Tag Archive for 'loss-of-function variants'

All genomes are dysfunctional: broken genes in healthy individuals

Breakdown of the number of loss-of-function variants in a "typical" genome

I don’t normally blog here about my own research, but I’m making an exception for this paper. There are a few reasons to single this paper out: firstly, it’s in Science (!); and secondly, no fewer than five Genomes Unzipped members (me, Luke, Joe, Don and Jeff) are co-authors. For me it also represents the culmination of a fantastic postdoc position at the Wellcome Trust Sanger Institute (for those who haven’t heard on Twitter, I’ll be starting up a new research group at Massachusetts General Hospital in Boston next month).

Readers who don’t have a Science¬†subscription can access a pre-formatted version of the manuscript here. In this post I wanted to give a brief overview of the study and then highlight what I see as some of the interesting messages that emerged from it.

First, some background

This is a project some three years in the making – the idea behind it was first conceived by my Sanger colleague Bryndis Yngvadottir and I back in 2009, and it subsequently expanded into a very productive collaboration with several groups, most notably Mark Gerstein’s group at Yale University, and the HAVANA gene annotation team at the Sanger Institute.

The idea is very simple. We’re interested in loss-of-function (LoF) variants – genetic changes that are predicted to be seriously disruptive to the function of protein-coding genes. These come in many forms, ranging from a single base change that creates a premature stop codon in the middle of a gene, all the way up to massive deletions that remove one or more genes completely. These types of DNA changes have long been of interest to geneticists, because they’re known to play a major role in really serious diseases like cystic fibrosis and muscular dystrophy.

But there’s also another reason that they’re interesting, which is more surprising: every complete human genome sequenced to date, including celebrities like James Watson and Craig Venter, has appeared to carry hundreds of these LoF variants. If those variants were all real, that would indicate a surprising degree of redundancy in the human genome. But the problem is we don’t actually know how many of these variants are real – no-one has ever taken a really careful look at them on a genome-wide scale.
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