Patterns of genetic variation in natural populations are shaped by, and hence carry valuable information about, the underlying recombination process. In the past five years, the increasing ...availability of large-scale population genetic data on dense sets of markers, coupled with advances in statistical methods for extracting information from these data, have led to several important advances in our understanding of the recombination process in humans. These advances include the identification of large numbers of ‘hotspots’, where recombination appears to take place considerably more frequently than in the surrounding sequence, and the identification of DNA sequence motifs that are associated with the locations of these hotspots.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK
The Inuit ancestors of the Greenlandic people arrived in Greenland close to 1,000 years ago.1 Since then, Europeans from many different countries have been present in Greenland. Consequently, the ...present-day Greenlandic population has ∼25% of its genetic ancestry from Europe.2 In this study, we investigated to what extent different European countries have contributed to this genetic ancestry. We combined dense SNP chip data from 3,972 Greenlanders and 8,275 Europeans from 14 countries and inferred the ancestry contribution from each of these 14 countries using haplotype-based methods. Due to the rapid increase in population size in Greenland over the past ∼100 years, we hypothesized that earlier European interactions, such as pre-colonial Dutch whalers and early German and Danish-Norwegian missionaries, as well as the later Danish colonists and post-colonial immigrants, all contributed European genetic ancestry. However, we found that the European ancestry is almost entirely Danish and that a substantial fraction is from admixture that took place within the last few generations.
•The present-day Greenlandic population has substantial amounts of European ancestry•Denmark is the main source of this European ancestry•There is little evidence of European ancestry from pre-colonial European contact•The timing of much of the European admixture is very recent
The Greenlandic Inuit have had extensive historical contact with Europeans, and the present-day Greenlandic population has substantial amounts of European ancestry. Waples et al. use genetic data to investigate the origin of this ancestry. They show that much of it is Danish and find little evidence of it being from pre-colonial European contact.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
We analysed DNA methylation data from 30 datasets comprising 3474 individuals, 19 tissues and 8 ethnicities at CpGs covered by the Illumina450K array. We identified 4143 hypervariable CpGs ('hvCpGs') ...with methylation in the top 5% most variable sites across multiple tissues and ethnicities. hvCpG methylation was influenced but not determined by genetic variation, and was not linked to probe reliability, epigenetic drift, age, sex or cell heterogeneity effects. hvCpG methylation tended to covary across tissues derived from different germ-layers and hvCpGs were enriched for proximity to ERV1 and ERVK retrovirus elements. hvCpGs were also enriched for loci previously associated with periconceptional environment, parent-of-origin-specific methylation, and distinctive methylation signatures in monozygotic twins. Together, these properties position hvCpGs as strong candidates for studying how stochastic and/or environmentally influenced DNA methylation states which are established in the early embryo and maintained stably thereafter can influence life-long health and disease.
Abstract
American populations are one of the most interesting examples of recently admixed groups, where ancestral components from three major continental human groups (Africans, Eurasians and Native ...Americans) have admixed within the last 15 generations. Recently, several genetic surveys focusing on thousands of individuals shed light on the geography, chronology and relevance of these events. However, even though gene flow could drive adaptive evolution, it is unclear whether and how natural selection acted on the resulting genetic variation in the Americas.
In this study, we analysed the patterns of local ancestry of genomic fragments in genome-wide data for ~ 6000 admixed individuals from 10 American countries. In doing so, we identified regions characterized by a divergent ancestry profile (DAP), in which a significant over or under ancestral representation is evident.
Our results highlighted a series of genomic regions with DAPs associated with immune system response and relevant medical traits, with the longest DAP region encompassing the human leukocyte antigen locus. Furthermore, we found that DAP regions are enriched in genes linked to cancer-related traits and autoimmune diseases. Then, analysing the biological impact of these regions, we showed that natural selection could have acted preferentially towards variants located in coding and non-coding transcripts and characterized by a high deleteriousness score.
Taken together, our analyses suggest that shared patterns of post admixture adaptation occurred at a continental scale in the Americas, affecting more often functional and impactful genomic variants.
Oesophageal cancer (EC) is the sixth leading cause of cancer-related deaths. Oesophageal adenocarcinoma (EA), with Barrett's oesophagus (BE) as a precursor lesion, is the most prevalent EC subtype in ...the Western world. This study aims to contribute to better understand the genetic causes of BE/EA by leveraging genome wide association studies (GWAS), genetic correlation analyses and polygenic risk modelling.
We combined data from previous GWAS with new cohorts, increasing the sample size to 16 790 BE/EA cases and 32 476 controls. We also carried out a transcriptome wide association study (TWAS) using expression data from disease-relevant tissues to identify BE/EA candidate genes. To investigate the relationship with reported BE/EA risk factors, a linkage disequilibrium score regression (LDSR) analysis was performed. BE/EA risk models were developed combining clinical/lifestyle risk factors with polygenic risk scores (PRS) derived from the GWAS meta-analysis.
The GWAS meta-analysis identified 27 BE and/or EA risk loci, 11 of which were novel. The TWAS identified promising BE/EA candidate genes at seven GWAS loci and at five additional risk loci. The LDSR analysis led to the identification of novel genetic correlations and pointed to differences in BE and EA aetiology. Gastro-oesophageal reflux disease appeared to contribute stronger to the metaplastic BE transformation than to EA development. Finally, combining PRS with BE/EA risk factors improved the performance of the risk models.
Our findings provide further insights into BE/EA aetiology and its relationship to risk factors. The results lay the foundation for future follow-up studies to identify underlying disease mechanisms and improving risk prediction.
Few phenomena have had as profound or long-lasting consequences in human history as the emergence of large-scale centralized states in the place of smaller scale and more local societies. This study ...examines a fundamental, and yet unexplored, consequence of state formation: its genetic legacy. We studied the genetic impact of state centralization during the formation of the eminent precolonial Kuba Kingdom of the Democratic Republic of the Congo (DRC) in the 17th century. We analyzed genome-wide data from over 690 individuals sampled from 27 different ethnic groups from the Kasai Central Province of the DRC. By comparing genetic patterns in the present-day Kuba, whose ancestors were part of the Kuba Kingdom, with those in neighboring non-Kuba groups, we show that the Kuba today are more genetically diverse and more similar to other groups in the region than expected, consistent with the historical unification of distinct subgroups during state centralization. We also found evidence of genetic mixing dating to the time of the Kingdom at its most prominent. Using this unique dataset, we characterize the genetic history of the Kasai Central Province and describe the historic late wave of migrations into the region that contributed to a Bantu-like ancestry component found across large parts of Africa today. Taken together, we show the power of genetics to evidence events of sociopolitical importance and highlight how DNA can be used to better understand the behaviors of both people and institutions in the past.
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BFBNIB, NMLJ, NUK, PNG, SAZU, UL, UM, UPUK
Background We performed a genome-wide association study (GWAS) to identify common risk variants for schizophrenia. Methods The discovery scan included 1606 patients and 1794 controls from Ireland, ...using 6,212,339 directly genotyped or imputed single nucleotide polymorphisms (SNPs). A subset of this sample (270 cases and 860 controls) was subsequently included in the Psychiatric GWAS Consortium-schizophrenia GWAS meta-analysis. Results One hundred eight SNPs were taken forward for replication in an independent sample of 13,195 cases and 31,021 control subjects. The most significant associations in discovery, corrected for genomic inflation, were (rs204999, p combined = 1.34 × 10−9 and in combined samples (rs2523722 p combined = 2.88 × 10−16 ) mapped to the major histocompatibility complex (MHC) region. We imputed classical human leukocyte antigen (HLA) alleles at the locus; the most significant finding was with HLA-C*01:02. This association was distinct from the top SNP signal. The HLA alleles DRB1*03:01 and B*08:01 were protective, replicating a previous study. Conclusions This study provides further support for involvement of MHC class I molecules in schizophrenia. We found evidence of association with previously reported risk alleles at the TCF4 , VRK2, and ZNF804A loci.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK
Abstract
Throughout human evolutionary history, large-scale migrations have led to intermixing (i.e., admixture) between previously separated human groups. Although classical and recent work have ...shown that studying admixture can yield novel historical insights, the extent to which this process contributed to adaptation remains underexplored. Here, we introduce a novel statistical model, specific to admixed populations, that identifies loci under selection while determining whether the selection likely occurred post-admixture or prior to admixture in one of the ancestral source populations. Through extensive simulations, we show that this method is able to detect selection, even in recently formed admixed populations, and to accurately differentiate between selection occurring in the ancestral or admixed population. We apply this method to genome-wide SNP data of ∼4,000 individuals in five admixed Latin American cohorts from Brazil, Chile, Colombia, Mexico, and Peru. Our approach replicates previous reports of selection in the human leukocyte antigen region that are consistent with selection post-admixture. We also report novel signals of selection in genomic regions spanning 47 genes, reinforcing many of these signals with an alternative, commonly used local-ancestry-inference approach. These signals include several genes involved in immunity, which may reflect responses to endemic pathogens of the Americas and to the challenge of infectious disease brought by European contact. In addition, some of the strongest signals inferred to be under selection in the Native American ancestral groups of modern Latin Americans overlap with genes implicated in energy metabolism phenotypes, plausibly reflecting adaptations to novel dietary sources available in the Americas.
Over the past few years, studies of DNA isolated from human fossils and archaeological remains have generated considerable novel insight into the history of our species. Several landmark papers have ...described the genomes of ancient humans across West Eurasia, demonstrating the presence of large-scale, dynamic population movements over the last 10,000 years, such that ancestry across present-day populations is likely to be a mixture of several ancient groups 1–7. While these efforts are bringing the details of West Eurasian prehistory into increasing focus, studies aimed at understanding the processes behind the generation of the current West Eurasian genetic landscape have been limited by the number of populations sampled or have been either too regional or global in their outlook 8–11. Here, using recently described haplotype-based techniques 11, we present the results of a systematic survey of recent admixture history across Western Eurasia and show that admixture is a universal property across almost all groups. Admixture in all regions except North Western Europe involved the influx of genetic material from outside of West Eurasia, which we date to specific time periods. Within Northern, Western, and Central Europe, admixture tended to occur between local groups during the period 300 to 1200 CE. Comparisons of the genetic profiles of West Eurasians before and after admixture show that population movements within the last 1,500 years are likely to have maintained differentiation among groups. Our analysis provides a timeline of the gene flow events that have generated the contemporary genetic landscape of West Eurasia.
•Recent admixture events involved outside groups at the edges of West Eurasia•Admixture within Europe tended to fall within the European Migration Period•West Eurasian genetic structure today is likely to have been maintained by admixture
Using cutting edge statistical machinery, Busby et al. show that recent admixture is ubiquitous across West Eurasia, with the majority of populations showing evidence of population mixing. Dating of these admixture events demonstrates that the Medieval Migration Period was a key period in establishing the current West Eurasian genetic landscape.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
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