Detection of Pathways Affected by Positive Selection in Primate Lineages Ancestral to Humans.

Gene set enrichment approaches have been increasingly successful in finding signals of recent polygenic selection in the human genome. In this study, we aim at detecting biological pathways affected by positive selection in more ancient human evolutionary history. Focusing on four branches of the primate tree that lead to modern humans, we tested all available protein coding gene trees of the Primates clade for signals of adaptation in these branches, using the likelihood-based branch site test of positive selection. The results of these locus-specific tests were then used as input for a gene set enrichment test, where whole pathways are globally scored for a signal of positive selection, instead of focusing only on outlier "significant" genes. We identified signals of positive selection in several pathways that are mainly involved in immune response, sensory perception, metabolism, and energy production. These pathway-level results are highly significant, even though there is no functional enrichment when only focusing on top scoring genes. Interestingly, several gene sets are found significant at multiple levels in the phylogeny, but different genes are responsible for the selection signal in the different branches. This suggests that the same function has been optimized in different ways at different times in primate evolution.

Long-distance dispersal suppresses introgression of local alleles during range expansions.

During range expansions, even low levels of interbreeding can lead to massive introgression of local alleles into an invader's genome. Nonetheless, this pattern is not always observed in human populations. For instance, European Americans in North America are barely introgressed by Amerindian genes in spite of known contact and admixture. With coalescent spatially explicit simulations, we examined the impact of long-distance dispersal (LDD) events on introgression of local alleles into the invading population using a set of different demographic scenarios applicable to a diverse range of natural populations and species. More specifically, we consider two distinct LDD models: one where LDD events originate in the range core and targets only the expansion front and a second one where LDD events can occur from any area to any other. We find that LDD generally prevents introgression, but that LDD events specifically targeting the expansion front are most efficient in suppressing introgression. This is likely due to the fact that LDD allows for the presence of a larger number of invader alleles at the wave front, where effective population size is thus increased and local introgressed alleles are rapidly outnumbered. We postulate that the documented settlement of pioneers directly on the wave front in North America has contributed to low levels of Amerindian admixture observed in European Americans and that this phenomenon may well explain the lack of introgression after a range expansion in natural populations without the need to evoke other mechanisms such as natural selection.

Genetic consequences of habitat fragmentation during a range expansion.

We investigate the effect of habitat fragmentation on the genetic diversity of a species experiencing a range expansion. These two evolutionary processes have not been studied yet, at the same time, owing to the difficulties of deriving analytic results for non-equilibrium models. Here we provide a description of their interaction by using extensive spatial and temporal coalescent simulations and we suggest guidelines for a proper genetic sampling to detect fragmentation. To model habitat fragmentation, we simulated a two-dimensional lattice of demes partitioned into groups (patches) by adding barriers to dispersal. After letting a population expand on this grid, we sampled lineages from the lattice at several scales and studied their coalescent history. We find that in order to detect fragmentation, one needs to extensively sample at a local level rather than at a landscape level. This is because the gene genealogy of a scattered sample is less sensitive to the presence of genetic barriers. Considering the effect of temporal changes of fragmentation intensities, we find that at least 10, but often >100, generations are needed to affect local genetic diversity and population structure. This result explains why recent habitat fragmentation does not always lead to detectable signatures in the genetic structure of populations. Finally, as expected, long-distance dispersal increases local genetic diversity and decreases levels of population differentiation, efficiently counteracting the effects of fragmentation.

On the accumulation of deleterious mutations during range expansions.

We investigate the effect of spatial range expansions on the evolution of fitness when beneficial and deleterious mutations cosegregate. We perform individual-based simulations of 1D and 2D range expansions and complement them with analytical approximations for the evolution of mean fitness at the edge of the expansion. We find that deleterious mutations accumulate steadily on the wave front during range expansions, thus creating an expansion load. Reduced fitness due to the expansion load is not restricted to the wave front, but occurs over a large proportion of newly colonized habitats. The expansion load can persist and represent a major fraction of the total mutation load for thousands of generations after the expansion. The phenomenon of expansion load may explain growing evidence that populations that have recently expanded, including humans, show an excess of deleterious mutations. To test the predictions of our model, we analyse functional genetic diversity in humans and find patterns that are consistent with our model.

Recent colonization of the Galápagos by the tree Geoffroea spinosa Jacq. (Leguminosae).

This study puts together genetic data and an approximate bayesian computation (ABC) approach to infer the time at which the tree Geoffroea spinosa colonized the Galápagos Islands. The genetic diversity and differentiation between Peru and Galápagos population samples, estimated using three chloroplast spacers and six microsatellite loci, reveal significant differences between two mainland regions separated by the Andes mountains (Inter Andean vs. Pacific Coast) as well as a significant genetic differentiation of island populations. Microsatellites identify two distinct geographical clusters, the Galápagos and the mainland, and chloroplast markers show a private haplotype in the Galápagos. The nuclear distinctiveness of the Inter Andean populations suggests current restricted pollen flow, but chloroplast points to cross-Andean dispersals via seeds, indicating that the Andes might not be an effective biogeographical barrier. The ABC analyses clearly point to the colonization of the Galápagos within the last 160,000 years and possibly as recently as 4750 years ago (475 generations). Founder events associated with colonization of the two islands where the species occurs are detected, with Española having been colonized after Floreana. We discuss two nonmutually exclusive possibilities for the colonization of the Galápagos, recent natural dispersal vs. human introduction.

PGDSpider: an automated data conversion tool for connecting population genetics and genomics programs.

UNLABELLED: The analysis of genetic data often requires a combination of several approaches using different and sometimes incompatible programs. In order to facilitate data exchange and file conversions between population genetics programs, we introduce PGDSpider, a Java program that can read 27 different file formats and export data into 29, partially overlapping, other file formats. The PGDSpider package includes both an intuitive graphical user interface and a command-line version allowing its integration in complex data analysis pipelines. AVAILABILITY: PGDSpider is freely available under the BSD 3-Clause license on http://cmpg.unibe.ch/software/PGDSpider/.

Patterns of morphological changes and hybridization between sympatric whitefish morphs (Coregonus spp.) in a Swiss lake: a role for eutrophication?

Whitefish, genus Coregonus, show exceptional levels of phenotypic diversity with sympatric morphs occurring in numerous postglacial lakes in the northern hemisphere. Here, we studied the effects of human-induced eutrophication on sympatric whitefish morphs in the Swiss lake, Lake Thun. In particular, we addressed the questions whether eutrophication (i) induced hybridization between two ecologically divergent summer-spawning morphs through a loss of environmental heterogeneity, and (ii) induced rapid adaptive morphological changes through changes in the food web structure. Genetic analysis based on 11 microsatellite loci of 282 spawners revealed that the pelagic and the benthic morph represent highly distinct gene pools occurring at different relative proportions on all seven known spawning sites. Gill raker counts, a highly heritable trait, showed nearly discrete distributions for the two morphs. Multilocus genotypes characteristic of the pelagic morph had more gill rakers than genotypes characteristic of benthic morph. Using Bayesian methods, we found indications of recent but limited introgressive hybridization. Comparisons with historical gill raker data yielded median evolutionary rates of 0.24 haldanes and median selection intensities of 0.27 for this trait in both morphs for 1948-2004 suggesting rapid evolution through directional selection at this trait. However, phenotypic plasticity as an alternative explanation for this phenotypic change cannot be discarded. We hypothesize that both the temporal shifts in mean gill raker counts and the recent hybridization reflect responses to changes in the trophic state of the lake induced by pollution in the 1960s, which created novel selection pressures with respect to feeding niches and spawning site preferences.

A statistical evaluation of models for the initial settlement of the american continent emphasizes the importance of gene flow with Asia.

Although there is agreement in that the Bering Strait was the entry point for the initial colonization of the American continent, there is considerable uncertainty regarding the timing and pattern of human migration from Asia to America. In order to perform a statistical assessment of the relative probability of alternative migration scenarios and to estimate key demographic parameters associated with them, we used an approximate Bayesian computation framework to analyze a data set of 401 autosomal microsatellite loci typed in 29 native American populations. A major finding is that a single, discrete, wave of colonization is highly inconsistent with observed levels of genetic diversity. A scenario with two discrete migration waves is also not supported by the data. The current genetic diversity of Amerindian populations is best explained by a third model involving recurrent gene flow between Asia and America, after initial colonization. We estimate that this colonization involved about 100 individuals and occurred some 13,000 years ago, in agreement with well-established archeological data.

Detecting loci under selection in a hierarchically structured population.

Patterns of genetic diversity between populations are often used to detect loci under selection in genome scans. Indeed, loci involved in local adaptations should show high F(ST) values, whereas loci under balancing selection should rather show low F(ST) values. Most tests of selection based on F(ST) use a null distribution generated under a simple island model of population differentiation. Although this model has been shown to be robust, many species have a more complex genetic structure, with some populations sharing a recent ancestry or due to the presence of barriers to gene flow between different parts of a species range. In this paper, we propose the use of a hierarchical island model, in which demes exchange more migrants within groups than between groups, to generate the joint distribution of genetic diversity within and between populations. We show that tests not accounting for a hierarchical structure, when it exists, do generate a large excess of false positive loci, whereas the hierarchical island model is robust to uncertainties about the exact number of groups and demes per group in the system. Our approach also explicitly takes into account the mutational process, and does not just rely on allele frequencies, which is important for short tandem repeat (STR) data. An application to human and stickleback STR data sets reveals a much lower number of significant loci than previously obtained under a non-hierarchical model. The elimination of false positive loci from genome scans should allow us to better determine on which specific class of genes selection is operating.

Large allele frequency differences between human continental groups are more likely to have occurred by drift during range expansions than by selection.

Several studies have found strikingly different allele frequencies between continents. This has been mainly interpreted as being due to local adaptation. However, demographic factors can generate similar patterns. Namely, allelic surfing during a population range expansion may increase the frequency of alleles in newly colonised areas. In this study, we examined 772 STRs, 210 diallelic indels, and 2834 SNPs typed in 53 human populations worldwide under the HGDP-CEPH Diversity Panel to determine to which extent allele frequency differs among four regions (Africa, Eurasia, East Asia, and America). We find that large allele frequency differences between continents are surprisingly common, and that Africa and America show the largest number of loci with extreme frequency differences. Moreover, more STR alleles have increased rather than decreased in frequency outside Africa, as expected under allelic surfing. Finally, there is no relationship between the extent of allele frequency differences and proximity to genes, as would be expected under selection. We therefore conclude that most of the observed large allele frequency differences between continents result from demography rather than from positive selection.

Genetic analysis of potential postglacial watershed crossings in Central Europe by the bullhead (Cottus gobio L.).

Natural colonizations across watersheds have been frequently proposed to explain the present distributions of many freshwater fish species. However, detailed studies of such potential watershed crossings are still missing. Here, we investigated potential postglacial watershed crossings of the widely distributed European bullhead (Cottus gobio L.) in two different areas along the Rhine-Rhône watershed using detailed genetic analysis. The main advantage of studying bullheads vs. other freshwater fish species is that their distribution has been lightly influenced by human activities and as such, interpretations of colonization history are not confounded by artificial transplantations. The genetic analyses of eight microsatellite loci revealed strong genetic similarities between populations of both sides of the Rhine-Rhône watershed in the Lake Geneva area, giving strong evidence for a natural watershed crossing of bullheads from the upper Rhine drainage into the Rhône drainage in the Lake Geneva area likely facilitated by the retreat of the glaciers after the last glacial maximum some 20,000 years ago. Populations from the Lake Geneva basin were genetically more similar to populations from across the watershed in the upper Rhine drainage than to populations further downstream in the lower Rhône. In contrast, populations from Belfort, an area, which was not covered by ice during the last glacial maximum, showed strong genetic differentiation between populations of the upper Rhine and Rhône drainages. Based on our results on the bullhead, we propose that glacial retreat may have eased the dispersal of numerous European freshwater fish species across several geological boundaries.

Bipolar gene flow in deep-sea benthic foraminifera.

Despite its often featureless appearance, the deep-ocean floor includes some of the most diverse habitats on Earth. However, the accurate assessment of global deep-sea diversity is impeded by a paucity of data on the geographical ranges of bottom-dwelling species, particularly at the genetic level. Here, we present molecular evidence for exceptionally wide distribution of benthic foraminifera, which constitute the major part of deep-sea meiofauna. Our analyses of nuclear ribosomal RNA genes revealed high genetic similarity between Arctic and Antarctic populations of three common deep-sea foraminiferal species (Epistominella exigua, Cibicides wuellerstorfi and Oridorsalis umbonatus), separated by distances of up to 17, 000 km. Our results contrast with the substantial level of cryptic diversity usually revealed by molecular studies, of shallow-water benthic and planktonic marine organisms. The very broad ranges of the deep-sea foraminifera that we examined support the hypothesis of global distribution of small eukaryotes and suggest that deep-sea biodiversity may be more modest at global scales than present estimates suggest.

Estimation of effective population size and detection of a recent population decline coinciding with habitat fragmentation in a ground beetle.

We assess the impact of habitat fragmentation on the effective size (N(e)) of local populations of the flightless ground beetle Carabus violaceus in a small (<25 ha) and a large (>80 ha) forest fragment separated by a highway. N(e) was estimated based on the temporal variation of allele frequencies at 13 microsatellite loci using two different methods. In the smaller fragment, N(e) estimates ranged between 59 and a few hundred, whereas values between 190 and positive infinity were estimated for the larger fragment. In both samples, we detected a signal of population decline, which was stronger in the small fragment. The estimated time of onset of this N(e) reduction was consistent with the hypothesis that recent road constructions have divided a continuous population into several isolated subpopulations. In the small fragment, N(e) of the local population may be so small that its long-term persistence is endangered.

A simulated annealing approach to define the genetic structure of populations.

We present a new approach for defining groups of populations that are geographically homogeneous and maximally differentiated from each other. As a by-product, it also leads to the identification of genetic barriers between these groups. The method is based on a simulated annealing procedure that aims to maximize the proportion of total genetic variance due to differences between groups of populations (spatial analysis of molecular variance; samova). Monte Carlo simulations were used to study the performance of our approach and, for comparison, the behaviour of the Monmonier algorithm, a procedure commonly used to identify zones of sharp genetic changes in a geographical area. Simulations showed that the samova algorithm indeed finds maximally differentiated groups, which do not always correspond to the simulated group structure in the presence of isolation by distance, especially when data from a single locus are available. In this case, the Monmonier algorithm seems slightly better at finding predefined genetic barriers, but can often lead to the definition of groups of populations not differentiated genetically. The samova algorithm was then applied to a set of European roe deer populations examined for their mitochondrial DNA (mtDNA) HVRI diversity. The inferred genetic structure seemed to confirm the hypothesis that some Italian populations were recently reintroduced from a Balkanic stock, as well as the differentiation of groups of populations possibly due to the postglacial recolonization of Europe or the action of a specific barrier to gene flow.

Multiple maternal origins and weak phylogeographic structure in domestic goats.

Domestic animals have played a key role in human history. Despite their importance, however, the origins of most domestic species remain poorly understood. We assessed the phylogenetic history and population structure of domestic goats by sequencing a hypervariable segment (481 bp) of the mtDNA control region from 406 goats representing 88 breeds distributed across the Old World. Phylogeographic analysis revealed three highly divergent goat lineages (estimated divergence >200,000 years ago), with one lineage occurring only in eastern and southern Asia. A remarkably similar pattern exists in cattle, sheep, and pigs. These results, combined with recent archaeological findings, suggest that goats and other farm animals have multiple maternal origins with a possible center of origin in Asia, as well as in the Fertile Crescent. The pattern of goat mtDNA diversity suggests that all three lineages have undergone population expansions, but that the expansion was relatively recent for two of the lineages (including the Asian lineage). Goat populations are surprisingly less genetically structured than cattle populations. In goats only approximately 10% of the mtDNA variation is partitioned among continents. In cattle the amount is >/=50%. This weak structuring suggests extensive intercontinental transportation of goats and has intriguing implications about the importance of goats in historical human migrations and commerce.

An extensive analysis of Y-chromosomal microsatellite haplotypes in globally dispersed human populations.

The genetic variance at seven Y-chromosomal microsatellite loci (or short tandem repeats [STRs]) was studied among 986 male individuals from 20 globally dispersed human populations. A total of 598 different haplotypes were observed, of which 437 (73.1%) were each found in a single male only. Population-specific haplotype-diversity values were.86-.99. Analyses of haplotype diversity and population-specific haplotypes revealed marked population-structure differences between more-isolated indigenous populations (e.g., Central African Pygmies or Greenland Inuit) and more-admixed populations (e.g., Europeans or Surinamese). Furthermore, male individuals from isolated indigenous populations shared haplotypes mainly with male individuals from their own population. By analysis of molecular variance, we found that 76.8% of the total genetic variance present among these male individuals could be attributed to genetic differences between male individuals who were members of the same population. Haplotype sharing between populations, phi(ST) statistics, and phylogenetic analysis identified close genetic affinities among European populations and among New Guinean populations. Our data illustrate that Y-chromosomal STR haplotypes are an ideal tool for the study of the genetic affinities between groups of male subjects and for detection of population structure.

Is the Gibraltar strait a barrier to gene flow for the bat Myotis myotis (Chiroptera: Vespertilionidae)?

Because of their role in limiting gene flow, geographical barriers like mountains or seas often coincide with intraspecific genetic discontinuities. Although the Strait of Gibraltar represents such a potential barrier for both plants and animals, few studies have been conducted on its impact on gene flow. Here we test this effect on a bat species (Myotis myotis) which is apparently distributed on both sides of the strait. Six colonies of 20 Myotis myotis each were sampled in southern Spain and northern Morocco along a linear transect of 1350 km. Results based on six nuclear microsatellite loci reveal no significant population structure within regions, but a complete isolation between bats sampled on each side of the strait. Variability at 600 bp of a mitochondrial gene (cytochrome b) confirms the existence of two genetically distinct and perfectly segregating clades, which diverged several million years ago. Despite the narrowness of the Gibraltar Strait (14 km), these molecular data suggest that neither males, nor females from either region have ever reproduced on the opposite side of the strait. Comparisons of molecular divergence with bats from a closely related species (M. blythii) suggest that the North African clade is possibly a distinct taxon warranting full species rank. We provisionally refer to it as Myotis cf punicus Felten 1977, but a definitive systematic understanding of the whole Mouse-eared bat species complex awaits further genetic sampling, especially in the Eastern Mediterranean areas.

Inferring the impact of linguistic boundaries on population differentiation: application to the Afro-Asiatic-Indo-European case.

We present here a quantitative way to assess the impact of language-family boundaries on population differentiation and to evaluate the homogeneity of the genetic processes along these boundaries. Our estimator (delta a) of the impact of the boundary is based on an isolation by distance (IBD) model and measures the added genetic distance between populations located on different sides of the boundary. We compare this statistic with another estimator of group differentiation (F(CT)) computed under an analysis of variance framework that does not assume any particular spatial structure of the populations. Monte Carlo simulations are used to study the behaviour of these statistics under a two-dimensional stepping-stone model. Simulations show that F(CT) can suggest the existence of a frontier when populations only differ because of IBD. This spurious behaviour is much less frequent for the delta a statistic. However, the large variance associated with the delta a statistic, and the fact that it should only be computed in the presence of IBD, may limit the use of this statistic. Overall, the origin and the effect of the boundary is best understood by comparing different statistics and by testing for the presence of IBD on each side of the boundary as well as across the boundary. We illustrate our approach by examining the boundary between Afro-Asiatic and Indo-European populations. These populations are globally genetically differentiated, but the effect of the linguistic boundary on gene flow seems geographically very heterogeneous. This boundary appears to be the result of a secondary contact between two differentiation centres rather than an enhancer of population differentiation.

Maternal and paternal lineages in Albania and the genetic structure of Indo-European populations.

Mitochondrial DNA HV1 sequences and Y chromosome haplotypes (DYS19 STR and YAP) were characterised in an Albanian sample and compared with those of several other Indo-European populations from the European continent. No significant difference was observed between Albanians and most other Europeans, despite the fact that Albanians are clearly different from all other Indo-Europeans linguistically. We observe a general lack of genetic structure among Indo-European populations for both maternal and paternal polymorphisms, as well as low levels of correlation between linguistics and genetics, even though slightly more significant for the Y chromosome than for mtDNA. Altogether, our results show that the linguistic structure of continental Indo-European populations is not reflected in the variability of the mitochondrial and Y chromosome markers. This discrepancy could be due to very recent differentiation of Indo-European populations in Europe and/or substantial amounts of gene flow among these populations.

A linkage disequilibrium map of the MHC region based on the analysis of 14 loci haplotypes in 50 French families.

A sample of 100 individuals from 50 French families of known pedigrees were typed for 14 loci of the HLA region (DPB1, DQB1, DQA1, DRB1, DRB3, 4, 5, C4B, C4A, Bf, C2, TNFa, TNFb, B, Cw, A). Linkage disequilibrium in each pair of loci was investigated by an exact test using a Markov chain algorithm. The results indicate no disequilibrium between DPB1 and the other loci, whereas the other class II genes are all significantly linked to each other. Linkage disequilibrium is also detected between some pairs of class I and class II-class I loci despite the long physical distance separating the loci (e.g. A-B, Cw-DRB1). On the other hand, some contiguous loci of the class III region are found to be in equilibrium with each other. Several hypotheses including selection, but also unequal allelic diversity at different MHC loci are discussed to explain this complex pattern of linkage disequilibrium.