Mining beyond the exome

In the late 18th century, Erasmus Darwin, Charles Darwin's grandfather, advocated evolutionary theory as a mean to "unravel the theory of disease". More than 200 years later, although Darwinian medicine is regaining some ground after having been muzzled during the second half of the 20th century, genomics has largely outcompeted evolution and has acquired a dictatorial success as a tool for studying disease etiology. From an evolution-inspired perspective, we have gradually drifted into the habit of focusing primarily on genomic data from sources such as genome-wide association studies (GWAS). As a result, understanding the how and why of human diseases and pathobiology has largely become a matter of crunching DNA sequences. Despite the popularity of GWAS, their reality remains unchanged: most of the susceptibility loci they allow to identify explain only a small fraction of the heritability of complex diseases. A number of reasons for the so-called "missing heritability" have been proposed, and our goal is not to review them all. Here we primarily reiterate that there is more to discover than non-synonymous point mutations and suggest that amid genetic deserts and genetic islands, there is also more to explore than the coding regions of the genome. We then highlight the importance and the necessity of designing efficient methods to mine beyond the exome.