scholarly journals Revisiting the Notion of Deleterious Sweeps

Genetics ◽  
2021 ◽  
Author(s):  
Parul Johri ◽  
Brian Charlesworth ◽  
Emma K Howell ◽  
Michael Lynch ◽  
Jeffrey D Jensen
Keyword(s):  
Positive Selection ◽  
Selective Sweep ◽  
Significant Proportion ◽  
Functional Genomic ◽  
Deleterious Mutations ◽  
Beneficial Mutations ◽  
Mating Population ◽  
Fixation Probabilities ◽  
Genomic Regions ◽  
Genomic Scans

Abstract It has previously been shown that, conditional on its fixation, the time to fixation of a semi-dominant deleterious autosomal mutation in a randomly mating population is the same as that of an advantageous mutation. This result implies that deleterious mutations could generate selective sweep-like effects. Although their fixation probabilities greatly differ, the much larger input of deleterious relative to beneficial mutations suggests that this phenomenon could be important. We here examine how the fixation of mildly deleterious mutations affects levels and patterns of polymorphism at linked sites - both in the presence and absence of interference amongst deleterious mutations - and how this class of sites may contribute to divergence between-populations and species. We find that, while deleterious fixations are unlikely to represent a significant proportion of outliers in polymorphism-based genomic scans within populations, minor shifts in the frequencies of deleterious mutations can influence the proportions of private variants and the value of FST after a recent population split. As sites subject to deleterious mutations are necessarily found in functional genomic regions, interpretations in terms of recurrent positive selection may require reconsideration.

scholarly journals Revisiting the notion of deleterious sweeps

2020 ◽  
Author(s):  
Parul Johri ◽  
Brian Charlesworth ◽  
Emma K. Howell ◽  
Michael Lynch ◽  
Jeffrey D. Jensen
Keyword(s):  
Positive Selection ◽  
Selective Sweep ◽  
Significant Proportion ◽  
Functional Genomic ◽  
Deleterious Mutations ◽  
Beneficial Mutations ◽  
Mating Population ◽  
Fixation Probabilities ◽  
Genomic Regions ◽  
Genomic Scans

ABSTRACTIt has previously been shown that, conditional on its fixation, the time to fixation of a semi-dominant deleterious autosomal mutation in a randomly mating population is the same as that of an advantageous mutation. This result implies that deleterious mutations may generate selective sweep effects. Although their fixation probabilities greatly differ, the much larger input of deleterious relative to beneficial mutations suggests that this phenomenon could be important. We here examine how the fixation of mildly deleterious mutations affects levels and patterns of polymorphism at linked sites, and how this class of sites may contribute to divergence between-populations and species. We find that, while deleterious sweeps are unlikely to represent a significant proportion of outliers in polymorphism-based genomic scans within populations, minor shifts in the frequencies of deleterious mutations can influence the proportions of private variants and the value of FST after a recent population split. As sites subject to deleterious mutations are necessarily found in functional genomic regions, interpretations in terms of recurrent positive selection may require reconsideration.

scholarly journals Identifying and classifying shared selective sweeps from multilocus data

2018 ◽  
Author(s):  
Alexandre M. Harris ◽  
Michael DeGiorgio
Keyword(s):  
Positive Selection ◽  
High Frequency ◽  
Selective Sweep ◽  
Ancestral Population ◽  
Human Populations ◽  
Platelet Response ◽  
Demographic Models ◽  
Asian Populations ◽  
Sub Saharan ◽  
Genomic Regions

AbstractPositive selection causes beneficial alleles to rise to high frequency, resulting in a selective sweep of the diversity surrounding the selected sites. Accordingly, the signature of a selective sweep in an ancestral population may still remain in its descendants. Identifying signatures of selection in the ancestor that are shared among its descendants is important to contextualize the timing of a sweep, but few methods exist for this purpose. We introduce the statistic SS-H12, which can identify genomic regions under shared positive selection across populations and is based on the theory of the expected haplotype homozygosity statistic H12, which detects recent hard and soft sweeps from the presence of high-frequency haplotypes. SS-H12, is distinct from other statistics that detect shared sweeps because it requires a minimum of only two populations, and properly identifies and differentiates between independent convergent sweeps and true ancestral sweeps, with high power and robustness to a variety of demographic models. Furthermore, we can apply SS-H12 in conjunction with the ratio of a different set of expected haplotype homozygosity statistics to further classify identified shared sweeps as hard or soft. Finally, we identified both previously-reported and novel shared sweep candidates from whole-genome sequences of global human populations. Previously-reported candidates include the well-characterized ancestral sweeps atLCTandSLC24A5in Indo-European populations, as well asGPHNworldwide. Novel candidates include an ancestral sweep atRGS18in sub-Saharan African populations involved in regulating the platelet response and implicated in sudden cardiac death, and a convergent sweep atC2CD5between European and East Asian populations that may explain their different insulin responses.Introduction

scholarly journals Identifying and Classifying Shared Selective Sweeps from Multilocus Data

Genetics ◽  
2020 ◽  
Vol 215 (1) ◽  
pp. 143-171 ◽  
Author(s):  
Alexandre M. Harris ◽  
Michael DeGiorgio
Keyword(s):  
Positive Selection ◽  
High Frequency ◽  
Selective Sweep ◽  
Ancestral Population ◽  
Platelet Response ◽  
Demographic Models ◽  
Asian Populations ◽  
Sub Saharan ◽  
Genomic Regions ◽  
Insulin Responses

Positive selection causes beneficial alleles to rise to high frequency, resulting in a selective sweep of the diversity surrounding the selected sites. Accordingly, the signature of a selective sweep in an ancestral population may still remain in its descendants. Identifying signatures of selection in the ancestor that are shared among its descendants is important to contextualize the timing of a sweep, but few methods exist for this purpose. We introduce the statistic SS-H12, which can identify genomic regions under shared positive selection across populations and is based on the theory of the expected haplotype homozygosity statistic H12, which detects recent hard and soft sweeps from the presence of high-frequency haplotypes. SS-H12 is distinct from comparable statistics because it requires a minimum of only two populations, and properly identifies and differentiates between independent convergent sweeps and true ancestral sweeps, with high power and robustness to a variety of demographic models. Furthermore, we can apply SS-H12 in conjunction with the ratio of statistics we term H2Tot and H1Tot to further classify identified shared sweeps as hard or soft. Finally, we identified both previously reported and novel shared sweep candidates from human whole-genome sequences. Previously reported candidates include the well-characterized ancestral sweeps at LCT and SLC24A5 in Indo-Europeans, as well as GPHN worldwide. Novel candidates include an ancestral sweep at RGS18 in sub-Saharan Africans involved in regulating the platelet response and implicated in sudden cardiac death, and a convergent sweep at C2CD5 between European and East Asian populations that may explain their different insulin responses.

scholarly journals The Signature of Positive Selection at Randomly Chosen Loci

Genetics ◽  
2002 ◽  
Vol 160 (3) ◽  
pp. 1179-1189 ◽  
Author(s):  
Molly Przeworski
Keyword(s):  
Linkage Disequilibrium ◽  
Positive Selection ◽  
High Frequency ◽  
Selective Sweep ◽  
Random Mating ◽  
Significant Excess ◽  
Independent Evidence ◽  
Constant Size ◽  
Mating Population ◽  
Unequal Sampling

Abstract In Drosophila and humans, there are accumulating examples of loci with a significant excess of high-frequency-derived alleles or high levels of linkage disequilibrium, relative to a neutral model of a random-mating population of constant size. These are features expected after a recent selective sweep. Their prevalence suggests that positive directional selection may be widespread in both species. However, as I show here, these features do not persist long after the sweep ends: The high-frequency alleles drift to fixation and no longer contribute to polymorphism, while linkage disequilibrium is broken down by recombination. As a result, loci chosen without independent evidence of recent selection are not expected to exhibit either of these features, even if they have been affected by numerous sweeps in their genealogical history. How then can we explain the patterns in the data? One possibility is population structure, with unequal sampling from different subpopulations. Alternatively, positive selection may not operate as is commonly modeled. In particular, the rate of fixation of advantageous mutations may have increased in the recent past.

scholarly journals Mutation accumulation and fitness in mutator subpopulations of Escherichia coli

2013 ◽  
Vol 9 (1) ◽  
pp. 20120961 ◽  
Author(s):  
Ram P. Maharjan ◽  
Bin Liu ◽  
Yang Li ◽  
Peter R. Reeves ◽  
Lei Wang ◽  
...  
Keyword(s):  
Escherichia Coli ◽  
Significant Proportion ◽  
Mutation Accumulation ◽  
Mutation Rates ◽  
Deleterious Mutations ◽  
Wild Type ◽  
Beneficial Mutations ◽  
Bacterial Populations ◽  
Neutral Mutations ◽  
Over Time

Bacterial populations in clinical and laboratory settings contain a significant proportion of mutants with elevated mutation rates (mutators). Mutators have a particular advantage when multiple beneficial mutations are needed for fitness, as in antibiotic resistance. Nevertheless, high mutation rates potentially lead to increasing numbers of deleterious mutations and subsequently to the decreased fitness of mutators. To test how fitness changed with mutation accumulation, genome sequencing and fitness assays of nine Escherichia coli mutY mutators were undertaken in an evolving chemostat population at three time points. Unexpectedly, the fitness in members of the mutator subpopulation became constant despite a growing number of mutations over time. To test if the accumulated mutations affected fitness, we replaced each of the known beneficial mutations with wild-type alleles in a mutator isolate. We found that the other 25 accumulated mutations were not deleterious. Our results suggest that isolates with deleterious mutations are eliminated by competition in a continuous culture, leaving mutators with mostly neutral mutations. Interestingly, the mutator–non-mutator balance in the population reversed after the fitness plateau of mutators was reached, suggesting that the mutator–non-mutator ratio in populations has more to do with competition between members of the population than the accumulation of deleterious mutations.

scholarly journals The Effect of Deleterious Alleles on Adaptation in Asexual Populations

Genetics ◽  
2002 ◽  
Vol 162 (1) ◽  
pp. 395-411 ◽  
Author(s):  
Toby Johnson ◽  
Nick H Barton
Keyword(s):  
Selective Sweep ◽  
Deleterious Mutation ◽  
Short Interval ◽  
Selective Advantage ◽  
Asexual Population ◽  
Restrictive Assumption ◽  
Deleterious Alleles ◽  
Fixation Probabilities ◽  
Asexual Populations ◽  
Beneficial Allele

Abstract We calculate the fixation probability of a beneficial allele that arises as the result of a unique mutation in an asexual population that is subject to recurrent deleterious mutation at rate U. Our analysis is an extension of previous works, which make a biologically restrictive assumption that selection against deleterious alleles is stronger than that on the beneficial allele of interest. We show that when selection against deleterious alleles is weak, beneficial alleles that confer a selective advantage that is small relative to U have greatly reduced probabilities of fixation. We discuss the consequences of this effect for the distribution of effects of alleles fixed during adaptation. We show that a selective sweep will increase the fixation probabilities of other beneficial mutations arising during some short interval afterward. We use the calculated fixation probabilities to estimate the expected rate of fitness improvement in an asexual population when beneficial alleles arise continually at some low rate proportional to U. We estimate the rate of mutation that is optimal in the sense that it maximizes this rate of fitness improvement. Again, this analysis relaxes the assumption made previously that selection against deleterious alleles is stronger than on beneficial alleles.

scholarly journals Selfish Genes, Pleiotropy and the Origin of Recombination

Genetics ◽  
1998 ◽  
Vol 149 (4) ◽  
pp. 2089-2097 ◽  
Author(s):  
Jody Hey
Keyword(s):  
Natural Selection ◽  
Simple Model ◽  
Computer Simulations ◽  
Recombination Rate ◽  
Evolutionary Origin ◽  
Deleterious Mutations ◽  
Beneficial Mutations ◽  
Selfish Genes ◽  
Simple Interaction

Abstract If multiple linked polymorphisms are under natural selection, then conflicts arise and the efficiency of natural selection is hindered relative to the case of no linkage. This simple interaction between linkage and natural selection creates an opportunity for mutations that raise the level of recombination to increase in frequency and have an enhanced chance of fixation. This important finding by S. Otto and N. Barton means that mutations that raise the recombination rate, but are otherwise neutral, will be selectively favored under fairly general circumstances of multilocus selection and linkage. The effect described by Otto and Barton, which was limited to neutral modifiers, can also be extended to include all modifiers of recombination, both beneficial and deleterious. Computer simulations show that beneficial mutations that also increase recombination have an increased chance of fixation. Similarly, deleterious mutations that also decrease recombination have an increased chance of fixation. The results suggest that a simple model of recombination modifiers, including both neutral and pleiotropic modifiers, is a necessary explanation for the evolutionary origin of recombination.

scholarly journals Learning a genome-wide score of human–mouse conservation at the functional genomics level

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Soo Bin Kwon ◽  
Jason Ernst
Keyword(s):  
Mouse Model ◽  
Functional Genomics ◽  
Functional Genomic ◽  
Transcriptomic Data ◽  
Model Studies ◽  
Genome Wide ◽  
A Genome ◽  
Important Challenge ◽  
Genomic Regions ◽  
Human And Mouse

AbstractIdentifying genomic regions with functional genomic properties that are conserved between human and mouse is an important challenge in the context of mouse model studies. To address this, we develop a method to learn a score of evidence of conservation at the functional genomics level by integrating information from a compendium of epigenomic, transcription factor binding, and transcriptomic data from human and mouse. The method, Learning Evidence of Conservation from Integrated Functional genomic annotations (LECIF), trains neural networks to generate this score for the human and mouse genomes. The resulting LECIF score highlights human and mouse regions with shared functional genomic properties and captures correspondence of biologically similar human and mouse annotations. Analysis with independent datasets shows the score also highlights loci associated with similar phenotypes in both species. LECIF will be a resource for mouse model studies by identifying loci whose functional genomic properties are likely conserved.

scholarly journals The Advantages of Segregation and the Evolution of Sex

Genetics ◽  
2003 ◽  
Vol 164 (3) ◽  
pp. 1099-1118 ◽  
Author(s):  
Sarah P Otto
Keyword(s):  
Sexual Reproduction ◽  
Asexual Reproduction ◽  
Deleterious Mutations ◽  
Evolution Of Sex ◽  
Beneficial Mutations ◽  
Selection Regime ◽  
Strong Selection ◽  
Genome Wide ◽  
Low Levels

AbstractIn diploids, sexual reproduction promotes both the segregation of alleles at the same locus and the recombination of alleles at different loci. This article is the first to investigate the possibility that sex might have evolved and been maintained to promote segregation, using a model that incorporates both a general selection regime and modifier alleles that alter an individual’s allocation to sexual vs. asexual reproduction. The fate of different modifier alleles was found to depend strongly on the strength of selection at fitness loci and on the presence of inbreeding among individuals undergoing sexual reproduction. When selection is weak and mating occurs randomly among sexually produced gametes, reductions in the occurrence of sex are favored, but the genome-wide strength of selection is extremely small. In contrast, when selection is weak and some inbreeding occurs among gametes, increased allocation to sexual reproduction is expected as long as deleterious mutations are partially recessive and/or beneficial mutations are partially dominant. Under strong selection, the conditions under which increased allocation to sex evolves are reversed. Because deleterious mutations are typically considered to be partially recessive and weakly selected and because most populations exhibit some degree of inbreeding, this model predicts that higher frequencies of sex would evolve and be maintained as a consequence of the effects of segregation. Even with low levels of inbreeding, selection is stronger on a modifier that promotes segregation than on a modifier that promotes recombination, suggesting that the benefits of segregation are more likely than the benefits of recombination to have driven the evolution of sexual reproduction in diploids.

scholarly journals Inference of distribution of fitness effects and proportion of adaptive substitutions from polymorphism data

2016 ◽  
Author(s):  
Paula Tataru ◽  
Maéva Mollion ◽  
Sylvain Glemin ◽  
Thomas Bataillon
Keyword(s):  
Molecular Evolution ◽  
Evolutionary Genetics ◽  
Deleterious Mutations ◽  
Probabilistic Framework ◽  
Evolutionary Trajectory ◽  
Beneficial Mutations ◽  
Fitness Effects ◽  
Polymorphism Data ◽  
Inference Methods ◽  
Biased Estimates

ABSTRACTThe distribution of fitness effects (DFE) encompasses deleterious, neutral and beneficial mutations. It conditions the evolutionary trajectory of populations, as well as the rate of adaptive molecular evolution (α). Inference of DFE and α from patterns of polymorphism (SFS) and divergence data has been a longstanding goal of evolutionary genetics. A widespread assumption shared by numerous methods developed so far to infer DFE and α from such data is that beneficial mutations contribute only negligibly to the polymorphism data. Hence, a DFE comprising only deleterious mutations tends to be estimated from SFS data, and α is only predicted by contrasting the SFS with divergence data from an outgroup. Here, we develop a hierarchical probabilistic framework that extends on previous methods and also can infer DFE and α from polymorphism data alone. We use extensive simulations to examine the performance of our method. We show that both a full DFE, comprising both deleterious and beneficial mutations, and α can be inferred without resorting to divergence data. We demonstrate that inference of DFE from polymorphism data alone can in fact provide more reliable estimates, as it does not rely on strong assumptions about a shared DFE between the outgroup and ingroup species used to obtain the SFS and divergence data. We also show that not accounting for the contribution of beneficial mutations to polymorphism data leads to substantially biased estimates of the DFE and α. We illustrate these points using our newly developed framework, while also comparing to one of the most widely used inference methods available.

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