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Human variation decoded

18 August 2016
New study reveals global patterns of genetic variation never before possible

A powerful new analysis of the protein-coding region of the human genome known as the exome will boost efforts to pinpoint clinically relevant genetic variations linked to human disease.

Published in today’s edition of Nature, the research led by Dr Monkol Lek of the University of Sydney and Dr Daniel MacArthur of The Broad Institute of MIT and Harvard Universities reveals patterns of genetic variation worldwide by sequencing the exomes of 60,706 individuals with diverse geographic ancestries, including European, African, South Asian, East Asian and Latino populations.

Exome sequencing is a method for sequencing a subset of the human DNA genome that encodes proteins, known as exons. Humans have about 180,000 exons, constituting about one per cent of the human genome, or approximately 30 million base pairs. A base pair is a unit comprising two nucleotide bases bound to each other that form the building blocks of the DNA double helix. The human genome contains about 3.2 billion nucleotides and about 23,500 genes.

This analysis reveals global patterns of genetic variation providing resolution that hasn’t been possible with smaller datasets of genetic variation.
Dr Monkol Lek, University of Sydney and The Broad Institute

Three-quarters of known genetic disease-causing variants are located in the protein-coding exome. Given the cost and technical challenges in analysing all genomic sequence data, researchers are focusing much of their research primarily on exome sequencing.

Interpreting findings is a significant challenge in genetic sequencing. Each exome contains about 13,500 single nucleotide variants and a large number of these are expected to be pathogenic. The daunting task for medical researchers is to distinguish variants that are pathogenic from those that have little or no detectable clinical effects.

Using a massive exome sequencing database made available through the Exome Aggregation Consortium (ExAC), the international research team analysed around 7.4 million genetic variants, including variants that occur rarely in human populations. ExAC catalogues exome data from 60,706 unrelated individuals sequenced from numerous disease-specific and population genetic studies. The ExAC website has been visited over 5.2 million times, and currently receives about 70,000 page views per week.

In a sub-analysis, the authors reported that just nine genetic variants were strongly associated with disease from among 192 variants that had been reported as pathogenic in other studies.

“Large-scale reference datasets of human genetic variation are critical for the medical and functional interpretation of DNA sequence changes,” says Dr Lek.

“This analysis reveals global patterns of genetic variation providing resolution that hasn’t been possible with smaller datasets of genetic variation.” 

Dr Lek's research was assisted by The Australian American Association Sir Keith Murdoch Fellowship and NHMRC CJ Martin Fellowship. He is a Universiy of Sydney alumnus. He received his PhD in Medicine in 2012.

Dr Daniel MacArthur is Assistant Professor at Harvard Medical School and a University of Sydney alumnus who received a BMedSc (Hons) in 2002 and a PhD in human genetics in 2007.

The Exome Aggregation Consortium - shedding light on human genetic variation

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