Despite these successes, much work is still needed to achieve a deep understanding of the genetic contribution to human phenotypes7. Once a region has been identified as harbouring a risk locus, detailed study of all genetic variants in the locus is required to discover the causal variant(s), to quantify their contribution to disease susceptibility, and to elucidate their roles in functional pathways. Low frequency and rare variants (here defined as 0.5% to 5% MAF, and below 0.5% MAF respectively) vastly outnumber common variants and also contribute significantly to the genetic architecture of disease but it has not yet been possible to study them systematically7-9. Meanwhile, advances in DNA sequencing technology have enabled the sequencing of individual genomes10-13, illuminating the gaps in the first generation of databases that contain mostly common variant sites. A much more complete catalogue of human DNA variation is a prerequisite to fully understanding the role of common and low frequency variants in human phenotypic variation.
