of the bottom of the well of genetic variation in humans. In human genetics, it is generally assumed that when the same variant is found in more than one individual, it arose once in an ancestor shared by those individuals, rather than through independent mutations of the same site. However, at a particular class of site, called CpG dinucleotides, the researchers make a convincing case that variants observed in multiple individuals often reflect mutational recurrence. In support of their assertion, the researchers find that discovery rates for new CpG dinucleo- tide mutations decrease in samples larger than 20,000 individuals. This provides further evidence that the size of the ExAC cohort is suf- ficiently large that we are beginning to saturate this class of human genetic variation, at least within the exome. It is worth noting, however, that CpG dinucleotides have a highly elevated mutation rate in human genomes, making the number of samples needed to observe such sat- uration much lower than for other kinds of vari- ants. Nonetheless, this exciting finding presages what lies ahead, as larger aggregate analyses of exomes and genomes are performed. Third, ExAC promotes the discovery of genes involved in rare diseases. In 2009, my group and others showed how exome sequenc- ing could be used to identify Mendelian-disease genes or to diagnose Mendelian disease 1,7,8 . Because there are tens of thousands of genetic variants in an exome, these strategies depended on effectively filtering out common variants, which are not likely to cause Mendelian dis- orders. At that time, databases of common variants were uneven and of suspect quality. Although ESP greatly improved the situation by uniformly and systematically cataloguing both common and rare variants across the exome 4 , ExAC is an order of magnitude larger, and so enables better filtering. This is especially rel- evant for exome sequencing of non-European, non-African-American individuals, because ExAC provides greater sampling of individuals from outside the United States than ESP does. On a related point, the study finds that hun- dreds of variants previously claimed to cause Mendelian disorders occur at implausibly high frequencies. As such, the authors suggest that they be reclassified as benign. A related study 9 shows how ExAC may also force a reassessment of whether some genes are involved at all in par- ticular rare disorders. There is little doubt that ExAC will both refine and accelerate Mende- lian-gene discovery and clinical genetics. Finally, the consortium’s approach to data aggregation and sharing is admirable. ExAC is both a technical and political achievement, requiring wrangling not only of data but also of investigators, consents and more from 14 stud- ies — most of which were directed at the genet- ics of various common diseases. An ongoing challenge in genomics is balanc- ing the privacy rights of human participants with a strong tradition of promptly and openly sharing data. Building on the precedent of ESP, ExAC hits this balance by publicly releasing aggregate analyses —a catalogue of variants and the frequencies at which they arise — but not data about associated traits or other individual-level information (although raw data for many studies in ExAC is theoretically acces- sible through restricted databases). In this way, the study maximizes benefit while minimizing harm. These data have already been available on a terrifically intuitive website for nearly two years (http://exac.broadinstitute.org/), and the site has accrued more than 4 million page views. If there is one take-home message, it is that there is incredible value in aggregating sequencing data across genomic studies. As the exomes aggregated by ExAC represent just a small fraction of the human samples that have been subjected to exome or genome sequencing so far, we can and should do better. In the coming decade, the number of human genomes that will be sequenced in some man- ner will grow to at least tens of millions and, by the end of this century, perhaps even billions. The beginnings of saturation seen here with CpG dinucleotides may eventually be observed deeply and at every site, providing a nucleo- tide-level footprint of the human genome. ■ Jay Shendure is in the Department of Genome Sciences, University of Washington, Seattle, Washington 98195, USA, and is an investigator of the Howard Hughes Medical Institute. e-mail: shendure@uw.edu 1. Ng, S. B. et al. Nature 461, 272–276 (2009). 2. Shendure, J. & Ji, H. Nature Biotechnol. 26, 1135–1145 (2008). 3. Lek, M. et al. Nature 536, 285–291 (2016). 4. Fu, W. et al. Nature 493, 216–220 (2013). 5. The 1000 Genomes Project Consortium Nature 526, 68–74 (2015). 6. The GTEx Consortium. Science 348, 648–660 (2015). 7. Ng, S. B. et al. Nature Genet. 42, 30–35 (2010). 8. Choi, M. et al. Proc. Natl Acad. Sci. USA 106, 19096–19101 (2009). 9. Walsh, R. et al. Genet. Med. http://dx.doi.org/ 10.1038/GIM.2016.90 (2016). Protein-coding AGACTATAGAGATC GATAGATATAGCGATA AGACAATAGAGATC GATACATATAGCTATA DNA Individual 1 Individual 2 ... ... AGACTATAGAGATC GATACATATAGCGATA ACACTATAGAGATC GATACATATAGCTATA Individual 60,705 Individual 60,706 – X –– X –––– X ––– X –––– X ––– X ––– X ––– Sites of variation Exome sequencing Figure 1 | Exome aggregation. The Exome Aggregation Consortium (ExAC) 3 reanalysed the raw DNA- sequencing data from the protein-coding part of the genome, known as the exome, of 60,706 individuals, aggregated from 14 distinct studies. Genetic variants (red) are compared to produce a database of all sites of variation between the individuals. NEUROSCIENCE Flipping the sleep switch Inactivation of a group of sleep-promoting neurons through dopamine signalling can cause acute or chronic wakefulness in flies, depending on changes in three different potassium-channel proteins. See Letter p.333 STEPHANE DISSEL & PAUL J. SHAW M any people have nodded off during a long road trip, or lain in bed desperately trying to fall asleep. These experiences illustrate real-world con- sequences of an improperly maintained bal- ance between sleep- and wake-promoting neural circuits. On page 333, Pimentel et al. 1 describe the identification of a bona fide molecular switch that allows wake-promoting signals to turn off individual sleep-promoting neurons to regulate waking. These find- ings open up avenues for understanding the complexity of sleep regulation in healthy individuals and during disease. Multiple sleep and wake circuits are found throughout the mammalian central nervous system and are believed to interact in a mutually inhibitory manner 2,3 . A similar organization is found in the fruitfly Drosophila, in which independent sleep and wake centres cooperate 278 | NATURE | VOL 536 | 18 AUGUST 2016 NEWS & VIEWS RESEARCH ©2016MacmillanPublishersLimited,partofSpringerNature.Allrightsreserved.