and some trait changes in the direction of crop varieties. Phenotypic selection analysis showed that modern trait values were often favoured by selection, especially in environmental treatments resembling modern conditions. Trait heritability in the antecedent population was five times as high as in the modern population, on average. In addition, phenotypic plasticity for some traits, such as flowering phenology, was present in the antecedent population but absent in the modern population. The combination of phenotypic and molecular information suggests that evolution has been influenced by crop-wild introgression, adaptive processes and drift. We discuss these results in the context of continued evolution in response to anthropogenic factors.
At least two electrophoretically distinct components of hemoglobin, B and C, occur in hemolysates of the bullfrog, Rana catesbeiana (Aggarwal, S.J., and Riggs, A. (1969) J. Biol. Chem. 244, 2372–2383). Component C polymerizes by disulfide bond formation between tetramers, but component B does not. Component C also has a higher oxygen affinity and a smaller Bohr effect than does component B.
The amino acid sequence of the first 105 of 141 residues has been determined for the β chain of component C. The sequences of segments of the remaining 35 residues have also been determined. The first 105 residues together with these segments differ in 29 of the 125 identified positions (excluding one deletion and one insertion) from the corresponding segment of the β chain of the European frog, Rana esculenta (CHAUVET, J.-P., AND ACHER, R. (1972) Biochemistry 11, 916–927). This large difference suggests that these frogs, although in the same genus, may have been separated from one another for as long as 150 to 250 x 10⁶ years if the procedure of Dickerson ((1971) J. Mol. Evol. 1, 26–45) is assumed. Alignment of the sequence with that of the human β chain shows that the first 6 residues of the NH2-terminal segment of the human chain are absent in the bullfrog β chain. Among the remainder (125 residues in the bullfrog), 67 of 125 (54%) are identical.
In mammalian hemoglobins a hydrogen bond between the imidazole group of the histidyl residue at β146 and the aspartyl residue at β94 appears responsible for about half the Bohr effect. The position corresponding to this aspartyl residue is a glycyl residue at β88 in the bullfrog. Therefore, if the COOH-terminal histidine of the β chain is involved in the Bohr effect it must be hydrogen-bonded to a different residue in unliganded bullfrog hemoglobin.
Precipitin techniques were used for cross-reactivity studies with rabbit antisera to seven different bird egg white lysozymes. A similar study was previously made with the same antisera by the micro-complement fixation technique. There is an excellent correlation between cross-reactivity measured by micro-complement fixation and that measured by the quantitative precipitin technique. However, the latter technique is less economical of materials and less able to discriminate between closely related lysozymes. Although cross-reactivity measured by immunodiffusion, a qualitative precipitin technique, is correlated with that measured by the above two techniques, it is far less sensitive to small antigenic differences.
The above correlations permitted a review of the dependence of immunological cross-reactivity upon amino acid sequence resemblance for several other proteins besides lysozyme. Even though the published data are fragmentary compared with those available for lysozyme, it seems to be a general rule that native proteins differing by more than 30 to 40% in sequence fail to cross-react in direct precipitin or complement fixation tests.
The multiple forms of lactate dehydrogenase that occur in trout were partially purified and examined by physical, catalytic, and immunological methods. Two major groups of isoenzymes were detected, which we refer to as the heart and muscle groups. Upon starch gel electrophoresis at pH 6, extracts prepared from white skeletal muscle gave rise to five closely spaced bands of lactate dehydrogenase activity with low mobility. Heart extracts exhibited another group of five (or, in some individuals, nine) closely spaced isoenzymes, which migrated rapidly toward the anode. Liver extracts contained predominantly one isoenzyme corresponding in mobility to one of the heart isoenzymes. When the lactate dehydrogenases of different species (brook, brown, and rainbow trout) were compared, differences were observed in the spacing between individual isoenzymes within the heart and muscle groups. In addition, the mobilities of the isoenzyme groups differed from species to species.
To determine whether the trout heart and muscle groups are homologous with the heart and muscle lactate dehydrogenases of higher vertebrates, a comparison was made with crystalline preparations of the pure H4 (heart) and M4 (muscle) homotetramers obtained from the chicken. The two isoenzyme groups of trout were similar in molecular size to the chicken enzymes, as judged by gel filtration experiments with a calibrated column of Sephadex G-200. The heart group, like the chicken H4 enzyme, survived heating at 65°, whereas the chicken M4 enzyme and the trout muscle group were inactivated rapidly by heating at 55°. The trout heart group was more susceptible to inhibition by pyruvate than the muscle group, a difference which is similar in magnitude and direction to that known to exist between the chicken H4 and M4 enzymes. Finally, the trout heart and muscle groups were tested for reactivity with specific antisera prepared in rabbits. Antisera prepared against the chicken H4 enzyme reacted with the trout heart group but not with the trout muscle isoenzymes. The reactions were detected by immunodiffusion, enzyme inhibition, and micro-complement fixation tests. Similarly, antisera prepared against the chicken M4 enzyme reacted with the trout muscle lactate dehydrogenases but not with the trout heart enzymes. Thus, by physical, catalytic, and immunological criteria, the trout heart and muscle groups of lactate dehydrogenases appear to be homologous with the H4 and M4 enzymes, respectively, of higher vertebrates.
In all the above tests, the trout liver isoenzyme behaved as a member of the heart group of lactate dehydrogenases, not as a member of the muscle group. The inclusion of the liver isoenzyme in the heart group was confirmed by experiments with an antiserum prepared against purified trout liver lactate dehydrogenase. These results, together with the published results of genetic experiments, appear to be consistent with the postulate that two distinct genes dictate the formation of the heart group of lactate dehydrogenases in trout.
We have studied genetic variation at 30-32 loci coding for enzymes in natural populations of five species of Drosophila. The average proportion of heterozygous loci per individual is 17.7 ± 0.4%. The average proportion of polymorphic loci per population is 69.2 ± 2.6% or 49.8 ± 2.2%, depending on what criterion of polymorphism is used. The following generalizations are advanced: (1) The amount of genetic polymorphism varies considerably from locus to locus. (2) At a given locus, populations of the same species are very similar in the amount and pattern of genetic variation. (3) However, at some loci large differences sometimes occur between local populations of the same species. (4) The amount of variation at a given locus is approximately the same in all five species. (5) When different species are compared, the pattern of the variation is either essentially identical or totally different at a majority of loci. We have tested the hypothesis that protein polymorphisms are selectively neutral by examining four predictions derived from the hypothesis. Our results are at variance with every one of the predictions. We have measured the amount of genetic differentiation, D, between taxa of various degrees of evolutionary divergence. The average value of D is 0.033 for local populations, 0.228 for subspecies, 0.226 for semispecies, 0.538 for sibling species, and 1.214 for morphologically distinguishable species. Our results indicate that a substantial degree of genetic differentiation (22.8 allelic substitutions for every 100 loci) occurs between allopatric populations that have diverged to the point where they might become different species if they were to become sympatric. However, very little additional genetic change is required for the development of complete reproductive isolation. After the speciation process is completed, species continue to diverge genetically from each other.
α1-Acid glycoprotein has been isolated in homogeneous form from Cohn's Fraction VI of chimpanzee plasma by carboxymethyl cellulose chromatography and also by electrofocusing. The sedimentation coefficient of this glycoprotein is 3.48 and the molecular weight is 39,000 as estimated by the Archibald sedimentation equilibrium method. By using sodium dodecyl sulfate-polyacrylamide gel electrophoresis, the molecular weights of both chimpanzee and human α1-acid glycoprotein were found to be 40,000. General properties of chimpanzee α1-acid glycoprotein, including amino acid composition, carbohydrate composition, and COOH-terminal and NH2-terminal amino acids, closely resemble those of human α1-acid glycoprotein. By electrofocusing, the isoelectric points of both human and chimpanzee α1-acid glycoprotein were found to be 1.82.
In spite of the close resemblance between human and chimpanzee α1-acid glycoprotein in chemical and physical properties, and the fact that they appear immunologically identical by the Ouchterlony double diffusion technique, an immunological difference between these two glycoproteins has been shown by quantitative precipitin analysis. The results suggest that these two glycoproteins are different either in the oligosaccharide or in the peptide sequences, or possibly in both oligosaccharide and peptide structures.
Eight variants of the α1-acid glycoprotein of human serum were isolated by column zone electrophoresis in a denaturing, viscous buffer. Six of these
monomers were analyzed and found to have similar molecular weights, to possess 11 or 12 oligosaccharide side chains, and to
have the same amino acid and carbohydrate compositions.
Eight variants were also observed when the protein thiol of the α1-acid glycoprotein was subjected to zone electrophoresis in a denaturing and reducing buffer.
The data indicate that the electrophoretic differences between the variants is not a result of differences in the primary
or tertiary structures.
Rabbit antisera were prepared against seven different lysozymes purified from the egg whites of chicken, bobwhite quail, turkey,
Japanese quail, ring-necked pheasant, and duck. Cross-reactivity tests by means of quantitative micro-complement fixation
were conducted among all possible pairs of these lysozymes as well as with three other lysozymes. The amino acid sequences
are known for five of the 10 proteins we examined. A correlation was observed between degree of immunological cross-reactivity
and degree of amino acid sequence similarity, with the limitation that proteins differing from each other by 40% or more in
sequence exhibited no cross-reactivity in micro-complement fixation tests. This relationship between sequence resemblance
and immunological resemblance is compatible not only with the fact that amino acid replacements have generally occurred on
the outer surface of the lysozyme molecule during bird evolution but also with current ideas about the size and number of
antigenic determinants on proteins and with the idea that the conformation of the polypeptide backbone is strongly conserved
during evolution.
Cross-reactivity measurements are affected by several parameters that were investigated, including the length of the immunization
program, variability among rabbits, and the degree to which the results of reciprocal tests agree. Antiserum specificity broadened
with time and reached a plateau after several months of immunization. Considerable variability among rabbits necessitated
pooling several sera in inverse proportion to their degree of reaction with the homologous antigen in order to obtain a more
representative measurement. The results of reciprocal tests advise measuring cross-reactivity in both directions to better
evaluate the degree of antigenic difference between two lysozymes.
Amino acid analysis, electron resonance spectroscopy, metal analysis, and analysis for subunit structure have been performed on bovine superoxide dismutase. The enzyme consists of two subunits of identical molecular weight held together by disulfide bonds.
Superoxide dismutase has been purified from bovine heart by a procedure which was previously developed for the isolation of this enzyme from bovine erythrocytes. The heart enzyme is judged to be identical with the erythrocyte enzyme on the basis of response to an unusual purification procedure, specific enzymatic activity, content of copper and zinc, molecular weight, amino acid composition, ultraviolet absorption spectrum, and electron paramagnetic resonance spectrum. The widespread distribution of superoxide dismutase in mammalian tissues is taken as one indication of its importance to the survival of the cells which constitute these diverse tissues.
A generalized distance for discrete variables which is analogous to the Mahalanobis generalized distance is presented. Comparisons are made with other distance measures which are closely related and the significance of the differences is discussed.
The processes of karyotypic and genic differentiation have proceeded independently in the evolution of pocket gophers of the Geomys bursarius group. In the peripheral relict G. tropicalis, a reduction in 2N chromosome number from ∼70 to 38 was not accompanied by an unusual degree of allelic substitution at structural gene loci. The possibility that a reduction in number of linkage groups and an apparent loss of variability at structural gene loci in G. tropicalis represent adaptation to an unusually uniform environment is discussed.
The probability of genotypic identity and probability of a unique genotype (expressions 5 and 7) together have several advantages over other genetic similarity measures. First of all, these two measures depend upon genotype frequencies and not gene frequencies. Secondly, the probability of genotypic identity is weighted thereby avoiding the frequency dependent attributes of other genetic similarity measures. Thirdly, the probability of a unique genotype allows special consideration to the absence or presence of a genotype in a population.
Albumin evolution and organismal evolution in tree frogs (Hylidae). Syst. Zool. 24:1–15.—To explore the relationship between organismal and protein evolution, a comparative study was made of the serum albumins of tree frogs (Hylidae). Attention was centered on those Holarctic hylines whose anatomy and way of life have been intensively studied, namely species of Acris, Hyla, and Pseudacris. An albumin phylogeny was constructed from immunological distance data obtained with rabbit antisera to the purified albumins of 12 hyline species by means of the micro-complement fixation test. An analogous study with antisera to purified hemoglobin from 4 of these species was in approximate agreement with the albumin phylogeny.
The albumin phylogeny revealed an apparent case of convergent morphological evolution involving H. wrightorum and H. regilla. These two species are similar enough in external morphology to have been classified in the same species by some recent authors. Yet their albumins differ as much from each other immunologically as from Acris albumin. This case is discussed more fully elsewhere (Maxson & Wilson, 1974).
Discrepancies between organismal resemblance and albumin resemblance can also arise because of unequal rates of organismal divergence. Acris provides an example of this. The albumin phylogeny, supported by hemoglobin evidence, shows that the Acris lineage falls cladistically within the North American assemblage of Hyla lineages. Acris is more similar at the protein level to some Hyla species than the latter are to other Hyla species. Yet Acris is very different from Hyla in anatomy and way of life. The Acris lineage evidently underwent unusually rapid organismal evolution. However, there is no indication of accelerated albumin evolution in this lineage. Limnaoedus and Pseudacris provide additional examples of this sort.
We infer that organismal and protein evolution can proceed at independent rates. This provides taxonomists with a dilemma: Should classifications be revised on the basis of protein data?
The albumin results are consistent with recent ideas about the historical biogeography of hyline tree frogs. By assuming that albumin behaves as an evolutionary clock, which evolves at the rate of 1.7 immunological distance units per million years, it is calculated that a) Australian hylines diverged from New World hylines about 75 million years ago, b) North American hylines diverged from South American hylines 65 million years ago, and c) Eurasian hylines diverged from North American hylines about 40 million years ago. These estimated times are in approximate agreement with non-molecular evidence concerning the times when land connections existed between these continents. The assumed rate of albumin evolution is similar to that estimated elsewhere for such diverse organisms as mammals, iguanid lizards, crocodilians and ranoid frogs. The inference that albumin behaves approximately as an evolutionary clock is thus extended to include tree frogs.
Two new indices are presented for the measurement of distances between populations on the basis of attribute data. The intermediate variables used to obtain these indices help to analyse attribute data in almost all the ways in which quantitative data could be analysed. The advantages and disadvantages of these and other indices are discussed.
The present work is a study of primate serum proteins. Blood samples of 88 individuals from 16 genera were examined by the high voltage electrophoresis in starch gel. In accordance with other authors we have observed only the haptoglobine 1-l phenotype atnong all the explored primates. The Pongidae and Homo have the same electrophoretical mobility of their haptoglobin haemoglobin complex ; this zone migrates slower in Symphalangus and faster in most of the other genera. An identical localisation of the Hp 1-1 band in native serum-without complexing with haemoglobin - was noted in Pongo, Gorilla and Homo. The corresponding zone of Pan troglody tes migrates probably more slowly, but 2 of the 3 examined Pan paniscus show the same mobility of Hp 1-1 as the other pongides. Contrasting with the unifonnity of the haptoglobin system in non human primates, characterized by the absence of the allele Hp2, there is a remarkable polymorphism of the transferrins. In the case of Pan and Gorilla transferrins were identified slower than the human Tf C, D- and E-transferrins in the sera of Pan (9 phenotypes) and D-transferrins in Gorilla (4 phenotypes); only one individual (G. g.g.) shows a C- transferrin. Our transferrin diagnoses in Pan troglodytes could he confirmed by family data. In Symphalangus we have observed such transferrins faster than the human TfC, so called A-und B-variants (1 phenotype). Most of the identified transferrins in the Cercopithecidae sera are A-transferrins (TfA1- Tf A5). In some genera we have also seen B-transferrins, i. e. in Macaca, Papio and Presbytis. The examined Cebidae are characterized by very fast A-transferrins (Cacajao with Tf A0, Cebus and Ateles with A1). There are also A-transferrins in the genus Lemur (A3 -A6), where as Tupaia shows A- and B-transferrins (A5 and B0). Obviously the Pongidae are mainly characterized by slow transferrins, while all the lower primates have fast Tf variants. We have found furthermore a certain polymorphism of the prealbumins. In the case of the Pongidae and the greater part of Cercopithecidae two prealhumins could be noted which are completely missing in some Cebiclae (Cebus, A teles) and in Tupaia. Lemur has only one prealbumin. In Pan and most of the Cercopithecidae the fust prealbumin zone is stronger than the second. Gorilla and Pan seldom show quantitative differences of the prealbumins. The postalbumins were found to be different among the Pongidae. Intraspecific group variations are present in Symphalangus and in Ateles.
Individual chimpanzee chromosomes have been identified by their characteristic banding revealed by quinacrine fluorescent staining. A fluorescent karyotype of this species was set up to be compared with the standard human fluorescent karyotype. It was found that chromosomes 1, 3, 11, 12, 14 and X-chromosome of the chimpanzee appear to have banding patterns similar to the equivalent human chromosomes. Chromosomes 6, 7, 8, 10 and 13 also had a fluorescent pattern corresponding to the human chromosomes of the same number, particularly in the long arm. Remarkable variation in intensity and/or size of fluorescent regions was frequently found in the short arm of satellited acrocentric chromosomes 13, 14, 15, 22 and 23. Variations occurred between homologues and between individuals. Such variable fluorescence in a specific chromosomal region of an individual animal is a reproducible characteristic. Unlike its human counterpart, the distal segment in the long arm of the chimp's Y-chromosome is not brightly fluorescent. An earlier report is thus confirmed.
Hominoid phylogeny was investigated in terms of unique DNA sequence homologies. In comparisons from the human standpoint the ΔTe50 DNA values were Man 0, chimpanzee 0·7, gorilla 1·4, gibbon 2·7, orangutan 2·9, and African green monkey 5·7. In comparisons from the orangutan standpoint the ΔTe50 DNA values were orangutan 0, chimpanzee 1·8, Man 1·9, gorilla 2·3, gibbon 2·4 and African green monkey 4·3. These results indicate that chimpanzee and gorilla are cladistically closer to Man than to orangutan and other primates, and that gorilla DNA may have diverged slightly more from the ancestral state than chimpanzee or human DNA. Comparisons from chimpanzee and gorilla DNA standpoints are needed to achieve a more definitive picture of hominoid phylogeny.
This study is concerned with comparing the DNA sequences of different mammals, mainly primates, by utilizing nucleic acid hybridization. Nucleotide sequence differences between different species have been quantitated. Rates of nucleotide sequence change have been calculated. These data suggest that nucleotide sequence change has been decreasing with the development of the primate line. They also indicate that the rate of nucleotide sequence change in Primates is 10 - 20 × lower than that for rodents during recent evolutionary times. When corrected for generation time the rodent and primate rates are essentially equal.
There is a finite upper limit to the number of gene loci which an organism can afford to have. An organism having 3 × 106 or so gene loci would exterminate itself from an unbearable mutation load. Yet, the mammalian genome is large enough to accommodate that many gene loci. Natural selection is essentially conservative. A new gene with a hitherto non-existent function can not be created unless a temporary escape from the relentless pressure of natural selection is provided by gene duplication. However, the chance of a redundant copy of an old gene emerging as a new gene is considerably smaller than of that copy becoming degenerate. Perhaps for this reason, evolution from simpler life forms to mammals appears to have been accompanied not only by successive additions of new gene loci, but also by accumulation in the genome of a great deal of degenerate "nonsense" DNA base sequences. At least 90% of the mammalian genomic DNA appears to represent "nonsense" DNA base sequence of various kinds. The creation of additional regulatory systems contributed more to big leaps in evolution than did the creation of new structural genes. Yet, in order not to be burdened with an unbearable mutation load, the necessary increase in the number of regulatory systems had to be compensated by simplification of each regulatory system. It would not be surprising if each mammalian regulatory system is shown to have fewer components than the lac-operon system of Escherichia coli.
The complete amino-acid sequences of the alpha chains of the common genetic variants of human haptoglobin confirm that the α2 chain has arisen by partial gene duplication of the Hp 1 locus. A homology in sequence between a portion of the haptoglobin alpha chain sequence and a series of Bence Jones light chains suggests that the functional similarity between haptoglobin and immunoglobin G may reflect a common evolutionary origin.
The amino acid compositions of soluble tryptic and chymotryptic peptides of the γ chain of chimpanzee foetal haemoglobin have been determined. The peptides, accounting for all 146 residues of the γ chain, were found to be identical in composition to the corresponding human γ chain peptides. As in man, position γ136 can be occupied by glycine (Gγ chain) as well as alanine (Aγ chain). The ratio of Gγ to Aγ chains in the infant chimpanzee is approx. 2:1, and in the adult approx. 1:2.
EXOTIC habitat, rarity, striking coloration, and an appealing countenance have combined to surround the giant panda (Ailuropda melanoleuca) with an aura of mystery unmatched by most other mammals. Nonetheless, we really know little about the species, a lack perhaps best exemplified by the long-standing controversy about the giant panda's phylogenetic position among the arctoid (canoid plus pinniped) carnivores. There is general agreement that its closest affinities are with the ursids (bears) or procyonids (raccoons), but then the argument begins. The usual possibilities considered are: (1) The giant panda's closest relative is the lesser panda (Ailurus fulgens); as this is usually classified among the procyonids, the giant panda should be also. (2) The two pandas belong together in a separate arctoid family. (3) The giant panda is a somewhat aberrant bear and therefore belongs among the Ursidae1,2.
In this rrport we illustrate the apparently great incidence in the number of different kinds of electrophoretically undetectable intraspecies variants found in the course of characterizing primate hemoglobin α, β and δ sequences. Our primary interest is to assess the significance of such findings in a setting provided by fixed amino acid differences that have accumulated between species during primate evolution. Observed non-randomness in fixed mutations, with respect to both linear distribution and certain kinds of change, is interpreted as due to the restrictive effects of natural selection rather than to either differential mutability at particular positions or disturbed permutations of the genetic code in general. Thus, in the micropatterns of accumulated mutation, we adduce strong evidence for Darwinism. However, we also find that the δ chain of minor hemoglobin A2 (α2δ2)—while apparently visible to selection—seems less restricted than the β chain of the major component, hemoglobin A (α2β2). Such findings are used to support our earlier presumption that comparative changes in β and δ can serve as a model for evaluating mechanisms of amino acid replacement during evolution. We believe that equivalence between β and δ in the numbers of recognizable fixed mutations is more easily explained by non-adaptive mechanisms than by adaptive ones.
Prometaphasic chromosomes of Gorilla, Homo and Pan are compared, using R, Q, T and H-bands techniques in complement of a previous work (Lejeune et al., 1973). Various mechanisms of chromosomal rearrangements are demonstrated with particular reference to heterochromatic segments. Some phylogenic conclusions are proposed.Prometaphase-Chromosomen von Gorilla, Mensch und Schimpanse werden mit hilfe der R-, Q-, T- und H-Bandentechnik verglichen; frhere Arbeiten (Lejeune et al., 1973) werden dadurch ergnzt. Verschiedene Mechanismen von Chromosomen-Rearrangements werden dargestellt; dabei finden die Heterochromatin-Segmente besondere Beachtung. Einige phylogenetische Folgerungen werden gezogen.
The antigenic determinants of the transferrins of 23 different primate species have been compared by a radioimmune inhibition of precipitation technique. Highest degrees of cross-reactivity with antisera to human transferrin were found in the transferrin of African apes, followed by that of the Asian apes, the Old World monkeys, the New World monkeys, and finally by the Prosimians. Thus, the evolution of the antigenic determinants on the transferrin molecule is in good agreement with the taxonomic classification of these species. Similar studies were carried out for 2-macroglobulin and various immunoglobulin chains. Parallel results were obtained except for the heavy chain of M macroglobulin in which gibbon, orangutan, and gorilla probably followed a divergent line of evolution from the other Hominoidea.
Human glucose 6-phosphate dehydrogenase (d-glucose 6-phosphate: NADP oxidoreductase, EC 1.1.1.49) (A+), an electrophoretically distinguishable variant found in Negroes, was purified by column chromatographic techniques. The sedimentation patterns of analytical ultracentrifugation and interference patterns of sedimentation equilibrium indicate a homogeneous preparation. The molecular weight (by sedimentation equilibrium method) was estimated as 230,000, which was closely similar to that of the normal wild type enzyme (B+). The sedimentation constant of the variant enzyme (S
20,w=9.0) was smaller than that of the B+ enzyme (S
20,w=10.0). The molecular weight was about 45,000 in 4 mguanidine hydrochloride, indicating that the A+ enzyme, as well as the B+ enzyme, consisted of six subunits of similar size. The optimal pH of the variant enzyme was slightly higher than that of the B+ enzyme. In contrast to the B+ enzyme, magnesium ion increased the A+ enzyme activity with NAD as substrate. The Michaelis constants and the turnover rate were similar to those of the B+ enzyme. The A+ enzyme was serologically indistinguishable from the B+ enzyme when the anti-B+ serum was used as antibody. No significant difference was found in the amino acid composition of acid hydrolysates of the B+ and the A+ enzymes. This does not exclude an amino acid substitution, and, in fact, a single amino acid substitution, i.e., asparagine in B+ and aspartic acid in A+ enzyme, has been found and is being being reported separately.
1.1. Human erythrocyte acid phosphatases of the two most frequently occurring phenotypes, B and BA, have been purified and resolved into five and seven components, respectively, by the use of a procedure that includes adsorption on Ca3(PO4)2 Sephadex gel filtration and DEAE-cellulose column chromatography.2.2. The use of 4-methylumbelliferyl phosphate as a fluorogenic substrate for the visualisation of the isoenzymes on starch gel greatly increases the sensitivity of the technique and reveals more complex patterns of enzymic activity than had previously been described.3.3. Gel filtration experiments suggest a molecular weight of 13 000 for all of the purified components of the B phenotype.4.4. The isoenzymes appear similar when their substrate specificities were examined but differed with respect to their values and their pH optima.5.5. Multiple forms of this acid phosphatase do not seem to arise from variations in sialic acid content.
1.1. The relationships of twelve non-human primate genera to man were studied using antisera produced against the human serum proteins, albumin, haptoglobin 2-1, ceruloplasmin, transferrin, γM-globulin, γG-globulin, group-specific component and immune globulin, by means of immuno-electrophoresis, immunodiffusion and turbidimetric precipitin tests.2.2. Cluster, correlation and principal component analyses revealed an almost constant order of primate relationships for each protein.3.3. A computer-drawn, three-dimensional spatial arrangement of the genera yielded family clusters in the sequence Hominidae, Pongidae, Cercopithecidae, Cebidae, Lorisidae and Tupaiidae.
The authors report family studies (51 families with 134 children) on the inheritance of the Pi phenotypes. Combining these data with a Norwegian family material (77 families with 323 children) published by Fagerhol and Gedde-Dahl (1969) a total of 128 families with 457 children is now available, which allows the following conclusion: The Pi phenotypes are inherited by a simple codominant mode of heredity and they are determined by a set of (at least nine) alleles. As up to now no exception to the role of inheritance has been observed, the application of the Pi system in cases of disputed paternity seems to be discussible. Some methodological problems in connection with this are shown.
Wallace, D. G., M. C. King and A. C. Wilson (Biochemistry Dept., University of California, Berkeley, California 94720) 1973. Albumin differences among ranid frogs: taxonomic and phylogenetic implications. Syst. Zool., 22:1–13.—Since morphological analysis of living and fossil material has provided little information on taxonomic and phylogenetic relationships among species in the frog family Ranidae, an attempt was made to obtain such information by comparing their serum albumins. Rabbit antisera were prepared against the purified serum albumins of seven ranid species and tested by the microcomplement fixation method for reactivity with the albumins of 36 ranid species. This method provides a measure of the degree of amino acid sequence difference between albumins.
The taxonomic and phylogenetic schemes we have derived from the albumin comparisons are generally in agreement with nonmolecular evidence. In some cases, they go beyond it, permitting demarcations among taxa that were previously unresolved. For example, it is proposed that the North American species of Rana are divisible into at least two major subgroups; an eastern subgroup, which includes R. pipiens and R. catesbeiana, and a western cluster, which includes R. aurora. The nearest relatives of the western cluster appear from albumin comparisons to be the R. temporaria cluster of the Palearctic region. The albumin results also permitted the construction of a phylogenetic tree with a very low percent standard deviation. With the aid of this tree and the molecular clock hypothesis we have estimated the approximate divergence times of various groups, subgroups and clusters of Holarctic ranid species.
The molecular differences among Rana species are at least as large as those usually found within orders of placental mammals. This raises an important question regarding the ranking of taxonomic categories. If the genus Rana is equivalent in terms of genetic dispersion to an order of mammals, should one elevate the rank of Rana to the ordinal level? We believe that the molecular findings provide taxonomists with a dilemma.
Two new electrophoretic variants in human serum ceruloplasmin are described. The first, called Cp New Haven (CpNH), is determined by an allele at the same autosomal locus which controls the previously described CpA and CpB variants. It migrates with a mobility between CpB and CpC. The variant has been encountered in American as well as Nigerian and Haitian Negroes. The minimal estimate of Cp
NH
gene frequency in American Negroes is about 0.006. The second variant, named Cp Bridgeport (Cp Bpt), has a mobility between CpA and CpB. It apparently has an extremely low frequency. Similar to CpNH, the Cp Bpt genetic determinant seems to be an autosomal codominant gene. Its relationship to Cp
A
, Cp
C
, and Cp
NH
is, however, unknown. The frequencies of Cp variants in a number of populations are presented.
Birds have lost the potential for interspecific hybridization slowly. This inference emerges from protein comparisons made on 36 pairs of bird species capable of hybridization. Micro-complement fixation tests show that hybridizable pairs of bird species differ by an average of 12 units of albumin immunological distance and 25 units of transferrin immunological distance. As these proteins evolve at a known and rather steady rate, it is inferred that the average hybridization species pair diverged from a common ancestor about 22 million years ago. The corresponding period for frog species pairs capable of hybridization is about 21 million years, while for hybridizable placental mammals it is only 2 to 3 million years. Thus birds resemble frogs in having lost the potential for interspecific hybridization about 10 times as slowly as have mammals. Birds have also been evolving very slowly at the anatomical level, particularly within the last 25 million years, according to Simpson, Romer, and many other vertebrate zoologists. In this respect they resemble frogs and differ from placental mammals, which have been undergoing unusually rapid anatomical evolution. Chromosomal evolution is also thought to have proceeded very slowly in both birds and frogs, relative to mammals. The above observations are consistent with the hypothesis that evolutionary changes in regulatory systems, that is, changes in the patterns of gene expression, provide the basis for both anatomical evolution and the evolutionary loss of hybridization potential.
Chimpanzee and human chromosomes have been compared after staining by Giemsa-11, trypsin banding, quinacrine fluorescence, and centromeric heterochromatin techniques. The Giemsa-11 technique appears to stain areas containing a particular DNA satellite fraction. All but three chimpanzee chromosomes could be assigned fairly definite homologs in the human karyotype. The most common form of rearrangement between chromosomes in the two species appears to be pericentric inversion.Copyright © 1973 S. Karger AG, Basel
Protein studies have uncovered an apparent case of convergent evolution among North American tree frogs. The species Hyla eximia and Hyla regilla are so similar in external morphology that the "wrightorum" subspecies is assigned by some authorities to H. eximia and by others to H. regilla. Yet microcomplement fixation experiments show that "wrightorum" albumin, though virtually indistinguishable from authentic H. eximia albumin, differs as much from H. regilla albumin as from albumins of species outside the genus Hyla, such as Acris crepitans. The morphological resemblance of "wrightorum" to H. regilla is thus probably due to convergence.
A standard nomenclature for chimpanzee chromosomes is proposed, based on banding patterns and measurements. Comparison of chromosome lengths suggests that the total amount of chromosome material is approximately the same in the human and chimpanzee. Correlation of banding patterns and measurements confirm that the chromosomes of the two species differ by rearrangement of heterochromatic material, several pericentric inversions, and at least one translocation.Copyright © 1973 S. Karger AG, Basel
As our knowledge of human albumin variants increases, their description
as electrophoretically ``slow'', ``faster'' and so on is becoming
inadequate for classification. The largest comparative
series1 found five different migration rates in sera from
nineteen families. Electrophoretic mobility is not the only criterion,
and an earlier classification2 used eight, variations of
mobility in different electro-phoretic media and dye-binding properties
among them. Such observations will not establish the identity of two
albumins but may prove their non-identity.
To assess the significance of macromolecular sequence differences among species, we compared the serum albumins of 81 pairs of vertebrate species capable of producing viable hybrids. Micro-complement fixation experiments showed that the average difference between the albumins within such pairs was only 3 immunological distance units for placental mammals (31 pairs), but 36 units for frogs (50 pairs). Albumin immunological distance is strongly correlated with other measures of genetic distance, including those made with DNA annealing techniques. It therefore seems likely that mammalian species pairs capable of hybridization are far more similar at the macromolecular sequence level than is the case for most hybridizable frogs.
We think the most likely explanation for the marked molecular restriction on hybridization among mammals is that the ratio of regulatory evolution to protein evolution is higher for mammals than for frogs. Mammals may have experienced unusually rapid regulatory evolution; indeed, this could be the factor responsible for their unusually rapid anatomical evolution.
1.
Electrophoresis of human tissue extracts has indicated a specific pattern in fibroblasts for the enzyme triose phosphate isomerase. In other human tissue extracts only two zones I and II of activity were seen. In fibroblasts extracts a more anodic III band was also visible.
2.
Electrophoretic band II was separated from bands I and III. From a study of dissociation by concentrated urea followed by electrophoresis, it was demonstrated that isozyme II is a hybrid between isozymes I and III. An immunological difference was found between isozyme I and II using an antiserum obtained by immunizing rabbits against purified isozyme I.
3.
An evolutionary study showed that other mammals and monkeys are lacking the fast bands II and III, while five species of Hominoids (including man) possess them.
4.
The tentative conclusion was drawn that isozyme III is made of twoβ subunits, isozyme I of twoα subunits and isozyme II is anαβ hybrid. The hypothesis is presented of a gene duplication having appeared at the time of differentiation of Hominoids.
THE question of whether the activities of NADPH-or NADH-glutathione reductase are caused by a single enzyme or by two different enzymes has never been satisfactorily resolved1-4. We have devised a new method for detecting glutathione reductase (GSSGR) activity after starch gel electrophoresis. The study of subjects with an electrophoretically fast mutant glutathione reductase has enabled us to present findings which strongly favour the suggestion that glutathione reductase activities with respect to both pyridine nucleotide coenzymes reside in the same molecule. Some observations have also been made in glutathione reductase deficient and NADH-diaphorase (NADH methaemoglobin oxido-reductase) deficient subjects.
A model emphasizing the possible genetic role of tandem duplications of reverse repeats has been developed as an extension of Crick's (1971) general model for the chromosomes of higher organisms. Although developed initially (1) to explain why random differences in the control regions of individual gene loci might confer a selective advantage on heterozygous individuals as well as (2) to offer the species a means by which such differences might be effected without mutational harm, it seems that control regions built on a foundation of tandemly duplicated reverse repeats would exhibit many properties previously observed in studies on mutable loci in various organisms.
We have compared the relative rates of protein evolution and chromosomal evolution in frogs and mammals. The average rate of change in chromosome number has been about 20 times faster in mammals than in frogs. Whereas it takes only 3.5 million years, on the average, for a pair of mammal species to develop a difference in chromosome number, the corresponding period for frogs is 70 million years. In contrast, the rate of protein evolution in mammals has been roughly equal to that in frogs. The rapid rate of gene rearrangement in mammals parallels both their rapid anatomical evolution and their rapid evolutionary loss of the potential for interspecific hybridization. Thus, gene rearrangements may be more important than point mutations as sources for evolutionary changes in anatomy and way of life.
The purpose of this article is to claim reason for optimism in the attempts to understand regulation of gene expression in cultured eukaryotic cells through biochemical studies in spite of the lack of genetic details. An apparent first order understanding of gene expression in cultured eukaryotic cells seems possible through biochemical studies with cultured cells without the necessity for regulatory mutants. Such studies have already contributed to the knowledge of mRNA biogenesis. When experiments concerning mRNA production can be coupled with experiments concerning the changing rate of specific protein synthesis in cells which respond to a known extracellular influence (such as hormones) at least some elementary information about modes of regulation should result.
The effect of mismatched base pairs on the thermal stability of renatured DNA · DNA duplexes was determined by specific alkali deamination of deoxycytosine residues to deoxyuridine residues. After annealing with unaltered DNA, the effect of the resulting G · U pairs on thermal stability was measured. The measurements of were made optically or by dissociation of filter- or hydroxylapatite-bound duplexes. The results suggest an effect such that 1 % G · U pairs reduces the thermal stability by about 2.2 °C. Considering the available data, an estimate is suggested for the effect of mismatching in heteroduplexes formed by naturally occurring DNA in which mutations have accumulated.
Two different estimates were obtained for the extent of nucleotide sequence divergence in the structural genes of the tryptophan synthetase alpha-chains of Escherichia coli, Salmonella typhimurium, and Aerobacter aerogenes. One estimate was based on comparisons of the amino acid sequences of the respective alpha chains. The other was derived from measurements of the thermal stability of RNA-DNA hybrids formed with phage DNA carrying the alpha-chain structural gene of E. coli and labeled messenger RNA from the three bacterial species. Comparison of the two estimates suggests that during the course of evolution synonymous codon changes have accumulated in the alpha-chain-structural genes.