Showing papers on "Genetic hitchhiking published in 2018"

A speed-fidelity trade-off determines the mutation rate and virulence of an RNA virus.

Abstract: Mutation rates can evolve through genetic drift, indirect selection due to genetic hitchhiking, or direct selection on the physicochemical cost of high fidelity. However, for many systems, it has been difficult to disentangle the relative impact of these forces empirically. In RNA viruses, an observed correlation between mutation rate and virulence has led many to argue that their extremely high mutation rates are advantageous because they may allow for increased adaptability. This argument has profound implications because it suggests that pathogenesis in many viral infections depends on rare or de novo mutations. Here, we present data for an alternative model whereby RNA viruses evolve high mutation rates as a byproduct of selection for increased replicative speed. We find that a poliovirus antimutator, 3DG64S, has a significant replication defect and that wild-type (WT) and 3DG64S populations have similar adaptability in 2 distinct cellular environments. Experimental evolution of 3DG64S under selection for replicative speed led to reversion and compensation of the fidelity phenotype. Mice infected with 3DG64S exhibited delayed morbidity at doses well above the lethal level, consistent with attenuation by slower growth as opposed to reduced mutational supply. Furthermore, compensation of the 3DG64S growth defect restored virulence, while compensation of the fidelity phenotype did not. Our data are consistent with the kinetic proofreading model for biosynthetic reactions and suggest that speed is more important than accuracy. In contrast with what has been suggested for many RNA viruses, we find that within-host spread is associated with viral replicative speed and not standing genetic diversity.

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

Abstract: Natural populations often grow, shrink, and migrate over time. Such demographic processes can affect genome-wide levels of genetic diversity. Additionally, 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 affect not only the sites directly under selection but also nearby neutral variation through genetic linkage via processes referred to as genetic hitchhiking in the context of positive selection and background selection (BGS) in the context of purifying selection. While there is extensive literature examining the consequences of selection at linked sites at demographic equilibrium, less is known about how non-equilibrium demographic processes influence 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 strong BGS regions. We replicate these findings in admixed populations by showing that non-African ancestral components of the genome have also been affected 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 the 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 of selection at linked sites and support the need for more work investigating the dynamic process of multiple evolutionary forces operating in concert.

Genetic Hitchhiking and Population Bottlenecks Contribute to Prostate Cancer Disparities in Men of African Descent.

Abstract: Prostate cancer incidence and mortality rates in African and African American men are greatly elevated compared with other ethnicities. This disparity is likely explained by a combination of social, environmental, and genetic factors. A large number of susceptibility loci have been reported by genome-wide association studies (GWAS), but the contribution of these loci to prostate cancer disparities is unclear. Here, we investigated the population structure of 68 previously reported GWAS loci and calculated genetic disparity contribution statistics to identify SNPs that contribute the most to differences in prostate cancer risk across populations. By integrating GWAS results with allele frequency data, we generated genetic risk scores for 45 African and 19 non-African populations. Tests of natural selection were used to assess why some SNPs have large allele frequency differences across populations. We report that genetic predictions of prostate cancer risks are highest for West African men and lowest for East Asian men. These differences may be explained by the out-of-Africa bottleneck and natural selection. A small number of loci appear to drive elevated prostate cancer risks in men of African descent, including rs9623117, rs6983267, rs10896449, rs10993994, and rs817826. Although most prostate cancer-associated loci are evolving neutrally, there are multiple instances where alleles have hitchhiked to high frequencies with linked adaptive alleles. For example, a protective allele at 2q37 appears to have risen to high frequency in Europe due to selection acting on pigmentation. Our results suggest that evolutionary history contributes to the high rates of prostate cancer in African and African American men.Significance: A small number of genetic variants cause an elevated risk of prostate cancer in men of West African descent. Cancer Res; 78(9); 2432-43. ©2018 AACR.

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

Abstract: Natural 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 hitchhiking 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.

Nearly Neutral Evolution across the Drosophila melanogaster Genome.

Abstract: Under the nearly neutral theory of molecular evolution, the proportion of effectively neutral mutations is expected to depend upon the effective population size (Ne). Here, we investigate whether this is the case across the genome of Drosophila melanogaster using polymorphism data from North American and African lines. We show that the ratio of the number of nonsynonymous and synonymous polymorphisms is negatively correlated to the number of synonymous polymorphisms, even when the nonindependence is accounted for. The relationship is such that the proportion of effectively neutral nonsynonymous mutations increases by ∼45% as Ne is halved. However, we also show that this relationship is steeper than expected from an independent estimate of the distribution of fitness effects from the site frequency spectrum. We investigate a number of potential explanations for this and show, using simulation, that this is consistent with a model of genetic hitchhiking: Genetic hitchhiking depresses diversity at neutral and weakly selected sites, but has little effect on the diversity of strongly selected sites.

A survey of functional genomic variation in domesticated chickens

Abstract: Deleterious genetic variation can increase in frequency as a result of mutations, genetic drift, and genetic hitchhiking. Although individual effects are often small, the cumulative effect of deleterious genetic variation can impact population fitness substantially. In this study, we examined the genome of commercial purebred chicken lines for deleterious and functional variations, combining genotype and whole-genome sequence data. We analysed over 22,000 animals that were genotyped on a 60 K SNP chip from four purebred lines (two white egg and two brown egg layer lines) and two crossbred lines. We identified 79 haplotypes that showed a significant deficit in homozygous carriers. This deficit was assumed to stem from haplotypes that potentially harbour lethal recessive variations. To identify potentially deleterious mutations, a catalogue of over 10 million variants was derived from 250 whole-genome sequenced animals from three purebred white-egg layer lines. Out of 4219 putative deleterious variants, 152 mutations were identified that likely induce embryonic lethality in the homozygous state. Inferred deleterious variation showed evidence of purifying selection and deleterious alleles were generally overrepresented in regions of low recombination. Finally, we found evidence that mutations, which were inferred to be evolutionally intolerant, likely have positive effects in commercial chicken populations. We present a comprehensive genomic perspective on deleterious and functional genetic variation in egg layer breeding lines, which are under intensive selection and characterized by a small effective population size. We show that deleterious variation is subject to purifying selection and that there is a positive relationship between recombination rate and purging efficiency. In addition, multiple putative functional coding variants were discovered in selective sweep regions, which are likely under positive selection. Together, this study provides a unique molecular perspective on functional and deleterious variation in commercial egg-laying chickens, which can enhance current genomic breeding practices to lower the frequency of undesirable variants in the population.

Why Should Mitochondria Define Species

Abstract: More than a decade of DNA barcoding encompassing about five million specimens covering 100,000 animal species supports the generalization that mitochondrial DNA clusters largely overlap with species as defined by domain experts. Most barcode clustering reflects synonymous substitutions. What evolutionary mechanisms account for synonymous clusters being largely coincident with species? The answer depends on whether variants are phenotypically neutral. To the degree that variants are selectable, purifying selection limits variation within species and neighboring species have distinct adaptive peaks. Phenotypically neutral variants are only subject to demographic processes: drift, lineage sorting, genetic hitchhiking, and bottlenecks. The evolution of modern humans has been studied from several disciplines with detail unique among animal species. Mitochondrial barcodes provide a commensurable way to compare modern humans to other animal species. Barcode variation in the modern human population is quantitatively similar to that within other animal species. Several convergent lines of evidence show that mitochondrial diversity in modern humans follows from sequence uniformity followed by the accumulation of largely neutral diversity during a population expansion that began approximately 100,000 years ago. A straightforward hypothesis is that the extant populations of almost all animal species have arrived at a similar result consequent to a similar process of expansion from mitochondrial uniformity within the last one to several hundred thousand years.

Why Should Mitochondria Define Species

Abstract: More than a decade of DNA barcoding encompassing about five million specimens covering 100,000 animal species supports the generalization that mitochondrial DNA clusters largely overlap with species as defined by domain experts. Most barcode clustering reflects synonymous substitutions. What evolutionary mechanisms account for synonymous clusters being largely coincident with species? The answer depends on whether variants are phenotypically neutral. To the degree that variants are selectable, purifying selection limits variation within species and neighboring species may have distinct adaptive peaks. Phenotypically neutral variants are only subject to demographic processes—drift, lineage sorting, genetic hitchhiking, and bottlenecks. The evolution of modern humans has been studied from several disciplines with detail unique among animal species. Mitochondrial barcodes provide a commensurable way to compare modern humans to other animal species. Barcode variation in the modern human population is quantitatively similar to that within other animal species. Several convergent lines of evidence show that mitochondrial diversity in modern humans follows from sequence uniformity followed by the accumulation of largely neutral diversity during a population expansion that began approximately 100,000 years ago. A straightforward hypothesis is that the extant populations of almost all animal species have arrived at a similar result consequent to a similar process of expansion from mitochondrial uniformity within the last one to several hundred thousand years.

Founder effects drive the genetic structure of passively dispersed aquatic invertebrates

Abstract: Populations of passively dispersed organisms in continental aquatic habitats typically show high levels of neutral genetic differentiation despite their high dispersal capabilities. Several evolutionary factors, including founder events, local adaptation, and life cycle features such as high population growth rates and the presence of propagule banks, have been proposed to be responsible for this paradox. Here, we have modeled the colonization process to assess the impact of migration rate, population growth rate, population size, local adaptation and life-cycle features on the population genetic structure in these organisms. Our simulations show that the strongest effect on population structure are persistent founder effects, resulting from the interaction of a few population founders, high population growth rates, large population sizes and the presence of diapausing egg banks. In contrast, the role of local adaptation, genetic hitchhiking and migration is limited to small populations in these organisms. Our results indicate that local adaptation could have different impact on genetic structure in different groups of zooplankters.

A speed-fidelity trade-off determines the mutation rate and virulence of an RNA virus

Abstract: Mutation rates can evolve through genetic drift, indirect selection due to genetic hitchhiking, or direct selection on the physicochemical cost of high fidelity. However, for many systems, it has been difficult to disentangle the relative impact of these forces empirically. In RNA viruses, an observed correlation between mutation rate and virulence has led many to argue that their extremely high mutation rates are advantageous, because they may allow for increased adaptability. This argument has profound implications, as it suggests that pathogenesis in many viral infections depends on rare or de novo mutations. Here we present data for an alternative model whereby RNA viruses evolve high mutation rates as a byproduct of selection for increased replicative speed. We find that a poliovirus antimutator, 3DG64S, has a significant replication defect and that wild type and 3DG64S populations have similar adaptability in two distinct cellular environments. Experimental evolution of 3DG64S under r-selection led to reversion and compensation of the fidelity phenotype. Mice infected with 3DG64S exhibited delayed morbidity at doses well above the LD50, consistent with attenuation by slower growth as opposed to reduced mutational supply. Furthermore, compensation of the 3DG64S growth defect restored virulence, while compensation of the fidelity phenotype did not. Our data are consistent with the kinetic proofreading model for biosynthetic reactions and suggest that speed is more important than accuracy. In contrast to what has been suggested for many RNA viruses, we find that within host spread is associated with viral replicative speed and not standing genetic diversity.

Determinants of selection in yeast evolved by genome shuffling

Abstract: Genome shuffling (GS) is a widely adopted methodology for the evolutionary engineering of desirable traits in industrially relevant microorganisms. We have previously used genome shuffling to generate a strain of Saccharomyces cerevisiae that is tolerant to the growth inhibitors found in a lignocellulosic hydrolysate. In this study, we expand on previous work by performing a population-wide genomic survey of our genome shuffling experiment and dissecting the molecular determinants of the evolved phenotype. Whole population whole-genome sequencing was used to survey mutations selected during the experiment and extract allele frequency time series. Using growth curve assays on single point mutants and backcrossed derivatives, we explored the genetic architecture of the selected phenotype and detected examples of epistasis. Our results reveal cohorts of strongly correlated mutations, suggesting prevalent genetic hitchhiking and the presence of pre-existing founder mutations. From the patterns of apparent selection and the results of direct phenotypic assays, our results identify key driver mutations and deleterious hitchhikers. We use these data to propose a model of inhibitor tolerance in our GS mutants. Our results also suggest a role for compensatory evolution and epistasis in our genome shuffling experiment and illustrate the impact of historical contingency on the outcomes of evolutionary engineering.

Using soybean pedigrees to identify genomic selection signatures associated with long-term breeding for cultivar improvement

Abstract: Genetic hitchhiking methods used to uncover selection signatures related to traits of agronomic importance in crops have primarily been used at the level of domestication by comparing groups of wil...

The Role of Phylogenetically Conserved Elements in Shaping Patterns of Human Genomic Diversity

Abstract: Evolutionary genetic studies have shown a positive correlation between levels of nucleotide diversity and either rates of recombination or genetic distance to genes. Both positive-directional and purifying selection have been offered as the source of these correlations via genetic hitchhiking and background selection, respectively. Phylogenetically conserved elements (CEs) are short (∼100 bp), widely distributed (comprising ∼5% of genome), sequences that are often found far from genes. While the function of many CEs is unknown, CEs also are associated with reduced diversity at linked sites. Using high coverage (>80×) whole genome data from two human populations, the Yoruba and the CEU, we perform fine scale evaluations of diversity, rates of recombination, and linkage to genes. We find that the local rate of recombination has a stronger effect on levels of diversity than linkage to genes, and that these effects of recombination persist even in regions far from genes. Our whole genome modeling demonstrates that, rather than recombination or GC-biased gene conversion, selection on sites within or linked to CEs better explains the observed genomic diversity patterns. A major implication is that very few sites in the human genome are predicted to be free of the effects of selection. These sites, which we refer to as the human "neutralome," comprise only 1.2% of the autosomes and 5.1% of the X chromosome. Demographic analysis of the neutralome reveals larger population sizes and lower rates of growth for ancestral human populations than inferred by previous analyses.

Genome Scans Reveal Homogenization and Local Adaptations in Populations of the Soybean Cyst Nematode.

Abstract: Determining the adaptive potential of alien invasive species in a new environment is a key concern for risk assessment. As climate change is affecting local climatic conditions, widespread modifications in species distribution are expected. Therefore, the genetic mechanisms underlying local adaptations must be understood in order to predict future species distribution. The soybean cyst nematode (SCN), Heterodera glycines Ichinohe, is a major pathogen of soybean that was accidentally introduced in most soybean-producing countries. In this study, we explored patterns of genetic exchange between North American populations of SCN and the effect of isolation by geographical distance. Genotyping-by-sequencing was used to sequence and compare 64 SCN populations from the United States and Canada. At large scale, only a weak correlation was found between genetic distance (Wright’s fixation index, FST) and geographic distance, but local effects were strong in recently infested states. Our results also showed a high level of genetic differentiation within some populations, allowing them to adapt to new environments and become established in new soybean-producing areas. Bayesian genome scan methods identified 15 loci under selection for climatic or geographic co-variables. Among these loci, two non-synonymous mutations were detected in SMAD 4 (mothers against decapentaplegic homolog 4) and DOP 3 (dopamine receptor 3). High-impact variants linked to these loci by genetic hitchhiking were also highlighted as putatively involved in local adaptation of SCN populations to new environments. Overall, it appears that strong selective pressure by resistant cultivars is causing a large scale homogenization with virulent populations.

Selective sweeps in populations of the broad host range plant pathogenic fungus Sclerotinia sclerotiorum

Abstract: The pathogenic fungus Sclerotinia sclerotiorum infects over 600 species of plant. It is present in numerous environments throughout the world and causes significant damage to many agricultural crops. Fragmentation and lack of gene flow between populations may lead to population sub-structure. Within discrete recombining populations, positive selection may lead to a "selective sweep". This is characterised by an increase in frequency of a favourable allele leading to reduction in genotypic diversity in a localised genomic region due to the phenomenon of genetic hitchhiking. We aimed to assess whether isolates of S. sclerotiorum from around the world formed genotypic clusters associated with geographical origin and to determine whether signatures of population-specific positive selection could be detected. To do this, we sequenced the genomes of 25 isolates of S. sclerotiorum collected from four different continents, Australia, Africa (north and south), Europe and North America (Canada and the northen United States) and conducted SNP based analyses of population structure and selective sweeps. Among the 25 isolates, there was evidence for four population clusters. One of these consisted of 11 isolates from Canada, the USA and France (population 1), another consisted of five isolates from Australia and one from Morocco (population 2). A further cluster was made up of Australian isolates, and the single South African isolate appeared to be from a separate population. We found that there was evidence of distinct selective sweeps between population 1 and population 2. Many of these sweeps overlapped genes involved in transcriptional regulation, such as transcription factors. It is possible that distinct populations of S. sclerotiorum from differing global environments have undergone selective sweeps at different genomic loci. This study lays the foundation for further work into investigation of the differing selective pressures that S. sclerotiorum populations are subjected to on a global scale.

Genetic draft and valley crossing

Abstract: Living systems are characterized by complex adaptations which require multiple coordinated mutations in order to function. Empirical studies of fitness landscapes that result from the many possible mutations in a gene region reveal many fitness peaks and valleys that connect them. Thus, it is possible that some complex adaptations have arisen by evolutionary paths whose intermediate states are neutral or even deleterious. When intermediates are deleterious, traversing such an evolutionary path is known as "crossing a fitness valley". Previous efforts at studying this problem have rigorously characterized the rate at which such complex adaptations evolve in populations of roughly equally fit individuals. However, populations that are very large or have broad fitness distributions, such as many microbial populations, adapt quickly, which substantially alters the fate and dynamics of individual mutations due to the action of genetic draft. We investigate the rate at which complex adaptations evolve in these rapidly adapting populations in regions without recombination. We confirm that rapid adaptation overall increases the time required to cross a valley; however, rapid adaptation can make it easier for deeper valleys to be crossed relative to the time required for single beneficial mutations to sweep to fixation.

Mutation rate variability as a driving force in adaptive evolution

Abstract: Mutation rate is a key determinant of the pace as well as outcome of evolution, and variability in this rate has been shown in different scenarios to play a key role in evolutionary adaptation and resistance evolution under stress. Here we investigate the dynamics of resistance fixation in a bacterial population with variable mutation rates and show that evolutionary outcomes are most sensitive to mutation rate variations when the population is subject to environmental and demographic conditions that suppress the evolutionary advantage of high-fitness subpopulations. By directly mapping a molecular-level biophysical fitness function to the system-level dynamics of the population we show that both low and very high, but not intermediate, levels of stress result in a disproportionate effect of hypermutation on resistance fixation and that traditional definitions of the selection coefficient are insufficient to account for this effect. We demonstrate how this behavior is directly tied to the extent of genetic hitchhiking in the system, the propagation of high-mutation rate cells through association with high-fitness mutations. Our results indicate a substantial role for mutation rate flexibility in the evolution of antibiotic resistance under conditions that present a weak advantage over wildtype to resistant cells.