Finally, the analysis of low-frequency variation demonstrates both the pervasive effects of purifying selection at functionally-relevant sites in the genome and how this can interact with population history to lead to substantial local differentiation, even when standard metrics of structure such as FST are very small. The effect arises primarily because rare variants tend to be recent and thus tend to be geographically restricted6-8. The implication is that the interpretation of rare variants in individuals with a particular disease should be within the context of the local (either geographic or ancestry-based) genetic background. Moreover, it argues for the value of continuing to sequence individuals from diverse populations to characterise the spectrum of human genetic variation and support disease studies across diverse groups. A further 1500 individuals from 11 new populations, including at least 15 high-depth trios, will form the final phase of this project.
