Editors' ChoiceHuman Genomics

Mapping Human Disease Risk

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Science Translational Medicine  13 Oct 2010:
Vol. 2, Issue 53, pp. 53ec159
DOI: 10.1126/scitranslmed.3001768

The past few years have seen a flurry of discoveries that have shed light on the genetic underpinnings of some of the most common and complex human diseases. The primary drivers of these transformative findings are genome-wide association studies (GWASs), which have been made possible by rapid advances in sequencing technology coupled with plummeting costs. However, despite these successes, much of the inherited component of the susceptibility to common human diseases remains unexplained. Enter the International HapMap Consortium with their third-generation human haplotype map (HapMap3), which should bolster efforts to decode this missing heritability and thus better understand human disease risk.

The first two versions of the HapMap divided the human genome into groups of highly correlated common sequence variants (single-nucleotide polymorphisms, or SNPs) that are inherited together. Notably, these versions genotyped only 270 individuals from four populations. Now, HapMap3 investigators have cast a much wider net, genotyping more than 1.5 million genome sequence variations in 1184 individuals from 11 independent populations across the globe. They also completely resequenced 10 100-kilobase regions in 692 of these individuals using polymerase chain reaction–based Sanger sequencing to catalog patterns of rare SNPs and other variants called copy number polymorphisms (CNPs) in diverse ethnic groups, which is an additional feature not present in the first two versions. Among the many findings revealed by HapMap3 are rare SNPs and CNPs that are specific to populations with similar ancestry. HapMap3 also reveals that African populations appear to carry more rare and common genetic variants than do non-African populations. Also, rare SNPs and structural sequence variants appear to reside within larger haplotype blocks than do more common variants, which typically are inherited in smaller blocks.

Although a remarkable achievement, HapMap3 catalogs a mere fraction of the total number of rare variants present in the human genome. Whole-genome sequencing of many individuals from around the globe, already under way by the 1000 Genomes Project, will be required to validate the HapMap3 findings and to provide a comprehensive database of both rare and common variants in the human genome. Such a database, together with HapMap3 and the arrival of super-fast third-generation sequencing machines, should help to decipher the missing heritability or so-called “dark matter” of human disease risk.

The International HapMap 3 Consortium, Integrating common and rare variation in diverse human populations. Nature 467, 52–58 (2010). [Abstract]

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