A global reference for human genetic variation.
TL;DR: 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, and has reconstructed the genomes of 2,504 individuals from 26 populations using a combination of low-coverage whole-generation sequencing, deep exome sequencing, and dense microarray genotyping.
Abstract: 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.
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TL;DR: Graphtyper as discussed by the authors realigns short-read sequence data to a pangenome, a variation-aware graph structure that encodes sequence variation within a population by representing possible haplotypes as graph paths.
Abstract: A fundamental requirement for genetic studies is an accurate determination of sequence variation. While human genome sequence diversity is increasingly well characterized, there is a need for efficient ways to use this knowledge in sequence analysis. Here we present Graphtyper, a publicly available novel algorithm and software for discovering and genotyping sequence variants. Graphtyper realigns short-read sequence data to a pangenome, a variation-aware graph structure that encodes sequence variation within a population by representing possible haplotypes as graph paths. Our results show that Graphtyper is fast, highly scalable, and provides sensitive and accurate genotype calls. Graphtyper genotyped 89.4 million sequence variants in the whole genomes of 28,075 Icelanders using less than 100,000 CPU days, including detailed genotyping of six human leukocyte antigen (HLA) genes. We show that Graphtyper is a valuable tool in characterizing sequence variation in both small and population-scale sequencing studies.
172 citations
TL;DR: The items used to measure neuroticism are genetically heterogeneous, and that biological understanding can be gained by studying them in genetically more homogeneous clusters, and genetic heterogeneity at the item-level is demonstrated.
Abstract: Genome-wide association studies (GWAS) of psychological traits are generally conducted on (dichotomized) sums of items or symptoms (e.g., case-control status), and not on the individual items or symptoms themselves. We conduct large-scale GWAS on 12 neuroticism items and observe notable and replicable variation in genetic signal between items. Within samples, genetic correlations among the items range between 0.38 and 0.91 (mean rg = .63), indicating genetic heterogeneity in the full item set. Meta-analyzing the two samples, we identify 255 genome-wide significant independent genomic regions, of which 138 are item-specific. Genetic analyses and genetic correlations with 33 external traits support genetic differences between the items. Hierarchical clustering analysis identifies two genetically homogeneous item clusters denoted depressed affect and worry. We conclude that the items used to measure neuroticism are genetically heterogeneous, and that biological understanding can be gained by studying them in genetically more homogeneous clusters.
172 citations
University of Leicester1, National Institute for Health Research2, University of Nottingham3, Queen's University Belfast4, University of Birmingham5, University of Glasgow6, University of Southampton7, Manchester Academic Health Science Centre8, National Institutes of Health9, University of Amsterdam10, Sir Charles Gairdner Hospital11, Imperial College London12, University of British Columbia13, University Medical Center Groningen14, Merck & Co.15, Laval University16
TL;DR: It is found that substantial shared genetic architecture between mild and moderate-to-severe asthma is found and candidate causal genes in these loci are identified and provide increased insight into this difficult to treat population.
171 citations
TL;DR: The idea that telomere dysfunction is involved in IPF pathogenesis is supported, as whole‐exome sequencing data identified TERT, RTEL1, and PARN—three telomeres‐related genes previously implicated in familial pulmonary fibrosis—as significant contributors to sporadic IPF.
Abstract: Rationale: Idiopathic pulmonary fibrosis (IPF) is an increasingly recognized, often fatal lung disease of unknown etiology.Objectives: The aim of this study was to use whole-exome sequencing to improve understanding of the genetic architecture of pulmonary fibrosis.Methods: We performed a case–control exome-wide collapsing analysis including 262 unrelated individuals with pulmonary fibrosis clinically classified as IPF according to American Thoracic Society/European Respiratory Society/Japanese Respiratory Society/Latin American Thoracic Association guidelines (81.3%), usual interstitial pneumonia secondary to autoimmune conditions (11.5%), or fibrosing nonspecific interstitial pneumonia (7.2%). The majority (87%) of case subjects reported no family history of pulmonary fibrosis.Measurements and Main Results: We searched 18,668 protein-coding genes for an excess of rare deleterious genetic variation using whole-exome sequence data from 262 case subjects with pulmonary fibrosis and 4,141 control subjects d...
170 citations
TL;DR: A tractable model of ordinary differential equations for the evolution of allele frequencies that is closely related to the diffusion approximation but avoids many of its limitations and approximations is proposed.
Abstract: Understanding variation in allele frequencies across populations is a central goal of population genetics. Classical models for the distribution of allele frequencies, using forward simulation, coalescent theory, or the diffusion approximation, have been applied extensively for demographic inference, medical study design, and evolutionary studies. Here we propose a tractable model of ordinary differential equations for the evolution of allele frequencies that is closely related to the diffusion approximation but avoids many of its limitations and approximations. We show that the approach is typically faster, more numerically stable, and more easily generalizable than the state-of-the-art software implementation of the diffusion approximation. We present a number of applications to human sequence data, including demographic inference with a five-population joint frequency spectrum and a discussion of the robustness of the out-of-Africa model inference to the choice of modern population.
168 citations
References
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TL;DR: A new approach to rapid sequence comparison, basic local alignment search tool (BLAST), directly approximates alignments that optimize a measure of local similarity, the maximal segment pair (MSP) score.
88,255 citations
TL;DR: SAMtools as discussed by the authors implements various utilities for post-processing alignments in the SAM format, such as indexing, variant caller and alignment viewer, and thus provides universal tools for processing read alignments.
Abstract: Summary: The Sequence Alignment/Map (SAM) format is a generic alignment format for storing read alignments against reference sequences, supporting short and long reads (up to 128 Mbp) produced by different sequencing platforms. It is flexible in style, compact in size, efficient in random access and is the format in which alignments from the 1000 Genomes Project are released. SAMtools implements various utilities for post-processing alignments in the SAM format, such as indexing, variant caller and alignment viewer, and thus provides universal tools for processing read alignments.
Availability: http://samtools.sourceforge.net
Contact: [email protected]
45,957 citations
TL;DR: A new software suite for the comparison, manipulation and annotation of genomic features in Browser Extensible Data (BED) and General Feature Format (GFF) format, which allows the user to compare large datasets (e.g. next-generation sequencing data) with both public and custom genome annotation tracks.
Abstract: Motivation: Testing for correlations between different sets of genomic features is a fundamental task in genomics research. However, searching for overlaps between features with existing webbased methods is complicated by the massive datasets that are routinely produced with current sequencing technologies. Fast and flexible tools are therefore required to ask complex questions of these data in an efficient manner. Results: This article introduces a new software suite for the comparison, manipulation and annotation of genomic features in Browser Extensible Data (BED) and General Feature Format (GFF) format. BEDTools also supports the comparison of sequence alignments in BAM format to both BED and GFF features. The tools are extremely efficient and allow the user to compare large datasets (e.g. next-generation sequencing data) with both public and custom genome annotation tracks. BEDTools can be combined with one another as well as with standard UNIX commands, thus facilitating routine genomics tasks as well as pipelines that can quickly answer intricate questions of large genomic datasets. Availability and implementation: BEDTools was written in C++. Source code and a comprehensive user manual are freely available at http://code.google.com/p/bedtools
18,858 citations
TL;DR: The Encyclopedia of DNA Elements project provides new insights into the organization and regulation of the authors' genes and genome, and is an expansive resource of functional annotations for biomedical research.
Abstract: The human genome encodes the blueprint of life, but the function of the vast majority of its nearly three billion bases is unknown. The Encyclopedia of DNA Elements (ENCODE) project has systematically mapped regions of transcription, transcription factor association, chromatin structure and histone modification. These data enabled us to assign biochemical functions for 80% of the genome, in particular outside of the well-studied protein-coding regions. Many discovered candidate regulatory elements are physically associated with one another and with expressed genes, providing new insights into the mechanisms of gene regulation. The newly identified elements also show a statistical correspondence to sequence variants linked to human disease, and can thereby guide interpretation of this variation. Overall, the project provides new insights into the organization and regulation of our genes and genome, and is an expansive resource of functional annotations for biomedical research.
13,548 citations
TL;DR: VCFtools is a software suite that implements various utilities for processing VCF files, including validation, merging, comparing and also provides a general Perl API.
Abstract: Summary: The variant call format (VCF) is a generic format for storing DNA polymorphism data such as SNPs, insertions, deletions and structural variants, together with rich annotations. VCF is usually stored in a compressed manner and can be indexed for fast data retrieval of variants from a range of positions on the reference genome. The format was developed for the 1000 Genomes Project, and has also been adopted by other projects such as UK10K, dbSNP and the NHLBI Exome Project. VCFtools is a software suite that implements various utilities for processing VCF files, including validation, merging, comparing and also provides a general Perl API.
Availability: http://vcftools.sourceforge.net
Contact: [email protected]
10,164 citations