scholarly journals Broad-scale variation in human genetic diversity levels is predicted by purifying selection on coding and non-coding elements

2021 ◽  
Author(s):  
David Murphy ◽  
Eyal Elyashiv ◽  
Guy Amster ◽  
Guy Sella
Keyword(s):  
Genetic Diversity ◽  
Purifying Selection ◽  
Dominant Mode ◽  
Background Selection ◽  
Selective Sweeps ◽  
Deleterious Mutations ◽  
Phylogenetic Conservation ◽  
Neutral Genetic Diversity ◽  
Polymorphism Data ◽  
Linked Selection

Analyses of genetic variation in many taxa have established that neutral genetic diversity is shaped by natural selection at linked sites. Whether the source of selection is primarily the fixation of strongly beneficial alleles (selective sweeps) or purifying selection on deleterious mutations (background selection) remains unknown, however. We address this question in humans by fitting a model of the joint effects of selective sweeps and background selection to autosomal polymorphism data from the 1000 Genomes Project. After controlling for variation in mutation rates along the genome, a model of background selection alone explains ~60% of the variance in diversity levels at the megabase scale. Adding the effects of selective sweeps driven by adaptive substitutions to the model does not improve the fit, and when both modes of selection are considered jointly, selective sweeps are estimated to have had little or no effect on linked neutral diversity. The regions under purifying selection are best predicted by phylogenetic conservation, with ~80% of the deleterious mutations affecting neutral diversity occurring in non-exonic regions. Thus, background selection is the dominant mode of linked selection in humans, with marked effects on diversity levels throughout autosomes.

scholarly journals Transition from background selection to associative overdominance promotes diversity in regions of low recombination

2019 ◽  
Author(s):  
Kimberly J. Gilbert ◽  
Fanny Pouyet ◽  
Laurent Excoffier ◽  
Stephan Peischl
Keyword(s):  
Genetic Diversity ◽  
Balancing Selection ◽  
Purifying Selection ◽  
Heterozygote Advantage ◽  
Background Selection ◽  
Deleterious Mutations ◽  
Recombination Rates ◽  
Locus Model ◽  
Genome Wide ◽  
Linked Selection

SummaryLinked selection is a major driver of genetic diversity. Selection against deleterious mutations removes linked neutral diversity (background selection, BGS, Charlesworth et al. 1993), creating a positive correlation between recombination rates and genetic diversity. Purifying selection against recessive variants, however, can also lead to associative overdominance (AOD, Ohta 1971, Zhao & Charlesworth, 2016), due to an apparent heterozygote advantage at linked neutral loci that opposes the loss of neutral diversity by BGS. Zhao & Charlesworth (2016) identified the conditions when AOD should dominate over BGS in a single-locus model and suggested that the effect of AOD could become stronger if multiple linked deleterious variants co-segregate. We present a model describing how and under which conditions multi-locus dynamics can amplify the effects of AOD. We derive the conditions for a transition from BGS to AOD due to pseudo-overdominance (Ohta & Kimura 1970), i.e. a form of balancing selection that maintains complementary deleterious haplotypes that mask the effect of recessive deleterious mutations. Simulations confirm these findings and show that multi-locus AOD can increase diversity in low recombination regions much more strongly than previously appreciated. While BGS is known to drive genome-wide diversity in humans (Pouyet et al. 2018), the observation of a resurgence of genetic diversity in regions of very low recombination is indicative of AOD. We identify 21 such regions in the human genome showing clear signals of multi-locus AOD. Our results demonstrate that AOD may play an important role in the evolution of low recombination regions of many species.

scholarly journals The Effect of Mating System Differences on Nucleotide Diversity at the Phosphoglucose Isomerase Locus in the Plant Genus Leavenworthia

Genetics ◽  
1999 ◽  
Vol 151 (1) ◽  
pp. 343-357 ◽  
Author(s):  
F Liu ◽  
D Charlesworth ◽  
M Kreitman
Keyword(s):  
Genetic Diversity ◽  
Nucleotide Diversity ◽  
Phosphoglucose Isomerase ◽  
Self Incompatibility ◽  
Background Selection ◽  
Selective Sweeps ◽  
Balanced Polymorphism ◽  
Neutral Genetic Diversity ◽  
Low Diversity ◽  
High Diversity

AbstractTo test the theoretical prediction that highly inbreeding populations should have low neutral genetic diversity relative to closely related outcrossing populations, we sequenced portions of the cytosolic phosphoglucose isomerase (PgiC) gene in the plant genus Leavenworthia, which includes both self-incompatible and inbreeding taxa. On the basis of sequences of intron 12 of this gene, the expected low diversity was seen in both populations of the selfers Leavenworthia uniflora and L. torulosa and in three highly inbreeding populations of L. crassa, while high diversity was found in self-incompatible L. stylosa, and moderate diversity in L. crassa populations with partial or complete self-incompatibility. In L. stylosa, the nucleotide diversity was strongly structured into three haplotypic classes, differing by several insertion/deletion sequences, with linkage disequilibrium between sequences of the three types in intron 12, but not in the adjacent regions. Differences between the three kinds of haplotypes are larger than between sequences of this gene region from different species. The haplotype divergence suggests the presence of a balanced polymorphism at this locus, possibly predating the split between L. stylosa and its two inbreeding sister taxa, L. uniflora and L. torulosa. It is therefore difficult to distinguish between different potential causes of the much lower sequence diversity at this locus in inbreeding than outcrossing populations. Selective sweeps during the evolution of these populations are possible, or background selection, or merely loss of a balanced polymorphism maintained by overdominance in the populations that evolved high selfing rates.

scholarly journals The effect of strong purifying selection on genetic diversity

2017 ◽  
Author(s):  
Ivana Cvijović ◽  
Benjamin H. Good ◽  
Michael M. Desai
Keyword(s):  
Genetic Diversity ◽  
Frequency Spectrum ◽  
Purifying Selection ◽  
Genomic Diversity ◽  
Small Samples ◽  
Direct Selection ◽  
Background Selection ◽  
Deleterious Mutations ◽  
Site Frequency Spectrum ◽  
Neutral Mutations

Purifying selection reduces genetic diversity, both at sites under direct selection and at linked neutral sites. This process, known as background selection, is thought to play an important role in shaping genomic diversity in natural populations. Yet despite its importance, the effects of background selection are not fully understood. Previous theoretical analyses of this process have taken a backwards-time approach based on the structured coalescent. While they provide some insight, these methods are either limited to very small samples or are computationally prohibitive. Here, we present a new forward-time analysis of the trajectories of both neutral and deleterious mutations at a nonrecombining locus. We find that strong purifying selection leads to remarkably rich dynamics: neutral mutations can exhibit sweep-like behavior, and deleterious mutations can reach substantial frequencies even when they are guaranteed to eventually go extinct. Our analysis of these dynamics allows us to calculate analytical expressions for the full site frequency spectrum. We find that whenever background selection is strong enough to lead to a reduction in genetic diversity, it also results in substantial distortions to the site frequency spectrum, which can mimic the effects of population expansions or positive selection. Because these distortions are most pronounced in the low and high frequency ends of the spectrum, they become particularly important in larger samples, but may have small effects in smaller samples. We also apply our forward-time framework to calculate other quantities, such as the ultimate fates of polymorphisms or the fitnesses of their ancestral backgrounds.

Regions of Lower Crossing Over Harbor More Rare Variants in African Populations ofDrosophila melanogaster

Genetics ◽  
2001 ◽  
Vol 158 (2) ◽  
pp. 657-665 ◽  
Author(s):  
Peter Andolfatto ◽  
Molly Przeworski
Keyword(s):  
Frequency Spectrum ◽  
Nucleotide Diversity ◽  
Rare Variants ◽  
Purifying Selection ◽  
Crossing Over ◽  
Background Selection ◽  
Deleterious Mutations ◽  
African Populations ◽  
Rapid Fixation ◽  
Parameter Values

AbstractA correlation between diversity levels and rates of recombination is predicted both by models of positive selection, such as hitchhiking associated with the rapid fixation of advantageous mutations, and by models of purifying selection against strongly deleterious mutations (commonly referred to as “background selection”). With parameter values appropriate for Drosophila populations, only the first class of models predicts a marked skew in the frequency spectrum of linked neutral variants, relative to a neutral model. Here, we consider 29 loci scattered throughout the Drosophila melanogaster genome. We show that, in African populations, a summary of the frequency spectrum of polymorphic mutations is positively correlated with the meiotic rate of crossing over. This pattern is demonstrated to be unlikely under a model of background selection. Models of weakly deleterious selection are not expected to produce both the observed correlation and the extent to which nucleotide diversity is reduced in regions of low (but nonzero) recombination. Thus, of existing models, hitchhiking due to the recurrent fixation of advantageous variants is the most plausible explanation for the data.

scholarly journals The effect of background selection against deleterious mutations on weakly selected, linked variants

1994 ◽  
Vol 63 (3) ◽  
pp. 213-227 ◽  
Author(s):  
Brian Charlesworth
Keyword(s):  
Genetic Diversity ◽  
Molecular Evolution ◽  
Effective Size ◽  
Background Selection ◽  
Deleterious Mutations ◽  
Deleterious Alleles ◽  
Rates Of Evolution ◽  
Selection Approach ◽  
Slightly Deleterious Mutations ◽  
Neutral Case

SummaryThis paper analyses the effects of selection against deleterious alleles maintained by mutation (‘ background selection’) on rates of evolution and levels of genetic diversity at weakly selected, completely linked, loci. General formulae are derived for the expected rates of gene substitution and genetic diversity, relative to the neutral case, as a function of selection and dominance coefficients at the loci in question, and of the frequency of gametes that are free of deleterious mutations with respect to the loci responsible for background selection. As in the neutral case, most effects of background selection can be predicted by considering the effective size of the population to be multiplied by the frequency of mutation-free gametes. Levels of genetic diversity can be sharply reduced by background selection, with the result that values for sites under selection approach those for neutral variants subject to the same regime of background selection. Rates of fixation of slightly deleterious mutations are increased by background selection, and rates of fixation of advantageous mutations are reduced. The properties of sex-linked and autosomal asexual and self-fertilizing populations are considered. The implications of these results for the interpretation of studies of molecular evolution and variation are discussed.

scholarly journals Background selection and patterns of genetic diversity in Drosophila melanogaster

1996 ◽  
Vol 68 (2) ◽  
pp. 131-149 ◽  
Author(s):  
Brian Charlesworth
Keyword(s):  
Genetic Diversity ◽  
Drosophila Melanogaster ◽  
Genetic Variability ◽  
Chromosomal Location ◽  
Theoretical Models ◽  
Distal Portion ◽  
Background Selection ◽  
Deleterious Mutations ◽  
Chromosome 4 ◽  
Selective Forces

SummaryTheoretical models of the effects of selection against deleterious mutations on variation at linked neutral sites (background selection) are used to predict the relations between chromosomal location and genetic variability at the DNA level, in Drosophila melanogaster. The sensitivity of the predictions to variation in the mutation, selection and recombination parameters on which they are based is examined. It is shown that many features of the observed relations between chromosomal location and level of genetic diversity in D. melanogaster can be explained by background selection, especially if the weak selective forces acting on transposable elements are taken into account. In particular, the gradient in diversity in the distal portion of the X chromosome, and the lack of diversity on chromosome 4 and at the bases of the major chromosomes, can be fully accounted for. There are, however, discrepancies between predicted and observed values for some loci in D. melanogaster, which may reflect the effects of forces other than background selection.

scholarly journals Asexual but not clonal: evolutionary processes in populations with automictic reproduction

2016 ◽  
Author(s):  
Jan Engelstädter
Keyword(s):  
Genetic Diversity ◽  
Clonal Reproduction ◽  
Deleterious Mutations ◽  
Clonal Interference ◽  
Evolutionary Processes ◽  
Beneficial Mutations ◽  
Numerical Investigations ◽  
Gene Shuffling ◽  
Rate Of Spread ◽  
Neutral Genetic Diversity

AbstractMany parthenogenetically reproducing animals produce offspring not clonally but through different mechanisms collectively referred to as automixis. Here, meiosis proceeds normally but is followed by the fusion of meiotic products that restores diploidy. This mechanism typically leads to a reduction in heterozygosity among the offspring compared to the mother. Following a derivation of the rate at which heterozygosity is lost at one and two loci, depending on the number of crossovers between loci and centromere, a number of models are developed to gain a better understanding of basic evolutionary processes in automictic populations. Analytical results are obtained for the expected equilibrium neutral genetic diversity, mutation-selection balance, selection with overdominance, the rate of spread of beneficial mutations, and selection on crossover rates. These results are complemented by numerical investigations elucidating how associative overdominance (two off-phase deleterious mutations at linked loci behaving like an overdominant locus) can in some cases maintain heterozygosity for prolonged times, and how clonal interference affects adaptation in automictic populations. These results suggest that although automictic populations are expected to suffer from the lack of gene shuffling with other individuals, they are nevertheless in some respects superior to both clonal and outbreeding sexual populations in the way they respond to beneficial and deleterious mutations. Implications for related genetic systems such as intratetrad mating, clonal reproduction, selfing as well as different forms of mixed sexual and automictic reproduction are discussed.

scholarly journals A New Model of Genetic Variation and Evolution Evaluates Relative Impacts of Background Selections and Selective Sweeps

2020 ◽  
Author(s):  
Xun Gu
Keyword(s):  
Genetic Diversity ◽  
Genetic Variation ◽  
Neutral Theory ◽  
Population Diversity ◽  
Simple Relationship ◽  
Small Contribution ◽  
Background Selection ◽  
Selective Sweeps ◽  
Recombination Rates ◽  
The One

AbstractIntra-population genetic variation and interspecies divergence in chromosome regions can be considerably affected by different local recombination rates. There are two models: (i) the selective sweeps that reduces the genetic diversity at linked sites and elevates the divergence rate; and (ii) the background selection that reduces the genetic diversity at linked sites and divergence rate. An intriguing question, yet highly controversial, is which one is dominant. In this paper, I develop a framework of generalize background selection, formulated by a diffusion model with two killing functions: the one associated with (negative) background selection is the rate to stop a fixation process of a mutation randomly, and the other associated with positive background selection (selective sweep) is the rate to stop a loss process of a mutation randomly. A simple relationship between the level of reduced diversity and the rate of divergence is derived, depending on the strength of generalized background selection (G) and the proportion of positive background selection (β). We analyzed the interspecies divergence and intra-population diversity in low-recombination regions of three organisms (fruitfly, soybean and human). Strikingly, all datasets demonstrated the dominance of (negative) background selection, and the positive background selection (selective sweeps) only has a small contribution (β∼10%). However, our analysis rejects the notion of β=0, namely, a complete negative background selection is unlikely. These findings may shed some lights on the long-term debates around Neutral Theory.

scholarly journals Human demographic history has amplified the effects of background selection across the genome

2017 ◽  
Author(s):  
Raul Torres ◽  
Zachary A. Szpiech ◽  
Ryan D. Hernandez
Keyword(s):  
Genetic Diversity ◽  
Natural Selection ◽  
Demographic History ◽  
Background Selection ◽  
Dynamic Changes ◽  
Genome Wide ◽  
Neutral Genetic Diversity ◽  
African Populations ◽  
Demographic Processes ◽  
Non Equilibrium

AbstractNatural populations often grow, shrink, and migrate over time. Demographic processes such as these can impact genome-wide levels of genetic diversity. In addition, genetic variation in functional regions of the genome can be altered by natural selection, which drives adaptive mutations to higher frequencies or purges deleterious ones. Such selective processes impact not only the sites directly under selection but also nearby neutral variation through genetic linkage through processes referred to as genetic hitch-hiking in the context of positive selection and background selection (BGS) in the context of purifying selection. While there is extensive literature examining the impact of selection at linked sites at demographic equilibrium, less is known about how non-equilibrium demographic processes impact the effects of hitchhiking and BGS. Utilizing a global sample of human whole-genome sequences from the Thousand Genomes Project and extensive simulations, we investigate how non-equilibrium demographic processes magnify and dampen the consequences of selection at linked sites across the human genome. When binning the genome by inferred strength of BGS, we observe that, compared to Africans, non-African populations have experienced larger proportional decreases in neutral genetic diversity in such regions. We replicate these findings in admixed populations by showing that non-African ancestral components of the genome have also been impacted more severely in these regions. We attribute these differences to the strong, sustained/recurrent population bottlenecks that non-Africans experienced as they migrated out of Africa and throughout the globe. Furthermore, we observe a strong correlation between FST and inferred strength of BGS, suggesting a stronger rate of genetic drift. Forward simulations of human demographic history with a model of BGS support these observations. Our results show that non-equilibrium demography significantly alters the consequences selection at linked sites and support the need for more work investigating the dynamic process of multiple evolutionary forces operating in concert.Author summaryPatterns of genetic diversity within a species are affected at broad and fine scales by population size changes (“demography”) and natural selection. From both population genetics theory and observation of genomic sequence data, it is known that demography can alter genome-wide average neutral genetic diversity. Additionally, natural selection can affect neutral genetic diversity regionally across the genome via selection at linked sites. During this process, natural selection acting on adaptive or deleterious variants in the genome will also impact diversity at nearby neutral sites due to genetic linkage. However, less is well known about the dynamic changes to diversity that occur in regions impacted by selection at linked sites when a population undergoes a size change. We characterize these dynamic changes using thousands of human genomes and find that the population size changes experienced by humans have shaped the consequences of linked selection across the genome. In particular, population contractions, such as those experienced by non-Africans, have disproportionately decreased neutral diversity in regions of the genome inferred to be under strong background selection (i.e., selection at linked sites that is caused by natural selection acting on deleterious variants), resulting in large differences between African and non-African populations.

scholarly journals Hitchhiking in space: ancestry in adapting, spatially-extended populations

2016 ◽  
Author(s):  
Brent Allman ◽  
Daniel B. Weissman
Keyword(s):  
Genetic Diversity ◽  
Small Region ◽  
Genomic Region ◽  
Spatial Distance ◽  
Selective Sweeps ◽  
Spatial Region ◽  
Neutral Genetic Diversity ◽  
Spatially Extended ◽  
Neutral Mutations ◽  
Spatial Locations

AbstractSelective sweeps reduce neutral genetic diversity. In sexual populations, this “hitchhiking” effect is thought to be limited to the local genomic region of the sweeping allele. While this is true in panmictic populations, we find that in spatially-extended populations the combined effects of many unlinked sweeps can affect patterns of ancestry (and therefore neutral genetic diversity) across the whole genome. Even low rates of sweeps can be enough to skew the spatial locations of ancestors such that neutral mutations that occur in an individual living outside a small region in the center of the range have virtually no chance of fixing in the population. The fact that nearly all ancestry rapidly traces back to a small spatial region also means that relatedness between individuals falls off very slowly as a function of the spatial distance between them.

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