Deep dive into exome data opens door to better identification of rare disease variants


Researchers have published the first analysis of the 60,000 people sequenced through the Exome Aggregation Consortium (ExAC). The analysis of the deeply-sequenced exomes suggest the database will further understanding of human genetics, both in terms of identifying disease-causing variants and showing other, currently suspect mutations to be benign.

The Broad Institute and its collaborators built the database by analyzing 60,706 human exomes, the part of the genome that codes for proteins. Notably, rather than cutting costs through shallow sequencing, like initiatives including the 1000 Genomes Project have done, ExAC took a deep dive into exomes. The upshot of this approach is the ExAC database allows researchers to say with confidence that a genetic variant seen in only one person is genuine.

Such confidence is important. ExAC identified close to 7.5 million variants. More than half of these variants are only seen once in the 60,000-person database.


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“These extremely rare variants are the ones that are most likely to be involved in very severe diseases like cystic fibrosis or muscular dystrophy,” the Broad Institute’s Daniel MacArthur, senior author of the research, told The Guardian.

The study also identified “3,230 genes with near-complete depletion of predicted protein-truncating variants.” More than 70% of these genes are yet to be linked to a disease, suggesting there is scope for ExAC to support the expansion of knowledge.

ExAC could prove as useful in dismissing existing false assumptions about the links between variants and diseases. On average, the exomes analyzed by ExAC feature 54 variants previously linked to rare diseases. As the participants don’t each have tens of rare diseases, this finding suggests previous studies have incorrectly linked variants to conditions.

“If [a particular genetic variant occurs in] one in every 6,000 people, it cannot be a fully causal variant for a disease that [affects] one in 100,000,” MacArthur said.

- read the Nature paper
- and the Guardian article

Related Articles:
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NIH lays out plan to work exome data into clinical research

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