Human Genetics: Questions, Challenges, and the Future

Since the studies of ‘‘mitochondrial Eve’’ in the 1980s indicating that all modern humans originated in Africa, new and less expensive technologies have been developed, giving us the potential to sequence millions of genomes from individuals across the globe as well as genomes of ancient hominids as old as 400,000 years. Integration of fossil, archeological, and genetic data elucidates the evolutionary processes resulting in uniquely human traits as well as traits that vary across individuals, including risk for disease. The evolutionary history of modern humans is a tangled path. There have been multiple migration events of the genus homo out of Africa and admixture of archaic populations such as Neanderthal and Denisovans with each other and with modern humans. By analyzing larger numbers of ancient genomes from geographically diverse regions (including the tropics, where bones are not well preserved) over multiple time periods, we can directly reconstruct the origins of complex traits including disease. Novel statistical models are needed to distinguish the effects of demographic history and natural selection on patterns of genetic variation in modern populations. Ultimately, we must determine the functional impact of genomic variants on human phenotypic diversity, which requires better understanding of gene regulation as well as gene-by-environment and gene-bygene interactions. High-throughput genome editing will enable us to systematically distinguish effects of genetic variants on protein activity and gene regulation across cell types. These advances will facilitate novel, and sometimes surprising, discoveries about the history of our species. From Genomes to Biology