Rapid evolution of a skin-lightening allele in southern African KhoeSan.

Skin pigmentation is under strong directional selection in northern European and Asian populations. The indigenous KhoeSan populations of far southern Africa have lighter skin than other sub-Saharan African populations, potentially reflecting local adaptation to a region of Africa with reduced UV radiation. Here, we demonstrate that a canonical Eurasian skin pigmentation gene, SLC24A5, was introduced to southern Africa via recent migration and experienced strong adaptive evolution in the KhoeSan. To reconstruct the evolution of skin pigmentation, we collected phenotypes from over 400 ≠Khomani San and Nama individuals and high-throughput sequenced candidate pigmentation genes. The derived causal allele in SLC24A5, p.Ala111Thr, significantly lightens basal skin pigmentation in the KhoeSan and explains 8 to 15% of phenotypic variance in these populations. The frequency of this allele (33 to 53%) is far greater than expected from colonial period European gene flow; however, the most common derived haplotype is identical among European, eastern African, and KhoeSan individuals. Using four-population demographic simulations with selection, we show that the allele was introduced into the KhoeSan only 2,000 y ago via a back-to-Africa migration and then experienced a selective sweep (s = 0.04 to 0.05 in ≠Khomani and Nama). The SLC24A5 locus is both a rare example of intense, ongoing adaptation in very recent human history, as well as an adaptive gene flow at a pigmentation locus in humans.

Genomic profiling of intestinal T-cell receptor repertoires in inflammatory bowel disease.

Growing evidence shows that inflammatory bowel disease (IBD) results from dysregulation of immune responses to gut microbes. T-cell receptors (TCRs) expressed on the T-cell surface play critical roles in discriminating pathogens from commensal intestinal microorganisms at the front line of the adaptive immune system. The breakdown of this interaction may trigger persistent inflammatory responses to gut bacteria, resulting in IBD. Taking advantage of high-throughput sequencing, we developed an integrated approach to dissect the intestinal TCR repertoires underlying IBD by collecting peripheral blood and inflamed intestine from the same set of 11 IBD cases. The intestinal TCR repertoires show lower clonotype diversity (p < 0.05) and stronger clonal expansion (p < 0.02) than those in the blood. This pattern becomes more profound in TCRs unique to the inflamed tissue compared with shared TCRs. Our approach further identified the increased usage of TRAV12-3 (false discovery rate, FDR < 5%), which biases its choices of J genes towards the reduction of TRAJ37 and TRAJ43 usage (FDR < 20%) in the inflamed intestine. Our genomic profiling suggests that this selective bias of V and J gene usage may lead to a loss of diversity in the intestinal TCR repertoires and result in mucosal inflammation in IBD.

Inferring the model and onset of natural selection under varying population size from the site frequency spectrum and haplotype structure.

A fundamental question about adaptation in a population is the time of onset of the selective pressure acting on beneficial alleles. Inferring this time, in turn, depends on the selection model. We develop a framework of approximate Bayesian computation (ABC) that enables the use of the full site frequency spectrum and haplotype structure to test the goodness-of-fit of selection models and estimate the timing of selection under varying population size scenarios. We show that our method has sufficient power to distinguish natural selection from neutrality even if relatively old selection increased the frequency of a pre-existing allele from 20% to 50% or from 40% to 80%. Our ABC can accurately estimate the time of onset of selection on a new mutation. However, estimates are prone to bias under the standing variation model, possibly due to the uncertainty in the allele frequency at the onset of selection. We further extend our approach to take advantage of ancient DNA data that provides information on the allele frequency path of the beneficial allele. Applying our ABC, including both modern and ancient human DNA data, to four pigmentation alleles in Europeans, we detected selection on standing variants that occurred after the dispersal from Africa even though models of selection on a new mutation were initially supported for two of these alleles without the ancient data.

Estimating the Ages of Selection Signals from Different Epochs in Human History.

Genetic variation harbors signatures of natural selection driven by selective pressures that are often unknown. Estimating the ages of selection signals may allow reconstructing the history of environmental changes that shaped human phenotypes and diseases. We have developed an approximate Bayesian computation (ABC) approach to estimate allele ages under a model of selection on new mutations and under demographic models appropriate for human populations. We have applied it to two resequencing data sets: An ultra-high depth data set from a relatively small sample of unrelated individuals and a lower depth data set in a larger sample with transmission information. In addition to evaluating the accuracy of our method based on simulations, for each SNP, we assessed the consistency between the posterior probabilities estimated by the ABC approach and the ancient DNA record, finding good agreement between the two types of data and methods. Applying this ABC approach to data for eight single nucleotide polymorphisms (SNPs), we were able to rule out an onset of selection prior to the dispersal out-of-Africa for three of them and more recent than the spread of agriculture for an additional three SNPs.

Confounding effects of microbiome on the susceptibility of TNFSF15 to Crohn's disease in the Ryukyu Islands.

Crohn's disease (CD) involves chronic inflammation in the gastrointestinal tract due to dysregulation of the host immune response to the gut microbiome. Even though the host-microbiome interactions are likely contributors to the development of CD, a few studies have detected genetic variants that change bacterial compositions and increase CD risk. We focus on one of the well-replicated susceptible genes, tumor necrosis factor superfamily member 15 (TNFSF15), and apply statistical analyses for personal profiles of genotypes and salivary microbiota collected from CD cases and controls in the Ryukyu Islands, southernmost islands of the Japanese archipelago. Our association test confirmed the susceptibility of TNFSF15 in the Ryukyu Islands. We found that the recessive model was supported to fit the observed genotype frequency of risk alleles slightly better than the additive model, defining the genetic effect on CD if a pair of the chromosomes in an individual consists of all risk alleles. The combined analysis of haplotypes and salivary microbiome from a small set of samples showed a significant association of the genetic effect with the increase of Prevotella, which led to a significant increase of CD risk. However, the genetic effect on CD disappeared if the abundance of Prevotella was low, suggesting the genetic contribution to CD is conditionally independent given a fixed amount of Prevotella. Although our statistical power is limited due to the small sample size, these results support an idea that the genetic susceptibility of TNFSF15 to CD may be confounded, in part, by the increase of Prevotella.

Genetics of Schizophrenia: Ready to Translate?

PURPOSE OF REVIEW: This is an era where we have significantly advanced the understanding of the genetic architecture of schizophrenia. In this review, we consider how this knowledge may translate into advances that will improve patient care. RECENT FINDINGS: Large-scale genome-wide association studies (GWAS) have identified more than a hundred loci each making a small contribution to illness risk. Meta-analysis of copy number variants (CNVs) in the Psychiatric Genomics Consortium (PGC) dataset has confirmed that some variants have a moderate or large impact on risk, although these are rare in the population. Genome sequencing advances allow a much more comprehensive evaluation of genomic variation. We describe the key findings from whole exome studies to date. These studies are happening against a backdrop of growing understanding of the regulation and expression of genes and better functional tools to investigate molecular mechanisms in model systems. We provide an overview of how recent approaches in schizophrenia genetics are converging and consider how they could impact on diagnostics, the development of personalized medicine, and drug discovery.

Model-based verification of hypotheses on the origin of modern Japanese revisited by Bayesian inference based on genome-wide SNP data.

Various hypotheses for the peopling of the Japanese archipelago have been proposed, which can be classified into three models: transformation, replacement, and hybridization. In recent years, one of the hybridization models ("dual-structure model") has been widely accepted. According to this model, Neolithic hunter-gatherers known as Jomon, who are assumed to have originated in southeast Asia and lived in the Japanese archipelago greater than 10,000 years ago, admixed with an agricultural people known as Yayoi, whom were migrants from the East Asian continent 2,000-3,000 years ago. Meanwhile, some anthropologists propose that rather, morphological differences between the Jomon and Yayoi people can be explained by microevolution following the lifestyle change. To resolve this controversy, we compared three demographic models by approximate Bayesian computation using genome-wide single nucleotide polymorphism (gwSNP) data from the Ainu people who are thought to be direct descendants of indigenous Jomon. If we assume Chinese people sampled in Beijing from HapMap have the same ancestry as Yayoi, then the hybridization model is predicted to be between 29 and 63 times more likely than the replacement and transformation models, respectively. Furthermore, our data provide strong support for a model in which the Jomon lineages had population structure diversified in local areas before the admixture event. Initial divergence between the Jomon and Yayoi ancestries was dated to late Pleistocene, followed by the divergence of Jomon lineages at early Holocene. These results suggest gwSNP data provides a detailed picture of the complex hybridization model for Japanese population history.

Genome-wide SNP analysis reveals population structure and demographic history of the ryukyu islanders in the southern part of the Japanese archipelago.

The Ryukyu Islands are located to the southwest of the Japanese archipelago. Archaeological evidence has revealed the existence of prehistoric cultural differentiation between the northern Ryukyu islands of Amami and Okinawa, and the southern Ryukyu islands of Miyako and Yaeyama. To examine a genetic subdivision in the Ryukyu Islands, we conducted genome-wide single nucleotide polymorphism typing of inhabitants from the Okinawa Islands, the Miyako Islands, and the Yaeyama Islands. Principal component and cluster analyses revealed genetic differentiation among the island groups, especially between Okinawa and Miyako. No genetic affinity was observed between aboriginal Taiwanese and any of the Ryukyu populations. The genetic differentiation observed between the inhabitants of the Okinawa Islands and the Miyako Islands is likely to have arisen due to genetic drift rather than admixture with people from neighboring regions. Based on the observed genetic differences, the divergence time between the inhabitants of Okinawa and Miyako islands was dated to the Holocene. These findings suggest that the Pleistocene inhabitants, whose bones have been found on the southern Ryukyu Islands, did not make a major genetic contribution, if any, to the present-day inhabitants of the southern Ryukyu Islands.

Natural allelic variations of xenobiotic-metabolizing enzymes affect sexual dimorphism in Oryzias latipes.

Sexual dimorphisms, which are phenotypic differences between males and females, are driven by sexual selection. Interestingly, sexually selected traits show geographical variations within species despite strong directional selective pressures. This paradox has eluded many evolutionary biologists for some time, and several models have been proposed (e.g. 'indicator model' and 'trade-off model'). However, disentangling which of these theories explains empirical patterns remains difficult, because genetic polymorphisms that cause variation in sexual differences are still unknown. In this study, we show that polymorphisms in cytochrome P450 (CYP) 1B1, which encodes a xenobiotic-metabolizing enzyme, are associated with geographical differences in sexual dimorphism in the anal fin morphology of medaka fish (Oryzias latipes). Biochemical assays and genetic cross experiments show that high- and low-activity CYP1B1 alleles enhanced and declined sex differences in anal fin shapes, respectively. Behavioural and phylogenetic analyses suggest maintenance of the high-activity allele by sexual selection, whereas the low-activity allele possibly has experienced positive selection due to by-product effects of CYP1B1 in inferred ancestral populations. The present data can elucidate evolutionary mechanisms behind genetic variations in sexual dimorphism and indicate trade-off interactions between two distinct mechanisms acting on the two alleles with pleiotropic effects of xenobiotic-metabolizing enzymes.

Kernel approximate Bayesian computation in population genetic inferences.

Approximate Bayesian computation (ABC) is a likelihood-free approach for Bayesian inferences based on a rejection algorithm method that applies a tolerance of dissimilarity between summary statistics from observed and simulated data. Although several improvements to the algorithm have been proposed, none of these improvements avoid the following two sources of approximation: 1) lack of sufficient statistics: sampling is not from the true posterior density given data but from an approximate posterior density given summary statistics; and 2) non-zero tolerance: sampling from the posterior density given summary statistics is achieved only in the limit of zero tolerance. The first source of approximation can be improved by adding a summary statistic, but an increase in the number of summary statistics could introduce additional variance caused by the low acceptance rate. Consequently, many researchers have attempted to develop techniques to choose informative summary statistics. The present study evaluated the utility of a kernel-based ABC method [Fukumizu, K., L. Song and A. Gretton (2010): "Kernel Bayes' rule: Bayesian inference with positive definite kernels," arXiv, 1009.5736 and Fukumizu, K., L. Song and A. Gretton (2011): "Kernel Bayes' rule. Advances in Neural Information Processing Systems 24." In: J. Shawe-Taylor and R. S. Zemel and P. Bartlett and F. Pereira and K. Q. Weinberger, (Eds.), pp. 1549-1557., NIPS 24: 1549-1557] for complex problems that demand many summary statistics. Specifically, kernel ABC was applied to population genetic inference. We demonstrate that, in contrast to conventional ABCs, kernel ABC can incorporate a large number of summary statistics while maintaining high performance of the inference.

Genomic imputation of ancient Asian populations contrasts local adaptation in pre- and post-agricultural Japan.

Early modern humans lived as hunter-gatherers for millennia before agriculture, yet the genetic adaptations of these populations remain a mystery. Here, we investigate selection in the ancient hunter-gatherer-fisher Jomon and contrast pre- and post-agricultural adaptation in the Japanese archipelago. Building on the successful validation of imputation with ancient Asian genomes, we identify selection signatures in the Jomon, particularly robust signals from KITLG variants, which may have influenced dark pigmentation evolution. The Jomon lacks well-known adaptive variants (EDAR, ADH1B, and ALDH2), marking their emergence after the advent of farming in the archipelago. Notably, the EDAR and ADH1B variants were prevalent in the archipelago 1,300 years ago, whereas the ALDH2 variant could have emerged later due to its absence in other ancient genomes. Overall, our study underpins local adaptation unique to the Jomon population, which in turn sheds light on post-farming selection that continues to shape contemporary Asian populations.

Crohn's disease risk alleles on the NOD2 locus have been maintained by natural selection on standing variation.

Risk alleles for complex diseases are widely spread throughout human populations. However, little is known about the geographic distribution and frequencies of risk alleles, which may contribute to differences in disease susceptibility and prevalence among populations. Here, we focus on Crohn's disease (CD) as a model for the evolutionary study of complex disease alleles. Recent genome-wide association studies and classical linkage analyses have identified more than 70 susceptible genomic regions for CD in Europeans, but only a few have been confirmed in non-European populations. Our analysis of eight European-specific susceptibility genes using HapMap data shows that at the NOD2 locus the CD-risk alleles are linked with a haplotype specific to CEU at a frequency that is significantly higher compared with the entire genome. We subsequently examined nine global populations and found that the CD-risk alleles spread through hitchhiking with a high-frequency haplotype (H1) exclusive to Europeans. To examine the neutrality of NOD2, we performed phylogenetic network analyses, coalescent simulation, protein structural prediction, characterization of mutation patterns, and estimations of population growth and time to most recent common ancestor (TMRCA). We found that while H1 was significantly prevalent in European populations, the H1 TMRCA predated human migration out of Africa. H1 is likely to have undergone negative selection because 1) the root of H1 genealogy is defined by a preexisting amino acid substitution that causes serious conformational changes to the NOD2 protein, 2) the haplotype has almost become extinct in Africa, and 3) the haplotype has not been affected by the recent European expansion reflected in the other haplotypes. Nevertheless, H1 has survived in European populations, suggesting that the haplotype is advantageous to this group. We propose that several CD-risk alleles, which destabilize and disrupt the NOD2 protein, have been maintained by natural selection on standing variation because the deleterious haplotype of NOD2 is advantageous in diploid individuals due to heterozygote advantage and/or intergenic interactions.

Biogeography revealed by mariner-like transposable element sequences via a Bayesian coalescent approach.

Genetic diversity of natural populations is useful in biogeographical studies. Here, we apply a Bayesian method based on the coalescent model to dating biogeographical events by using published DNA sequences of wild silkworms, Bombyx mandarina, and the domesticated model organisms B. mori, both of which categorized into the order of Lepidoptera, sampled from China, Korea, and Japan. The sequences consist of the BmTNML locus and the flanking intergenic regions. The BmTNML locus is composed of cecropia-type mariner-like element (MLE) with inverted terminal repeats, and three different transposable elements (TE), including L1BM, BMC1 retrotransposons, and BmamaT1, are inserted into the MLE. Based on the genealogy defined by TE insertions/deletions (indels), we estimated times to the most recent common ancestor and these indels events using the flanking, MLE, and indels sequences, respectively. These estimates by using MLE sequences strongly correlated with those by using flanking sequences, implying that cecropia-type MLEs can be used as a molecular clock. MLEs are thought to have transmitted horizontally among different species. By using a pair of published cecropia-type MLE sequences from lepidopteran insect, an emperor moth, and a coral in Ryukyu Islands, we demonstrated dating of horizontal transmission between species which are distantly related but inhabiting geographically close region.

Genomic insights into a tripartite ancestry in the Southern Ryukyu Islands.

A tripartite structure for the genetic origin of Japanese populations states that present-day populations are descended from three main ancestors: (1) the indigenous Jomon hunter-gatherers; (2) a Northeast Asian component that arrived during the agrarian Yayoi period; and (3) a major influx of East Asian ancestry in the imperial Kofun period. However, the genetic heterogeneity observed in different regions of the Japanese archipelago highlights the need to assess the applicability and suitability of this model. Here, we analyse historic genomes from the southern Ryukyu Islands, which have unique cultural and historical backgrounds compared with other parts of Japan. Our analysis supports the tripartite structure as the best fit in this region, with significantly higher estimated proportions of Jomon ancestry than mainland Japanese. Unlike the main islands, where each continental ancestor was directly brought by immigrants from the continent, those who already possessed the tripartite ancestor migrated to the southern Ryukyu Islands and admixed with the prehistoric people around the eleventh century AD, coinciding with the emergence of the Gusuku period. These results reaffirm the tripartite model in the southernmost extremes of the Japanese archipelago and show variability in how the structure emerged in diverse geographic regions.

Ancient genomics reveals tripartite origins of Japanese populations.

Prehistoric Japan underwent rapid transformations in the past 3000 years, first from foraging to wet rice farming and then to state formation. A long-standing hypothesis posits that mainland Japanese populations derive dual ancestry from indigenous Jomon hunter-gatherer-fishers and succeeding Yayoi farmers. However, the genomic impact of agricultural migration and subsequent sociocultural changes remains unclear. We report 12 ancient Japanese genomes from pre- and postfarming periods. Our analysis finds that the Jomon maintained a small effective population size of ~1000 over several millennia, with a deep divergence from continental populations dated to 20,000 to 15,000 years ago, a period that saw the insularization of Japan through rising sea levels. Rice cultivation was introduced by people with Northeast Asian ancestry. Unexpectedly, we identify a later influx of East Asian ancestry during the imperial Kofun period. These three ancestral components continue to characterize present-day populations, supporting a tripartite model of Japanese genomic origins.

Sex-specific phenotypic effects and evolutionary history of an ancient polymorphic deletion of the human growth hormone receptor.

The common deletion of the third exon of the growth hormone receptor gene (GHRd3) in humans is associated with birth weight, growth after birth, and time of puberty. However, its evolutionary history and the molecular mechanisms through which it affects phenotypes remain unresolved. We present evidence that this deletion was nearly fixed in the ancestral population of anatomically modern humans and Neanderthals but underwent a recent adaptive reduction in frequency in East Asia. We documented that GHRd3 is associated with protection from severe malnutrition. Using a novel mouse model, we found that, under calorie restriction, Ghrd3 leads to the female-like gene expression in male livers and the disappearance of sexual dimorphism in weight. The sex- and diet-dependent effects of GHRd3 in our mouse model are consistent with a model in which the allele frequency of GHRd3 varies throughout human evolution as a response to fluctuations in resource availability.

Population-specific susceptibility to Crohn's disease and ulcerative colitis; dominant and recessive relative risks in the Japanese population.

Crohn's disease (CD), a type of chronic inflammatory bowel disease (IBD), is commonly found in European and East Asian countries. The calculated heritability of CD appears to be higher than that of ulcerative colitis (UC), another type of IBD. Recent genome-wide association studies (GWAS) have identified more than thirty CD-associated genes/regions in the European population. In the East Asian population, however, a clear association between CD and an associated gene has only been detected with TNFSF15. In order to determine if CD susceptibility differs geographically, nine SNPs from seven of the European CD-associated genomic regions were selected for analysis. The genotype frequencies for these SNPs were compared among the 380 collected Japanese samples, which consisted of 212 IBD cases and 168 controls. We detected a significant association of both CD and UC with only the TNFSF15 gene. Analysis by the modified genotype relative risk test (mGRR) indicated that the risk allele of TNFSF15 is dominant for CD, but is recessive for UC. These results suggest that CD and UC susceptibility differs between the Japanese and European populations. Furthermore, it is also likely that CD and UC share a causative factor which exhibits a different dominant/recessive relative risk in the Japanese population.

The evolving Japanese: the dual structure hypothesis at 30.

The population history of Japan has been one of the most intensively studied anthropological questions anywhere in the world, with a huge literature dating back to the nineteenth century and before. A growing consensus over the 1980s that the modern Japanese comprise an admixture of a Neolithic population with Bronze Age migrants from the Korean peninsula was crystallised in Kazuro Hanihara's influential 'dual structure hypothesis' published in 1991. Here, we use recent research in biological anthropology, historical linguistics and archaeology to evaluate this hypothesis after three decades. Although the major assumptions of Hanihara's model have been supported by recent work, we discuss areas where new findings have led to a re-evaluation of aspects of the hypothesis and emphasise the need for further research in key areas including ancient DNA and archaeology.

Ancient Jomon genome sequence analysis sheds light on migration patterns of early East Asian populations.

Anatomically modern humans reached East Asia more than 40,000 years ago. However, key questions still remain unanswered with regard to the route(s) and the number of wave(s) in the dispersal into East Eurasia. Ancient genomes at the edge of the region may elucidate a more detailed picture of the peopling of East Eurasia. Here, we analyze the whole-genome sequence of a 2,500-year-old individual (IK002) from the main-island of Japan that is  characterized with a typical Jomon culture. The phylogenetic analyses support multiple waves of migration, with IK002 forming a basal lineage to the East and Northeast Asian genomes examined, likely representing some of the earliest-wave migrants who went north from Southeast Asia to East Asia. Furthermore, IK002 shows strong genetic affinity with the indigenous Taiwan aborigines, which may support a coastal route of the Jomon-ancestry migration. This study highlights the power of ancient genomics to provide new insights into the complex history of human migration into East Eurasia.

Unequal rates of Y chromosome gene divergence during speciation of the family Ursidae.

Evolution of the bear family Ursidae is well investigated in terms of morphological, paleontological, and genetic features. However, several phylogenetic ambiguities occur within the subfamily Ursinae (the family Ursidae excluding the giant panda and spectacled bear), which may correlate with behavioral traits of female philopatry and male-biased dispersal which form the basis of the observed matriarchal population structure in these species. In the process of bear evolution, we investigate the premise that such behavioral traits may be reflected in patterns of variation among genes with different modes of inheritance: matrilineal mitochondrial DNA (mtDNA), patrilineal Y chromosome, biparentally inherited autosomes, and the X chromosome. In the present study, we sequenced 3 Y-linked genes (3,453 bp) and 4 X-linked genes (4,960 bp) and reanalyzed previously published sequences from autosome genes (2,347 bp) in ursid species to investigate differences in evolutionary rates associated with patterns of inheritance. The results describe topological incongruence between sex-linked genes and autosome genes and between nuclear DNA and mtDNA. In more ancestral branches within the bear phylogeny, Y-linked genes evolved faster than autosome and X-linked genes, consistent with expectations based on male-driven evolution. However, this pattern changes among branches leading to each species within the lineage of Ursinae whereby the evolutionary rates of Y-linked genes have fewer than expected substitutions. This inconsistency between more recent nodes of the bear phylogeny with more ancestral nodes may reflect the influences of sex-biased dispersal as well as molecular evolutionary characteristics of the Y chromosome, and stochastic events in species natural history, and phylogeography unique to ursine bears.