Anthropology, Population Genetics & Evolutionary Simulations

Mathias Currat

Senior Lecturer

  • T: +41 22 379 69 79
  • office 4-418 (Sciences II)

Our main research themes deal with the evolution of genetic diversity in human populations. We specialize in the development of computational methods to study the combined effects of various evolutionary forces on molecular diversity, such as the occurrence of new mutations, natural selection, demographic variation and migration.

Our main research topics are:

  • making inferences on human history and evolution through the analysis of their genetic diversity, with a special focus on European populations;
  • developing spatially-explicit computer simulations to analyze ancient genetic and genomic data retrieved from fossils;
  • modeling hybridization processes in a population dynamics context;
  • disentangling the effects of demography and natural selection on the shaping of molecular diversity.

List of current and past research project

  • Ancestry and demography and descendants of Iron Age nomads of the Eurasian Steppe. Nat Commun 2017 Mar;8():14615. ncomms14615. 10.1038/ncomms14615.

    abstract

    During the 1(st) millennium before the Common Era (BCE), nomadic tribes associated with the Iron Age Scythian culture spread over the Eurasian Steppe, covering a territory of more than 3,500 km in breadth. To understand the demographic processes behind the spread of the Scythian culture, we analysed genomic data from eight individuals and a mitochondrial dataset of 96 individuals originating in eastern and western parts of the Eurasian Steppe. Genomic inference reveals that Scythians in the east and the west of the steppe zone can best be described as a mixture of Yamnaya-related ancestry and an East Asian component. Demographic modelling suggests independent origins for eastern and western groups with ongoing gene-flow between them, plausibly explaining the striking uniformity of their material culture. We also find evidence that significant gene-flow from east to west Eurasia must have occurred early during the Iron Age.

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  • Early Neolithic genomes from the eastern Fertile Crescent. Science 2016 Jul;353(6298):499-503. science.aaf7943. 10.1126/science.aaf7943.

    abstract

    We sequenced Early Neolithic genomes from the Zagros region of Iran (eastern Fertile Crescent), where some of the earliest evidence for farming is found, and identify a previously uncharacterized population that is neither ancestral to the first European farmers nor has contributed substantially to the ancestry of modern Europeans. These people are estimated to have separated from Early Neolithic farmers in Anatolia some 46,000 to 77,000 years ago and show affinities to modern-day Pakistani and Afghan populations, but particularly to Iranian Zoroastrians. We conclude that multiple, genetically differentiated hunter-gatherer populations adopted farming in southwestern Asia, that components of pre-Neolithic population structure were preserved as farming spread into neighboring regions, and that the Zagros region was the cradle of eastward expansion.

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  • Early farmers from across Europe directly descended from Neolithic Aegeans. Proc. Natl. Acad. Sci. U.S.A. 2016 Jun;113(25):6886-91. 1523951113. 10.1073/pnas.1523951113. PMC4922144.

    abstract

    Farming and sedentism first appeared in southwestern Asia during the early Holocene and later spread to neighboring regions, including Europe, along multiple dispersal routes. Conspicuous uncertainties remain about the relative roles of migration, cultural diffusion, and admixture with local foragers in the early Neolithization of Europe. Here we present paleogenomic data for five Neolithic individuals from northern Greece and northwestern Turkey spanning the time and region of the earliest spread of farming into Europe. We use a novel approach to recalibrate raw reads and call genotypes from ancient DNA and observe striking genetic similarity both among Aegean early farmers and with those from across Europe. Our study demonstrates a direct genetic link between Mediterranean and Central European early farmers and those of Greece and Anatolia, extending the European Neolithic migratory chain all the way back to southwestern Asia.

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  • Long-Distance Dispersal Shaped Patterns of Human Genetic Diversity in Eurasia. Mol. Biol. Evol. 2016 Apr;33(4):946-58. msv332. 10.1093/molbev/msv332. PMC4776706.

    abstract

    Most previous attempts at reconstructing the past history of human populations did not explicitly take geography into account or considered very simple scenarios of migration and ignored environmental information. However, it is likely that the last glacial maximum (LGM) affected the demography and the range of many species, including our own. Moreover, long-distance dispersal (LDD) may have been an important component of human migrations, allowing fast colonization of new territories and preserving high levels of genetic diversity. Here, we use a high-quality microsatellite data set genotyped in 22 populations to estimate the posterior probabilities of several scenarios for the settlement of the Old World by modern humans. We considered models ranging from a simple spatial expansion to others including LDD and a LGM-induced range contraction, as well as Neolithic demographic expansions. We find that scenarios with LDD are much better supported by data than models without LDD. Nevertheless, we show evidence that LDD events to empty habitats were strongly prevented during the settlement of Eurasia. This unexpected absence of LDD ahead of the colonization wave front could have been caused by an Allee effect, either due to intrinsic causes such as an inbreeding depression built during the expansion or due to extrinsic causes such as direct competition with archaic humans. Overall, our results suggest only a relatively limited effect of the LGM contraction on current patterns of human diversity. This is in clear contrast with the major role of LDD migrations, which have potentially contributed to the intermingled genetic structure of Eurasian populations.

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  • Upper Palaeolithic genomes reveal deep roots of modern Eurasians. Nat Commun 2015 ;6():8912. ncomms9912. 10.1038/ncomms9912. PMC4660371.

    abstract

    We extend the scope of European palaeogenomics by sequencing the genomes of Late Upper Palaeolithic (13,300 years old, 1.4-fold coverage) and Mesolithic (9,700 years old, 15.4-fold) males from western Georgia in the Caucasus and a Late Upper Palaeolithic (13,700 years old, 9.5-fold) male from Switzerland. While we detect Late Palaeolithic-Mesolithic genomic continuity in both regions, we find that Caucasus hunter-gatherers (CHG) belong to a distinct ancient clade that split from western hunter-gatherers ∼45 kya, shortly after the expansion of anatomically modern humans into Europe and from the ancestors of Neolithic farmers ∼25 kya, around the Last Glacial Maximum. CHG genomes significantly contributed to the Yamnaya steppe herders who migrated into Europe ∼3,000 BC, supporting a formative Caucasus influence on this important Early Bronze age culture. CHG left their imprint on modern populations from the Caucasus and also central and south Asia possibly marking the arrival of Indo-Aryan languages.

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  • Computer simulation of human leukocyte antigen genes supports two main routes of colonization by human populations in East Asia. BMC Evol. Biol. 2015 ;15():240. 10.1186/s12862-015-0512-0. 10.1186/s12862-015-0512-0. PMC4632674.

    abstract

    Recent genetic studies have suggested that the colonization of East Asia by modern humans was more complex than a single origin from the South, and that a genetic contribution via a Northern route was probably quite substantial.

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  • Modelling interspecific hybridization with genome exclusion to identify conservation actions: the case of native and invasive Pelophylax waterfrogs. Evol Appl 2015 Feb;8(2):199-210. 10.1111/eva.12245. PMC4319866.

    abstract

    Interspecific hybridization occurs in nature but can also be caused by human actions. It often leads to infertile or fertile hybrids that exclude one parental genome during gametogenesis, escaping genetic recombination and introgression. The threat that genome-exclusion hybridization might represent on parental species is poorly understood, especially when invasive species are involved. Here, we show how to assess the effects of genome-exclusion hybridization and how to elaborate conservation actions by simulating scenarios using a model of nonintrogressive hybridization. We examine the case of the frog Pelophylax ridibundus, introduced in Western Europe, which can hybridize with the native Pelophylax lessonae and the pre-existing hybrid Pelophylax esculentus, maintained by hybridogenesis. If translocated from Southern Europe, P. ridibundus produces new sterile hybrids and we show that it mainly threatens P. esculentus. Translocation from Central Europe leads to new fertile hybrids, threatening all native waterfrogs. Local extinction is demographically mediated via wasted reproductive potential or via demographic flow through generations towards P. ridibundus. We reveal that enlarging the habitat size of the native P. lessonae relative to that of the invader is a promising conservation strategy, avoiding the difficulties of fighting the invader. We finally stress that nonintrogressive hybridization is to be considered in conservation programmes.

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  • Correction to: "Forward-in-Time, Spatially Explicit Modeling Software to Simulate Genetic Lineages Under Selection". Evol. Bioinform. Online 2015 ;11(Suppl 2):69. 10.4137/EBO.S39777. ebo-suppl.2-2015-069. PMC4939849.

    abstract

    [This corrects the article DOI: 10.4137/EBO.S33488.].

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  • Forward-in-Time, Spatially Explicit Modeling Software to Simulate Genetic Lineages Under Selection. Evol. Bioinform. Online 2015 ;11(Suppl 2):27-39. 10.4137/EBO.S33488. ebo-suppl.2-2015-027. PMC4768942.

    abstract

    SELECTOR is a software package for studying the evolution of multiallelic genes under balancing or positive selection while simulating complex evolutionary scenarios that integrate demographic growth and migration in a spatially explicit population framework. Parameters can be varied both in space and time to account for geographical, environmental, and cultural heterogeneity. SELECTOR can be used within an approximate Bayesian computation estimation framework. We first describe the principles of SELECTOR and validate the algorithms by comparing its outputs for simple models with theoretical expectations. Then, we show how it can be used to investigate genetic differentiation of loci under balancing selection in interconnected demes with spatially heterogeneous gene flow. We identify situations in which balancing selection reduces genetic differentiation between population groups compared with neutrality and explain conflicting outcomes observed for human leukocyte antigen loci. These results and three previously published applications demonstrate that SELECTOR is efficient and robust for building insight into human settlement history and evolution.

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  • Models of hybridization during range expansions and their application to recent human evolution In book: Cultural Developments in the Eurasian Paleolithic and the Origin of Anatomically Modern Humans, Publisher: Derevianko, AP; Shunkov, M, pp.122-137

    abstract

    see on external website

  • A general model of distant hybridization reveals the conditions for extinction in Atlantic salmon and brown trout. PLoS ONE 2014 ;9(7):e101736. 10.1371/journal.pone.0101736. PONE-D-14-07667. PMC4086968.

    abstract

    Interspecific hybridization is common in nature but can be increased in frequency or even originated by human actions, such as species introduction or habitat modification, which may threaten species persistence. When hybridization occurs between distantly related species, referred to as "distant hybridization," the resulting hybrids are generally infertile or fertile but do not undergo chromosomal recombination during gametogenesis. Here, we present a model describing this frequent but poorly studied interspecific hybridization to assess its consequences on parental species and to anticipate the conditions under which they can reach extinction. Our general model fully incorporates three important processes: density-dependent competition, dominance/recessivity inheritance of traits and assortative mating. We demonstrate its use and flexibility by assessing population extinction risk between Atlantic salmon and brown trout in Norway, whose interbreeding has recently increased due to farmed fish releases into the wild. We identified the set of conditions under which hybridization may threaten salmonid species. Thanks to the flexibility of our model, we evaluated the effect of an additional risk factor, a parasitic disease, and showed that the cumulative effects dramatically increase the extinction risk. The consequences of distant hybridization are not genetically, but demographically mediated. Our general model is useful to better comprehend the evolution of such hybrid systems and we demonstrated its importance in the field of conservation biology to set up management recommendations when this increasingly frequent type of hybridization is in action.

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  • Recipient of the 2013 Molecular Ecology Prize: Laurent Excoffier. Mol. Ecol. 2014 Jan;23(1):16-9. 10.1111/mec.12604.

    abstract

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  • Investigating European genetic history through computer simulations. Hum. Hered. 2013 ;76(3-4):142-53. 000360162. 10.1159/000360162.

    abstract

    The genetic diversity of Europeans has been shaped by various evolutionary forces including their demographic history. Genetic data can thus be used to draw inferences on the population history of Europe using appropriate statistical methods such as computer simulation, which constitutes a powerful tool to study complex models.

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  • Human neutral genetic variation and forensic STR data. PLoS ONE 2012 ;7(11):e49666. 10.1371/journal.pone.0049666. PONE-D-12-16962. PMC3504113.

    abstract

    The forensic genetics field is generating extensive population data on polymorphism of short tandem repeats (STR) markers in globally distributed samples. In this study we explored and quantified the informative power of these datasets to address issues related to human evolution and diversity, by using two online resources: an allele frequency dataset representing 141 populations summing up to almost 26 thousand individuals; a genotype dataset consisting of 42 populations and more than 11 thousand individuals. We show that the genetic relationships between populations based on forensic STRs are best explained by geography, as observed when analysing other worldwide datasets generated specifically to study human diversity. However, the global level of genetic differentiation between populations (as measured by a fixation index) is about half the value estimated with those other datasets, which contain a much higher number of markers but much less individuals. We suggest that the main factor explaining this difference is an ascertainment bias in forensics data resulting from the choice of markers for individual identification. We show that this choice results in average low variance of heterozygosity across world regions, and hence in low differentiation among populations. Thus, the forensic genetic markers currently produced for the purpose of individual assignment and identification allow the detection of the patterns of neutral genetic structure that characterize the human population but they do underestimate the levels of this genetic structure compared to the datasets of STRs (or other kinds of markers) generated specifically to study the diversity of human populations.

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  • Influence of admixture and paleolithic range contractions on current European diversity gradients. Mol. Biol. Evol. 2013 Jan;30(1):57-61. mss203. 10.1093/molbev/mss203.

    abstract

    Cavalli-Sforza and Edwards (Analysis of human evolution. 1963. In: Geerts SJ, editor. Genetics today: Proceedings of the 11th International Congress of Genetics, The Hague, The Netherlands. New York: Pergamon. p. 923-993.) initiated the representation of genetic relationships among human populations with principal component (PC) analysis (PCA). Their study revealed the presence of a southeast-northwest (SE-NW) gradient of genetic variation in current European populations, which was interpreted as the result of the demic diffusion of early neolithic farmers during their expansion from the near east. However, this interpretation has been questioned, as PCA gradients can occur even when there is no expansion and because the first PC axis is often orthogonal to the expansion axis. Here, we revisit PCA patterns obtained under realistic scenarios of the settlement of Europe, focusing on the effects of various levels of admixture between paleolithic and neolithic populations, and of range contractions during the last glacial maximum (LGM). Using extensive simulations, we find that the first PC (PC1) gradients are orthogonal to the expansion axis, but only when the expansion is recent (neolithic). More ancient (paleolithic) expansions alter the orientation of the PC1 gradient due to a spatial homogenization of genetic diversity over time, and to the exact location of LGM refugia from which re-expansions proceeded. Overall we find that PC1 gradients consistently follow an SE-NW orientation if there is a large paleolithic contribution to the current European gene pool, and if the main refuge area during the last ice age was in the Iberian Peninsula. Our study suggests that an SE-NW PC1 gradient is compatible with little genetic impact of neolithic populations on the current European gene pool, and that range contractions have affected observed genetic patterns.

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  • The genetic history of Europeans. Trends Genet. 2012 Oct;28(10):496-505. S0168-9525(12)00095-9. 10.1016/j.tig.2012.06.006.

    abstract

    The evolutionary history of modern humans is characterized by numerous migrations driven by environmental change, population pressures, and cultural innovations. In Europe, the events most widely considered to have had a major impact on patterns of genetic diversity are the initial colonization of the continent by anatomically modern humans (AMH), the last glacial maximum, and the Neolithic transition. For some decades it was assumed that the geographical structuring of genetic diversity within Europe was mainly the result of gene flow during and soon after the Neolithic transition, but recent advances in next-generation sequencing (NGS) technologies, computer simulation modeling, and ancient DNA (aDNA) analyses are challenging this simplistic view. Here we review the current knowledge on the evolutionary history of humans in Europe based on archaeological and genetic data.

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  • Consequences of population expansions on European genetic diversity Kaiser, E. & Burger, J. & Schier, W. Population Dynamics in Prehistory and Early History: New Approaches Using Stable Isotopes and Genetics. Berlin : Walter de Gruyter & Co, 2012, p. 3-16

    abstract

    Population movements over space and time played a crucial role in generating the genetic patterns that are observed in the present day. Numerous factors, such as climate changes or cultural innovations, have the potential to induce large-scale movements, such as population expansions (i.e. increases both in density and range) or contractions to refugee areas. It is thus very important to take the spatial dynamic of populations into account when trying to reconstruct their history from genetic data. Computer simulation constitutes a very powerful tool for the study of the combined impacts of biological and demographic factors on the genetic structure of populations. The rapid increase of computer power opens many new possibilities for research in that specific area. A series of recent studies have focused on the consequences of population expansions on their genetic diversity. These studies extensively described one potentially important genetic process which may occur during a range expansion: the "mutation surfing" phenomenon. In this paper, we describe in detail this process and its potential implications for the establishment of the current genetic diversity in Europe. We also discuss the limitations and perspectives of such computer simulation studies in the field, and possible future improvements to them.

    see on external website

  • Distinct evolutionary strategies of human leucocyte antigen loci in pathogen-rich environments. Philos. Trans. R. Soc. Lond., B, Biol. Sci. 2012 Mar;367(1590):830-9. rstb.2011.0312. 10.1098/rstb.2011.0312. PMC3267122.

    abstract

    Human leucocyte antigen (HLA) loci have a complex evolution where both stochastic (e.g. genetic drift) and deterministic (natural selection) forces are involved. Owing to their extraordinary level of polymorphism, HLA genes are useful markers for reconstructing human settlement history. However, HLA variation often deviates significantly from neutral expectations towards an excess of genetic diversity. Because HLA molecules play a crucial role in immunity, this observation is generally explained by pathogen-driven-balancing selection (PDBS). In this study, we investigate the PDBS model by analysing HLA allelic diversity on a large database of 535 populations in relation to pathogen richness. Our results confirm that geographical distances are excellent predictors of HLA genetic differentiation worldwide. We also find a significant positive correlation between genetic diversity and pathogen richness at two HLA class I loci (HLA-A and -B), as predicted by PDBS, and a significant negative correlation at one HLA class II locus (HLA-DQB1). Although these effects are weak, as shown by a loss of significance when populations submitted to rapid genetic drift are removed from the analysis, the inverse relationship between genetic diversity and pathogen richness at different loci indicates that HLA genes have adopted distinct evolutionary strategies to provide immune protection in pathogen-rich environments.

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  • Strong reproductive isolation between humans and Neanderthals inferred from observed patterns of introgression. Proc. Natl. Acad. Sci. U.S.A. 2011 Sep;108(37):15129-34. 1107450108. 10.1073/pnas.1107450108. PMC3174651.

    abstract

    Recent studies have revealed that 2-3% of the genome of non-Africans might come from Neanderthals, suggesting a more complex scenario of modern human evolution than previously anticipated. In this paper, we use a model of admixture during a spatial expansion to study the hybridization of Neanderthals with modern humans during their spread out of Africa. We find that observed low levels of Neanderthal ancestry in Eurasians are compatible with a very low rate of interbreeding (<2%), potentially attributable to a very strong avoidance of interspecific matings, a low fitness of hybrids, or both. These results suggesting the presence of very effective barriers to gene flow between the two species are robust to uncertainties about the exact demography of the Paleolithic populations, and they are also found to be compatible with the observed lack of mtDNA introgression. Our model additionally suggests that similarly low levels of introgression in Europe and Asia may result from distinct admixture events having occurred beyond the Middle East, after the split of Europeans and Asians. This hypothesis could be tested because it predicts that different components of Neanderthal ancestry should be present in Europeans and in Asians.

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  • Consequences of range contractions and range shifts on molecular diversity. Mol. Biol. Evol. 2012 Jan;29(1):207-18. msr187. 10.1093/molbev/msr187.

    abstract

    Due to past and current climatic changes, range contractions and range shifts are essential stages in the history of a species. However, unlike range expansions, the molecular consequences of these processes have been little investigated. In order to fill this gap, we simulated patterns of molecular diversity within and between populations for various types of range contractions and range shifts. We show that range contractions tend to decrease genetic diversity as compared with population with stable ranges but quite counterintuitively fast range contractions preserve higher levels of diversity and induce lower levels of genetic differentiation among refuge areas than slow contractions. Contrastingly, fast range shifts lead to lower levels of diversity than slow range shifts. At odds with our expectations, we find that species actively migrating toward refuge areas can only preserve higher levels of diversity in refugia if the contraction is rapid. Under slow range contraction or slow range shift, active migration toward refugia lead to a larger loss of diversity as compared with scenarios with isotropic migration and may thus not be a good evolutionary strategy. These results suggest that the levels of diversity preserved after a climate change both within and between refuge areas will not only depend on the dispersal abilities of a species but also on the speed of the change. It also implies that a given episode of climatic change will impact differently species with different generation times.

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  • Combining genetic, historical and geographical data to reconstruct the dynamics of bioinvasions: application to the cane toad Bufo marinus. Mol Ecol Resour 2010 Sep;10(5):886-901. 10.1111/j.1755-0998.2010.02882.x.

    abstract

    We developed a spatially explicit model of a bioinvasion and used an approximate Bayesian computation (ABC) framework to make various inferences from a combination of genetic (microsatellite genotypes), historical (first observation dates) and geographical (spatial coordinates of introduction and sampled sites) information. Our method aims to discriminate between alternative introduction scenarios and to estimate posterior densities of demographically relevant parameters of the invasive process. The performance of our landscape-ABC method is assessed using simulated data sets differing in their information content (genetic and/or historical data). We apply our methodology to the recent introduction and spatial expansion of the cane toad, Bufo marinus, in northern Australia. We find that, at least in the context of cane toad invasion, historical data are more informative than genetic data for discriminating between introduction scenarios. However, the combination of historical and genetic data provides the most accurate estimates of demographic parameters. For the cane toad, we find some evidence for a strong bottleneck prior to introduction, a small initial number of founder individuals (about 15), a large population growth rate (about 400% per generation), a standard deviation of dispersal distance of 19 km per generation and a high invasion speed at equilibrium (50 km per year). Our approach strengthens the application of the ABC method to the field of bioinvasion by allowing statistical inferences to be made on the introduction and the spatial expansion dynamics of invasive species using a combination of various relevant sources of information.

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  • Evolution of lactase persistence: an example of human niche construction. Philos. Trans. R. Soc. Lond., B, Biol. Sci. 2011 Mar;366(1566):863-77. 366/1566/863. 10.1098/rstb.2010.0268. PMC3048992.

    abstract

    Niche construction is the process by which organisms construct important components of their local environment in ways that introduce novel selection pressures. Lactase persistence is one of the clearest examples of niche construction in humans. Lactase is the enzyme responsible for the digestion of the milk sugar lactose and its production decreases after the weaning phase in most mammals, including most humans. Some humans, however, continue to produce lactase throughout adulthood, a trait known as lactase persistence. In European populations, a single mutation (-13910*T) explains the distribution of the phenotype, whereas several mutations are associated with it in Africa and the Middle East. Current estimates for the age of lactase persistence-associated alleles bracket those for the origins of animal domestication and the culturally transmitted practice of dairying. We report new data on the distribution of -13910*T and summarize genetic studies on the diversity of lactase persistence worldwide. We review relevant archaeological data and describe three simulation studies that have shed light on the evolution of this trait in Europe. These studies illustrate how genetic and archaeological information can be integrated to bring new insights to the origins and spread of lactase persistence. Finally, we discuss possible improvements to these models.

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  • SPLATCHE2: a spatially explicit simulation framework for complex demography, genetic admixture and recombination. Bioinformatics 2010 Dec;26(23):2993-4. btq579. 10.1093/bioinformatics/btq579.

    abstract

    SPLATCHE2 is a program to simulate the demography of populations and the resulting molecular diversity for a wide range of evolutionary scenarios. The spatially explicit simulation framework can account for environmental heterogeneity and fluctuations, and it can manage multiple population sources. A coalescent-based approach is used to generate genetic markers mostly used in population genetics studies (DNA sequences, SNPs, STRs or RFLPs). Various combinations of independent, fully or partially linked genetic markers can be produced under a recombination model based on the ancestral recombination graph. Competition between two populations (or species) can also be simulated with user-defined levels of admixture between the two populations. SPLATCHE2 may be used to generate the expected genetic diversity under complex demographic scenarios and can thus serve to test null hypotheses. For model parameter estimation, SPLATCHE2 can easily be integrated into an Approximate Bayesian Computation (ABC) framework.

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  • Human genetic differentiation across the Strait of Gibraltar. BMC Evol. Biol. 2010 ;10():237. 1471-2148-10-237. 10.1186/1471-2148-10-237. PMC3020631.

    abstract

    The Strait of Gibraltar is a crucial area in the settlement history of modern humans because it represents a possible connection between Africa and Europe. So far, genetic data were inconclusive about the fact that this strait constitutes a barrier to gene flow, as previous results were highly variable depending on the genetic locus studied. The present study evaluates the impact of the Gibraltar region in reducing gene flow between populations from North-Western Africa and South-Western Europe, by comparing formally various genetic loci. First, we compute several statistics of population differentiation. Then, we use an original simulation approach in order to infer the most probable evolutionary scenario for the settlement of the area, taking into account the effects of both demography and natural selection at some loci.

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  • Signals of recent spatial expansions in the grey mouse lemur (Microcebus murinus). BMC Evol. Biol. 2010 ;10():105. 1471-2148-10-105. 10.1186/1471-2148-10-105. PMC2875232.

    abstract

    Pleistocene events have shaped the phylogeography of many taxa worldwide. Their genetic signatures in tropical species have been much less explored than in those living in temperate regions. We analysed the genetic structure of a Malagasy primate species, a mouse lemur with a wide distribution (M. murinus), in order to investigate such phylogeographic processes on a large tropical island. We also evaluated the effects of anthropogenic pressures (fragmentation/deforestation) and natural features (geographic distance, rivers) on genetic structure in order to complement our understanding of past and present processes of genetic differentiation.

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  • Principal component analysis under population genetic models of range expansion and admixture. Mol. Biol. Evol. 2010 Jun;27(6):1257-68. msq010. 10.1093/molbev/msq010.

    abstract

    In a series of highly influential publications, Cavalli-Sforza and colleagues used principal component (PC) analysis to produce maps depicting how human genetic diversity varies across geographic space. Within Europe, the first axis of variation (PC1) was interpreted as evidence for the demic diffusion model of agriculture, in which farmers expanded from the Near East approximately 10,000 years ago and replaced the resident hunter-gatherer populations with little or no interbreeding. These interpretations of the PC maps have been recently questioned as the original results can be reproduced under models of spatially covarying allele frequencies without any expansion. Here, we study PC maps for data simulated under models of range expansion and admixture. Our simulations include a spatially realistic model of Neolithic farmer expansion and assume various levels of interbreeding between farmer and resident hunter-gatherer populations. An important result is that under a broad range of conditions, the gradients in PC1 maps are oriented along a direction perpendicular to the axis of the expansion, rather than along the same axis as the expansion. We propose that this surprising pattern is an outcome of the "allele surfing" phenomenon, which creates sectors of high allele-frequency differentiation that align perpendicular to the direction of the expansion.

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  • Impact of selection and demography on the diffusion of lactase persistence. PLoS ONE 2009 ;4(7):e6369. 10.1371/journal.pone.0006369. PMC2711333.

    abstract

    The lactase enzyme allows lactose digestion in fresh milk. Its activity strongly decreases after the weaning phase in most humans, but persists at a high frequency in Europe and some nomadic populations. Two hypotheses are usually proposed to explain the particular distribution of the lactase persistence phenotype. The gene-culture coevolution hypothesis supposes a nutritional advantage of lactose digestion in pastoral populations. The calcium assimilation hypothesis suggests that carriers of the lactase persistence allele(s) (LCT*P) are favoured in high-latitude regions, where sunshine is insufficient to allow accurate vitamin-D synthesis. In this work, we test the validity of these two hypotheses on a large worldwide dataset of lactase persistence frequencies by using several complementary approaches.

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  • Local population structure in Arabian Peninsula revealed by Y-STR diversity. Hum. Hered. 2009 ;68(1):45-54. 000210448. 10.1159/000210448.

    abstract

    Genetic studies have been underway on Arabian Peninsula populations because of their pivotal geographic location for population migration and times of occurrence. To assist in better understanding population dynamics in this region, evidence is presented herein on local population structure in the Arabian Peninsula, based on Y-STR characterisation in four Arabian samples and its comparison in a broad geographical scale. Our results demonstrate that geography played an important role in shaping the genetic structure of the region around the Near-East. Populations are grouped regionally but none of these groups is significantly differentiated from others and all groups merge in the Near-East, in keeping with this important migration corridor for the human species. Focusing on the Arabian Peninsula, we show that Dubai and Oman share genetic affinities with other Near-Eastern populations, while Saudi Arabia and Yemen show a relative distinctive isolated background. Those two populations may have been kept relatively separated from migration routes, maybe due to their location in a desert area.

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  • The hidden side of invasions: massive introgression by local genes. Evolution 2008 Aug;62(8):1908-20. EVO413. 10.1111/j.1558-5646.2008.00413.x.

    abstract

    Despite hundreds of reports involving both plants and animals, the mechanisms underlying introgression remain obscure, even if some form of selection is frequently invoked. Introgression has repeatedly been reported in species that have recently colonized a new habitat, suggesting that demographic processes should be given more attention for understanding the mechanisms of introgression. Here we show by spatially explicit simulations that massive introgression of neutral genes takes place during the invasion of an occupied territory if interbreeding is not severely prevented between the invading and the local species. We also demonstrate that introgression occurs almost exclusively from the local to the invading species, especially for populations located far away from the source of the invasion, and this irrespective of the relative densities of the two species. This pattern is strongest at markers experiencing reduced gene flow, in keeping with the observation that organelle genes are often preferentially introgressed across species boundaries. A survey of the literature shows that a majority of published empirical studies of introgression during range expansions, in animals and in plants, follow the predictions of our model. Our results imply that speciation genes can be identified by comparing genomes of interfertile native and invading species pairs.

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  • Colonization history of the Swiss Rhine basin by the bullhead (Cottus gobio): inference under a Bayesian spatially explicit framework. Mol. Ecol. 2008 Feb;17(3):757-72. MEC3621. 10.1111/j.1365-294X.2007.03621.x.

    abstract

    The present distribution of freshwater fish in the Alpine region has been strongly affected by colonization events occurring after the last glacial maximum (LGM), some 20,000 years ago. We use here a spatially explicit simulation framework to model and better understand their colonization dynamics in the Swiss Rhine basin. This approach is applied to the European bullhead (Cottus gobio), which is an ideal model organism to study fish past demographic processes since it has not been managed by humans. The molecular diversity of eight sampled populations is simulated and compared to observed data at six microsatellite loci under an approximate Bayesian computation framework to estimate the parameters of the colonization process. Our demographic estimates fit well with current knowledge about the biology of this species, but they suggest that the Swiss Rhine basin was colonized very recently, after the Younger Dryas some 6600 years ago. We discuss the implication of this result, as well as the strengths and limits of the spatially explicit approach coupled to the approximate Bayesian computation framework.

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  • Molecular diversity after a range expansion in heterogeneous environments. Genetics 2006 Dec;174(4):2009-20. genetics.106.062851. 10.1534/genetics.106.062851. PMC1698655.

    abstract

    Recent range expansions have probably occurred in many species, as they often happen after speciation events, after ice ages, or after the introduction of invasive species. While it has been shown that range expansions lead to patterns of molecular diversity distinct from those of a pure demographic expansion, the fact that many species do live in heterogeneous environments has not been taken into account. We develop here a model of range expansion with a spatial heterogeneity of the environment, which is modeled as a gamma distribution of the carrying capacities of the demes. By allowing temporal variation of these carrying capacities, our model becomes a new metapopulation model linking ecological parameters to molecular diversity. We show by extensive simulations that environmental heterogeneity induces a loss of genetic diversity within demes and increases the degree of population differentiation. We find that metapopulations with low average densities are much more affected by environmental heterogeneity than metapopulations with high average densities, which are relatively insensitive to spatial and temporal variations of the environment. Spatial heterogeneity is shown to have a larger impact on genetic diversity than temporal heterogeneity. Overall, temporal heterogeneity and local extinctions are not found to leave any specific signature on molecular diversity that cannot be produced by spatial heterogeneity.

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  • Comment on "Ongoing adaptive evolution of ASPM, a brain size determinant in Homo sapiens" and "Microcephalin, a gene regulating brain size, continues to evolve adaptively in humans". Science 2006 Jul;313(5784):172; author reply 172. 313/5784/172a. 10.1126/science.1122712.

    abstract

    Mekel-Bobrov et al. and Evans et al. (Reports, 9 Sept. 2005, p. 1720 and p. 1717, respectively) examined sequence data from modern humans within two gene regions associated with brain development, ASPM and microcephalin, and concluded that selection of these genes must be ongoing. We show that models of human history that include both population growth and spatial structure can generate the observed patterns without selection.

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  • The fate of mutations surfing on the wave of a range expansion. Mol. Biol. Evol. 2006 Mar;23(3):482-90. msj057. 10.1093/molbev/msj057.

    abstract

    Many species, including humans, have dramatically expanded their range in the past, and such range expansions had certainly an impact on their genetic diversity. For example, mutations arising in populations at the edge of a range expansion can sometimes surf on the wave of advance and thus reach a larger spatial distribution and a much higher frequency than would be expected in stationary populations. We study here this surfing phenomenon in more detail, by performing extensive computer simulations under a two-dimensional stepping-stone model. We find that the probability of survival of a new mutation depends to a large degree on its proximity to the edge of the wave. Demographic factors such as deme size, migration rate, and local growth rate also influence the fate of these new mutations. We also find that the final spatial and frequency distributions depend on the local deme size of a subdivided population. This latter result is discussed in the light of human expansions in Europe as it should allow one to distinguish between mutations having spread with Paleolithic or Neolithic expansions. By favoring the spread of new mutations, a consequence of the surfing phenomenon is to increase the rate of evolution of spatially expanding populations.

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  • Recovering the geographic origin of early modern humans by realistic and spatially explicit simulations. Genome Res. 2005 Aug;15(8):1161-7. 15/8/1161. 10.1101/gr.3708505. PMC1182229.

    abstract

    Most genetic and archeological evidence argue in favor of a recent and unique origin of modern humans in sub-Saharan Africa, but no attempt has ever been made at quantifying the likelihood of this model, relative to alternative hypotheses of human evolution. In this paper, we investigate the possibility of using multilocus genetic data to correctly infer the geographic origin of humans, and to distinguish between a unique origin (UO) and a multiregional evolution (ME) model. We introduce here an approach based on realistic simulations of the genetic diversity expected after an expansion process of modern humans into the Old World from different possible areas and their comparison to observed data. We find that the geographic origin of the expansion can be correctly recovered provided that a large number of independent markers are used, and that precise information on past demography and potential places of origins is available. In that case, it is also possible to unambiguously distinguish between a unique origin and a multiregional model of human evolution. Application to a real human data set of 377 STR markers tested in 22 populations points toward a unique but surprising North African origin of modern humans. We show that this result could be due to ascertainment bias in favor of markers selected to be polymorphic in Europeans. A new estimation modeling this bias explicitly reveals that East Africa is the most likely place of origin for modern humans.

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  • The effect of the Neolithic expansion on European molecular diversity. Proc. Biol. Sci. 2005 Apr;272(1564):679-88. VN58861K817V11M0. 10.1098/rspb.2004.2999. PMC1602044.

    abstract

    We performed extensive and realistic simulations of the colonization process of Europe by Neolithic farmers, as well as their potential admixture and competition with local Palaeolithic hunter-gatherers. We find that minute amounts of gene flow between Palaeolithic and Neolithic populations should lead to a massive Palaeolithic contribution to the current gene pool of Europeans. This large Palaeolithic contribution is not expected under the demic diffusion (DD) model, which postulates that agriculture diffused over Europe by a massive migration of individuals from the Near East. However, genetic evidence in favour of this model mainly consisted in the observation of allele frequency clines over Europe, which are shown here to be equally probable under a pure DD or a pure acculturation model. The examination of the consequence of range expansions on single nucleotide polymorphism (SNP) diversity reveals that an ascertainment bias consisting of selecting SNPs with high frequencies will promote the observation of genetic clines (which are not expected for random SNPs) and will lead to multimodal mismatch distributions. We conclude that the different patterns of molecular diversity observed for Y chromosome and mitochondrial DNA can be at least partly owing to an ascertainment bias when selecting Y chromosome SNPs for studying European populations.

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  • Bayesian estimation of recent migration rates after a spatial expansion. Genetics 2005 May;170(1):409-17. genetics.104.034199. 10.1534/genetics.104.034199. PMC1449703.

    abstract

    Approximate Bayesian computation (ABC) is a highly flexible technique that allows the estimation of parameters under demographic models that are too complex to be handled by full-likelihood methods. We assess the utility of this method to estimate the parameters of range expansion in a two-dimensional stepping-stone model, using samples from either a single deme or multiple demes. A minor modification to the ABC procedure is introduced, which leads to an improvement in the accuracy of estimation. The method is then used to estimate the expansion time and migration rates for five natural common vole populations in Switzerland typed for a sex-linked marker and a nuclear marker. Estimates based on both markers suggest that expansion occurred <10,000 years ago, after the most recent glaciation, and that migration rates are strongly male biased.

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  • Modern humans did not admix with Neanderthals during their range expansion into Europe. PLoS Biol. 2004 Dec;2(12):e421. 10.1371/journal.pbio.0020421. PMC532389.

    abstract

    The process by which the Neanderthals were replaced by modern humans between 42,000 and 30,000 before present is still intriguing. Although no Neanderthal mitochondrial DNA (mtDNA) lineage is found to date among several thousands of Europeans and in seven early modern Europeans, interbreeding rates as high as 25% could not be excluded between the two subspecies. In this study, we introduce a realistic model of the range expansion of early modern humans into Europe, and of their competition and potential admixture with local Neanderthals. Under this scenario, which explicitly models the dynamics of Neanderthals' replacement, we estimate that maximum interbreeding rates between the two populations should have been smaller than 0.1%. We indeed show that the absence of Neanderthal mtDNA sequences in Europe is compatible with at most 120 admixture events between the two populations despite a likely cohabitation time of more than 12,000 y. This extremely low number strongly suggests an almost complete sterility between Neanderthal females and modern human males, implying that the two populations were probably distinct biological species.

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  • Intra-deme molecular diversity in spatially expanding populations. Mol. Biol. Evol. 2003 Jan;20(1):76-86.

    abstract

    We report here a simulation study examining the effect of a recent spatial expansion on the pattern of molecular diversity within a deme. We first simulate a range expansion in a virtual world consisting in a two-dimensional array of demes exchanging a given proportion of migrants (m) with their neighbors. The recorded demographic and migration histories are then used under a coalescent approach to generate the genetic diversity in a sample of genes. We find that the shape of the gene genealogies and the overall pattern of diversity within demes depend not only on the age of the expansion but also on the level of gene flow between neighboring demes, as measured by the product Nm, where N is the size of a deme. For small Nm values (< approximately 20 migrants sent outwards per generation), a substantial proportion of coalescent events occur early in the genealogy, whereas with larger levels of gene flow, most coalescent events occur around the time of the onset of the spatial expansion. Gene genealogies are star shaped, and mismatch distributions are unimodal after a range expansion for large Nm values. In contrast, gene genealogies present a mixture of both very short and very long branch lengths, and mismatch distributions are multimodal for small Nm values. It follows that statistics used in tests of selective neutrality like Tajima's D statistic or Fu's F(S) statistic will show very significant negative values after a spatial expansion only in demes with high Nm values. In the context of human evolution, this difference could explain very simply the fact that analyses of samples of mitochondrial DNA sequences reveal multimodal mismatch distributions in hunter-gatherers and unimodal distributions in post-Neolithic populations. Indeed, the current simulations show that a recent increase in deme size (resulting in a larger Nm value) is sufficient to prevent recent coalescent events and thus lead to unimodal mismatch distributions, even if deme sizes (and therefore Nm values) were previously much smaller. The fact that molecular diversity within deme is so dependent on recent levels of gene flow suggests that it should be possible to estimate Nm values from samples drawn from a single deme.

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  • Molecular analysis of the beta-globin gene cluster in the Niokholo Mandenka population reveals a recent origin of the beta(S) Senegal mutation. Am. J. Hum. Genet. 2002 Jan;70(1):207-23. S0002-9297(07)61294-4. 10.1086/338304. PMC384889.

    abstract

    A large and ethnically well-defined Mandenka sample from eastern Senegal was analyzed for the polymorphism of the beta-globin gene cluster on chromosome 11. Five RFLP sites of the 5' region were investigated in 193 individuals revealing the presence of 10 different haplotypes. The frequency of the sickle-cell anemia causing mutation (beta(S)) in the Mandenka estimated from this sample is 11.7%. This mutation was found strictly associated with the single Senegal haplotype. Approximately 600 bp of the upstream region of the beta-globin gene were sequenced for a subset of 94 chromosomes, showing the presence of four transversions, five transitions, and a composite microsatellite polymorphism. The sequence of 22 beta(S) chromosomes was also identical to the previously defined Senegal haplotype, suggesting that this mutation is very recent. Monte Carlo simulations (allowing for a specific balancing selection model, a logistic growth of the population, and variable initial frequencies of the Senegal haplotype) were used to estimate the age of the beta(S) mutation. Resulting maximum-likelihood estimates are 45-70 generations (1,350-2,100 years) for very different demographic scenarios. Smallest confidence intervals (25-690 generations) are obtained under the hypothesis that the Mandenka population is large (N(e) >5,000) and stationary or that it has undergone a rapid demographic expansion to a current size of >5,000 reproducing individuals, which is quite likely in view of the great diversity found on beta(A) chromosomes.

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Bioinformatics tools

  • SELECTOR - Forward-in-Time, Spatially Explicit Modeling Software to Simulate Genetic Lineages Under Selection.
  • SPLATCHE 2 - SPatiaL And Temporal Coalescent in a Heterogeneous Environment.
  • R scripts for modeling admixture in conservation genetics.
  • SPLATCHE - A program to simulate genetic diversity taking into account environmental heterogeneity.