The geographic spread of the CCR5 Delta32 HIV-resistance allele

The Delta32 mutation at the CCR5 locus is a well-studied example of natural selection acting in humans. The mutation is found principally in Europe and western Asia, with higher frequencies generally in the north. Homozygous carriers of the Delta32 mutation are resistant to HIV-1 infection because the mutation prevents functional expression of the CCR5 chemokine receptor normally used by HIV-1 to enter CD4+ T cells. HIV has emerged only recently, but population genetic data strongly suggest Delta32 has been under intense selection for much of its evolutionary history. To understand how selection and dispersal have interacted during the history of the Delta32 allele, we implemented a spatially explicit model of the spread of Delta32. The model includes the effects of sampling, which we show can give rise to local peaks in observed allele frequencies. In addition, we show that with modest gradients in selection intensity, the origin of the Delta32 allele may be relatively far from the current areas of highest allele frequency. The geographic distribution of the Delta32 allele is consistent with previous reports of a strong selective advantage (>10%) for Delta32 carriers and of dispersal over relatively long distances (>100 km/generation). When selection is assumed to be uniform across Europe and western Asia, we find support for a northern European origin and long-range dispersal consistent with the Viking-mediated dispersal of Delta32 proposed by G. Lucotte and G. Mercier. However, when we allow for gradients in selection intensity, we estimate the origin to be outside of northern Europe and selection intensities to be strongest in the northwest. Our results describe the evolutionary history of the Delta32 allele and establish a general methodology for studying the geographic distribution of selected alleles.     

The Origins of Lactase Persistence in Europe

Lactase persistence (LP) is common among people of European ancestry, but with the exception of some African, Middle Eastern and southern Asian groups, is rare or absent elsewhere in the world. Lactase gene haplotype conservation around a polymorphism strongly associated with LP in Europeans (−13,910 C/T) indicates that the derived allele is recent in origin and has been subject to strong positive selection. Furthermore, ancient DNA work has shown that the −13,910*T (derived) allele was very rare or absent in early Neolithic central Europeans. It is unlikely that LP would provide a selective advantage without a supply of fresh milk, and this has lead to a gene-culture coevolutionary model where lactase persistence is only favoured in cultures practicing dairying, and dairying is more favoured in lactase persistent populations. We have developed a flexible demic computer simulation model to explore the spread of lactase persistence, dairying, other subsistence practices and unlinked genetic markers in Europe and western Asia''s geographic space. Using data on −13,910*T allele frequency and farming arrival dates across Europe, and approximate Bayesian computation to estimate parameters of interest, we infer that the −13,910*T allele first underwent selection among dairying farmers around 7,500 years ago in a region between the central Balkans and central Europe, possibly in association with the dissemination of the Neolithic Linearbandkeramik culture over Central Europe. Furthermore, our results suggest that natural selection favouring a lactase persistence allele was not higher in northern latitudes through an increased requirement for dietary vitamin D. Our results provide a coherent and spatially explicit picture of the coevolution of lactase persistence and dairying in Europe.     

The Geographic Spread of the CCR5 Δ32 HIV-Resistance Allele

The Δ32 mutation at the CCR5 locus is a well-studied example of natural selection acting in humans. The mutation is found principally in Europe and western Asia, with higher frequencies generally in the north. Homozygous carriers of the Δ32 mutation are resistant to HIV-1 infection because the mutation prevents functional expression of the CCR5 chemokine receptor normally used by HIV-1 to enter CD4+ T cells. HIV has emerged only recently, but population genetic data strongly suggest Δ32 has been under intense selection for much of its evolutionary history. To understand how selection and dispersal have interacted during the history of the Δ32 allele, we implemented a spatially explicit model of the spread of Δ32. The model includes the effects of sampling, which we show can give rise to local peaks in observed allele frequencies. In addition, we show that with modest gradients in selection intensity, the origin of the Δ32 allele may be relatively far from the current areas of highest allele frequency. The geographic distribution of the Δ32 allele is consistent with previous reports of a strong selective advantage (>10%) for Δ32 carriers and of dispersal over relatively long distances (>100 km/generation). When selection is assumed to be uniform across Europe and western Asia, we find support for a northern European origin and long-range dispersal consistent with the Viking-mediated dispersal of Δ32 proposed by G. Lucotte and G. Mercier. However, when we allow for gradients in selection intensity, we estimate the origin to be outside of northern Europe and selection intensities to be strongest in the northwest. Our results describe the evolutionary history of the Δ32 allele and establish a general methodology for studying the geographic distribution of selected alleles.     

A global view of the OCA2-HERC2 region and pigmentation

Mutations in the gene OCA2 are responsible for oculocutaneous albinism type 2, but polymorphisms in and around OCA2 have also been associated with normal pigment variation. In Europeans, three haplotypes in the region have been shown to be associated with eye pigmentation and a missense SNP (rs1800407) has been associated with green/hazel eyes (Branicki et al. in Ann Hum Genet 73:160-170, 2009). In addition, a missense mutation (rs1800414) is a candidate for light skin pigmentation in East Asia (Yuasa et al. in Biochem Genet 45:535-542, 2007; Anno et al. in Int J Biol Sci 4, 2008). We have genotyped 3,432 individuals from 72 populations for 21 SNPs in the OCA2-HERC2 region including those previously associated with eye or skin pigmentation. We report that the blue-eye associated alleles at all three haplotypes were found at high frequencies in Europe; however, one is restricted to Europe and surrounding regions, while the other two are found at moderate to high frequencies throughout the world. We also observed that the derived allele of rs1800414 is essentially limited to East Asia where it is found at high frequencies. Long-range haplotype tests provide evidence of selection for the blue-eye allele at the three haplotyped systems but not for the green/hazel eye SNP allele. We also saw evidence of selection at the derived allele of rs1800414 in East Asia. Our data suggest that the haplotype restricted to Europe is the strongest marker for blue eyes globally and add further inferential evidence that the derived allele of rs1800414 is an East Asian skin pigmentation allele.     

The Geographic Spread of the CCR5 Δ32 HIV-Resistance Allele

The Δ32 mutation at the CCR5 locus is a well-studied example of natural selection acting in humans. The mutation is found principally in Europe and western Asia, with higher frequencies generally in the north. Homozygous carriers of the Δ32 mutation are resistant to HIV-1 infection because the mutation prevents functional expression of the CCR5 chemokine receptor normally used by HIV-1 to enter CD4+ T cells. HIV has emerged only recently, but population genetic data strongly suggest Δ32 has been under intense selection for much of its evolutionary history. To understand how selection and dispersal have interacted during the history of the Δ32 allele, we implemented a spatially explicit model of the spread of Δ32. The model includes the effects of sampling, which we show can give rise to local peaks in observed allele frequencies. In addition, we show that with modest gradients in selection intensity, the origin of the Δ32 allele may be relatively far from the current areas of highest allele frequency. The geographic distribution of the Δ32 allele is consistent with previous reports of a strong selective advantage (>10%) for Δ32 carriers and of dispersal over relatively long distances (>100 km/generation). When selection is assumed to be uniform across Europe and western Asia, we find support for a northern European origin and long-range dispersal consistent with the Viking-mediated dispersal of Δ32 proposed by G. Lucotte and G. Mercier. However, when we allow for gradients in selection intensity, we estimate the origin to be outside of northern Europe and selection intensities to be strongest in the northwest. Our results describe the evolutionary history of the Δ32 allele and establish a general methodology for studying the geographic distribution of selected alleles.     

Roles of maternal effects in maintaining genetic variation: Maternal storage effect

Understanding the maintenance of genetic variation remains a central challenge in evolutionary biology. Recent empirical studies suggest the importance of temporally varying selection, as allele frequencies have been found to fluctuate substantially in the wild. However, previous theory suggests that the conditions for the maintenance of genetic variation under temporally fluctuating selection are quite restrictive. Using mathematical models, we demonstrate that maternal genetic effects, whereby maternal genotypes affect offspring phenotypes, can facilitate the maintenance of polymorphism in temporally varying environments. Maternal effects result in mismatches between genotypes and phenotypes, thereby buffering the influence of selection on allele frequency. This decreases the magnitude of allele‐frequency fluctuations and creates conditions for the maintenance of variation when selection causes fluctuations. Therefore, maternal effects may result in a temporal storage effect (“maternal storage effect”). On the other hand, when selection does not cause fluctuations (e.g., linear negative frequency‐dependent selection), maternal genetic effects moderate the relative importance of selection compared to genetic drift and promote stochastic allele extinction in finite populations. Thus, maternal effects can play an important role in the maintenance of polymorphism, but the direction of the effect depends on the nature of selection.     

Allelic diversity of metallothionein in Orchesella cincta (L.): traces of natural selection by environmental pollution

The advances made in statistical methods to detect selection from DNA sequence variation has resulted in an enormous increase in the number of studies reporting positive selection. However, a disadvantage of such statistical tests is that often no insight into the actual source of selection is obtained. Finer understanding of evolution can be obtained when those statistical tests are combined with field observations on allele frequencies. We assessed whether the metallothionein (mt) gene of Orchesella cincta (Collembola), which codes for a metal-binding protein, is subject to selection, by investigating alleles and allele frequencies among European metal-stressed and reference populations. Eight highly divergent alleles were resolved in Northwest Europe. At the nucleotide level, a total of 51 polymorphic sites (five of them implying amino-acid changes) were observed. Although statistical tests applied to the sequences alone showed no indication of selection, a G-test rejected the null hypothesis that alleles are homogeneously distributed over metal-stressed and reference populations. Analysis of molecular variance assigned a small, but significant amount of the total variance to differences between metal-stressed and non-stressed populations. In addition, it was shown that metal-stressed populations tend to be more genetically diversified at this locus than non-stressed ones. These results suggest that the mt gene and its surrounding DNA region are affected by environmental metal contamination. This study illustrates that, in addition to statistical tests, field observations on allele frequencies are needed to gain understanding of selection and adaptive evolution.     

The evolutionary history of the CCR5-Delta32 HIV-resistance mutation

The CCR5 chemokine receptor is exploited by HIV-1 to gain entry into CD4+ T cells. A deletion mutation (Delta32) confers resistance against HIV by obliterating the expression of the receptor on the cell surface. Intriguingly, this allele is young in evolutionary time, yet it has reached relatively high frequencies in Europe. These properties indicate that the mutation has been under intense positive selection. HIV-1 has not exerted selection for long enough on the human population to drive the CCR5-Delta32 allele to current frequencies, fueling debate regarding the selective pressure responsible for rise of the allele. The allele exists at appreciable frequencies only in Europe, and within Europe, the frequency is higher in the north. Here we review the population genetics of the CCR5 locus, the debate over the historical selective pressure acting on CCR5-Delta32, the inferences that can potentially be drawn from the geographic distribution of CCR5-Delta32 and the role that other genetic polymorphisms play in conferring resistance against HIV. We also discuss parallel evolution that has occurred at the CCR5 locus of other primate species. Finally, we highlight the promise that therapies based on interfering with the CCR5 receptor could have in the treatment of HIV.     

Genetic consequences of an invasion through a patchy environment — the cynipid gallwasp Andricus quercuscalicis (Hymenoptera: Cynipidae)

Over the last 300–400 years, the cynipid gallwasp Andricus quercuscalicis has invaded northern and western Europe following human introduction of an obligate host plant, the Turkey oak ( Quercus cerris ) from south-eastern Europe. In the introduced range, distances between Turkey oak patches are greater and the numbers of oaks in each patch are far lower than in its native range. These changes in spatial distribution of Turkey oak are predicted to result in high genetic subdivision of A. quercuscalicis in invaded areas relative to its native range. Allozyme electrophoresis was used to examine genetic variation in 823 gall wasps from 39 populations of A. quercuscalicis. No new electrophoretic variants were found in the invaded range and both allelic diversity and mean heterozygosity decreased significantly with distance from the native range. Spatial autocorrelation analysis and values of Wright's F_st indicate that differences in allele frequences between populations were substantially greater in the invaded range than in the native range. Spatial autocorrelation analysis also suggests that changes in allele frequencies across Europe are unlikely to be the results of selection, but rather of strong directional migration followed by limited gene flow between populations. Patterns of genetic differentiation across Europe suggest that populations of A. quercuscalicis have been founded sequentially from the east through a process of random genetic subsampling and not by source-sink colonization directly from the native range.     

In search of clinal variation in the period and clock timing genes in Australian Drosophila melanogaster populations

Clinal variation for repeat number in the Thr-Gly region of the period circadian timing gene in Drosophila melanogaster was described in Europe and has subsequently been used as evidence of thermal selection on period alleles. To test for clinal variation in this gene along the east coast of Australia, the period polymorphism was scored on flies from multiple samples collected repeatedly over a 5-year interval, along with variation at another circadian rhythm locus, clock. For period, there was no consistent evidence of clinal variation in the 17 and/or 20 repeat alleles, although when average allele length was examined a weak consistent clinal pattern was detected. For clock there was no evidence of clinal variation in the two most common alleles or in average repeat size. These data are inconsistent with the reported patterns in Europe and suggest that clinal variation in timing genes needs to be re-examined in this region.     

论替换负荷与Haldane进退维谷

在等位基因A优于等位基因α的选择下,种群中不存在有现实意义的H－W平衡;用平衡频率导出的Haldane进退维谷只是一种数学佯谬;替换负荷是选择下的非平衡种群的遗传负荷,且亲代负荷最大,随着世代的增加,后代负荷越来越小,种群对选择越来越适应。     

Simulating genealogies of selected alleles in a population of variable size

An importance-sampling method is presented that allows the simulation of the history of a selected allele in a population of variable size. A sample path describing the number of copies of an allele that arose as a single mutant is generated by simulating backwards from the current frequency until the allele is lost. The mathematical expectation of a quantity or statistic is then estimated by taking averages over replicate simulations, weighting each replicate by the ratio of its probabilities under the Markov chains for the forward and backwards processes. This method was used to find the average age of a selected allele in an exponentially growing population. In terms of the effect on average allele age, selection in favour of an allele is not equivalent to exponential growth. To generate gene genealogies of a sample of copies of a selected allele, the neutral coalescent model is simulated for the subpopulation containing only the selected allele. From the resulting intra-allelic genealogy, it is possible to calculate the likelihood of the selection intensity as a function of the observed level of variability at marker loci closely linked to the selected allele. This method was used to estimate the intensity of selection affecting the delta 32 allele at the CCR5 locus in Europeans and a mutant at the MLH1 locus associated with colorectal cancer in the Finnish population.     

Migration/selection balance and ecotypic differentiation in the mosquito Culex pipiens

Ecotypic differentiation is well described in the mosquito Culex pipiens , separating populations breeding in subterranean and human-made sites (hypogeous habitat) from those in open-air sites (epigeous habitat). The pattern of population differentiation observed at the Aat-1 locus has been suspected to be associated with such ecotypic differentiation via habitat-dependent selection, but this supposition is still the subject of debate in the literature. We analysed differentiation patterns for Aat-1 and another four loci among populations from both habitat types in the French Alps. We showed that the Aat-1^A allele is favoured within hypogeous habitats but selected against within epigeous habitats. Comparisons of our results with other data reported in the literature indicate that the Aat-1^A allele is generally evolving under habitat-differential selection, but that the precise balance of migration and selection that determines equilibrium allele frequencies varies greatly across Europe. The nature of this habitat-dependent selection, and its resulting (geographically varying) equilibrium point, are discussed in relation to the biology of this mosquito species.     

Natural history of Ashkenazi intelligence

This paper elaborates the hypothesis that the unique demography and sociology of Ashkenazim in medieval Europe selected for intelligence. Ashkenazi literacy, economic specialization, and closure to inward gene flow led to a social environment in which there was high fitness payoff to intelligence, specifically verbal and mathematical intelligence but not spatial ability. As with any regime of strong directional selection on a quantitative trait, genetic variants that were otherwise fitness reducing rose in frequency. In particular we propose that the well-known clusters of Ashkenazi genetic diseases, the sphingolipid cluster and the DNA repair cluster in particular, increase intelligence in heterozygotes. Other Ashkenazi disorders are known to increase intelligence. Although these disorders have been attributed to a bottleneck in Ashkenazi history and consequent genetic drift, there is no evidence of any bottleneck. Gene frequencies at a large number of autosomal loci show that if there was a bottleneck then subsequent gene flow from Europeans must have been very large, obliterating the effects of any bottleneck. The clustering of the disorders in only a few pathways and the presence at elevated frequency of more than one deleterious allele at many of them could not have been produced by drift. Instead these are signatures of strong and recent natural selection.     

Kin selection and evolution of infectious disease resistance

Discoveries of mutations conferring resistance to infectious diseases have led to increased interest in the evolutionary dynamics of disease resistance. Several recent papers have estimated the historical strength of selection for mutations conferring disease resistance. These studies are based on simple population genetic models that do not take account of factors such as spatial and family structure. Such factors may have a substantial impact on the strength of natural selection through inclusive fitness effects. That is, people have a strong tendency to live with relatives and therefore have a high probability of transmitting infectious diseases to them. Thus, an allele that protects an individual against disease infection also protects that individual's family members. Because some of these family members are likely to also be carrying the allele, selection for that allele is magnified by family structure. In this paper, I use mathematical modeling techniques to explore the impact of such kin selection on the strength of selection for infectious disease resistance alleles. I show that if the resistance allele has the same proportional effect on both within- and between-family transmission, then the impact of kin selection is relatively minor. Selection coefficients are increased by 5-35%, with a greater benefit for weaker alleles. The reason is that an individual with a strong resistance allele does not need much protection from infection by family members and thus does not benefit much from their alleles. The effect of kin selection can be dramatic, however, if the resistance allele has a larger effect on between-family transmission than within-family transmission (which can occur if between-family infection rates are much smaller than within-family rates), increasing selection coefficients by as much as two- to threefold. These results show conditions when it is important to consider family structure in estimates of the strength of selection for infectious disease resistance alleles.     

On the fixation process of a beneficial mutation in a variable environment

A population that adapts to gradual environmental change will typically experience temporal variation in its population size and the selection pressure. On the basis of the mathematical theory of inhomogeneous branching processes, we present a framework to describe the fixation process of a single beneficial allele under these conditions. The approach allows for arbitrary time-dependence of the selection coefficient s(t) and the population size N(t), as may result from an underlying ecological model. We derive compact analytical approximations for the fixation probability and the distribution of passage times for the beneficial allele to reach a given intermediate frequency. We apply the formalism to several biologically relevant scenarios, such as linear or cyclic changes in the selection coefficient, and logistic population growth. Comparison with computer simulations shows that the analytical results are accurate for a large parameter range, as long as selection is not very weak.     

European ACP1*C allele has recessive deleterious effects on early life viability

The acid phosphatase locus (ACP1) is a classical polymorphism that has been surveyed in hundreds of human populations worldwide. Among individuals of European ancestry, the ACP1*C allele occurs with an average frequency of approximately 0.05, whereas it is nearly absent in all other human populations. It has been hypothesized that this allele is maintained by overdominant selection among European populations. Here, we analyze ACP1 protein polymorphism data from more than 50,000 individuals previously surveyed in 67 populations across Europe as well as inheritance data from more than 6,000 European parent-offspring pairs to assess the signature of natural selection currently acting on this allele. Although we see a significant excess of ACP1*C heterozygotes relative to Hardy-Weinberg expectations, we find no evidence that natural selection favors ACP1*C heterozygotes. Instead, ACP1*C appears to have a strongly deleterious and recessive fitness effect. We observed only 48.9% of expected homozygous offspring from heterozygous parents and significantly fewer homozygotes than expected within populations. Because parent-offspring pairs indicate a significant deficiency of ACP1*C homozygotes, we infer that viability selection is acting on ACP1*C homozygotes very early in life, perhaps before birth. We estimate that approximately 1.2% of all couples of European ancestry are composed of individuals who both carry the APC1*C allele. As such, selection against ACP1*C homozygotes may represent a nonnegligible contribution to the overall number of spontaneous abortions among women of European ancestry and may cause substantial fertility reductions among some combinations of parental genotypes.     

Allele frequency distribution of 1691G>A F5 (which confers Factor V Leiden) across Europe, including Slavic populations

The allele 1691A F5, conferring Factor V Leiden, is a common risk factor in venous thromboembolism. The frequency distribution for this allele in Western Europe has been well documented; but here data from Central, Eastern and South-Eastern Europe has been included. In order to assess the significance of the collated data, a chi-squared test was applied, and Tukey tests and z-tests with Bonferroni correction were compared. Results: A distribution with a North-Southeast band of high frequency of the 1691A F5 allele was discovered with a pocket including some Southern Slavic populations with low frequency. European countries/regions can be arbitrarily delimited into low (group 1, <2.8 %, mean 1.9 % 1691A F5 allele) or high (group 2, ≥2.8 %, mean 4.0 %) frequency groups, with many significant differences between groups, but only one intra-group difference (the Tukey test is suggested to be superior to the z-tests). Conclusion: In Europe a North-Southeast band of 1691A F5 high frequency has been found, clarified by inclusion of data from Central, Eastern and South-Eastern Europe, which surrounds a pocket of low frequency in the Balkans which could possibly be explained by Slavic migration. There seem to be no indications of variation in environmental selection due to geographical location.     

Post-glacial colonization of brown trout, Salmo trutta L.: Ldh-5 as a phylogeographic marker locus

The Ldh-5 locus, which codes for the eye-specific lactate dehydrogenase in brown trout, has been shown to be polymorphic for two codominant alleles, Ldh-5 (100) and Ldh-5 (90). The Ldh-5 (100 ) allele is present in 11 other salmonid species and is therefore likely to be the ancestral one, whereas the unique brown trout Ldh-5 (90 ) allele would seem to be the result of a mutation in that lineage. The Ldh-5 (90 ) allele appears to have arisen in north-west Europe during or after the last glaciation, with allelic substitution taking place under the action of natural selection. The Ldh-5 (90 ) allele can be used as a phylogeographic marker to trace the post-glacial spread of the populations possessing it. Examination of the current distribution of the two alleles suggests that, in the formerly glaciated area of north-west Europe, there have been two post-glacial colonizations by brown trout. The first was by an 'ancestral' race fixed for the Ldh-5(100 ) allele. This was later replaced by, or introgressed with, the later-arriving 'modern' race characterized by the Ldh-5 (90 ) allele, except where physical barriers prevented colonization by this latter form. Artificial stocking has resulted in 'genetic contamination' of many populations of the ancestral race and there is an urgent need to conserve the remaining pristine populations, especially in view of the likely genetic propensity for longevity and ultimate large size exhibited by this race.     

Adaptive Introgression Facilitates Adaptation to High Latitudes in European Aspen (Populus tremula L.)

Understanding local adaptation has become a key research area given the ongoing climate challenge and the concomitant requirement to conserve genetic resources. Perennial plants, such as forest trees, are good models to study local adaptation given their wide geographic distribution, largely outcrossing mating systems, and demographic histories. We evaluated signatures of local adaptation in European aspen (Populus tremula) across Europe by means of whole-genome resequencing of a collection of 411 individual trees. We dissected admixture patterns between aspen lineages and observed a strong genomic mosaicism in Scandinavian trees, evidencing different colonization trajectories into the peninsula from Russia, Central and Western Europe. As a consequence of the secondary contacts between populations after the last glacial maximum, we detected an adaptive introgression event in a genome region of ∼500 kb in chromosome 10, harboring a large-effect locus that has previously been shown to contribute to adaptation to the short growing seasons characteristic of Northern Scandinavia. Demographic simulations and ancestry inference suggest an Eastern origin—probably Russian—of the adaptive Nordic allele which nowadays is present in a homozygous state at the north of Scandinavia. The strength of introgression and positive selection signatures in this region is a unique feature in the genome. Furthermore, we detected signals of balancing selection, shared across regional populations, that highlight the importance of standing variation as a primary source of alleles that facilitate local adaptation. Our results, therefore, emphasize the importance of migration–selection balance underlying the genetic architecture of key adaptive quantitative traits.