The 1000 Genomes Project set out to provide a comprehensive description of common human genetic variation by applying whole-genome sequencing to a diverse set of individuals from multiple populations. Here we report completion of the project, having reconstructed the genomes of 2,504 individuals from 26 populations using a combination of low-coverage whole-genome sequencing, deep exome sequencing, and dense microarray genotyping. We characterized a broad spectrum of genetic variation, in total over 88 million variants (84.7 million single nucleotide polymorphisms (SNPs), 3.6 million short insertions/deletions (indels), and 60,000 structural variants), all phased onto high-quality haplotypes. This resource includes >99% of SNP variants with a frequency of >1% for a variety of ancestries. We describe the distribution of genetic variation across the global sample, and discuss the implications for common disease studies.

The past fifty years have seen the development and application of numerous statistical methods to identify genomic regions that appear to be shaped by natural selection. These methods have been used to investigate the macro-and microevolution of a broad range of organisms, including humans. Here we provide a comprehensive outline of these methods, explaining their conceptual motivations and statistical interpretations. We highlight areas of recent and future development in evolutionary genomics methods, and discuss ongoing challenges for researchers employing such tests. In particular, we emphasize the importance of functional follow-up studies to characterize putative selected alleles, and the use of selection scans as hypothesis-generating tools for investigating evolutionary histories.

Summary The 2013-2015 West African epidemic of Ebola virus disease (EVD) reminds us how little is known about biosafety level-4 viruses. Like Ebola virus, Lassa virus (LASV) can cause hemorrhagic fever with high case fatality rates. We generated a genomic catalog of almost 200 LASV sequences from clinical and rodent reservoir samples. We show that whereas the 2013-2015 EVD epidemic is fueled by human-to-human transmissions, LASV infections mainly result from reservoir-to-human infections. We elucidated the spread of LASV across West Africa and show that this migration was accompanied by changes in LASV genome abundance, fatality rates, codon adaptation, and translational efficiency. By investigating intrahost evolution, we found that mutations accumulate in epitopes of viral surface proteins, suggesting selection for immune escape. This catalog will serve as a foundation for the development of vaccines and diagnostics.

Methods to identify signatures of selective sweeps in population genomics data have been actively developed, but mostly do not identify the specific mutation favored by selection. We present a method, iSAFE, that uses a statistic derived solely from population genetics signals to accurately pinpoint the favored mutation in a large region (~5 Mbp). iSAFE does not require any knowledge of demography, specific phenotype under selection, or functional annotations of mutations.

No abstract

Genome-wide computational studies can now identify targets of natural selection. The unique information about humans these studies reveal – and the media attention they attract – indicate the need for caution and precision in communicating results. This need is exacerbated by ways evolutionary and genetic considerations have been misapplied to support discriminatory policies, by persistent misconceptions of these fields, and by the social sensitivity surrounding discussions of racial ancestry. We discuss the foundations, accomplishments and future directions of evolutionary genomics, attending to ways the interpretation of good science can go awry, and offer suggestions for researchers to prevent misapplication of their work.

No abstract

While genome-wide association studies (GWAS) and selection scans identify genomic loci driving human phenotypic diversity, functional validation is required to discover the variant(s) responsible. We dissected the IVD locus, implicated by selection statistics, multiple GWAS, and clinical genetics as important to function and fitness. We combined luciferase assays, CRISPR/Cas9 genome-editing, massively parallel reporter assays (MPRA), and bashing of regulatory loci. We identified three regulatory variants, including an indel, that may underpin GWAS signals for pulmonary fibrosis and testosterone, and that are linked on a positively selected haplotype in the Japanese population. These regulatory variants exhibit synergistic and opposing effects on IVD expression experimentally. Alleles at these variants lie on a haplotype tagged by the variant most strongly associated with IVD expression and metabolites, but with no functional evidence itself. This work demonstrates how comprehensive functional investigation and multiple technologies are needed to discover the true genetic drivers of phenotypic diversity.