Measuring the efficiency of purging by non-random mating in human populations.

Human populations harbour a high concentration of deleterious genetic variants. Here, we tested the hypothesis that non-random mating practices affect the distribution of these variants, through exposure in the homozygous state, leading to their purging from the population gene pool. To do so, we produced whole-genome sequencing data for two pairs of Asian populations exhibiting different alliance rules and rates of inbreeding, but with similar effective population sizes. The results show that populations with higher rates of inbred matings do not purge deleterious variants more efficiently. Purging therefore has a low efficiency in human populations, and different mating practices lead to a similar mutational load.Keywords: purifying selection, kinship, mate choice, inbreeding, genomics, deleterious variants, mutational load.

Patrilineal segmentary systems provide a peaceful explanation for the post-Neolithic Y-chromosome bottleneck.

Studies have found a pronounced decline in male effective population sizes worldwide around 3000-5000 years ago. This bottleneck was not observed for female effective population sizes, which continued to increase over time. Until now, this remarkable genetic pattern was interpreted as the result of an ancient structuring of human populations into patrilineal groups (gathering closely related males) violently competing with each other. In this scenario, violence is responsible for the repeated extinctions of patrilineal groups, leading to a significant reduction in male effective population size. Here, we propose an alternative hypothesis by modelling a segmentary patrilineal system based on anthropological literature. We show that variance in reproductive success between patrilineal groups, combined with lineal fission (i.e., the splitting of a group into two new groups of patrilineally related individuals), can lead to a substantial reduction in the male effective population size without resorting to the violence hypothesis. Thus, a peaceful explanation involving ancient changes in social structures, linked to global changes in subsistence systems, may be sufficient to explain the reported decline in Y-chromosome diversity.

Cultural transmission of reproductive success impacts genomic diversity, coalescent tree topologies, and demographic inferences.

Cultural transmission of reproductive success has been observed in many human populations as well as other animals. Cultural transmission of reproductive success consists of a positive correlation of nongenetic origin between the progeny size of parents and children. This correlation can result from various factors, such as the social influence of parents on their children, the increase of children's survival through allocare from uncles and aunts, or the transmission of resources. Here, we study the evolution of genomic diversity over time under cultural transmission of reproductive success. Cultural transmission of reproductive success has a threefold impact on population genetics: (1) the effective population size decreases when cultural transmission of reproductive success starts, mimicking a population contraction, and increases back to its original value when cultural transmission of reproductive success stops; (2) coalescent tree topologies are distorted under cultural transmission of reproductive success, with higher imbalance and a higher number of polytomies; and (3) branch lengths are reduced nonhomogenously, with a higher impact on older branches. Under long-lasting cultural transmission of reproductive success, the effective population size stabilizes but the distortion of tree topology and the nonhomogenous branch length reduction remain, yielding U-shaped site frequency spectra under a constant population size. We show that this yields a bias in site frequency spectra-based demographic inference. Considering that cultural transmission of reproductive success was detected in numerous human and animal populations worldwide, one should be cautious because inferring population past histories from genomic data can be biased by this cultural process.

Detection of sexually antagonistic transmission distortions in trio datasets.

Sexual dimorphisms are widespread in animals and plants, for morphological as well as physiological traits. Understanding the genetic basis of sexual dimorphism and its evolution is crucial for understanding biological differences between the sexes. Genetic variants with sex-antagonistic effects on fitness are expected to segregate in populations at the early phases of sexual dimorphism emergence. Detecting such variants is notoriously difficult, and the few genome-scan methods employed so far have limited power and little specificity. Here, we propose a new framework to detect a signature of sexually antagonistic (SA) selection. We rely on trio datasets where sex-biased transmission distortions can be directly tracked from parents to offspring, and identify signals of SA transmission distortions in genomic regions. We report the genomic location of six candidate regions detected in human populations as potentially under sexually antagonist selection. We find an enrichment of genes associated with embryonic development within these regions. Last, we highlight two candidate regions for SA selection in humans.

Complex genetic admixture histories reconstructed with Approximate Bayesian Computation.

Admixture is a fundamental evolutionary process that has influenced genetic patterns in numerous species. Maximum-likelihood approaches based on allele frequencies and linkage-disequilibrium have been extensively used to infer admixture processes from genome-wide data sets, mostly in human populations. Nevertheless, complex admixture histories, beyond one or two pulses of admixture, remain methodologically challenging to reconstruct. We developed an Approximate Bayesian Computation (ABC) framework to reconstruct highly complex admixture histories from independent genetic markers. We built the software package MetHis to simulate independent SNPs or microsatellites in a two-way admixed population for scenarios with multiple admixture pulses, monotonically decreasing or increasing recurring admixture, or combinations of these scenarios. MetHis allows users to draw model-parameter values from prior distributions set by the user, and, for each simulation, MetHis can calculate numerous summary statistics describing genetic diversity patterns and moments of the distribution of individual admixture fractions. We coupled MetHis with existing machine-learning ABC algorithms and investigated the admixture history of admixed populations. Results showed that random forest ABC scenario-choice could accurately distinguish among most complex admixture scenarios, and errors were mainly found in regions of the parameter space where scenarios were highly nested, and, thus, biologically similar. We focused on African American and Barbadian populations as two study-cases. We found that neural network ABC posterior parameter estimation was accurate and reasonably conservative under complex admixture scenarios. For both admixed populations, we found that monotonically decreasing contributions over time, from Europe and Africa, explained the observed data more accurately than multiple admixture pulses. This approach will allow for reconstructing detailed admixture histories when maximum-likelihood methods are intractable.

From matrimonial practices to genetic diversity in Southeast Asian populations: the signature of the matrilineal puzzle.

In matrilineal populations, the descent group affiliation is transmitted by women whereas the socio-political power frequently remains in the hands of men. This situation, named the 'matrilineal puzzle', is expected to promote local endogamy as a coping mechanism allowing men to maintain their decision-making power over their natal descent group. In this paper, we revisit this 'matrilineal puzzle' from a population genetics' point of view. Indeed, such tendency for local endogamy in matrilineal populations is expected to increase their genetic inbreeding and generate isolation-by-distance patterns between villages. To test this hypothesis, we collected ethno-demographic data for 3261 couples and high-density genetic data for 675 individuals from 11 Southeast Asian populations with a wide range of social organizations: matrilineal and matrilocal populations (M), patrilineal and patrilocal populations (P) or cognatic populations with predominant matrilocal residence (C). We observed that M and C populations have higher levels of village endogamy than P populations, and that such higher village endogamy leads to higher genetic inbreeding. M populations also exhibit isolation-by-distance patterns between villages. We interpret such genetic patterns as the signature of the 'matrilineal puzzle'. Notably, our results suggest that any form of matrilocal marriage (whatever the descent rule is) increases village endogamy. These findings suggest that male dominance, when combined with matrilocality, constrains inter-village migrations, and constitutes an underexplored cultural process shaping genetic patterns in human populations. This article is part of the theme issue 'The evolution of female-biased kinship in humans and other mammals'.

Genomic evidence for MHC disassortative mating in humans.

Although pervasive in many animal species, the evidence for major histocompatibility complex (MHC) disassortative mating in humans remains inconsistent across studies. Here, to revisit this issue, we analyse dense genotype data for 883 European and Middle Eastern couples. To distinguish MHC-specific effects from socio-cultural confounders, the pattern of relatedness between spouses in the MHC region is compared to the rest of the genome. Couples from Israel exhibit no significant pattern of relatedness across the MHC region, whereas across the genome, they are more similar than random pairs of individuals, which may reflect social homogamy and/or cousin marriages. On the other hand, couples from The Netherlands and more generally from Northern Europe are significantly more MHC-dissimilar than random pairs of individuals, and this pattern of dissimilarity is extreme when compared with the rest of the genome. Our findings support the hypothesis that the MHC influences mate choice in humans in a context-dependent way: MHC-driven preferences may exist in all populations but, in some populations, social constraints over mate choice may reduce the ability of individuals to rely on such biological cues when choosing their mates.

Residence rule flexibility and descent groups dynamics shape uniparental genetic diversities in South East Asia.

OBJECTIVES: Social organization plays a major role in shaping human population genetic diversity. In particular, matrilocal populations tend to exhibit less mitochondrial diversity than patrilocal populations, and the other way around for Y chromosome diversity. However, several studies have not replicated such findings. The objective of this study is to understand the reasons for such inconsistencies and further evaluate the influence of social organization on genetic diversity. MATERIALS AND METHODS: We explored uniparental diversity patterns using mitochondrial HV1 sequences and 17 Y-linked short tandem repeats (STRs) in 12 populations (n = 619) from mainland South-East Asia exhibiting a wide range of social organizations, along with quantitative ethno-demographic information sampled at the individual level. RESULTS: MtDNA diversity was lower in matrilocal than in multilocal and patrilocal populations while Y chromosome diversity was similar among these social organizations. The reasons for such asymmetry at the genetic level were understood by quantifying sex-specific migration rates from our ethno-demographic data: while female migration rates varied between social organizations, male migration rates did not. This unexpected lack of difference in male migrations resulted from a higher flexibility in residence rule in patrilocal than in matrilocal populations. In addition, our data suggested an impact of clan fission process on uniparental genetic patterns. CONCLUSIONS: The observed lack of signature of patrilocality on Y chromosome patterns might be attributed to the higher residence flexibility in the studied patrilocal populations, thus providing a potential explanation for the apparent discrepancies between social and genetic structures. Altogether, this study highlights the need to quantify the actual residence and descent patterns to fit social to genetic structures.

Detection of Allelic Frequency Differences between the Sexes in Humans: A Signature of Sexually Antagonistic Selection.

Sexually antagonistic (SA) selection, a form of selection that can occur when both sexes have different fitness optima for a trait, is a major force shaping the evolution of organisms. A seminal model developed by Rice (Rice WR. 1984. Sex chromosomes and the evolution of sexual dimorphism. Evolution 38:735-742.) predicts that the X chromosome should be a hotspot for the accumulation of loci under SA selection as compared with the autosomes. Here, we propose a methodological framework designed to detect a specific signature of SA selection on viability, differences in allelic frequencies between the sexes. Applying this method on genome-wide single nucleotide polymorphism (SNP) data in human populations where no sex-specific population stratification could be detected, we show that there are overall significantly more SNPs exhibiting differences in allelic frequencies between the sexes on the X chromosome as compared with autosomes, supporting the predictions of Rice's model. This pattern is consistent across populations and is robust to correction for potential biases such as differences in linkage disequilibrium, sample size, and genotyping errors between chromosomes. Although SA selection is not the only factor resulting in allelic frequency differences between the sexes, we further show that at least part of the identified X-linked loci is caused by such a sex-specific processes.

Patrilineal populations show more male transmission of reproductive success than cognatic populations in Central Asia, which reduces their genetic diversity.

OBJECTIVE: The extent to which social organization of human societies impacts the patterns of genetic diversity remains an open question. Here, we investigate the transmission of reproductive success in patrilineal and cognatic populations from Central Asia using a coalescent approach. METHODS: We performed a study on the mitochondrial DNA (mtDNA) and Y chromosome polymorphism of patrilineal and cognatic populations from Central Asia. We reconstructed the gene genealogies in each population for both kind of markers and inferred the imbalance level of these genealogies, a parameter directly related to the level of transmission of reproductive success. RESULTS: This imbalance level appeared much stronger for the Y chromosome in patrilineal populations than in cognatic populations, while no difference was found for mtDNA. Furthermore, we showed that this imbalance level correlates negatively with Y-chromosomal, mtDNA, and autosomal genetic diversity. CONCLUSIONS: This shows that patrilineality might be one of the factors explaining the male transmission of reproductive success, which, in turn, lead to a reduction of genetic diversity. Thus, notwithstanding the fact that our population genetic approach clearly shows that there is a strong male-biased transmission of reproductive success in patrilineal societies, it also highlights the fact that a social process such as cultural transmission of reproductive success could play an important role in shaping human genetic diversity, although we cannot formally exclude that this transmission has also a genetic component.

Pulmonary alveolar proteinosis in children on La Réunion Island: a new inherited disorder?

BACKGROUND: Pulmonary alveolar proteinosis (PAP) is very rare in children. Only a few small series have been published, with little information about long-term progression. The objective of our study was to describe the clinical, radiological and pathological features, and the long-term course of PAP in a cohort of 34 children from La Réunion Island. METHODS: Data were retrospectively collected from medical files. Radiological and pathological elements were reviewed by two pediatric radiologists and three pathologists, respectively. RESULTS: Thirteen cases were familial and 32/34 (94%) cases were family connected. Disease onset occurred in the first six months of life in 82% of the patients. Thoracic computed tomography scans showed the typical "crazy-paving" pattern in 94% of cases. Respiratory disease was associated with a liver disorder, with the detection of liver enlargement at diagnosis in 56% of cases. The course of the disease was characterized by frequent progression to chronic respiratory insufficiency, accompanied by the appearance of cholesterol granulomas and pulmonary fibrosis. Overall prognosis was poor, with a mortality of 59% and an overall five-year survival rate from birth of 64%. Whole-lung lavages were performed in 21 patients, with no significant effect on survival. Liver disease progressed to cirrhosis in 18% of children, with no severe complication. CONCLUSIONS: PAP in children from la Réunion Island is characterized by an early onset, associated liver involvement, poor prognosis and frequent progression to lung fibrosis, despite whole-lung lavages treatment. The geographic clustering of patients and the detection of many familial links between most of the cases strongly suggest a genetic etiology, with an autosomal recessive mode of inheritance.

Positive selection of protective variants for type 2 diabetes from the Neolithic onward: a case study in Central Asia.

The high prevalence of type 2 diabetes and its uneven distribution among human populations is both a major public health concern and a puzzle in evolutionary biology. Why is this deleterious disease so common, while the associated genetic variants should be removed by natural selection? The 'thrifty genotype' hypothesis proposed that the causal genetic variants were advantageous and selected for during the majority of human evolution. It remains, however, unclear whether genetic data support this scenario. In this study, we characterized patterns of selection at 10 variants associated with type 2 diabetes, contrasting one herder and one farmer population from Central Asia. We aimed at identifying which alleles (risk or protective) are under selection, dating the timing of selective events, and investigating the effect of lifestyle on selective patterns. We did not find any evidence of selection on risk variants, as predicted by the thrifty genotype hypothesis. Instead, we identified clear signatures of selection on protective variants, in both populations, dating from the beginning of the Neolithic, which suggests that this major transition was accompanied by a selective advantage for non-thrifty variants. Combining our results with worldwide data further suggests that East Asia was particularly prone to such recent selection of protective haplotypes. As much effort has been devoted so far to searching for thrifty variants, we argue that more attention should be paid to the evolution of non-thrifty variants.

Impact of fertility transmission and other sociodemographic factors on reproductive success and coalescent trees.

Summary Fertility transmission (FT) is a phenomenon with a cultural and/or genetic basis, whereby a positive correlation exists between the number of offspring of an individual and that of his/her parents. Theoretical studies using a haploid individual-based model have shown that FT increases the variance and intergenerational correlation in reproductive success and results in an imbalance in the coalescent tree of sampled genes. This phenomenon has been documented in several demographic studies conducted on the correlation in fertility between generations, or through the reconstruction of the genealogical trees of mitochondrial DNA sequences. However, as mtDNA is a single locus, potentially subject to other forces (e.g. natural selection), it is of interest to extend the theory of FT to nuclear loci. We show that because random mating between individuals leads to a mixing of their fertility profiles, FT in these cases will have less influence on the variance and intergenerational correlation of reproductive success. This, in turn, results in less impact on the shape of the coalescent trees. Nevertheless, in the presence of FT, high heterogeneity in reproductive success and homogamy for family size will increase the imbalance in the coalescent tree. Thus, FT should be easier to detect when occurring in conjunction with these other factors. We also show the utility of analysing different kinds of loci (X-linked, Y-linked, mitochondrial and autosomal) to assess whether FT is matrilineal, patrilineal or biparental. Finally, we demonstrate that the shape of the coalescent tree depends upon population size, in contrast to the classical Kingman's model.

Autochthony and HLA frequencies in the Netherlands: when surnames are useless markers.

To study the genetic variability of the HLA loci A, B, DR, and DQ in the Netherlands, we analyzed more than 13,000 typings provided by the Dutch National Reference Laboratory for Histocompatibility. To investigate any possibly existing population structure, we subdivided the typings by the geographic location of residency of donors and by the historical belonging of their surnames to given provinces. Concerning possible geographic patterns, we found no significant differences between the four provinces examined (North Holland, South Holland, Utrecht, Zeeland). To assess whether such a negative result was related to recent immigration to the area (the richest of the country) that erased possible preexisting patterns of HLA diversity, we reprocessed the database according to the surnames of HLA donors. We obtained two groups: (1) those having a surname typical of the four provinces they inhabit and (2) those with surnames coming from elsewhere. Such an analysis was made possible because of the availability of a database concerning the geographic origin of most Dutch surnames. Even with this surname-based approach, no major differences were found. We conclude that either the western part of the Netherlands was genetically homogeneous before the official introduction of Dutch surnames two centuries ago by Napoleon or surnames have no power in dissecting HLA variability; that is, such variability is the result of recombination phenomena that surnames cannot mirror because they are transmitted virtually unchanged generation after generation. A comparable study by other investigators recommended the use of family names to identify rare HLA haplotypes in France, but now, concerning the Netherlands, we find opposite results. We suggest that a few typing centers may be sufficient to type bone marrow donors, because HLA genetic differences between the different provinces of the Netherlands are extremely low. To maximize the number of donors, such centers should be located in areas providing the easiest access to the largest population of possible donors, thus disregarding the search for a local variability that we did not find.

Impact of inbreeding on fertility in a pre-industrial population.

Little is known about the effects of inbreeding on reproduction in modern human societies. It appears indeed that biological effects are hidden by socioeconomic factors, which are the major determinants of fertility. It has been established, in particular, that socially induced reproductive compensation tends to homogenize the number of offspring per family in a given population. Besides, in the field of evolutionary biology, a number of empirical and theoretical studies have shown that the effects of inbreeding are condition dependent. In particular, theoretical developments on the evolution of senescence predict that the deleterious effects of inbreeding should increase with age. We rely on these developments to examine the effects of inbreeding on fertility in a cohort of Canadian women born in the late 19th century. The analysis does not allow for the detection of any effect of inbreeding on the overall number of offspring of women. However, results indicate that high levels of close father inbreeding are associated with a reduction of the productivity of parents during the second half of their reproductive period, as compared with the first half. We suggest that inbreeding depression affects reproduction in modern societies through an interaction with age.

Do surname differences mirror dialect variation?

Our focus in this paper is the analysis of surnames, which have been proven to be reliable genetic markers because in patrilineal systems they are transmitted along generations virtually unchanged, similarly to a genetic locus on the Y chromosome. We compare the distribution of surnames to the distribution of dialect pronunciations, which are clearly culturally transmitted. Because surnames, at the time of their introduction, were words subject to the same linguistic processes that otherwise result in dialect differences, one might expect their geographic distribution to be correlated with dialect pronunciation differences. In this paper we concentrate on the Netherlands, an area of only 40,000 km2, where two official languages are spoken, Dutch and Frisian. We analyze 19,910 different surnames, sampled in 226 locations, and 125 different words, whose pronunciation was recorded in 252 sites. We find that, once the collinear effects of geography on both surname and cultural transmission are taken into account, there is no statistically significant association between the two, suggesting that surnames cannot be taken as a proxy for dialect variation, even though they can be safely used as a proxy for Y-chromosome genetic variation. We find the results historically and geographically insightful, hopefully leading to a deeper understanding of the role that local migrations and cultural diffusion play in surname and dialect diversity.

Transmission of migration propensity increases genetic divergence between populations.

The advent of molecular genetics has brought invaluable information, which is now routinely used by anthropologists in their attempt to reconstruct our demographic past. Since mitochondrial DNA loci are much more similar between populations than are Y-chromosome loci, it is suggested that women had a much higher migration rate than men throughout history. Based on an examination of intergenerational migration patterns in three large demographic databases, we bring this inference into question. In some early Canadian settlements (St. Lawrence Valley and Saguenay), and in the former Krummhörn region of northwest Germany, men whose fathers were migrants were more likely to migrate, while the migration probability of women was largely independent of that of their mothers. As a result, men's movements were less effective in preventing genetic differentiation between populations than women's movements. In order to account for the impact of transmission, we propose a slight modification of Wright's island model. We also address the relevance of this model at the regional scale, and we discuss the supporting historical and anthropological literature. We conclude that the widespread patrilocal rules of postmarital residence have generated both a higher female migration rate and a patrilineal dependency in the propensity to migrate.

Anatomy of a founder effect: myotonic dystrophy in Northeastern Quebec.

Founder effects are largely responsible for changes in frequency profiles of genetic variants in local populations or isolates. They are often recognized by elevated incidence of certain hereditary disorders as observed in regions of Charlevoix and Saguenay-Lac-Saint-Jean (SLSJ) in Northeastern Quebec. Dominantly transmitted myotonic dystrophy (DM1) is highly prevalent in SLSJ where its carrier rate reaches 1/550, compared with 1/5,000 to 1/50,000 elsewhere. To shed light on the origin of DM1 in this region, we have screened 50 nuclear DM1 families from SLSJ and studied the genetic variation in a 2.05 Mb (2.9 cM) segment spanning the site of the expansion mutation. The markers analyzed included 22 biallelic SNPs and two microsatellites. Among 50 independent DM1 chromosomes, we distinguished ten DM1-associated haplotypes and grouped them into three haplotype families, A, B and C, based on the relevant extent of allele sharing between them. To test whether the data were consistent with a single entry of the mutation into SLSJ, we evaluated the age of the founder effect from the proportion of recombinant haplotypes. Taking the prevalent haplotype A1_21 (58%) as ancestral to all the disease-associated haplotypes in this study, the estimated age of the founder effect was 19 generations, long predating the colonization of Nouvelle-France. In contrast, considering A1_21 as ancestral to the haplotype family A only, yielded the estimated founder age of nine generations, consistent with the settlement of Charlevoix at the turn of 17th century and subsequent colonization of SLSJ. We conclude that it was the carrier of haplotype A (present day carrier rate of 1/730) that was a "driver" of the founder effect, while minor haplotypes B and C, with corresponding carrier rates of 1/3,000 and 1/10,000, respectively, contribute DM1 to the incidence level known in other populations. Other studies confirm that this might be a general scenario in which a major "driver" mutation/haplotype issued from a founder effect is found accompanied by distinct minor mutations/haplotypes occurring at background population frequencies.

New method for surname studies of ancient patrilineal population structures, and possible application to improvement of Y-chromosome sampling.

Several studies showed that surnames are good markers to infer patrilineal genetic structures of populations, both on regional and microregional scales. As a case study, the spatial patterns of the 9,929 most common surnames of the Netherlands were analyzed by a clustering method called self-organizing maps (SOMs). The resulting clusters grouped surnames with a similar geographic distribution and origin. The analysis was shown to be in agreement with already known features of Dutch surnames, such as 1) the geographic distribution of some well-known locative suffixes, 2) historical census data, 3) the distribution of foreign surnames, and 4) polyphyletic surnames. Thus, these results validate the SOM clustering of surnames, and allow for the generalization of the technique. This method can be applied as a new strategy for a better Y-chromosome sampling design in retrospective population genetics studies, since the idenfication of surnames with a defined geographic origin enables the selection of the living descendants of those families settled, centuries ago, in a given area. In other words, it becomes possible to virtually sample the population as it was when surnames started to be in use. We show that, in a given location, the descendants of those individuals who inhabited the area at the time of origin of surnames can be as low as approximately 20%. This finding suggests 1) the major role played by recent migrations that are likely to have distorted or even defaced ancient genetic patterns, and 2) that standard-designed samplings can hardly portray a reliable picture of the ancient Y-chromosome variability of European populations.

Sex-specific selection on the human X chromosome?

Genes involved in major biological functions, such as reproductive or cognitive functions, are choice targets for natural selection. However, the extent to which these genes are affected by selective pressures remains undefined. The apparent clustering of these genes on sex chromosomes makes this genomic region an attractive model system to study the effects of evolutionary forces. In the present study, we analysed the genetic diversity of a X-linked microsatellite in 1410 X-chromosomes from 10 different human populations. Allelic frequency distributions revealed an unexpected discrepancy between the sexes. By evaluating the different scenarios that could have led to this pattern, we show that sex-specific selection on the tightly linked VCX gene could be the most likely cause of such a distortion.