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The universal practice, up to now, is to make the judgement “paternity excluded” whenever there are more than some established number—such as two—of loci in which the genetic pattern, barring mutation, is inconsistent with paternity. Such a rule is founded on the implicit assumption that the probability of two mutations is vanishingly small. Howeve...
Contexts in source publication
Context 1
... mutation rate among STR markers appears to average about 1/400 [1-3 and unpublished data]. Assuming a 13-marker paternity test and binomial model, the expectations are shown in Table 1. Clearly, two inconsistencies is the critical case. ...Context 2
... Table 1 shows, two inconsistencies is modest prima facie favoring non-paternity. Table 2 shows that taking into account the rarity of shared alleles and the plausibility as mutations of inconsistencies-i.e. ...Context 3
... significance of covert mutations is that since mutation rates are estimated from paternity studies, all published mutation rates for autosomal loci are too low by a possibly significant amount. The rate of apparent mutations is the right number to use to calculate Table 1, but for case calculations- Table 2-the covert-adjusted A must be used. For example, in CSF1PO apparent A = 3/1000 but the true A = 4/1000. ...Citations
... Detection of mutations via the Mendelian incompatibilities approach has been already criticized, as it ignores the possible occurrence of hidden events [4][5][6][7][8][9]. We will briefly explain the rationale behind this claim for the two types of family material (duos or trios) mostly used in this detection method. ...
Mutation is the key player in evolutionary change, both in micro and macro scenarios. Defined as any hereditary change in the transmitted genome from progenitor to offspring, it embraces a heterogeneous set of phenomena, in terms of molecular bases and consequences. Here we limit our analyses to those corresponding to site-specific changes in nucleic acid sequence composition, without alteration in the genome size, i.e., substitutions. These analyses will be performed in the framework of the classical Mendelian diploid mode of transmission, without sex-linkage, under a simple Hardy-Weinberg model. Under these conditions, we show that: (i) per site mutation rates are evolutionarily uninformative, biallelically defined parameters being required to predict the genetic behavior of the population and are also essential to medical and forensic applications; (ii) at polymorphic sites (heterozygosity > 0), estimates of mutation rates through the simple counting of Mendelian incompatibilities in pedigrees are always underestimations, depending heavily on the allelic frequencies, a fact that may lead to erroneous evolutionary inferences, such as that (iii) apparently equal forward and reverse mutation rates, as estimated from Mendelian incompatibilities, do not equate to stable equilibrium. An approach allowing to correct the underestimation, by adopting a sequential strategy of allele specific estimation is presented.
... In both autosomal and heterosomal modes of transmission, when no Mendelian incompatibilities are detected in parent(s)-child duos or trios, it is assumed that no mutation occurred. This unavoidably leads to an underestimation of the mutation rates, since 'hidden' or 'covert' mutations may be present [17][18][19] . ...
Microsatellites, or Short Tandem Repeats (STRs), are subject to frequent length mutations that involve the loss or gain of an integer number of repeats. This work aimed to investigate the correlation between STRs’ specific repetitive motif composition and mutational dynamics, specifically the occurrence of single- or multistep mutations. Allelic transmission data, comprising 323,818 allele transfers and 1,297 mutations, were gathered for 35 Y-chromosomal STRs with simple structure. Six structure groups were established: ATT, CTT, TCTA/GATA, GAAA/CTTT, CTTTT, and AGAGAT, according to the repetitive motif present in the DNA leading strand of the markers. Results show that the occurrence of multistep mutations varies significantly among groups of markers defined by the repetitive motif. The group of markers with the highest frequency of multistep mutations was the one with repetitive motif CTTTT (25% of the detected mutations) and the lowest frequency corresponding to the group with repetitive motifs TCTA/GATA (0.93%). Statistically significant differences (α = 0.05) were found between groups with repetitive motifs with different lengths, as is the case of TCTA/GATA and ATT (p = 0.0168), CTT (p < 0.0001) and CTTTT (p < 0.0001), as well as between GAAA/CTTT and CTTTT (p = 0.0102). The same occurred between the two tetrameric groups GAAA/CTTT and TCTA/GATA (p < 0.0001) – the first showing 5.7 times more multistep mutations than the second. When considering the number of repeats of the mutated paternal alleles, statistically significant differences were found for alleles with 10 or 12 repeats, between GATA and ATT structure groups. These results, which demonstrate the heterogeneity of mutational dynamics across repeat motifs, have implications in the fields of population genetics, epidemiology, or phylogeography, and whenever STR mutation models are used in evolutionary studies in general.
... The standard method for estimating microsatellite mutation rates is detecting and quantifying Mendelian incompatibility rates in one-generation family genotypic configurations, considering either the father or the mother and the child (the socalled duos), or considering both parents and the child (trios) [22,[24][25][26][27]. However, except in the case of simple structure markers in haploid systems [21,28,29], this methodology entails the underestimation of mutation rates, as mutations may not necessarily lead to incompatibilities between parent(s) and child genotypes, originating 'hidden' or 'covert' mutations [29][30][31][32] (see Figure 1 for examples). ...
Microsatellites (or short-tandem repeats (STRs)) are widely used in anthropology and evolutionary studies. Their extensive polymorphism and rapid evolution make them the ideal genetic marker for dating events, such as the age of a gene or a population. This usage requires the estimation of mutation rates, which are usually estimated by counting the observed Mendelian incompatibilities in one-generation familial configurations (typically parent(s)–child duos or trios). Underestimations are inevitable when using this approach, due to the occurrence of mutational events that do not lead to incompatibilities with the parental genotypes (‘hidden’ or ‘covert’ mutations). It is known that the likelihood that one mutation event leads to a Mendelian incompatibility depends on the mode of genetic transmission considered, the type of familial configuration (duos or trios) considered, and the genotype(s) of the progenitor(s). In this work, we show how the magnitude of the underestimation of autosomal microsatellite mutation rates varies with the populations’ allele frequency distribution spectrum. The Mendelian incompatibilities approach (MIA) was applied to simulated parent(s)/offspring duos and trios in different populational scenarios. The results showed that the magnitude and type of biases depend on the population allele frequency distribution, whatever the type of familial data considered, and are greater when duos, instead of trios, are used to obtain the estimates. The implications for molecular anthropology are discussed and a simple framework is presented to correct the naïf estimates, along with an informatics tool for the correction of incompatibility rates obtained through the MIA.
... Many of mutation models used in case work dictates all transitions to be possible, with the disadvantage that exclusion becomes trivially impossible. The one-step mutation model, or other models that assign zero probabilities to some transitions [29], can give positive exclusion probability. Our practical suggestion is to apply such a model for those markers where the reference data is inconsistent (i.e., a mutation has clearly happened) and disable mutations for the remaining markers. ...
Missing person identification typically involves genetic matching of a person of interest against relatives of the missing person. In cases with few available relatives, exhumations or other substantial efforts may be necessary in order to secure adequate statistical power. We propose a simulation approach for solving prioritisation problems arising in such cases. Conditioning on the already typed individuals we estimate the power of each alternative, both to detect the true person, and to exclude false candidates. Graphical summaries of the simulations are given in complementary power plots, facilitating interpretation and decision making. Through a series of examples originating from the well-known Missing grandchildren of Argentina we demonstrate that our method may untangle complex prioritisation problems and other power-related questions. In particular we offer novel insights in recent cases where only children of the potential match are available for testing. We also show that X-chromosomal markers may give high statistical power in missing person identification, but that this requires careful selection of relatives for genotyping. All simulations, power calculations and plots are done with the R package forrel.
... Single inconsistencies are routinely seen among the true trios, even in the 13-marker testing [19]. This may result from a variety of causes according to current research. ...
When using microsatellite loci for DNA paternity testing, genetic inconsistencies sometimes occur in true trios and duos and may be erroneously attributed to germline mutations of microsatellite alleles. Here, we reported a typical case and discussed the issue of how to find out the cause of a genetic inconsistency. In our case, a genetic inconsistency in a true trio was observed at the D8S1179 locus, where the father has only allele 10 as compared to only allele 16 of his son. A set of tests were then performed. The results showed that the inconsistency was not result from the germline mutation of allele 10 to allele 16, or from the presence of null alleles due to primer binding site mutations, but from the microdeletion at 8q24.13, about 2.99 to 49.76 kb, detected in both the father and his son, which revealed by deletion mapping using short tandem repeats (STRs) and single nucleotide polymorphisms (SNPs). In conclusion, genetic inconsistencies observed in true trios or duos cannot be rashly attributed to germline STR mutations, especially multistep mutations, in the absence of verification or specification; otherwise, the reliability of the genetic proofs established will be challenged.
... The results are in agreement with earlier reports describing the capacity of the MPS technique for determining the maternal or paternal origin of isoalleles in paternity tests [17] and differentiating homozygous twins or evidence material collected from them [18]. Sequence variation may be of importance in the context of possible overestimation of the PI value, since the frequencies of mutations published on the basis of analysis of length polymorphism in autosomal loci are probably considerably undervalued [19]. Other authors have noted that the D12S391, D2S1338, D21S11, D8S1179, VWA and D3S1358 loci actually contain about twice as many alleles differing in sequence than alleles differing in length [20]. ...
... Capillary electrophoresis genotyping results PI, gdyż częstości występowania mutacji publikowane na podstawie analizy polimorfizmu długości loci autosomalnych są prawdopodobnie znacznie zaniżone[19]. Inni autorzy zauważyli, że loci D12S391, D2S1338, D21S11, D8S1179, VWA i D3S1358 faktycznie wykazują ok. 2 razy większą liczbę alleli różniących się sekwencją, niż alleli różniących się długością[20]. W analizowanym przypadku innych niezgodności nie stwierdzono. ...
AIM OF THE STUDY
We present the application of massively parallel sequencing (MPS) to extend the scope of analysis in a disputed paternity case.
MATERIAL AND METHODS
A standard paternity test comprising 16 autosomal STRs was performed by capillary electrophoresis (CE) using 3130xl Genetic Analyzer. Additionally, MPS was performed with ForenSeq DNA Signature Prep Kit and Illumina MiSeq FGx™ Forensic Genomics System. Paternity index (PI) was calculated using DNAStat v.2.1 software. Results>: CE revealed two mismatches, at D21S11 and VWA, between the putative father and the child. Based on MPS results, the mismatches were analyzed and a nonconsensus sequence of allele 14 at the VWA locus in the mother - child pair was identified. Different sequence variants were also detected in 16-16 homozygote alleles at the D3S1358 locus in the child.
CONCLUSIONS
MPS helped to formulate a definite conclusion regarding the paternity of the defendant and provided full information on intra-allelic polymorphism.
... When there is no allele sharing at only one locus, called ''single locus exclusion " , in a parent–child test, the relatedness cannot be ruled out, because a mutational event or a null allele may be involved; the need for inconsistency at two or more loci is traditionally called the ''two exclusion " rule [1]. However, in the current era of STR multiplex systems even such a case of double inconsistency is no longer exclusive234. Because advanced systems such as GlobalFiler TM and PowerPlex 21 TM contain more STR markers than the conventional 15 ones used in the AmpF'STR Identifiler Ò system, such inconsistent cases are expected to be encountered more often. ...
... When there is no allele sharing at only one locus, called ''single locus exclusion " , in a parent–child test, the relatedness cannot be ruled out, because a mutational event or a null allele may be involved; the need for inconsistency at two or more loci is traditionally called the ''two exclusion " rule [1]. However, in the current era of STR multiplex systems even such a case of double inconsistency is no longer exclusive234. Because advanced systems such as GlobalFiler TM and PowerPlex 21 TM contain more STR markers than the conventional 15 ones used in the AmpF'STR Identifiler Ò system, such inconsistent cases are expected to be encountered more often. ...
... When there is no allele sharing at only one locus, called ''single locus exclusion", in a parent-child test, the relatedness cannot be ruled out, because a mutational event or a null allele may be involved; the need for inconsistency at two or more loci is traditionally called the ''two exclusion" rule [1]. However, in the current era of STR multiplex systems even such a case of double inconsistency is no longer exclusive [2][3][4]. Because advanced systems such as GlobalFiler TM and PowerPlex 21 TM contain more STR markers than the conventional 15 ones used in the AmpF'STR Identifiler Ò system, such inconsistent cases are expected to be encountered more often. ...
Parent–child analyses sometimes reveal inconsistency of shared alleles at only one locus. This is conventionally called “single locus exclusion”, which results from mutational events and the presence of null alleles. Here, in parent–child analyses of the Japanese population, we detected exclusions by using the GlobalFiler™ system comprising 21 short tandem repeat loci. One- or two-step mutations resulting from strand slippage causing gain or loss were observed in seven of 221 parent–child transmissions. The incidences of single locus inconsistency of alleles were 5.88 × 10−2 and 8.40 × 10−3 for paternal and maternal relationships, respectively. With calculation using a set of 15 loci in the Identifiler® multiplex system, the combined likelihood ratio (CLR) values were limited to less than 100 in all five cases accompanied by single inconsistency. The addition of six loci recovered the CLR values to over 10,000 in three cases. Application of this advanced system may increase the detected occurrence of mutational events, but it should be beneficial for inference in parent–child analyses, particularly in cases accompanied by genetic inconsistency.
... In Appendix A we will give another, shorter, derivation of the latter formula. Brenner described results of a simulation study of the same phenomenon in [1], calling a mutation that does not lead to an inconsistency a covert mutation. ...
... It Forensic Science International: Genetics 7 (2013) [337][338][339][340][341][342][343][344] It is well known in forensic genetics that mutations on STR loci need not lead to genetic inconsistencies between the genotypes of parents and children (cf. [3,6,1]). In this article we look at a generalization of this phenomenon of ''hidden'' mutations: we investigate the probability with which a mutation of d repeat units appears to be one of k < d repeat units, in the sense that a mutation of k repeat units is sufficient to explain the observed genotypes. ...
