Abstract The field of human genetics is being reshaped by exome and genome sequencing. Several lessons are evident from observing the rapid development of this area over the past 2 years, and these may be instructive with respect to what we should expect from 'next-generation human genetics' in the next few years.
Challenges and opportunities Even with the rapid maturation of this field, there are a number of areas that are still, to varying degrees, a work-in-progress; these are described as follows. (1) Exome sequencing fails to solve a substantial proportion of presumably Mendelian phenotypes, even in model organisms where the genetics are crystal clear . If we are to conceive of solving all of the Mendelian disorders for which the causative gene(s) remains unknown, understanding the basis of these failures will be critical. Analogously, there are types of cancer where exome sequencing has not been that successful, due perhaps to marked genetic heterogeneity or the fact that many of the underlying driver mutations may be structural or non-coding. (2) There is tremendous interest in understanding the contribution of rare variation to the genetic basis of common diseases. Many such studies have been initiated using exome sequencing, but are still ongoing as they require large sample sizes to achieve power. These studies will set the stage for understanding the contribution of all rare variants, coding and non-coding, to these same diseases via whole-genome sequencing. (3) The discrete prioritization of all protein-altering variation over all other variation has clearly proven useful, but is undeniably crude. As we shift from exomes to genomes, we incur a 100-fold increase in noise for an unknown gain in signal. We are desperately in need of more sophisticated methods for assigning more appropriate 'priors' to coding and non-coding variants alike. (4) To date, attempts to interpret 'personal exomes' or 'personal genomes' for clinically relevant facts have been mostly disappointing. If we are to be successful in deploying these tools in a clinical setting, we have a very long way to go in terms of predicting phenotype from genotype.
We are only a few years into an incredible trajectory in which exome sequencing and genome sequencing are reshaping the landscape of human genetics. For some problems, it is clear that these technologies were exactly what were needed, and the application of high-yield paradigms by diverse research groups is leading to a plethora of rapid discoveries. For other problems, the removal of one rate-limiting step has only given way to a new rate-limiting step, and we are likely to have our work cut out for us for the foreseeable future.