scholarly journals Linkage disequilibrium between rare mutations

Genetics ◽  
2022 ◽  
Author(s):  
Benjamin H Good
Keyword(s):  
Linkage Disequilibrium ◽  
Genetic Drift ◽  
Deleterious Mutations ◽  
Fitness Costs ◽  
Theoretical Understanding ◽  
Evolutionary Forces ◽  
Frequency Scale ◽  
Rare Mutations ◽  
Site Frequency Spectrum ◽  
Analytical Expressions

Abstract The statistical associations between mutations, collectively known as linkage disequilibrium (LD), encode important information about the evolutionary forces acting within a population. Yet in contrast to single-site analogues like the site frequency spectrum, our theoretical understanding of linkage disequilibrium remains limited. In particular, little is currently known about how mutations with different ages and fitness costs contribute to expected patterns of LD, even in simple settings where recombination and genetic drift are the major evolutionary forces. Here, I introduce a forward-time framework for predicting linkage disequilibrium between pairs of neutral and deleterious mutations as a function of their present-day frequencies. I show that the dynamics of linkage disequilibrium become much simpler in the limit that mutations are rare, where they admit a simple heuristic picture based on the trajectories of the underlying lineages. I use this approach to derive analytical expressions for a family of frequency-weighted LD statistics as a function of the recombination rate, the frequency scale, and the additive and epistatic fitness costs of the mutations. I find that the frequency scale can have a dramatic impact on the shapes of the resulting LD curves, reflecting the broad range of time scales over which these correlations arise. I also show that the differences between neutral and deleterious LD are not purely driven by differences in their mutation frequencies, and can instead display qualitative features that are reminiscent of epistasis. I conclude by discussing the implications of these results for recent LD measurements in bacteria. This forward-time approach may provide a useful framework for predicting linkage disequilibrium across a range of evolutionary scenarios.

scholarly journals Linkage disequilibrium between rare mutations

2020 ◽  
Author(s):  
Benjamin H. Good
Keyword(s):  
Linkage Disequilibrium ◽  
Genetic Drift ◽  
Deleterious Mutations ◽  
Fitness Costs ◽  
Theoretical Understanding ◽  
Evolutionary Forces ◽  
Frequency Scale ◽  
Rare Mutations ◽  
Site Frequency Spectrum ◽  
Analytical Expressions

The statistical associations between mutations, collectively known as linkage disequilibrium (LD), encode important information about the evolutionary forces acting within a population. Yet in contrast to single-site analogues like the site frequency spectrum, our theoretical understanding of linkage disequilibrium remains limited. In particular, little is currently known about how mutations with different ages and fitness costs contribute to expected patterns of LD, even in simple settings where recombination and genetic drift are the major evolutionary forces. Here, we introduce a forward-time framework for predicting linkage disequilibrium between pairs of neutral and deleterious mutations as a function of their present-day frequencies. We show that the dynamics of linkage disequilibrium become much simpler in the limit that mutations are rare, where they admit a simple heuristic picture based on the trajectories of the underlying lineages. We use this approach to derive analytical expressions for a family of frequency-weighted LD statistics as a function of the recombination rate, the frequency scale, and the additive and epistatic fitness costs of the mutations. We find that the frequency scale can have a dramatic impact on the shapes of the resulting LD curves, reflecting the broad range of time scales over which these correlations arise. We also show that the differences between neutral and deleterious LD are not purely driven by differences in their mutation frequencies, and can instead display qualitative features that are reminiscent of epistasis. We conclude by discussing the implications of these results for recent LD measurements in bacteria. This forward-time approach may provide a useful framework for predicting linkage disequilibrium across a range of evolutionary scenarios.

scholarly journals Intra-Species Differences in Population Size shape Life History and Genome Evolution

2019 ◽  
Author(s):  
David Willemsen ◽  
Rongfeng Cui ◽  
Martin Reichard ◽  
Dario Riccardo Valenzano
Keyword(s):  
Life History ◽  
Population Size ◽  
Genetic Drift ◽  
Sex Chromosome ◽  
Purifying Selection ◽  
Life History Trait ◽  
Deleterious Mutations ◽  
Effective Population ◽  
Annual Life Cycle ◽  
Evolutionary Forces

AbstractThe evolutionary forces shaping life history trait divergence within species are largely unknown. Killifish (oviparous Cyprinodontiformes) evolved an annual life cycle as an exceptional adaptation to life in arid savannah environments characterized by seasonal water availability. The turquoise killifish (Nothobranchius furzeri) is the shortest-lived vertebrate known to science and displays differences in lifespan among wild populations, representing an ideal natural experiment in the evolution and diversification of life history. Here, by combining genome sequencing and population genetics, we investigate the evolutionary forces shaping lifespan among turquoise killifish populations. We generate an improved reference assembly for the turquoise killifish genome, trace the evolutionary origin of the sex chromosome, and identify genes under strong positive and purifying selection, as well as those evolving neutrally. We find that the shortest-lived turquoise killifish populations, which dwell in fragmented and isolated habitats at the outer margin of the geographical range of the species, are characterized by small effective population size and accumulate throughout the genome several small to large-effect deleterious mutations due to genetic drift. The genes most affected by drift in the shortest-lived turquoise killifish populations are involved in the WNT signalling pathway, neurodegenerative disorders, cancer and the mTOR pathway. As the populations under stronger genetic drift are the shortest-lived ones, we propose that limited population size due to habitat fragmentation and repeated population bottlenecks, by causing the genome-wide accumulation of deleterious mutations, cumulatively contribute to the short adult lifespan in turquoise killifish populations.

scholarly journals The rate and molecular spectrum of mutation are selectively maintained in yeast

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Haoxuan Liu ◽  
Jianzhi Zhang
Keyword(s):  
Natural Selection ◽  
Genetic Drift ◽  
Fundamental Question ◽  
Molecular Spectrum ◽  
Mutational Bias ◽  
Stabilizing Selection ◽  
Deleterious Mutations ◽  
Random Mutation ◽  
Evolutionary Forces ◽  
Yeast Strains

AbstractWhat determines the rate (μ) and molecular spectrum of mutation is a fundamental question. The prevailing hypothesis asserts that natural selection against deleterious mutations has pushed μ to the minimum achievable in the presence of genetic drift, or the drift barrier. Here we show that, contrasting this hypothesis, μ substantially exceeds the drift barrier in diverse organisms. Random mutation accumulation (MA) in yeast frequently reduces μ, and deleting the newly discovered mutator gene PSP2 nearly halves μ. These results, along with a comparison between the MA and natural yeast strains, demonstrate that μ is maintained above the drift barrier by stabilizing selection. Similar comparisons show that the mutation spectrum such as the universal AT mutational bias is not intrinsic but has been selectively preserved. These findings blur the separation of mutation from selection as distinct evolutionary forces but open the door to alleviating mutagenesis in various organisms by genome editing.

scholarly journals Negative linkage disequilibrium between amino acid changing variants reveals interference among deleterious mutations in the human genome

PLoS Genetics ◽  
2021 ◽  
Vol 17 (7) ◽  
pp. e1009676
Author(s):  
Jesse A. Garcia ◽  
Kirk E. Lohmueller
Keyword(s):  
Linkage Disequilibrium ◽  
Human Genome ◽  
Natural Populations ◽  
Physical Distance ◽  
Deleterious Mutations ◽  
High Coverage ◽  
Evolutionary Forces ◽  
Recessive Mutations ◽  
Genome Wide ◽  
Negative Epistasis

Evolutionary forces like Hill-Robertson interference and negative epistasis can lead to deleterious mutations being found on distinct haplotypes. However, the extent to which these forces depend on the selection and dominance coefficients of deleterious mutations and shape genome-wide patterns of linkage disequilibrium (LD) in natural populations with complex demographic histories has not been tested. In this study, we first used forward-in-time simulations to predict how negative selection impacts LD. Under models where deleterious mutations have additive effects on fitness, deleterious variants less than 10 kb apart tend to be carried on different haplotypes relative to pairs of synonymous SNPs. In contrast, for recessive mutations, there is no consistent ordering of how selection coefficients affect LD decay, due to the complex interplay of different evolutionary effects. We then examined empirical data of modern humans from the 1000 Genomes Project. LD between derived alleles at nonsynonymous SNPs is lower compared to pairs of derived synonymous variants, suggesting that nonsynonymous derived alleles tend to occur on different haplotypes more than synonymous variants. This result holds when controlling for potential confounding factors by matching SNPs for frequency in the sample (allele count), physical distance, magnitude of background selection, and genetic distance between pairs of variants. Lastly, we introduce a new statistic HR(j) which allows us to detect interference using unphased genotypes. Application of this approach to high-coverage human genome sequences confirms our finding that nonsynonymous derived alleles tend to be located on different haplotypes more often than are synonymous derived alleles. Our findings suggest that interference may play a pervasive role in shaping patterns of LD between deleterious variants in the human genome, and consequently influences genome-wide patterns of LD.

scholarly journals Genomic and demographic processes differentially influence genetic variation across the X chromosome

2021 ◽  
Author(s):  
Daniel J. Cotter ◽  
Timothy H. Webster ◽  
Melissa A. Wilson
Keyword(s):  
Genetic Diversity ◽  
Genetic Variation ◽  
Linkage Disequilibrium ◽  
X Chromosome ◽  
Global Scale ◽  
Careful Consideration ◽  
Human Populations ◽  
Evolutionary Forces ◽  
Ideal System ◽  
Demographic Patterns

AbstractMutation, recombination, selection, and demography affect genetic variation across the genome. Increased mutation and recombination both lead to increases in genetic diversity in a region-specific manner, while complex demographic patterns shape patterns of diversity on a more global scale. The X chromosome is particularly interesting because it contains several distinct regions that are subject to different combinations and strengths of these processes, notably the pseudoautosomal regions (PARs) and the X-transposed region (XTR). The X chromosome thus can serve as a unique model for studying how genetic and demographic forces act in different contexts to shape patterns of observed variation. Here we investigate diversity, divergence, and linkage disequilibrium in each region of the X chromosome using genomic data from 26 human populations. We find that both diversity and substitution rate are consistently elevated in PAR1 and the XTR compared to the rest of the X chromosome. In contrast, linkage disequilibrium is lowest in PAR1 and highest on the non-recombining X chromosome, with the XTR falling in between, suggesting that the XTR (usually included in the non-recombining X) may need to be considered separately in future studies. We also observed strong population-specific effects on genetic diversity; not only does genetic variation differ on the X and autosomes among populations, but the effects of linked selection on the X relative to autosomes have been shaped by population-specific history. The substantial variation in patterns of variation across these regions provides insight into the unique evolutionary history contained within the X chromosome.Significance StatementDemography and selection affect the X chromosome differently from non-sex chromosomes. However, the X chromosome can be subdivided into multiple distinct regions that facilitate even more fine-scaled assessment of these processes. Here we study regions of the human X chromosome in 26 populations to find evidence that recombination may be mutagenic in humans and that the X-transposed region may undergo recombination. Further we observe that the effects of selection and demography act differently on the X chromosome relative to the autosomes across human populations. Together, our results highlight profound regional differences across the X chromosome, simultaneously making it an ideal system for exploring the action of evolutionary forces as well as necessitating its careful consideration and treatment in genomic analyses.

scholarly journals Evolution of gene regulatory networks by means of selection and random genetic drift

2018 ◽  
Author(s):  
Antonios Kioukis ◽  
Pavlos Pavlidis
Keyword(s):  
Natural Selection ◽  
Positive Selection ◽  
Genetic Drift ◽  
Regulatory Networks ◽  
Fitness Landscape ◽  
Random Genetic Drift ◽  
Maturation Period ◽  
Evolutionary Forces ◽  
Gene Regulatory

The evolution of a population by means of genetic drift and natural selection operating on a gene regulatory network (GRN) of an individual has not been scrutinized in depth. Thus, the relative importance of various evolutionary forces and processes on shaping genetic variability in GRNs is understudied. Furthermore, it is not known if existing tools that identify recent and strong positive selection from genomic sequences, in simple models of evolution, can detect recent positive selection when it operates on GRNs. Here, we propose a simulation framework, called EvoNET, that simulates forward-in-time the evolution of GRNs in a population. Since the population size is finite, random genetic drift is explicitly applied. The fitness of a mutation is not constant, but we evaluate the fitness of each individual by measuring its genetic distance from an optimal genotype. Mutations and recombination may take place from generation to generation, modifying the genotypic composition of the population. Each individual goes through a maturation period, where its GRN reaches equilibrium. At the next step, individuals compete to produce the next generation. As time progresses, the beneficial genotypes push the population higher in the fitness landscape. We examine properties of the GRN evolution such as robustness against the deleterious effect of mutations and the role of genetic drift. We confirm classical results from Andreas Wagner’s work that GRNs show robustness against mutations and we provide new results regarding the interplay between random genetic drift and natural selection.

scholarly journals Linkage disequilibrium in experimental populations of Drosophila simulans: a test of the random drift hypothesis

1987 ◽  
Vol 50 (3) ◽  
pp. 187-193
Author(s):  
Catherine Montchamp-Moreau ◽  
Mariano Katz
Keyword(s):  
Linkage Disequilibrium ◽  
Genetic Drift ◽  
Natural Populations ◽  
Aldehyde Oxidase ◽  
Drosophila Simulans ◽  
Random Drift ◽  
Esterase 6 ◽  
Experimental Populations ◽  
Experimental Values ◽  
Neutralist Hypothesis

SummaryLinkage disequilibrium between five polymorphic enzymic loci of the third chromosome (Esterase-6, Phosphoglucomutase, Esterase-C, Aldehyde Oxidase and Acid Phosphatase) was studied in experimental populations of Drosophila simulans. Gametic data were obtained by mating sampled males with homozygous females at the five loci. Four cage populations were initiated with flies caught from natural populations. Extensive linkage disequilibrium was detected after 25 or 34 generations. The effective size of these populations was estimated about 400. Monte-Carlo simulations were performed in order to determine whether the observed disequilibria could be due to genetic drift. The observed probability distribution of the experimental values of r (the gametic correlation coefficient) was consistent with the distribution expected under random genetic drift. Our results are thus in accordance with the neutralist hypothesis.

scholarly journals A theoretical analysis of linkage disequilibrium produced by genetic drift in Drosophila populations

1986 ◽  
Vol 48 (3) ◽  
pp. 161-166 ◽  
Author(s):  
Catherine Montchamp-Moreau ◽  
Mariano Katz
Keyword(s):  
Linkage Disequilibrium ◽  
Genetic Drift ◽  
Statistical Tests ◽  
Burst Size ◽  
Natural Populations ◽  
Finite Size ◽  
Gene Frequencies ◽  
Accurate Knowledge ◽  
Maximum Value ◽  
Cyclical Fluctuations

SummaryWe analyse the progression of linkage disequilibrium produced by random genetic drift in populations subject to cyclical fluctuations in size. Our model is applied to natural populations of Drosophila which show an annual demographic cycle of bottleneck (finite size) and demographic burst (size supposed to be infinite). In these populations, linkage disequilibrium stabilizes in such a way that, at equilibrium, the expected square of the correlation of gene frequencies E(r2) shows a stable cycle from year to year. If two loci are tightly linked, E(r2) barely varies during the annual cycle. Its values remain close to the value expected in a population of the same but constant effective size. If two loci are loosely linked, fluctuations in E(r2) are large. The maximum value, reached at the end of the bottleneck, is 10 to 100 times greater than the value obtained at the end of the burst. Our results show that the interpretation of observed linkage disequilibrium, by means of statistical tests, requires an accurate knowledge of population demography.

scholarly journals Uncorrelated genetic drift of gene frequencies and linkage disequilibrium in some models of linked overdominant polymorphisms

1974 ◽  
Vol 24 (3) ◽  
pp. 281-294 ◽  
Author(s):  
Joseph Felsenstein
Keyword(s):  
Linkage Disequilibrium ◽  
Covariance Matrix ◽  
Genetic Drift ◽  
Conditional Distribution ◽  
Large Population ◽  
Multivariate Normal ◽  
Gene Frequencies ◽  
Constant Variance ◽  
Population Sizes ◽  
Multiplicative Family

SUMMARYFor large population sizes, gene frequencies p and q at two linked over-dominant loci and the linkage disequilibrium parameter D will remain close to their equilibrium values. We can treat selection and recombination as approximately linear forces on p, q and D, and we can treat genetic drift as a multivariate normal perturbation with constant variance-covariance matrix. For the additive-multiplicative family of two-locus models, p, q and D are shown to be (approximately) uncorrelated. Expressions for their variances are obtained. When selection coefficients are small the variances of p and q are those previously given by Robertson for a single locus. For small recombination fractions the variance of D is that obtained for neutral loci by Ohta & Kimura. For larger recombination fractions the result differs from theirs, so that for unlinked loci r2 ≃ 2/(3N) instead of 1/(2N). For the Lewontin-Kojima and Bodmer symmetric viability models, and for a model symmetric at only one of the loci, a more exact argument is possible. In the asymptotic conditional distribution in these cases, various of p, q and D are uncorrelated, depending on the type of symmetiy in the model.

scholarly journals Linkage disequilibrium under polysomic inheritance

2020 ◽  
Author(s):  
Kang Huang ◽  
Derek W. Dunn ◽  
Wenkai Li ◽  
Dan Wang ◽  
Baoguo Li
Keyword(s):  
Linkage Disequilibrium ◽  
Equilibrium State ◽  
Genetic Drift ◽  
Recombination Rate ◽  
Mating Systems ◽  
Correlation Coefficients ◽  
Effective Population ◽  
Under Five ◽  
Polysomic Inheritance ◽  
Linkage Disequilibrium Measure

AbstractThe influence of genetic drift on linkage disequilibrium in finite populations has been extensively studied in diploids. However, to date the effects of ploidy on LD has not been extensively studied. We here extend the linkage disequilibrium measure D and Burrow’s Δ statistic to include polysomic inheritance, as well as their corresponding squared correlation coefficients r2 and , where the former is for phased genotypes and the latter for unphased genotypes. Weir & Hill’s double non-identity framework is also extended to include polysomic inheritance, and the expressions of double non-identity coefficients are derived under five mating systems. On this basis, the approximated expectations of estimated r2 and at equilibrium state, d2 and δ2, are derived under five mating systems. We assess the behaviors of the estimated r2 and and the influence of the recombination rate on d2 or δ2, simulate the application of estimating effective population size, and evaluate the statistical performance of the method of estimating.

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