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PubMed2005

Distinguishing between selective sweeps and demography using DNA polymorphism data.

In 2002 Kim and Stephan proposed a promising composite-likelihood method for localizing and estimating the fitness advantage of a recently fixed beneficial mutation. Here, we demonstrate that their composite-likelihood-ratio (CLR) test comparing selective and neutral hypotheses is not robust to undetected population structure or a recent bottleneck, with some parameter combinations resulting in a false positive rate of nearly 90%. We also propose a goodness-of-fit test for discriminating rejections due to directional selection (true positive) from those due to population and demographic forces (false positives) and demonstrate that the new method has high sensitivity to differentiate the two classes of rejections.

Computer Simulation↗
PubMed1994

Detecting selective sweeps in naturally occurring Escherichia coli.

The nucleotide sequences of the gapA and pabB genes (separated by approximately 32.5 kb) were determined in 12 natural isolates of Escherichia coli. Three analyses were performed on the data. First, the levels of polymorphism at the loci were compared within and between E. coli and Salmonella strains relative to their degrees of constraint. Second, the gapA and pabB loci were analyzed by the Hudson-Kreitman-Aguadé (HKA) test for selective neutrality. Four additional dispersed genes (crr, putP, trp and gnd) were added to the analysis to provide the necessary frame of reference. Finally, the gene genealogies of gapA and pabB were examined for topological consistency within and between the loci. These lines of evidence indicate that some evolutionary event has recently purged the variability in the region surrounding the gapA and pabB loci in E. coli. This can best be explained by the spread of a selected allele through the global E. coli population by directional selection and the resulting loss in variability in the surrounding regions due to genetic hitchhiking.

Alleles↗
PubMed1998

The effect of selective sweeps on the variance of the allele distribution of a linked multiallele locus: hitchhiking of microsatellites.

Microsatellite variation and the mechanisms which are responsible for this variation have received much attention in the last few years. Most theoretical studies of microsatellite allele distributions, however, did not incorporate the evolutionary dynamics of linked sites. The dynamics is usually modeled by invoking a special mutation mechanism such as stepwise mutation, which leads to a stepwise increase or decrease of the number of motif repeats on the occasion of mutation. It is shown here that selection at a locus, which itself is not subject to mutation, but which is adjacent to a microsatellite locus has an influence on statistics of the microsatellite allele distribution, provided that mutation rates are low to intermediate, when compared to 1/t1, the inverse of the time to fixation of a linked favorable substitution. If mutation rates are high, as for example in humans, a selective effect upon the microsatellite locus, such as hitchhiking, will quickly be obscured by mutations. In particular, in the latter case, the model shows that no correlation is to be expected between recombination rates and variability of microsatellites--such as had been predicted and experimentally demonstrated for nucleotide variability and recombination rates in Drosophila. The present model is a generalization of the two locus two allele hitchhiking model which had been studied by Stephan and co-workers.

Alleles↗
PubMed2004

Variation after a selective sweep in a subdivided population.

The effect of genetic hitchhiking on neutral variation is analyzed in subdivided populations with differentiated demes. After fixation of a favorable mutation, the consequences on particular subpopulations can be radically different. In the subpopulation where the mutation first appeared by mutation, variation at linked neutral loci is expected to be reduced, as predicted by the classical theory. However, the effect in the other subpopulations, where the mutation is introduced by migration, can be the opposite. This effect depends on the level of genetic differentiation of the subpopulations, the selective advantage of the mutation, the recombination frequency, and the population size, as stated by analytical derivations and computer simulations. The characteristic outcomes of the effect are three. First, the genomic region of reduced variation around the selected locus is smaller than that predicted in a panmictic population. Second, for more distant neutral loci, the amount of variation increases over the level they had before the hitchhiking event. Third, for these loci, the spectrum of gene frequencies is dominated by an excess of alleles at intermediate frequencies when compared with the neutral theory. At these loci, hitchhiking works like a system that takes variation from the between-subpopulation component and introduces it into the subpopulations. The mechanism can also operate in other systems in which the genetic variation is distributed in clusters with limited exchange of variation, such as chromosome arrangements or genomic regions closely linked to targets of balancing selection.

Animals↗
PubMed2004

Strong selective sweep associated with a transposon insertion in Drosophila simulans.

We know little about several important properties of beneficial mutations, including their mutational origin, their phenotypic effects (e.g., protein structure changes vs. regulatory changes), and the frequency and rapidity with which they become fixed in a population. One signature of the spread of beneficial mutations is the reduction of heterozygosity at linked sites. Here, we present population genetic data from several loci across chromosome arm 2R in Drosophila simulans. A 100-kb segment from a freely recombining region of this chromosome shows extremely reduced heterozygosity in a California population sample, yet typical levels of divergence between species, suggesting that at least one episode of strong directional selection has occurred in the region. The 5' flanking sequence of one gene in this region, Cyp6g1 (a cytochrome P450), is nearly fixed for a Doc transposable element insertion. Presence of the insertion is correlated with increased transcript abundance of Cyp6g1, a phenotype previously shown to be associated with insecticide resistance in Drosophila melanogaster. Surveys of nucleotide variation in the same genomic region in an African D. simulans population revealed no evidence for a high-frequency Doc element and no evidence for reduced polymorphism. These data are consistent with the notion that the Doc element is a geographically restricted beneficial mutation. Data from D. simulans Cyp6g1 are paralleled in many respects by data from its sister species D. melanogaster.

Animals↗
PubMed2000

A selective sweep associated with a recent gene transposition in Drosophila miranda.

In Drosophila miranda, a chromosome fusion between the Y chromosome and the autosome corresponding to Muller's element C has created a new sex chromosome system. The chromosome attached to the ancestral Y chromosome is transmitted paternally and hence is not exposed to crossing over. This chromosome, conventionally called the neo-Y, and the homologous neo-X chromosome display many properties of evolving sex chromosomes. We report here the transposition of the exuperantia1 (exu1) locus from a neo-sex chromosome to the ancestral X chromosome of D. miranda. Exu1 is known to have several critical developmental functions, including a male-specific role in spermatogenesis. The ancestral location of exu1 is conserved in the sibling species of D. miranda, as well as in a more distantly related species. The transposition of exu1 can be interpreted as an adaptive fixation, driven by a selective advantage conferred by its effect on dosage compensation. This explanation is supported by the pattern of within-species sequence variation at exu1 and the nearby exu2 locus. The implications of this phenomenon for genome evolution are discussed.

Alleles↗
PubMed2005

Selective sweeps and intercontinental migration in the cosmopolitan moss Ceratodon purpureus (Hedw.) Brid.

The moss Ceratodon purpureus has long been used as a model system in plant development and physiology. However, the molecular population genetics of the species remains virtually unexplored. In this study, we used population genetic analyses of DNA sequence data from three unlinked loci (atpB-rbcL spacer, adk, and phy2) to examine biogeographical patterns in a global sample of this species. The three loci differed significantly in mutation frequency spectra and implied population structure. Pairs of haplotypes from single populations were frequently more divergent than haplotypes sampled from widely disjunct populations. In the atpB-rbcL spacer and adk samples, Australasian haplotypes were more closely related to Northern Hemisphere haplotypes than to haplotypes found in the equatorial regions. In contrast, the phy2 sample showed that the north and south temperate regions were genetically divergent, with the equatorial regions intermediate. Maximum-likelihood estimates (MLE) of the rates of migration between the two hemispheres were significantly different for the two nuclear genes. The frequency spectra of mutations indicated that differences in implied population structure among the three loci resulted from directional selection on the chloroplast genome and on the chromosomal segment containing adk. Collectively, these data suggest that long-distance migration within the Northern Hemisphere and Australasian regions is common (relative to the mutation rate) and that migration between these two regions, potentially via equatorial populations, is more frequent than migration among equatorial populations.

Adenosine Kinase↗
PubMed2006

The utility of QTL-Linked markers to detect selective sweeps in natural populations--a case study of the EDA gene and a linked marker in threespine stickleback.

Sequence polymorphisms in coding genes and variability in quantitative trait loci (QTL)-linked markers can be used to uncover the evolutionary mechanisms of traits involved in adaptive processes. We studied sequence variation in the EDA gene and allelic variation in 18 microsatellites - one of which (Gac4174) is linked with the EDA QTL - in low, partially and completely plated morphs from eight threespine stickleback European populations. The results agree with previous studies in that EDA polymorphism is closely related to plate number variation: EDA sequences grouped populations into low and completely plated morphs, whereas microsatellites failed to do so. Furthermore, partially plated fish were heterozygous with respect to the distinctive EDA alleles for completely and low plated morphs, indicating that completely plated morph alleles are not entirely dominant in controlling the expression of lateral plate number. An examination of population differentiation in plate number with quantitative genetic methods revealed that the degree of differentiation exceeded that expected from genetic drift alone (Q(ST) > F(ST)). Our results support the adaptive genetic differentiation of plate morphs and the view that distinctive EDA gene polymorphism occurs in similar sites across the distribution range of this species. Yet, allele frequency differentiation in the Gac4174 microsatellite locus, informative in experimental crosses for plate number variation, did not differ from that of neutral markers and, was therefore unable to detect the signature of natural selection responsible for population divergence.

Animals↗
PubMed2005

Reduced variation around drug-resistant dhfr alleles in African Plasmodium falciparum.

We have measured microsatellite diversity at 26 markers around the dhfr gene in pyrimethamine-sensitive and -resistant parasites collected in southeast Africa. Through direct comparison with diversity on sensitive chromosomes we have found significant loss of diversity across a region of 70 kb around the most highly resistant allele which is evidence of a selective sweep attributable to selection through widespread use of pyrimethamine (in combination with sulfadoxine) as treatment for malaria. Retrospective analysis through four years of direct and continuous selection from use of sulfadoxine-pyrimethamine as first-line malaria treatment on a Plasmodium falciparum population in KwaZulu Natal, South Africa, has revealed how recombination significantly narrowed the margins of the selective sweep over time. A deterministic model incorporating selection coefficients measured during the same interval indicates that the transition was toward a state of recombination-selection equilibrium. We compared loss of diversity around the same resistance allele in two populations at either extreme of the range of entomological inoculation rates (EIRs), namely, under one infective bite per year in Mpumalanga, South Africa, and more than one per day in southern Tanzania. EIRs determine effective recombination rates and are expected to profoundly influence the dimensions of the selective sweep. Surprisingly, the dimensions were broadly consistent across both populations. We conclude that despite different recombination rates and contrasting drug selection histories in neighboring countries, the region-wide movement of resistant parasites has played a key role in the establishment of resistance in these populations and the dimensions of the selective sweep are dominated by the influence of high initial starting frequencies.

Africa↗
PubMed2001

An investigation of the cause of low variability on the fourth chromosome of Drosophila melanogaster.

The fourth chromosome of Drosophila melanogaster lacks meiotic recombination. There is also a lack of nucleotide variation on the chromosome. This lack of variation could have been caused by a recent selective sweep, by background selection, or by a combination of these two forces. It should be possible to differentiate between the two mechanisms by studying the frequencies of polymorphic sites on the chromosome: a selective sweep should have resulted in low-frequency polymorphisms, whereas higher frequency polymorphisms would indicate the action of background selection. We have analyzed retrotransposable element insertions on the fourth chromosome in 11 strains of D. melanogaster. The polymorphisms found have a range of frequencies, with the presence of some insertions with high frequencies suggesting that the lack of variation is the result of background selection. We summarize the data using two statistics: the number of sites shared by more than one of the sample of 11 chromosomes (internal sites) and the mean number of transposable element differences in presence or absence between the sampled chromosomes. Simulations indicate that a selective sweep occurring more than 15,000 (0.03N) generations ago cannot be ruled out from the number of internal sites, although the number of differences between the chromosomes suggests either background selection or a sweep occurring more than 60,000 (0.12N) generations ago. Our results show no homoplasies and are thus consistent with no recombination occurring on the chromosome. The difficulties of distinguishing between the models using polymorphism data are discussed.

Animals↗
PubMed2005

Molecular population genetics of herbivore-induced protease inhibitor genes in European aspen (Populus tremula L., Salicaceae).

Plants defend themselves against the attack of natural enemies by using an array of both constitutively expressed and induced defenses. Long-lived woody perennials are overrepresented among plant species that show strong induced defense responses, whereas annual plants and crop species are underrepresented. However, most studies of plant defense genes have been performed on annual or short-lived perennial weeds or crop species. Here I use molecular population genetic methods to survey six wound-inducible protease inhibitors (PIs) in a long-lived woody, perennial plant species, the European aspen (Populus tremula), to evaluate the likelihood of either recurrent selective sweeps or balancing selection maintaining amino acid polymorphisms in these genes. The results show that none of the six PI genes have reduced diversities at synonymous sites, as would be expected in the presence of recurrent selective sweeps. However, several genes show some evidence of nonneutral evolution such as enhanced linkage disequilibrium and a large number of high-frequency-derived mutations. A group of at least four Kunitz trypsin inhibitor genes appear to have experienced elevated levels of nonsynonymous substitutions, indicating allelic turnover on an evolutionary timescale. One gene, TI1, has enhanced levels of intraspecific polymorphism at nonsynonymous sites and also has an unusual haplotype structure characterized by two divergent haplotypes occurring at roughly equal frequencies in the sample. One haplotype has very low levels of intraallelic nucleotide diversity, whereas the other haplotype has levels of diversity comparable to other genes in P. tremula. Patterns of sequence diversity at TI1 do not fit a simple model of either balancing selection or recurrent selective sweeps. This suggests that selection at TI1 is more complex, possibly involving allelic cycling.

Base Sequence↗
PubMed1996

Selection on X-linked genes during speciation in the Drosophila athabasca complex.

We present the results of a restriction site survey of variation at five loci in Drosophila athabasca, complimenting a previous study of the period locus. There is considerably greater differentiation between the three semispecies of D. athabasca at the period locus and two other X-linked genes (no-on-transient-A and E74A) than at three autosomal genes (Xdh, Adh and RC98). Using a modification of the HKA test, which uses fixed differences between the semispecies and a test based on differences in Fst among loci, we show that the greater differentiation of the X-linked loci compared with the autosomal loci is inconsistent with a neutral model of molecular evolution. We explore several evolutionary scenarios by computer simulation, including differential migration of X and autosomal genes, very low levels of migration among the semispecies, selective-sweeps, and background selection, and conclude that X-linked selective sweeps in at least two of the semispecies are the best explanation for the data. This evidence that natural selection acted on the X-chromosome suggests that another X-linked trait, mating song differences among the semispecies, may have been the target of selection.

Alcohol Dehydrogenase↗
PubMed2004

Pattern of polymorphism after strong artificial selection in a domestication event.

The process of strong artificial selection during a domestication event is modeled, and its effect on the pattern of DNA polymorphism is investigated. The model also considers population bottleneck during domestication. Artificial selection during domestication is different from a regular selective sweep because artificial selection acts on alleles that may have been neutral variants before domestication. Therefore, the fixation of such a beneficial allele does not always wipe out DNA variation in the surrounding region. The amount by which variation is reduced largely depends on the initial frequency of the beneficial allele, p. As a consequence, p has a strong effect on the likelihood of detecting the signature of selection during domestication from patterns of polymorphism. These theoretical results are discussed in light of data collected from maize. Although the main focus of this article is on domestication, this model can also be generalized to describe selective sweeps from standing genetic variation.

Alleles↗
PubMed2005

Extreme population structure and high interspecific divergence of the Silene Y chromosome.

Previous studies have demonstrated that the diversity of Y-linked genes is substantially lower than that of their X-linked homologs in the plant Silene latifolia. This difference has been attributed to selective sweeps, Muller's ratchet, and background selection, processes that are predicted to severely affect the evolution of the nonrecombining Y chromosome. We studied the DNA diversity of a noncoding region of the homologous genes DD44Y and DD44X, sampling S. latifolia populations from a wide geographical area and also including the closely related species S. dioica, S. diclinis, and S. heuffelii. On the Y chromosome of S. latifolia, we found substantial DNA diversity. Geographical population structure was far higher than on the X chromosome and differentiation between the species was also higher for the Y than for the X chromosome. Our findings indicate that the loss of genetic diversity on the Y chromosome in Silene occurs within local populations rather than within entire species. These results are compatible with background selection, Muller's ratchet, and local selective sweeps, but not with species-wide selective sweeps. The higher interspecific divergence of DD44Y, compared to DD44X, supports the hypothesis that Y chromosome differentiation between incipient species precedes reproductive isolation of the entire genome, forming an early stage in the process of speciation.

Base Sequence↗
PubMed1998

Mutation and evolution of microsatellites in Drosophila melanogaster.

Levels of nucleotide polymorphism in the Drosophila melanogaster genome are correlated with rates of recombination. This relationship may be due to hitchhiking of advantageous mutations (selective sweeps) or to continual removal of deleterious mutations from the genome (background selection). One test of the relative contributions of selective sweeps and background selection to the observed levels of variation in the genome of D. melanogaster is to compare levels of nucleotide variability (with a mutation rate on the order of 10(-9) per nucleotide per generation) with more rapidly evolving DNA loci such as microsatellites. This test depends critically on details of the mutational process of microsatellites. In this paper, we summarize our studies of microsatellite characteristics and mutation rates in D. melanogaster. We find that D. melanogaster microsatellites are short and have a mutation rate (6.5 x 10(-6) per locus per generation) several orders of magnitude lower than mammals studied to date. We further show that genetic variation at 18 dinucleotide repeat microsatellites in a population of D. melanogaster from Maryland is correlated with regional rates of recombination. These and other microsatellite data suggest that both background selection and selective sweeps may contribute to the correlation between DNA sequence variation and recombination in Drosophila.

Alleles↗
PubMed2006

Assortative mating for fitness and the evolution of recombination.

To understand selection on recombination, we need to consider how linkage disequilibria develop and how recombination alters these disequilibria. Any factor that affects the development of disequilibria, including nonrandom mating, can potentially change selection on recombination. Assortative mating is known to affect linkage disequilibria but its effects on the evolution of recombination have not been previously studied. Given that assortative mating for fitness can arise indirectly via a number of biologically realistic scenarios, it is plausible that weak assortative mating occurs across a diverse set of taxa. Using a modifier model, we examine how assortative mating for fitness affects the evolution of recombination under two evolutionary scenarios: selective sweeps and mutation-selection balance. We find there is no net effect of assortative mating during a selective sweep. In contrast, assortative mating could have a large effect on recombination when deleterious alleles are maintained at mutation-selection balance but only if assortative mating is sufficiently strong. Upon considering reasonable values for the number of loci affecting fitness components, the strength of selection, and the mutation rate, we conclude that the correlation in fitness between mates is unlikely to be sufficiently high for assortative mating to affect the evolution of recombination in most species.

Animals↗
PubMed2005

Fast accumulation of nonsynonymous mutations on the female-specific W chromosome in birds.

Following cessation of recombination during sex chromosome evolution, the nonrecombining sex chromosome is affected by a number of degenerative forces, possibly resulting in the fixation of deleterious mutations. This might take place because of weak selection against recessive or partly recessive deleterious mutations due to permanent heterozygosity of nonrecombining chromosomes. Furthermore, population genetic processes, such as selective sweeps, background selection, and Muller's ratchet, result in a reduction in Ne, which increase the likelihood of fixation of deleterious mutations. Theory thus predicts that nonrecombining genes should show increased levels of nonsynonymous (dN) to synonymous substitutions (dS). We tested this in an avian system by estimating the ratio between dN and dS in six gametologous gene pairs located on the Z chromosome and the nonrecombining, female-specific W chromosome. In comparisons, we found a significantly higher dN/dS ratio for the W-linked than the Z-linked copy in three of the investigated genes. In a concatenated alignment of all six genes, the dN/dS ratio was six times higher for W-linked than Z-linked genes. By using human and mouse as outgroup in maximum likelihood analyses, W-linked genes were found to evolve differently compared with their Z-linked gametologues and outgroup sequences. This seems not to be a consequence of functional diversification because d(N)/d(S) ratios between gametologous gene copies were consistently low. We conclude that deleterious mutations are accumulating at a high rate on the avian W chromosome, probably as a result of the lack of recombination in this female-specific chromosome.

Animals↗