Evidence of gene conversion associated with a selective sweep in Drosophila melanogaster

Since Drosophila melanogaster colonized Europe from tropical Africa 10 to 15 thousand years ago, it is expected that adaptation has played a major role in this species in recent times. A previously conducted multilocus scan of noncoding DNA sequences on the X chromosome in an ancestral and a derived population of D. melanogaster revealed that some loci have been affected by directional selection in the European population. We investigated if the pattern of DNA sequence polymorphism in a region surrounding one of these loci can be explained by a hitchhiking event. We found strong evidence that the studied region around the gene unc-119 was shaped by a recent selective sweep, including a valley of reduced heterozygosity of 83.4 kb, a skew in the frequency spectrum, and significant linkage disequilibrium on one side of the valley. This region, however, was interrupted by gene conversion events leading to a strong haplotype structure in the center of the valley of reduced variation.     

Hitchhiking mapping reveals a candidate genomic region for natural selection in three-spined stickleback chromosome VIII

Identification of genes and genomic regions under directional natural selection has become one of the major goals in evolutionary genetics, but relatively little work to this end has been done by applying hitchhiking mapping to wild populations. Hitchhiking mapping starts from a genome scan using a randomly spaced set of molecular markers followed by a fine-scale analysis in the flanking regions of the candidate regions under selection. We used the hitchhiking mapping approach to narrow down a selective sweep in the genomic region flanking a candidate locus (Stn90) in chromosome VIII in the three-spined stickleback (Gasterosteus aculeatus). Twenty-four microsatellite markers were screened in an approximately 800-kb region around the candidate locus in three marine and four freshwater populations. The patterns of genetic diversity and differentiation in the candidate region were compared to those of a putatively neutral set of markers. The Bayesian FST-test indicated an elevated genetic differentiation, deviating significantly from neutral expectations, at a continuous region of approximately 20 kb upstream from the candidate locus. Furthermore, a method developed for an array of microsatellite markers rejected neutrality in a region of approximately 90 kb flanking the candidate locus supporting the selective sweep hypothesis. Likewise, the genomewide pattern of genetic diversity differed from the candidate region in a bottleneck analysis suggesting that selection, rather than demography, explains the reduced genetic diversity at the candidate interval. The neutrality tests suggest that the selective sweep had occurred mainly in the Lake Pulmanki population, but the results from bottleneck analyses indicate that selection might have operated in other populations as well. These results suggest that the narrow interval around locus Stn90 has likely been under directional selection, but the region contains several predicted genes, each of which can be the actual targets of selection. Understanding of the functional significance of this genomic region in an ecological context will require a more detailed sequence analysis.     

Evidence of selection on fatty acid biosynthetic genes during the evolution of cultivated sunflower

The identification of genes underlying the phenotypic transitions that took place during crop evolution, as well as the genomic extent of resultant selective sweeps, is of great interest to both evolutionary biologists and applied plant scientists. In this study, we report the results of a molecular evolutionary analysis of 11 genes that underlie fatty acid biosynthesis and metabolism in wild and cultivated sunflower (Helianthus annuus). Seven of these 11 genes showed evidence of selection at the nucleotide level, with 1 (FAD7) having experienced selection prior to domestication, 2 (FAD2-3 and FAD3) having experienced selection during domestication, and 4 (FAB1, FAD2-1, FAD6, and FATB) having experienced selection during the subsequent period of improvement. Sequencing of a subset of these genes from an extended panel of sunflower cultivars revealed little additional variation, and an analysis of the genomic region surrounding one of these genes (FAD2-1) revealed the occurrence of an extensive selective sweep affecting a region spanning at least ca. 100 kb. Given that previous population genetic analyses have revealed a relatively rapid decay of linkage disequilibrium in sunflower, this finding indicates the occurrence of strong selection and a rapid sweep.     

The impact of natural selection on an ABCC11 SNP determining earwax type

A nonsynonymous single nucleotide polymorphism (SNP), rs17822931-G/A (538G>A; Gly180Arg), in the ABCC11 gene determines human earwax type (i.e., wet or dry) and is one of most differentiated nonsynonymous SNPs between East Asian and African populations. A recent genome-wide scan for positive selection revealed that a genomic region spanning ABCC11, LONP2, and SIAH1 genes has been subjected to a selective sweep in East Asians. Considering the potential functional significance as well as the population differentiation of SNPs located in that region, rs17822931 is the most plausible candidate polymorphism to have undergone geographically restricted positive selection. In this study, we estimated the selection intensity or selection coefficient of rs17822931-A in East Asians by analyzing two microsatellite loci flanking rs17822931 in the African (HapMap-YRI) and East Asian (HapMap-JPT and HapMap-CHB) populations. Assuming a recessive selection model, a coalescent-based simulation approach suggested that the selection coefficient of rs17822931-A had been approximately 0.01 in the East Asian population, and a simulation experiment using a pseudo-sampling variable revealed that the mutation of rs17822931-A occurred 2006 generations (95% credible interval, 1,023-3,901 generations) ago. In addition, we show that absolute latitude is significantly associated with the allele frequency of rs17822931-A in Asian, Native American, and European populations, implying that the selective advantage of rs17822931-A is related to an adaptation to a cold climate. Our results provide a striking example of how local adaptation has played a significant role in the diversification of human traits.     

Geographic variation in adaptation at the molecular level: a case study of plant immunity genes

Natural selection imposed by interacting species frequently varies among geographic locations and can lead to local adaptation, where alternative phenotypes are found in different populations. Little is known, however, about whether geographically variable selection acting on traits that mediate species interactions is consistent or strong enough to influence patterns of nucleotide variation at individual loci. To investigate this question, we examined patterns of nucleotide diversity and population structure at 16 plant innate immunity genes, with putative functions in defending plants against pathogens or herbivores, from six populations of teosinte (Zea mays ssp. parviglumis). Specifically, we tested whether patterns of population structure and within-population diversity at immunity genes differed from patterns found at nonimmunity (reference) loci and from neutral expectations derived from coalescent simulations of structured populations. For the majority of genes, we detected no strong evidence of geographically variable selection. However, in the wound-induced serine protease inhibitor (wip1), which inhibits the hydrolysis of dietary proteins in insect herbivores, one population showed unusually high levels of genetic differentiation, very low levels of nucleotide polymorphism, and was fixed for a novel replacement substitution in the active site of the protein. Taken together, these data suggest that wip1 experienced a recent selective sweep in one geographic region; this pattern may reflect local adaptation or an ongoing species-wide sweep. Overall, our results indicate that a signature of local adaptation at the molecular level may be uncommon-particularly for traits that are under complex genetic control.     

Soft Selective Sweeps in Complex Demographic Scenarios

Adaptation from de novo mutation can produce so-called soft selective sweeps, where adaptive alleles of independent mutational origin sweep through the population at the same time. Population genetic theory predicts that such soft sweeps should be likely if the product of the population size and the mutation rate toward the adaptive allele is sufficiently large, such that multiple adaptive mutations can establish before one has reached fixation; however, it remains unclear how demographic processes affect the probability of observing soft sweeps. Here we extend the theory of soft selective sweeps to realistic demographic scenarios that allow for changes in population size over time. We first show that population bottlenecks can lead to the removal of all but one adaptive lineage from an initially soft selective sweep. The parameter regime under which such “hardening” of soft selective sweeps is likely is determined by a simple heuristic condition. We further develop a generalized analytical framework, based on an extension of the coalescent process, for calculating the probability of soft sweeps under arbitrary demographic scenarios. Two important limits emerge within this analytical framework: In the limit where population-size fluctuations are fast compared to the duration of the sweep, the likelihood of soft sweeps is determined by the harmonic mean of the variance effective population size estimated over the duration of the sweep; in the opposing slow fluctuation limit, the likelihood of soft sweeps is determined by the instantaneous variance effective population size at the onset of the sweep. We show that as a consequence of this finding the probability of observing soft sweeps becomes a function of the strength of selection. Specifically, in species with sharply fluctuating population size, strong selection is more likely to produce soft sweeps than weak selection. Our results highlight the importance of accurate demographic estimates over short evolutionary timescales for understanding the population genetics of adaptation from de novo mutation.     

An analysis of signatures of selective sweeps in natural populations of the house mouse

Population and locus-specific reduction of variability of polymorphic loci could be an indication of positive selection at a linked site (selective sweep) and therefore point toward genes that have been involved in recent adaptations. Analysis of microsatellite variability offers a way to identify such regions and to ask whether they occur more often than expected by chance. We studied four populations of the house mouse (Mus musculus) to assess the frequency of such signatures of selective sweeps under natural conditions. Three samples represent the subspecies Mus m. dometicus [corrected] and came from Germany, France, and Cameroon. One sample came from Kazakhstan and constitutes a population of the subspecies Mus m. [corrected] musculus. Mitochondrial D-loop sequences from all animals confirm their respective assignments. Approximately 200 microsatellite loci were typed for up to 60 unrelated individuals from each population and evaluated for signs of selective sweeps on the basis of Schl?tterer's ln RV and ln RH statistics. Our data suggest that there are slightly more signs of selective sweeps than would have been expected by chance alone in each of the populations and also highlights some of the statistical challenges faced in genome scans for detecting selection. Single-nucleotide polymorphism typing of one sweep signature in the M. m. domesticus populations around the beta-defensin 6 locus confirms a lowered nucleotide diversity in this region and limits the potential sweep region to about 20 kb. However, no amino acid exchange has occurred in the coding region when compared to M. m. musculus. If this sweep signature is due to a recent adaptation, it is expected that a regulatory change would have caused it. Our data provide a framework for conducting a systematic whole genome scan for signatures of selective sweeps in the mouse genome.     

Geographical delimitation of a partial selective sweep in African Drosophila melanogaster

Positive selection leaves characteristic footprints on DNA variation but detecting such patterns is challenging as the age, the intensity and the mode of selection as well as demography and evolutionary parameters (mutation and recombination rates) all play roles and these are difficult to disentangle. We recorded nucleotide variation in a sample of isogenic chromosomes from a western African population of Drosophila melanogaster at a locus (Fbp2) for which a partial selective sweep had previously been reported. We compared this locus to four other genes from the same chromosomes and from a European and an East African population. Then, we assessed Fbp2 variation in a sample of 370 chromosomes covering a comprehensive geographic sampling of 16 African localities. The signature of selection was tested while accounting for the demographic history of the populations. We found a significant signal of selection in two West African localities including Ivory Coast. Variation at Fpb2 would thus represent a case of an ongoing selective sweep in the range of this species. A weaker, nonsignificant, signal of selection was, however, apparent in some other populations, thus leaving open several possibilities: (i) the selective sweep originated in Ivory Coast and has spread to the rest of the continent; (ii) several African populations report the signature of a selective event having occurred in an ancestral population; (iii) this genome region is subject to independent selective events in African populations; and (iv) A neutral scenario with population subdivision and local bottleneck cannot be fully excluded to explain the molecular patterns observed in some populations.     

Selective sweep of a cis-regulatory sequence in a non-African population of Drosophila melanogaster

Although it is thought that changes in gene expression play an important role in adaptation, the identification of gene-regulatory sequences that have been targets of positive selection has proved difficult. Here, we identify a cis-regulatory element of the Drosophila melanogaster CG9509 gene that is associated with a selective sweep in a derived non-African population of the species. Expression analyses indicate that CG9509 consistently shows greater expression in non-African than in African strains of D. melanogaster. We find that a 1.8 kb region located just upstream of the CG9509 coding region is devoid of DNA sequence polymorphism in a European population sample and that this is best explained by the recent action of positive selection (within the past 4,000-10,000 years). Using a reporter gene construct and phiC31-mediated site-specific integration, we show that the European version of the CG9509 upstream region drives 2-3 times greater expression than the African version in an otherwise identical genetic background. This expression difference corresponds well to that of the native gene and indicates that sequence variation within the CG9509 upstream region can completely account for its high expression in the European population. Selection appears to have favored a quantitative increase in gene expression in the Malphigian tubule, the tissue where CG9509 is predominantly expressed.     

Positive Selection in the Chromosome 16 VKORC1 Genomic Region Has Contributed to the Variability of Anticoagulant Response in Humans

VKORC1 (vitamin K epoxide reductase complex subunit 1, 16p11.2) is the main genetic determinant of human response to oral anticoagulants of antivitamin K type (AVK). This gene was recently suggested to be a putative target of positive selection in East Asian populations. In this study, we genotyped the HGDP-CEPH Panel for six VKORC1 SNPs and downloaded chromosome 16 genotypes from the HGDP-CEPH database in order to characterize the geographic distribution of footprints of positive selection within and around this locus. A unique VKORC1 haplotype carrying the promoter mutation associated with AVK sensitivity showed especially high frequencies in all the 17 HGDP-CEPH East Asian population samples. VKORC1 and 24 neighboring genes were found to lie in a 505 kb region of strong linkage disequilibrium in these populations. Patterns of allele frequency differentiation and haplotype structure suggest that this genomic region has been submitted to a near complete selective sweep in all East Asian populations and only in this geographic area. The most extreme scores of the different selection tests are found within a smaller 45 kb region that contains VKORC1 and three other genes (BCKDK, MYST1 (KAT8), and PRSS8) with different functions. Because of the strong linkage disequilibrium, it is not possible to determine if VKORC1 or one of the three other genes is the target of this strong positive selection that could explain present-day differences among human populations in AVK dose requirement. Our results show that the extended region surrounding a presumable single target of positive selection should be analyzed for genetic variation in a wide range of genetically diverse populations in order to account for other neighboring and confounding selective events and the hitchhiking effect.     

Non-African origin of a local beneficial mutation in D. melanogaster

It is well understood that the out-of-Africa habitat expansion of D. melanogaster was associated with the fixation of many beneficial mutations. Nevertheless, it is not clear yet whether these beneficial mutations segregated already in Africa or originated outside of Africa. In this article, we describe an ongoing selective sweep specific to one European population. One microsatellite allele has increased in a population from The Netherlands to a frequency of 18%, whereas it is virtually absent in 12 other European populations. The selective sweep resulted in a genomic region of more than 600 kb that is identical by descent. This is probably the first evidence of a beneficial mutation that has arisen outside of Africa and has resulted in a selective sweep localized in a population from The Netherlands.     

McSwan: A joint site frequency spectrum method to detect and date selective sweeps across multiple population genomes

Inferring the mode and tempo of natural selection helps further our understanding of adaptation to past environmental changes. Here, we introduce McSwan, a method to detect and date past and recent natural selection events in the case of a hard sweep. The method is based on the comparison of site frequency spectra obtained under various demographic models that include selection. McSwan demonstrated high power (high sensitivity and specificity) in capturing hard selective sweep events without requiring haplotype phasing. It performed slightly better than SweeD when the recent effective population size was low and the genomic region was small. We then applied our method to a European (CEU) and an African (LWK) human re‐sequencing data set. Most hard sweeps were detected in the CEU population (96%). Moreover, hard sweeps in the African population were estimated to have occurred further back in time (mode: 43,625 years BP) compared to those of Europeans (mode: 24,850 years BP). Most of the estimated ages of hard sweeps in Europeans were associated with the Last Glacial Maximum and were enriched in immunity‐associated genes.     

Population history and natural selection shape patterns of genetic variation in 132 genes

Identifying regions of the human genome that have been targets of natural selection will provide important insights into human evolutionary history and may facilitate the identification of complex disease genes. Although the signature that natural selection imparts on DNA sequence variation is difficult to disentangle from the effects of neutral processes such as population demographic history, selective and demographic forces can be distinguished by analyzing multiple loci dispersed throughout the genome. We studied the molecular evolution of 132 genes by comprehensively resequencing them in 24 African-Americans and 23 European-Americans. We developed a rigorous computational approach for taking into account multiple hypothesis tests and demographic history and found that while many apparent selective events can instead be explained by demography, there is also strong evidence for positive or balancing selection at eight genes in the European-American population, but none in the African-American population. Our results suggest that the migration of modern humans out of Africa into new environments was accompanied by genetic adaptations to emergent selective forces. In addition, a region containing four contiguous genes on Chromosome 7 showed striking evidence of a recent selective sweep in European-Americans. More generally, our results have important implications for mapping genes underlying complex human diseases.     

Strong signature of natural selection within an FHIT intron implicated in prostate cancer risk

Previously, a candidate gene linkage approach on brother pairs affected with prostate cancer identified a locus of prostate cancer susceptibility at D3S1234 within the fragile histidine triad gene (FHIT), a tumor suppressor that induces apoptosis. Subsequent association tests on 16 SNPs spanning approximately 381 kb surrounding D3S1234 in Americans of European descent revealed significant evidence of association for a single SNP within intron 5 of FHIT. In the current study, re-sequencing and genotyping within a 28.5 kb region surrounding this SNP further delineated the association with prostate cancer risk to a 15 kb region. Multiple SNPs in sequences under evolutionary constraint within intron 5 of FHIT defined several related haplotypes with an increased risk of prostate cancer in European-Americans. Strong associations were detected for a risk haplotype defined by SNPs 138543, 142413, and 152494 in all cases (Pearson's chi(2) = 12.34, df 1, P = 0.00045) and for the homozygous risk haplotype defined by SNPs 144716, 142413, and 148444 in cases that shared 2 alleles identical by descent with their affected brothers (Pearson's chi(2) = 11.50, df 1, P = 0.00070). In addition to highly conserved sequences encompassing SNPs 148444 and 152413, population studies revealed strong signatures of natural selection for a 1 kb window covering the SNP 144716 in two human populations, the European American (pi = 0.0072, Tajima's D = 3.31, 14 SNPs) and the Japanese (pi = 0.0049, Fay & Wu's H = 8.05, 14 SNPs), as well as in chimpanzees (Fay & Wu's H = 8.62, 12 SNPs). These results strongly support the involvement of the FHIT intronic region in an increased risk of prostate cancer.     

Selective sweep at the Drosophila melanogaster Suppressor of Hairless locus and its association with the In(2L)t inversion polymorphism.

The hitchhiking model of population genetics predicts that an allele favored by Darwinian selection can replace haplotypes from the same locus previously established at a neutral mutation-drift equilibrium. This process, known as "selective sweep," was studied by comparing molecular variation between the polymorphic In(2L)t inversion and the standard chromosome. Sequence variation was recorded at the Suppressor of Hairless (Su[H]) gene in an African population of Drosophila melanogaster. We found 47 nucleotide polymorphisms among 20 sequences of 1.2 kb. Neutrality tests were nonsignificant at the nucleotide level. However, these sites were strongly associated, because 290 out of 741 observed pairwise combinations between them were in significant linkage disequilibrium. We found only seven haplotypes, two occurring in the 9 In(2L)t chromosomes, and five in the 11 standard chromosomes, with no shared haplotype. Two haplotypes, one in each chromosome arrangement, made up two-thirds of the sample. This low haplotype diversity departed from neutrality in a haplotype test. This pattern supports a selective sweep hypothesis for the Su(H) chromosome region.     

High nucleotide sequence variation in a region of low recombination in Drosophila simulans is consistent with the background selection model

We surveyed nucleotide sequence variation at glucose dehydrogenase (Gld), in a region of low recombination on chromosome 3R, from a population sample of Drosophila simulans. The levels of nucleotide variation were surprisingly high. There was no departure from the expectation of a neutral model for the level of polymorphism, indicating no evidence of a selective sweep in this region. There was a significant deficiency of singleton polymorphisms according to the Fu and Li test, although Tajima and Hudson, Kreitman, and Aguade (HKA) tests do not provide evidence of a significant elevation of variation due to balancing selection. Genetic map data for the D. simulans third chromosome were used to calculate expected values of pi for Gld under a current model of background selection, varying the values for the parameter sh (selection coefficient against deleterious mutations). We show that the recombinational landscape of D. simulans is sufficiently different from that of D. melanogaster that we expect higher variation under the background selection model, even when effective population sizes are assumed to be equal. The data for Gld were tested against the predictions using computer simulations of the distribution of the number of segregating sites conditioned on pi. Background selection alone can explain our observations as long as sh is larger than 0.005 and species-level effective population size is assumed to be several- fold larger than in D. melanogaster. Alternatively, the deleterious mutation rate may be smaller in D. simulans, or balancing selection may be acting nearby, thereby reducing the effect of background selection.      

Convergent loss of an anciently duplicated, functionally divergent RH2 opsin gene in the fugu and Tetraodon pufferfish lineages

We describe the complete opsin gene families from the sequenced fugu and Tetraodon pufferfish genomes. We report the convergent loss of function of an anciently duplicated, functionally divergent RH2 or “green-sensitive” opsin gene in both pufferfish lineages, designated RH2-2. In fugu, RH2-2 apparently ceased to function very recently following a transposon-induced deletion that truncated the N-terminal 115 amino acids from the translated protein. Although a lack of frameshift or nonsense mutations in the fugu RH2-2 pseudogene suggests that the gene was lost very recently in this lineage, we were unable to detect any evidence of a selective sweep associated with the fixation of the truncated allele from population data. Interspecific comparison of the remaining fugu RH2-2 coding sequence paradoxically indicates that the gene was under strong purifying selection until the truncation occurred.     

Identifying selected regions from heterozygosity and divergence using a light-coverage genomic dataset from two human populations

When a selective sweep occurs in the chromosomal region around a target gene in two populations that have recently separated, it produces three dramatic genomic consequences: 1) decreased multi-locus heterozygosity in the region; 2) elevated or diminished genetic divergence (F(ST)) of multiple polymorphic variants adjacent to the selected locus between the divergent populations, due to the alternative fixation of alleles; and 3) a consequent regional increase in the variance of F(ST) (S(2)F(ST)) for the same clustered variants, due to the increased alternative fixation of alleles in the loci surrounding the selection target. In the first part of our study, to search for potential targets of directional selection, we developed and validated a resampling-based computational approach; we then scanned an array of 31 different-sized moving windows of SNP variants (5-65 SNPs) across the human genome in a set of European and African American population samples with 183,997 SNP loci after correcting for the recombination rate variation. The analysis revealed 180 regions of recent selection with very strong evidence in either population or both. In the second part of our study, we compared the newly discovered putative regions to those sites previously postulated in the literature, using methods based on inspecting patterns of linkage disequilibrium, population divergence and other methodologies. The newly found regions were cross-validated with those found in nine other studies that have searched for selection signals. Our study was replicated especially well in those regions confirmed by three or more studies. These validated regions were independently verified, using a combination of different methods and different databases in other studies, and should include fewer false positives. The main strength of our analysis method compared to others is that it does not require dense genotyping and therefore can be used with data from population-based genome SNP scans from smaller studies of humans or other species.     

Maximum-likelihood methods for detecting recent positive selection and localizing the selected site in the genome

Two maximum-likelihood methods are proposed for detecting recent, strongly positive selection and for localizing the target of selection along a recombining chromosome. The methods utilize the compact mutation frequency spectrum at multiple neutral loci that are partially linked to the selected site. Using simulated data, we show that the power of the tests lies between 80 and 98% in most cases, and the false positive rate could be as low as approximately 10% when the number of sampled marker loci is sufficiently large (> or = 20). The confidence interval around the estimated position of selection is reasonably narrow. The methods are applied to X chromosome data of Drosophila melanogaster from a European and an African population. Evidence of selection was found for both populations (including a selective sweep that was shared between both populations).     

Selection under domestication: evidence for a sweep in the rice waxy genomic region

Rice (Oryza sativa) was cultivated by Asian Neolithic farmers >11,000 years ago, and different cultures have selected for divergent starch qualities in the rice grain during and after the domestication process. An intron 1 splice donor site mutation of the Waxy gene is responsible for the absence of amylose in glutinous rice varieties. This mutation appears to have also played an important role in the origin of low amylose, nonglutinous temperate japonica rice varieties, which form a primary component of Northeast Asian cuisines. Waxy DNA sequence analyses indicate that the splice donor mutation is prevalent in temperate japonica rice varieties, but rare or absent in tropical japonica, indica, aus, and aromatic varieties. Sequence analysis across a 500-kb genomic region centered on Waxy reveals patterns consistent with a selective sweep in the temperate japonicas associated with the mutation. The size of the selective sweep (>250 kb) indicates very strong selection in this region, with an inferred selection coefficient that is higher than similar estimates from maize domestication genes or wild species. These findings demonstrate that selection pressures associated with crop domestication regimes can exceed by one to two orders of magnitude those observed for genes under even strong selection in natural systems.