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

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.

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The effect of strong purifying selection on genetic diversity

10.1101/211557 ◽

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.

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

10.1101/748004 ◽

2019 ◽

Cited By ~ 5

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.

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Relaxed selection during a recent human expansion

10.1101/064691 ◽

2016 ◽

Cited By ~ 4

Author(s):

S. Peischl ◽

I. Dupanloup ◽

A. Foucal ◽

M. Jomphe ◽

V. Bruat ◽

...

Keyword(s):

Wave Front ◽

Rare Variants ◽

Genetic Diseases ◽

Low Frequency ◽

Purifying Selection ◽

Genomic Diversity ◽

Human Populations ◽

Deleterious Mutations ◽

Relaxed Selection ◽

French Canadians

AbstractHumans have colonized the planet through a series of range expansions, which deeply impacted genetic diversity in newly settled areas and potentially increased the frequency of deleterious mutations on expanding wave fronts. To test this prediction, we studied the genomic diversity of French Canadians who colonized Quebec in the 17th century. We used historical information and records from ∼4000 ascending genealogies to select individuals whose ancestors lived mostly on the colonizing wave front and individuals whose ancestors remained in the core of the settlement. Comparison of exomic diversity reveals that i) both new and low frequency variants are significantly more deleterious in front than in core individuals, ii) equally deleterious mutations are at higher frequencies in front individuals, and iii) front individuals are two times more likely to be homozygous for rare very deleterious mutations present in Europeans. These differences have emerged in the past 6-9 generations and cannot be explained by differential inbreeding, but are consistent with relaxed selection on the wave front. Modeling the evolution of rare variants allowed us to estimate their associated selection coefficients as well as front and core effective sizes. Even though range expansions had a limited impact on the overall fitness of French Canadians, they could explain the higher prevalence of recessive genetic diseases in recently settled regions. Since we show that modern human populations are experiencing differential strength of purifying selection, similar processes might have happened throughout human history, contributing to a higher mutation load in populations that have undergone spatial expansions.

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Highly pleiotropic variants of human traits are enriched in genomic regions with strong background selection

Human Genetics ◽

10.1007/s00439-021-02308-w ◽

2021 ◽

Author(s):

Irene Novo ◽

Eugenio López-Cortegano ◽

Armando Caballero

Keyword(s):

Complex Traits ◽

Rare Variants ◽

Purifying Selection ◽

Frequency Effect ◽

Background Selection ◽

The Mean ◽

Using Data ◽

Genomic Regions ◽

Human Complex ◽

Gwas Catalog

AbstractRecent studies have shown the ubiquity of pleiotropy for variants affecting human complex traits. These studies also show that rare variants tend to be less pleiotropic than common ones, suggesting that purifying natural selection acts against highly pleiotropic variants of large effect. Here, we investigate the mean frequency, effect size and recombination rate associated with pleiotropic variants, and focus particularly on whether highly pleiotropic variants are enriched in regions with putative strong background selection. We evaluate variants for 41 human traits using data from the NHGRI-EBI GWAS Catalog, as well as data from other three studies. Our results show that variants involving a higher degree of pleiotropy tend to be more common, have larger mean effect sizes, and contribute more to heritability than variants with a lower degree of pleiotropy. This is consistent with the fact that variants of large effect and frequency are more likely detected by GWAS. Using data from four different studies, we also show that more pleiotropic variants are enriched in genome regions with stronger background selection than less pleiotropic variants, suggesting that highly pleiotropic variants are subjected to strong purifying selection. From the above results, we hypothesized that a number of highly pleiotropic variants of low effect/frequency may pass undetected by GWAS.

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Patterns of genetic variability in genomic regions with low rates of recombination

10.1101/739888 ◽

2019 ◽

Cited By ~ 1

Author(s):

Hannes Becher ◽

Benjamin C. Jackson ◽

Brian Charlesworth

Keyword(s):

Genetic Variability ◽

Rare Variants ◽

Genomic Region ◽

Human Populations ◽

Crossing Over ◽

Deleterious Mutations ◽

Effective Population ◽

Genomic Studies ◽

New Perspective ◽

Genomic Regions

SUMMARYSurveys of DNA sequence variation have shown that the level of genetic variability in a genomic region is often strongly positively correlated with its rate of crossing over (CO) [1–3]. This pattern is caused by selection acting on linked sites, which reduces genetic variability and can also cause the frequency distribution of segregating variants to contain more rare variants than expected without selection (skew). These effects of selection may involve the spread of beneficial mutations (selective sweeps, SSWs), the elimination of deleterious mutations (background selection, BGS) or both together, and are expected to be stronger with lower rates of crossing over [1–3]. However, in a recent study of human populations, the skew was reduced in the lowest CO regions compared with regions with somewhat higher CO rates [4]. A similar pattern is seen in the population genomic studies of Drosophila simulans described here. We propose an explanation for this paradoxical observation, and validate it using computer simulations. This explanation is based on the finding that partially recessive, linked deleterious mutations can increase rather than reduce neutral variability when the product of the effective population size (Ne) and the selection coefficient against homozygous carriers of mutations (s) is ≤ 1, i.e. there is associative overdominance (AOD) rather than BGS [5]. We show that AOD can operate in a genomic region with a low rate of CO, opening up a new perspective on how selection affects patterns of variability at linked sites.

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

10.1101/2021.07.02.450762 ◽

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.

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The Age of Nonsynonymous and Synonymous Mutations in Animal mtDNA and Implications for the Mildly Deleterious Theory

Genetics ◽

10.1093/genetics/153.1.497 ◽

1999 ◽

Vol 153 (1) ◽

pp. 497-506 ◽

Cited By ~ 4

Author(s):

Rasmus Nielsen ◽

Daniel M Weinreich

Keyword(s):

Dna Sequences ◽

Purifying Selection ◽

Data Sets ◽

Deleterious Mutations ◽

Synonymous Mutations ◽

Weak Evidence ◽

Mitochondrial Data ◽

The Mean ◽

Excess Number ◽

Neutral Mutations

Abstract McDonald/Kreitman tests performed on animal mtDNA consistently reveal significant deviations from strict neutrality in the direction of an excess number of polymorphic nonsynonymous sites, which is consistent with purifying selection acting on nonsynonymous sites. We show that under models of recurrent neutral and deleterious mutations, the mean age of segregating neutral mutations is greater than the mean age of segregating selected mutations, even in the absence of recombination. We develop a test of the hypothesis that the mean age of segregating synonymous mutations equals the mean age of segregating nonsynonymous mutations in a sample of DNA sequences. The power of this age-of-mutation test and the power of the McDonald/Kreitman test are explored by computer simulations. We apply the new test to 25 previously published mitochondrial data sets and find weak evidence for selection against nonsynonymous mutations.

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Chromosomal Patterns of Microsatellite Variability Contrast Sharply in African and Non-African Populations of Drosophila melanogaster

Genetics ◽

10.1093/genetics/160.1.247 ◽

2002 ◽

Vol 160 (1) ◽

pp. 247-256

Author(s):

M Kauer ◽

B Zangerl ◽

D Dieringer ◽

C Schlötterer

Keyword(s):

Chromosomal Polymorphism ◽

Background Selection ◽

Selective Sweeps ◽

X Chromosomes ◽

Evolutionary Forces ◽

Relative Contribution ◽

African Populations ◽

Neutral Variation ◽

Colonization Process ◽

The Subject

Abstract Levels of neutral variation are influenced by background selection and hitchhiking. The relative contribution of these evolutionary forces to the distribution of neutral variation is still the subject of ongoing debates. Using 133 microsatellites, we determined levels of variability on X chromosomes and autosomes in African and non-African D. melanogaster populations. In the ancestral African populations microsatellite variability was higher on X chromosomes than on autosomes. In non-African populations X-linked polymorphism is significantly more reduced than autosomal variation. In non-African populations we observed a significant positive correlation between X chromosomal polymorphism and recombination rate. These results are consistent with the interpretation that background selection shapes levels of neutral variability in the ancestral populations, while the pattern in derived populations is determined by multiple selective sweeps during the colonization process. Further research, however, is required to investigate the influence of inversion polymorphisms and unequal sex ratios.

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Molecular population genetics of sequence length diversity in the Adh region of Drosophila pseudoobscura

Genetics Research ◽

10.1017/s0016672302005955 ◽

2002 ◽

Vol 80 (3) ◽

pp. 163-175 ◽

Cited By ~ 48

Author(s):

STEPHEN W. SCHAEFFER

Keyword(s):

Negative Selection ◽

Genome Rearrangement ◽

Rare Variants ◽

Natural Populations ◽

Population Expansion ◽

Purifying Selection ◽

Sequence Length ◽

Nucleotide Sequence Analysis ◽

Drosophila Pseudoobscura ◽

Indel Variation

Positive and negative selection on indel variation may explain the correlation between intron length and recombination levels in natural populations of Drosophila. A nucleotide sequence analysis of the 3·5 kilobase sequence of the alcohol dehydrogenase (Adh) region from 139 Drosophila pseudoobscura strains and one D. miranda strain was used to determine whether positive or negative selection acts on indel variation in a gene that experiences high levels of recombination. A total of 30 deletion and 36 insertion polymorphisms were segregating within D. pseudoobscura populations and no indels were fixed between D. pseudoobscura and its two sibling species D. miranda and D. persimilis. The ratio of Tajima's D to its theoretical minimum value (Dmin) was proposed as a metric to assess the heterogeneity in D among D. pseudoobscura loci when the number of segregating sites differs among loci. The magnitude of the D/Dmin ratio was found to increase as the rate of population expansion increases, allowing one to assess which loci have an excess of rare variants due to population expansion versus purifying selection. D. pseudoobscura populations appear to have had modest increases in size accounting for some of the observed excess of rare variants. The D/Dmin ratio rejected a neutral model for deletion polymorphisms. Linkage disequilibrium among pairs of indels was greater than between pairs of segregating nucleotides. These results suggest that purifying selection removes deletion variation from intron sequences, but not insertion polymorphisms. Genome rearrangement and size-dependent intron evolution are proposed as mechanisms that limit runaway intron expansion.

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Population differentiation between Australian and Chinese Helicoverpa armigera occurs in distinct blocks on the Z-chromosome

Bulletin of Entomological Research ◽

10.1017/s0007485318000081 ◽

2018 ◽

Vol 108 (6) ◽

pp. 817-830 ◽

Cited By ~ 1

Author(s):

S.V. Song ◽

C. Anderson ◽

R.T. Good ◽

S. Leslie ◽

Y. Wu ◽

...

Keyword(s):

Population Structure ◽

Helicoverpa Armigera ◽

Nucleotide Diversity ◽

Selective Sweep ◽

Rare Variants ◽

Population Expansion ◽

Z Chromosome ◽

Chinese Populations ◽

Continental Population ◽

Helicoverpa Armígera

AbstractOver the last 40 years, many types of population genetic markers have been used to assess the population structure of the pest moth species Helicoverpa armigera. While this species is highly vagile, there is evidence of inter-continental population structure. Here, we examine Z-chromosome molecular markers within and between Chinese and Australian populations. Using 1352 polymorphic sites from 40 Z-linked loci, we compared two Chinese populations of moths separated by 700 km and found virtually no population structure (n = 41 and n = 54, with <1% of variation discriminating between populations). The levels of nucleotide diversity within these populations were consistent with previous estimates from introns in Z-linked genes of Australian samples (π = 0.028 vs. 0.03). Furthermore, all loci surveyed in these Chinese populations showed a skew toward rare variants, with ten loci having a significant Tajima's D statistic, suggesting that this species could have undergone a population expansion. Eight of the 40 loci had been examined in a previous study of Australian moths, of which six revealed very little inter-continental population structure. However, the two markers associated with the Cyp303a1 locus that has previously been proposed to be a target of a selective sweep, exhibited allele structuring between countries. Using a separate dataset of 19 Australian and four Chinese moths, we scanned the molecular variation distributed across the entire Z-chromosome and found distinct blocks of differentiation that include the region containing Cyp303a1. We recommend some of these loci join those associated with insecticide resistance to form a set of genes best suited to analyzing population structure in this global pest.

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