Knockout! Knockout! Who’s Not There?

The deeper we look at human genomes, the more unexpected things we find. And increasingly we are surprised by what each of us lacks. In particular, in recent years we have learned that naturally occurring human gene knockouts are prevalent. The results of the Exome Aggregation Consortium (ExAC) now paint a rich and detailed picture of gene redundancy and essentiality in humans (Lek et al., 2016). The breadth of individuals who had their protein-coding regions of their genomes sequenced by ExAC is impressive, with the effort cataloging variation in more than 60,000 individuals from diverse ancestries. Within this cohort, more than 7 million individual variants are reported, which averages out to a variant occurring every eight base pairs throughout protein-coding regions. Just more than half of these are observed only once—that is, in a single individual—and the vast majority of these were not observed in previous sequencing efforts, such as the 1000Genomes Project. This suggests that many more variants will be uncovered by sequencing yet more people, but the sample size is sufficient to begin to approach saturation for some kinds of mutation, including the most common type, transition variants at CpG sites. For example, a majority of all of the theoretically possible variants are observed synonymous mutations at CpG sites. With this depth of variant identification, we now have a clear understanding of which individual genes and gene classes are more commonly the target of protein truncating variants. The frequency or infrequency of such protein-truncating variants tells us which are so critical as to never tolerate disruption and those that can seemingly be lost without repercussion. Reassuringly, the gene classes most intolerant of loss-of-function (LOF) protein-truncating variants are core to the basic workings of the cell (components of the ribosome, proteasome, spliceosome, etc.), whereas the gene family that is least constrained by mutational tinkering is olfactory receptors. The grouping of genes least tolerant of protein-truncating variants also contains nearly all known haploinsufficient human disease genes,