scholarly journals The impact of genetic modifiers on variation in germline mutation rates within and among human populations

2021 ◽  
Author(s):  
William R. Milligan ◽  
Guy Amster ◽  
Guy Sella
Keyword(s):  
Genetic Modifier ◽  
Purifying Selection ◽  
Mutation Rates ◽  
Ancestral Population ◽  
Human Populations ◽  
Demographic Model ◽  
Genetic Modifiers ◽  
Genome Wide ◽  
Demographic Processes ◽  
The Impact

AbstractMutation rates and spectra differ among human populations. Here, we examine whether this variation could be explained by evolution at mutation modifiers. To this end, we consider genetic modifier sites at which mutations, “mutator alleles”, increase genome-wide mutation rates and model their evolution under purifying selection due to the additional deleterious mutations that they cause, genetic drift, and demographic processes. We solve the model analytically for a constant population size and characterize how evolution at modifier sites impacts variation in mutation rates within and among populations. We then use simulations to study the effects of modifier sites under a plausible demographic model for Africans and Europeans. When comparing populations that evolve independently, weakly selected modifier sites (2Nes ≈ 1), which evolve slowly, contribute the most to variation in mutation rates. In contrast, when populations recently split from a common ancestral population, strongly selected modifier sites (2Nes ≫ 1), which evolve rapidly, contribute the most to variation between them. Moreover, a modest number of modifier sites (e.g., 10 per mutation type in the standard classification into 96 types) subject to moderate to strong selection (2Nes > 1) could account for the variation in mutation rates observed among human populations. If such modifier sites indeed underlie differences among populations, they should also cause variation in mutation rates within populations and their effects should be detectable in pedigree studies.

scholarly journals Transfer RNA genes experience exceptionally elevated mutation rates

2018 ◽  
Vol 115 (36) ◽  
pp. 8996-9001 ◽  
Author(s):  
Bryan P. Thornlow ◽  
Josh Hough ◽  
Jacquelyn M. Roger ◽  
Henry Gong ◽  
Todd M. Lowe ◽  
...  
Keyword(s):  
Mutation Rate ◽  
Trna Gene ◽  
Gene Evolution ◽  
Purifying Selection ◽  
Mutation Rates ◽  
Model Organisms ◽  
Biological Synthesis ◽  
Human Populations ◽  
Trna Genes ◽  
Simple Method

Transfer RNAs (tRNAs) are a central component for the biological synthesis of proteins, and they are among the most highly conserved and frequently transcribed genes in all living things. Despite their clear significance for fundamental cellular processes, the forces governing tRNA evolution are poorly understood. We present evidence that transcription-associated mutagenesis and strong purifying selection are key determinants of patterns of sequence variation within and surrounding tRNA genes in humans and diverse model organisms. Remarkably, the mutation rate at broadly expressed cytosolic tRNA loci is likely between 7 and 10 times greater than the nuclear genome average. Furthermore, evolutionary analyses provide strong evidence that tRNA genes, but not their flanking sequences, experience strong purifying selection acting against this elevated mutation rate. We also find a strong correlation between tRNA expression levels and the mutation rates in their immediate flanking regions, suggesting a simple method for estimating individual tRNA gene activity. Collectively, this study illuminates the extreme competing forces in tRNA gene evolution and indicates that mutations at tRNA loci contribute disproportionately to mutational load and have unexplored fitness consequences in human populations.

scholarly journals Contribution of retrotransposition to developmental disorders

2019 ◽  
Vol 10 (1) ◽  
Author(s):  
Eugene J. Gardner ◽  
Elena Prigmore ◽  
Giuseppe Gallone ◽  
Petr Danecek ◽  
Kaitlin E. Samocha ◽  
...  
Keyword(s):  
Developmental Disorders ◽  
De Novo ◽  
Purifying Selection ◽  
Selective Constraint ◽  
Protein Coding ◽  
Genome Wide ◽  
De Novo Gene ◽  
The Impact ◽  
Transcribed Sequences

Abstract Mobile genetic Elements (MEs) are segments of DNA which can copy themselves and other transcribed sequences through the process of retrotransposition (RT). In humans several disorders have been attributed to RT, but the role of RT in severe developmental disorders (DD) has not yet been explored. Here we identify RT-derived events in 9738 exome sequenced trios with DD-affected probands. We ascertain 9 de novo MEs, 4 of which are likely causative of the patient’s symptoms (0.04%), as well as 2 de novo gene retroduplications. Beyond identifying likely diagnostic RT events, we estimate genome-wide germline ME mutation rate and selective constraint and demonstrate that coding RT events have signatures of purifying selection equivalent to those of truncating mutations. Overall, our analysis represents a comprehensive interrogation of the impact of retrotransposition on protein coding genes and a framework for future evolutionary and disease studies.

scholarly journals Inferring biophysical models of evolution from genome-wide patterns of codon usage

2019 ◽  
Author(s):  
Willow B. Kion-Crosby ◽  
Michael Manhart ◽  
Alexandre V. Morozov
Keyword(s):  
Population Genetics ◽  
Codon Usage ◽  
Codon Bias ◽  
Purifying Selection ◽  
Mutation Rates ◽  
Nucleotide Position ◽  
Mutational Robustness ◽  
Translation Speed ◽  
Genome Wide ◽  
Speed And Accuracy

AbstractFrequencies of synonymous codons are typically non-uniform, despite the fact that such codons correspond to the same amino acid in the genetic code. This phenomenon, known as codon bias, is broadly believed to be due to a combination of factors including genetic drift, mutational biases, and selection for speed and accuracy of codon translation; however, quantitative modeling of codon bias has been elusive. We have developed a biophysical population genetics model which explains genome-wide codon frequencies observed across 20 organisms. We assume that codons evolve independently of each other under the influence of mutation and selection forces, and that the codon population has reached evolutionary steady state. Our model implements codon-level treatment of mutations with transition/transversion biases, and includes two contributions to codon fitness which describe codon translation speed and accuracy. Furthermore, our model includes wobble pairing – the possibility of codon-anticodon base pairing mismatches at the 3’ nucleotide position of the codon. We find that the observed patterns of genome-wide codon usage are consistent with a strong selective penalty for mistranslated amino acids. Thus codons undergo purifying selection and their relative frequencies are affected in part by mutational robustness. We find that the dependence of codon fitness on translation speed is weaker on average compared to the strength of selection against mistranslation. Although no constraints on codon-anticodon pairing are imposed a priori, a reasonable hierarchy of pairing rates, which conforms to the wobble hypothesis and is consistent with available structural evidence, emerges spontaneously as a model prediction. Finally, treating the translation process explicitly in the context of a finite ribosomal pool has allowed us to estimate mutation rates per nucleotide directly from the coding sequences. Reminiscent of Drake’s observation that mutation rates are inversely correlated with the genome size, we predict that mutation rates are inversely proportional to the number of genes. Overall, our approach offers a unified biophysical and population genetics framework for studying codon bias across all domains of life.

scholarly journals Demography and mating system shape the genome-wide impact of purifying selection in Arabis alpina

2017 ◽  
Author(s):  
Benjamin Laenen ◽  
Andrew Tedder ◽  
Michael D. Nowak ◽  
Per Toräng ◽  
Jörg Wunder ◽  
...  
Keyword(s):  
Genetic Diversity ◽  
Mating System ◽  
Purifying Selection ◽  
Mixed Mating ◽  
Genome Wide ◽  
Outcrossing Rates ◽  
Arabis Alpina ◽  
Whole Genome Resequencing ◽  
Evolutionary Consequences ◽  
The Impact

Plant mating systems have profound effects on levels and structuring of genetic variation, and can affect the impact of natural selection. While theory predicts that intermediate outcrossing rates may allow plants to prevent accumulation of deleterious alleles, few studies have empirically tested this prediction using genomic data. Here, we study the effect of mating system on purifying selection by conducting population genomic analyses on whole-genome resequencing data from 38 European individuals of the arctic-alpine crucifer Arabis alpina. We find that outcrossing and mixed-mating populations maintain genetic diversity at similar levels, whereas highly self-fertilizing Scandinavian A. alpina show a strong reduction in genetic diversity, most likely as a result of a postglacial colonization bottleneck. We further find evidence for accumulation of genetic load in highly self-fertilizing populations, whereas the genome-wide impact of purifying selection does not differ greatly between mixed-mating and outcrossing populations. Our results demonstrate that intermediate levels of outcrossing may allow efficient selection against harmful alleles whereas demographic effects can be important for relaxed purifying selection in highly selfing populations. Thus, both mating system and demography shape the impact of purifying selection on genomic variation in A. alpina. These results are important for an improved understanding of the evolutionary consequences of mating system variation and the maintenance of mixed-mating strategies.SignificanceIntermediate outcrossing rates are theoretically predicted to maintain effective selection against harmful alleles, but few studies have empirically tested this prediction using genomic data. We used whole-genome resequencing data from alpine rock-cress to study how genetic variation and purifying selection vary with mating system. We find that populations with intermediate outcrossing rates have similar levels of genetic diversity as outcrossing populations, and that purifying selection against harmful alleles is efficient in mixed-mating populations. In contrast, self-fertilizing populations from Scandinavia have strongly reduced genetic diversity, and accumulate harmful mutations, likely as a result of demographic effects of postglacial colonization. Our results suggest that mixed-mating populations can avoid the negative evolutionary consequences of high self-fertilization rates.

scholarly journals Sex-biased reduction in reproductive success drives selective constraint on human genes

2020 ◽  
Author(s):  
Eugene J. Gardner ◽  
Matthew D. C. Neville ◽  
Kaitlin E. Samocha ◽  
Kieron Barclay ◽  
Martin Kolk ◽  
...  
Keyword(s):  
Sexual Selection ◽  
Reproductive Success ◽  
Genetic Variants ◽  
Purifying Selection ◽  
Female Mate Choice ◽  
Selective Constraint ◽  
Human Populations ◽  
Protein Coding ◽  
Genome Wide ◽  
Human Genes

SummaryGenome-wide sequencing of human populations has revealed substantial variation among genes in the intensity of purifying selection acting on damaging genetic variants. While genes under the strongest selective constraint are highly enriched for Mendelian disorders, most of these genes are not associated with disease and therefore the nature of the selection acting on them is not known. Here we show that genetic variants that damage these genes reduce reproductive success substantially in males but much less so in females. We present evidence that this reduction is mediated primarily by cognitive and behavioural traits, which renders male carriers of such variants less likely to find mating partners. These findings represent strong genetic evidence that sexual selection mediated through female mate choice is shaping the gene pool of contemporary human populations. Furthermore, these results suggest that sexual selection accounts for 21% of purifying selection against heterozygous variants that ablate protein-coding genes.

scholarly journals A Pathway-Centered Analysis of Pig Domestication and Breeding in Eurasia

2017 ◽  
Vol 7 (7) ◽  
pp. 2171-2184 ◽  
Author(s):  
Jordi Leno-Colorado ◽  
Nick J Hudson ◽  
Antonio Reverter ◽  
Miguel Pérez-Enciso
Keyword(s):  
Statistical Significance ◽  
Purifying Selection ◽  
Wide Distribution ◽  
Physiological Basis ◽  
Genome Variability ◽  
Genome Wide ◽  
Biological Interpretation ◽  
The Impact ◽  
The Brain ◽  
Different Levels

Abstract Ascertaining the molecular and physiological basis of domestication and breeding is an active area of research. Due to the current wide distribution of its wild ancestor, the wild boar, the pig (Sus scrofa) is an excellent model to study these processes, which occurred independently in East Asia and Europe ca. 9000 yr ago. Analyzing genome variability patterns in terms of metabolic pathways is attractive since it considers the impact of interrelated functions of genes, in contrast to genome-wide scans that treat genes or genome windows in isolation. To that end, we studied 40 wild boars and 123 domestic pig genomes from Asia and Europe when metabolic pathway was the unit of analysis. We computed statistical significance for differentiation (Fst) and linkage disequilibrium (nSL) statistics at the pathway level. In terms of Fst, we found 21 and 12 pathways significantly differentiated at a q-value < 0.05 in Asia and Europe, respectively; five were shared across continents. In Asia, we found six significant pathways related to behavior, which involved essential neurotransmitters like dopamine and serotonin. Several significant pathways were interrelated and shared a variable percentage of genes. There were 12 genes present in >10 significant pathways (in terms of Fst), comprising genes involved in the transduction of a large number of signals, like phospholipase PCLB1, which is expressed in the brain, or ITPR3, which has an important role in taste transduction. In terms of nSL, significant pathways were mainly related to reproductive performance (ovarian steroidogenesis), a similarly important target trait during domestication and modern animal breeding. Different levels of recombination cannot explain these results, since we found no correlation between Fst and recombination rate. However, we did find an increased ratio of deleterious mutations in domestic vs. wild populations, suggesting a relaxed functional constraint associated with the domestication and breeding processes. Purifying selection was, nevertheless, stronger in significantly differentiated pathways than in random pathways, mainly in Europe. We conclude that pathway analysis facilitates the biological interpretation of genome-wide studies. Notably, in the case of pig, behavior played an important role, among other physiological and developmental processes.

scholarly journals Transfer RNA genes experience exceptionally elevated mutation rates

2017 ◽  
Author(s):  
Bryan P. Thornlow ◽  
Josh Hough ◽  
Jacquelyn M. Roger ◽  
Henry Gong ◽  
Todd M. Lowe ◽  
...  
Keyword(s):  
Mutation Rate ◽  
Sequence Variation ◽  
Trna Gene ◽  
Purifying Selection ◽  
Transfer Rna ◽  
Mutation Rates ◽  
Biological Synthesis ◽  
Human Populations ◽  
Trna Genes ◽  
Mutational Load

AbstractTransfer RNAs (tRNAs) are a central component for the biological synthesis of proteins, and they are among the most highly conserved and frequently transcribed genes in all living things. Despite their clear significance for fundamental cellular processes, the forces governing tRNA evolution are poorly understood. We present evidence that transcription-associated mutagenesis and strong purifying selection are key determinants of patterns of sequence variation within and surrounding tRNA genes in humans and diverse model organisms. Remarkably, the mutation rate at broadly expressed cytosolic tRNA loci is likely between seven and ten times greater than the nuclear genome average. Furthermore, evolutionary analyses provide strong evidence that tRNA genes, but not their flanking sequences, experience strong purifying selection, acting against this elevated mutation rate. We also find a strong correlation between tRNA expression levels and the mutation rates in their immediate flanking regions, suggesting a simple new method for estimating individual tRNA gene activity. Collectively, this study illuminates the extreme competing forces in tRNA gene evolution, and implies that mutations at tRNA loci contribute disproportionately to mutational load and have unexplored fitness consequences in human populations.Significance StatementWhile transcription-associated mutagenesis (TAM) has been demonstrated for protein coding genes, its implications in shaping genome structure at transfer RNA (tRNA) loci in metazoans have not been fully appreciated. We show that cytosolic tRNAs are a striking example of TAM because of their variable rates of transcription, well-defined boundaries and internal promoter sequences. tRNA loci have a mutation rate approximately seven-to tenfold greater than the genome-wide average, and these mutations are consistent with signatures of TAM. These observations indicate that tRNA loci are disproportionately large contributors to mutational load in the human genome. Furthermore, the correlations between tRNA locus variation and transcription implicate that prediction of tRNA gene expression based on sequence variation data is possible.

scholarly journals Demography and mating system shape the genome-wide impact of purifying selection in Arabis alpina

2018 ◽  
Vol 115 (4) ◽  
pp. 816-821 ◽  
Author(s):  
Benjamin Laenen ◽  
Andrew Tedder ◽  
Michael D. Nowak ◽  
Per Toräng ◽  
Jörg Wunder ◽  
...  
Keyword(s):  
Genetic Diversity ◽  
Mating System ◽  
Purifying Selection ◽  
Mating Strategies ◽  
Genomic Variation ◽  
The Arctic ◽  
Mixed Mating ◽  
Genome Wide ◽  
Arabis Alpina ◽  
The Impact

Plant mating systems have profound effects on levels and structuring of genetic variation and can affect the impact of natural selection. Although theory predicts that intermediate outcrossing rates may allow plants to prevent accumulation of deleterious alleles, few studies have empirically tested this prediction using genomic data. Here, we study the effect of mating system on purifying selection by conducting population-genomic analyses on whole-genome resequencing data from 38 European individuals of the arctic-alpine crucifer Arabis alpina. We find that outcrossing and mixed-mating populations maintain genetic diversity at similar levels, whereas highly self-fertilizing Scandinavian A. alpina show a strong reduction in genetic diversity, most likely as a result of a postglacial colonization bottleneck. We further find evidence for accumulation of genetic load in highly self-fertilizing populations, whereas the genome-wide impact of purifying selection does not differ greatly between mixed-mating and outcrossing populations. Our results demonstrate that intermediate levels of outcrossing may allow efficient selection against harmful alleles, whereas demographic effects can be important for relaxed purifying selection in highly selfing populations. Thus, mating system and demography shape the impact of purifying selection on genomic variation in A. alpina. These results are important for an improved understanding of the evolutionary consequences of mating system variation and the maintenance of mixed-mating strategies.

scholarly journals Contribution of Retrotransposition to Developmental Disorders

2018 ◽  
Author(s):  
Eugene J. Gardner ◽  
Elena Prigmore ◽  
Giuseppe Gallone ◽  
Petr Danecek ◽  
Kaitlin E. Samocha ◽  
...  
Keyword(s):  
Developmental Disorders ◽  
De Novo ◽  
Purifying Selection ◽  
Mobile Genetic Elements ◽  
Protein Coding ◽  
Protein Coding Genes ◽  
Genome Wide ◽  
The Impact ◽  
Transcribed Sequences

AbstractMobile genetic Elements (MEs) are segments of DNA which, through an RNA intermediate, can generate new copies of themselves and other transcribed sequences through the process of retrotransposition (RT). In humans several disorders have been attributed to RT, but the role of RT in severe developmental disorders (DD) has not yet been explored. As such, we have identified RT-derived events in 9,738 exome sequenced trios with DD-affected probands as part of the Deciphering Developmental Disorders (DDD) study. We have ascertained 9 de novo MEs, 4 of which are likely causative of the patient’s symptoms (0.04% of probands), as well as 2 de novo gene retroduplications. Beyond identifying likely diagnostic RT events, we have estimated genome-wide germline ME mutagenesis and constraint and demonstrated that coding RT events have signatures of purifying selection equivalent to those of truncating mutations. Overall, our analysis represents a comprehensive interrogation of the impact of retrotransposition on protein coding genes and a framework for future evolutionary and disease studies.

scholarly journals Analysis of DNM3 and VAMP4 as genetic modifiers of LRRK2 Parkinson’s disease

2019 ◽  
Author(s):  
EE Brown ◽  
C Blauwendraat ◽  
J Trinh ◽  
M Rizig ◽  
MA Nalls ◽  
...  
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Linear Regression ◽  
Genetic Modifier ◽  
Age At Onset ◽  
Published Data ◽  
Significant Heterogeneity ◽  
Genetic Modifiers ◽  
Risk Variant ◽  
The Impact

AbstractObjectiveTo assess genetic modifiers of Parkinson’s disease (PD) age at onset (AAO) penetrance in individuals carrying common and rare LRRK2 risk allelesMethodsWe analysed reported genetic modifier DNM3 rs2421947 in 724 LRRK2 p.G2019S heterozygotes using linear regression of AAO. We meta-analysed our data with previously published data (n=754). VAMP4 is in close proximity to DNM3 and is associated with PD. We analysed the effect of the rs11578699 VAMP4 variant on pG2019S penetrance in 786 LRRK2 p.G2019S heterozygotes. We also evaluated the impact of VAMP4 variants using AAO regression in 4882 patients with PD carrying a common LRRK2 risk variant (rs10878226).ResultsThere was no evidence for linkage disequilibrium between DNM3 rs2421947 and VAMP4 rs11578699. Our linear regression AAO of 724 p.G2019S carriers showed no relationship between DNM3 rs2421947 and AAO (beta = −1.19, p = 0.55, n =708). Meta-analysis with previously published data did not indicate a significant effect on AAO (beta = −2.21, p = 0.083, n = 1304), but there was significant heterogeneity in the analyses of new and previously published data. VAMP4 rs11578699 was nominally associated with AAO in patients dichotomized by the common LRRK2 risk variant rs10878226 (beta=1.68, se=0.81 p=0.037).InterpretationAnalysis of DNM3 in previously unpublished data does not show an interaction between DNM3 and LRRK2 G2019S for AAO, however the inter-study heterogeneity may indicate ethnic-specific effects of DNM3 rs2421947. Analysis of sporadic PD patients stratified by the PD risk variant rs10878226 indicates a possible interaction between LRRK2 and VAMP4.

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