Analysis of protein-coding genetic variation in 60,706 humans

Abstract

SummaryLarge-scale reference data sets of human genetic variation are critical for the medical and functional interpretation of DNA sequence changes. We describe the aggregation and analysis of high-quality exome (protein-coding region) sequence data for 60,706 individuals of diverse ethnicities generated as part of the Exome Aggregation Consortium (ExAC). This catalogue of human genetic diversity contains an average of one variant every eight bases of the exome, and provides direct evidence for the presence of widespread mutational recurrence. We have used this catalogue to calculate objective metrics of pathogenicity for sequence variants, and to identify genes subject to strong selection against various classes of mutation; identifying 3,230 genes with near-complete depletion of truncating variants with 72% having no currently established human disease phenotype. Finally, we demonstrate that these data can be used for the efficient filtering of candidate disease-causing variants, and for the discovery of human "knockout" variants in proteincoding genes. BackgroundOver the last five years, the widespread availability of high-throughput DNA sequencing technologies has permitted the sequencing of the whole genomes or exomes (the proteincoding regions of genomes) of hundreds of thousands of humans. In theory, these data represent a powerful source of information about the global patterns of human genetic variation, but in practice, are difficult to access for practical, logistical, and ethical reasons; in addition, their utility is complicated by the heterogeneity in the experimental methodologies and variant calling pipelines used to generate them. Current publicly available datasets of human DNA sequence variation contain only a small fraction of all Users may view, print, copy, and download text and data-mine the content in such documents, for the purposes of academic research, subject always to the full Conditions of use

Inherited platelet disorders: toward DNA-based diagnosis

“…Several initiatives such as the 1000 Genomes 89 and UK10K 90 projects and initiatives to aggregate results from many smaller WES projects, as achieved by the Exome Aggregation Consortium (ExAC), 91 have provided information on exonic variants observed in .71 000 individuals of mainly European ancestry. This catalog has made an immense contribution to improving the accuracy of assignment of pathogenicity to DNA variants observed in IPD cases.…”

Scaling accurate genetic variant discovery to tens of thousands of samples

“…and medical genetic studies [18,4,25,14]. Although high-throughput sequencing platforms currently generate up to four billion paired-end reads per run, low signal-to-noise ratios necessitate the use of data processing algorithms that differentiate true variants from machine-generated artifacts [19,11].…”

Comprehensive screening shows that mutations in the known syndromic genes are rare in individuals presenting with hyperinsulinaemic hypoglycaemia

“…As the incidence of HH in outbred populations is estimated to be between 1 in 27,000 [20] and 1 in 50,000 [21] we excluded all variants that were present in gnomAD controls [22] at a frequency greater than 1 in 27,000. In addition, we excluded variants which did not fit the known inheritance pattern of the syndrome: excluding single variants in recessive genes and variants inherited from an unaffected parent in dominant genes.…”

“…Whilst there are some disadvantages of this approach in terms of the difficulties with variant interpretation in the absence of additional clinical features, the benefits that an early and an accurate genetic diagnosis has on patient care outweigh the extra-time required for the analysis of the genetic data. It is also anticipated that variant interpretation will become easier through data sharing initiatives such as ClinVar [25] and as the number of publically available control datasets increase, enabling more variants to be excluded by frequency [22].…”