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.

Summary Structural variants (SVs) are implicated in numerous diseases and make up the majority of varying nucleotides among human genomes. Here we describe an integrated set of eight SV classes comprising both balanced and unbalanced variants, which we constructed using short-read DNA sequencing data and statistically phased onto haplotype-blocks in 26 human populations. Analyzing this set, we identify numerous gene-intersecting SVs exhibiting population stratification and describe naturally occurring homozygous gene knockouts suggesting the dispensability of a variety of human genes. We demonstrate that SVs are enriched on haplotypes identified by genome-wide association studies and exhibit enrichment for expression quantitative trait loci. Additionally, we uncover appreciable levels of SV complexity at different scales, including genic loci subject to clusters of repeated rearrangement and complex SVs with multiple breakpoints likely formed through individual mutational events. Our catalog will enhance future studies into SV demography, functional impact and disease association.

The best understood system for the transport of macromolecules between the cytoplasm and the nucleus is the classical nuclear import pathway. In this pathway, a protein containing a classical basic nuclear localization signal (NLS) is imported by a heterodimeric import receptor consisting of the ␤-karyopherin importin ␤, which mediates interactions with the nuclear pore complex, and the adaptor protein importin ␣, which directly binds the classical NLS. Here we review recent studies that have advanced our understanding of this pathway and also take a bioinformatics approach to analyze the likely prevalence of this system in vivo. Finally, we describe how a predicted NLS within a protein of interest can be confirmed experimentally to be functionally important.In eukaryotic cells, the genetic material and transcriptional machinery of the nucleus are separated from the translational machinery and metabolic systems of the cytoplasm by the nuclear envelope. This segregation facilitates the precise regulation of cellular processes such as gene expression (1), signal transduction (2), and cell cycle progression (3) through selective regulation of bidirectional transport between the nucleus and the cytoplasm. However, this physical separation also necessitates the existence of molecular machinery that specifically recognizes cargo in one compartment, translocates it through the nuclear pore, and releases it in the other compartment. Nuclear transport systems of this kind were first proposed when a nuclear targeting signal in the simian virus 40 (SV40) 2 large T antigen was characterized more than 20 years ago (4, 5). Since then, several pathways for nucleocytoplasmic transport have been described, of which the classical nuclear import pathway is the best characterized. The integration of detailed structural information on the components of the pathway, whole genome surveys, and extensive molecular analysis has generated powerful insight into the crucial interactions that underlie this pathway. Here we review recent studies that have defined key aspects of the cargo/import receptor interaction in the classical nuclear import cycle and present results of a bioinformatics-based assessment of the likely prevalence of this system within the model eukaryotic organism, Saccharomyces cerevisiae. Overview of Nucleocytoplasmic TransportTransport of macromolecules into and out of the nucleus occurs through large, proteinaceous structures called nuclear pore complexes (NPCs) (6 -9). Nuclear pore complexes allow passive diffusion of ions and small proteins (Ͻ40 kDa) but restrict passage of larger molecules to those containing an appropriate targeting signal (10, 11). The pores are constructed from a class of proteins called "nucleoporins," a subset of which contains a tandem series of phenylalanine-glycine (FG) repeats that line the central transport channel of the pore (8,(12)(13)(14).The active transport of macromolecular cargo between the cytoplasmic and nuclear compartments is facilitated by specific soluble carrier proteins. Th...

Long-read and strand-specific sequencing technologies together facilitate the de novo assembly of high-quality haplotype-resolved human genomes without parent–child trio data. We present 64 assembled haplotypes from 32 diverse human genomes. These highly contiguous haplotype assemblies (average contig N50: 26 Mbp) integrate all forms of genetic variation even across complex loci. We identify 107,590 structural variants (SVs), of which 68% are not discovered by short-read sequencing, and 278 SV hotspots (spanning megabases of gene-rich sequence). We characterize 130 of the most active mobile element source elements and find that 63% of all SVs arise by homology-mediated mechanisms. This resource enables reliable graph-based genotyping from short reads of up to 50,340 SVs, resulting in the identification of 1,526 expression quantitative trait loci as well as SV candidates for adaptive selection within the human population.

The incomplete identification of structural variants (SVs) from whole-genome sequencing data limits studies of human genetic diversity and disease association. Here, we apply a suite of long-read, short-read, strand-specific sequencing technologies, optical mapping, and variant discovery algorithms to comprehensively analyze three trios to define the full spectrum of human genetic variation in a haplotype-resolved manner. We identify 818,054 indel variants (<50 bp) and 27,622 SVs (≥50 bp) per genome. We also discover 156 inversions per genome and 58 of the inversions intersect with the critical regions of recurrent microdeletion and microduplication syndromes. Taken together, our SV callsets represent a three to sevenfold increase in SV detection compared to most standard high-throughput sequencing studies, including those from the 1000 Genomes Project. The methods and the dataset presented serve as a gold standard for the scientific community allowing us to make recommendations for maximizing structural variation sensitivity for future genome sequencing studies.