Insights into human genetic variation and population history from 929 diverse genomes.

Genome sequences from diverse human groups are needed to understand the structure of genetic variation in our species and the history of, and relationships between, different populations. We present 929 high-coverage genome sequences from 54 diverse human populations, 26 of which are physically phased using linked-read sequencing. Analyses of these genomes reveal an excess of previously undocumented common genetic variation private to southern Africa, central Africa, Oceania, and the Americas, but an absence of such variants fixed between major geographical regions.

Distance from sub-Saharan Africa predicts mutational load in diverse human genomes.

The Out-of-Africa (OOA) dispersal ∼ 50,000 y ago is characterized by a series of founder events as modern humans expanded into multiple continents. Population genetics theory predicts an increase of mutational load in populations undergoing serial founder effects during range expansions. To test this hypothesis, we have sequenced full genomes and high-coverage exomes from seven geographically divergent human populations from Namibia, Congo, Algeria, Pakistan, Cambodia, Siberia, and Mexico.

Transcriptome sequencing from diverse human populations reveals differentiated regulatory architecture.

Large-scale sequencing efforts have documented extensive genetic variation within the human genome. However, our understanding of the origins, global distribution, and functional consequences of this variation is far from complete. While regulatory variation influencing gene expression has been studied within a handful of populations, the breadth of transcriptome differences across diverse human populations has not been systematically analyzed.

The complete genome sequence of a Neanderthal from the Altai Mountains.

We present a high-quality genome sequence of a Neanderthal woman from Siberia. We show that her parents were related at the level of half-siblings and that mating among close relatives was common among her recent ancestors. We also sequenced the genome of a Neanderthal from the Caucasus to low coverage.

Positive selection in the chromosome 16 VKORC1 genomic region has contributed to the variability of anticoagulant response in humans.

VKORC1 (vitamin K epoxide reductase complex subunit 1, 16p11.2) is the main genetic determinant of human response to oral anticoagulants of antivitamin K type (AVK). This gene was recently suggested to be a putative target of positive selection in East Asian populations.

Similarity in recombination rate and linkage disequilibrium at CYP2C and CYP2D cytochrome P450 gene regions among Europeans indicates signs of selection and no advantage of using tagSNPs in population isolates.

Objective: Linkage disequilibrium (LD) and recombination rate variations are known to vary considerably between human genome regions and populations mostly because of the combined effects of mutation, recombination, and demographic history. Thus, the pattern of LD is a key issue to disentangle variants associated with complex traits. Here, we aim to describe the haplotype structure and LD variation at the pharmacogenetically relevant cytochrome P450 CYP2C and CYP2D gene regions among European populations.

Consanguinity around the world: what do the genomic data of the HGDP-CEPH diversity panel tell us?

Inbreeding coefficients and consanguineous mating types are usually inferred from population surveys or pedigree studies. Here, we present a method to estimate them from dense genome-wide single-nucleotide polymorphism genotypes and apply it to 940 unrelated individuals from the Human Genome Diversity Panel (HGDP-CEPH). Inbreeding is observed in almost all populations of the panel, and the highest inbreeding levels and frequencies of inbred individuals are found in populations of the Middle East, Central South Asia and the Americas.

Building the sequence map of the human pan-genome.

Here we integrate the de novo assembly of an Asian and an African genome with the NCBI reference human genome, as a step toward constructing the human pan-genome. We identified approximately 5 Mb of novel sequences not present in the reference genome in each of these assemblies. Most novel sequences are individual or population specific, as revealed by their comparison to all available human DNA sequence and by PCR validation using the human genome diversity cell line panel.

Worldwide human relationships inferred from genome-wide patterns of variation.

Human genetic diversity is shaped by both demographic and biological factors and has fundamental implications for understanding the genetic basis of diseases. We studied 938 unrelated individuals from 51 populations of the Human Genome Diversity Panel at 650,000 common single-nucleotide polymorphism loci. Individual ancestry and population substructure were detectable with very high resolution.

Genotype, haplotype and copy-number variation in worldwide human populations.

Genome-wide patterns of variation across individuals provide a powerful source of data for uncovering the history of migration, range expansion, and adaptation of the human species. However, high-resolution surveys of variation in genotype, haplotype and copy number have generally focused on a small number of population groups. Here we report the analysis of high-quality genotypes at 525,910 single-nucleotide polymorphisms (SNPs) and 396 copy-number-variable loci in a worldwide sample of 29 populations.

Sequence variants of estrogen receptor beta and risk of prostate cancer in the National Cancer Institute Breast and Prostate Cancer Cohort Consortium.

Background: Estrogen receptor beta (ESR2) may play a role in modulating prostate carcinogenesis through the regulation of genes related to cell proliferation and apoptosis.

Methods: We conducted nested case-control studies in the Breast and Prostate Cancer Cohort Consortium (BPC3) that pooled 8,323 prostate cancer cases and 9,412 controls from seven cohorts. Whites were the predominant ethnic group.

Haplotype analysis of the HSD17B1 gene and risk of breast cancer: a comprehensive approach to multicenter analyses of prospective cohort studies.

The 17beta-hydroxysteroid dehydrogenase 1 gene (HSD17B1) encodes 17HSD1, which catalyzes the final step of estradiol biosynthesis. Despite the important role of HSD17B1 in hormone metabolism, few epidemiologic studies of HSD17B1 and breast cancer have been conducted. This study includes 5,370 breast cancer cases and 7,480 matched controls from five large cohorts in the Breast and Prostate Cancer Cohort Consortium.

The portability of tagSNPs across populations: a worldwide survey.

In the search for common genetic variants that contribute to prevalent human diseases, patterns of linkage disequilibrium (LD) among linked markers should be considered when selecting SNPs. Genotyping efficiency can be increased by choosing tagging SNPs (tagSNPs) in LD with other SNPs. However, it remains to be seen whether tagSNPs defined in one population efficiently capture LD in other populations; that is, how portable tagSNPs are.

Genetic variation in the HSD17B1 gene and risk of prostate cancer.

Steroid hormones are believed to play an important role in prostate carcinogenesis, but epidemiological evidence linking prostate cancer and steroid hormone genes has been inconclusive, in part due to small sample sizes or incomplete characterization of genetic variation at the locus of interest. Here we report on the results of a comprehensive study of the association between HSD17B1 and prostate cancer by the Breast and Prostate Cancer Cohort Consortium, a large collaborative study. HSD17B1 encodes 17beta-hydroxysteroid dehydrogenase 1, an enzyme that converts dihydroepiandrosterone to the testosterone precursor Delta5-androsterone-3beta,17beta-diol and converts estrone to estradiol.

The heritage of pathogen pressures and ancient demography in the human innate-immunity CD209/CD209L region.

The innate immunity system constitutes the first line of host defense against pathogens. Two closely related innate immunity genes, CD209 and CD209L, are particularly interesting because they directly recognize a plethora of pathogens, including bacteria, viruses, and parasites. Both genes, which result from an ancient duplication, possess a neck region, made up of seven repeats of 23 amino acids each, known to play a major role in the pathogen-binding properties of these proteins.

Geographic stratification of linkage disequilibrium: a worldwide population study in a region of chromosome 22.

Recent studies of haplotype diversity in a number of genomic regions have suggested that long stretches of DNA are preserved in the same chromosome, with little evidence of recombination events. The knowledge of the extent and strength of these haplotypes could become a powerful tool for future genetic analysis of complex traits. Different patterns of linkage disequilibrium (LD) have been found when comparing individuals of African and European descent, but there is scarce knowledge about the worldwide population stratification.

A 3.9-centimorgan-resolution human single-nucleotide polymorphism linkage map and screening set.

Recent advances in technologies for high-throughout single-nucleotide polymorphism (SNP)-based genotyping have improved efficiency and cost so that it is now becoming reasonable to consider the use of SNPs for genomewide linkage analysis. However, a suitable screening set of SNPs and a corresponding linkage map have yet to be described. The SNP maps described here fill this void and provide a resource for fast genome scanning for disease genes.

Genetic structure of human populations.

We studied human population structure using genotypes at 377 autosomal microsatellite loci in 1056 individuals from 52 populations. Within-population differences among individuals account for 93 to 95% of genetic variation; differences among major groups constitute only 3 to 5%. Nevertheless, without using prior information about the origins of individuals, we identified six main genetic clusters, five of which correspond to major geographic regions, and subclusters that often correspond to individual populations.