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    The ever expanding Exome Dataset reshapes the links between genes and diseases

    'The deadly mutations that weren't' by Nature

    With information from 126,216 human exomes and 15,136 whole human genomes, the Genome Aggregation Database (gnomAD), hosted by the Broad Institute of MIT and Harvard, has launched in beta. Members of the Exome Aggregation Consortium (ExAC), the leaders of gnomAD, have accumulated nearly “40 terabytes of raw variant data that need to be parsed for analysis,” co-principal investigator Daniel MacArthur of the Broad announced on October 19 at the American Society for Human Genetics (ASHG) annual meeting, held in Vancouver this week. ExAC has officially become the largest-ever catalogue of genetic variation in the protein-coding regions of the human genome. The team is now looking at 17.7 million variants identified from exome data and 254.2 million variants pulled from the whole-genome data.
    One of the major findings of the ExAC is that many genetic mutations have been misclassified as harmful (M. Lek et al. Nature 536, 285–291; 2016). Authors of that study estimate that each person has lurking in their genome an average of 54 mutations that are currently considered pathogenic — but that about 41 of these occur so frequently in the human population that they aren’t in fact likely to cause severe disease. That finding is having major consequences for some people with such variants, lifting the equivalent of genetic death sentences.
    That raises two challenges for researchers: how to sort out which mutations currently considered pathogenic are actually benign, and how to apply more rigorous tests to future research that aims to find the genetic causes of disease.
    Working out which mutations are actually linked to illness will be a long and arduous task. To reassess the links between diseases and mutations, researchers must have access to a group of people whose detailed genetic and clinical information are known, and that’s rare. It also takes time and some cost; multiply that by the huge numbers of ‘pathogenic’ variants that have been called into question, and researchers are looking at a major undertaking. It’s a crucial one, because geneticists are being asked every day to make judgements about the harm that could be caused by mutations found in patients’ genomes. Researchers hope that planned or existing projects to link people’s genomes to their detailed health records — such as the US president’s Precision Medicine Initiative, which aims to sequence at least 1 million Americans, and the UK 100,000 Genomes Project — will help.
    ExAC is quietly becoming a standard tool in medical genetics. Clinical labs around the world now check it before telling a patient that a particular glitch in their genome might be disease causing. If the mutation is common in ExAC, it’s unlikely to be harmful. ExAC has also been repeatedly accused of lacking the view of human genetic diversity as it fails to include people from Asian, African, Latino and other non-European ancestries, holding back the understanding of how genes influence diseases. There is now a fresh impetus to include under-represented groups in planed study linking genetics and health information on larger numbers of people.