Analysis of protein-coding genetic variation in 60,706 humans

Lek M. et al. Nature 536, 285-291 (18 August 2016)​

Reviewed by Mikhail vysotskiy

The Exome Aggregation Consortium (ExAC) has brought together the exome sequences of over 60,000 individuals from a diverse set of populations, the largest such project to date. The team was able to discover millions of variants, the majority of which are extremely rare. They confirmed that deleterious loss-of-function mutations are not widespread in the population while CpG mutations are common, and noted that mutations tend to arise independently across populations. ExAC is also extremely valuable in medical genetics. As the article showed, ExAC does a much better job at filtering through mutations based on allele frequencies and can classify specific genes on their ability to tolerate loss of function mutations, which is going to be (and already is) of great value to doctors trying to find the cause for their patients' rare diseases. Surprisingly, an ExAC analysis on known disease mutations has shown that what we know about disease-causing variation may be wrong! It is clear that ExAC is going to be a game-changer in genetics, and thanks to upcoming new larger cohorts (exome and whole-genome) and ways to handle large genetic datasets, our knowledge is about to deepen even further.