A DNA Polymorphism Discovery Resource for Research on Human Genetic Variation (original) (raw)

1. Francis S. Collins1,
2. Lisa D. Brooks1,3, and
3. Aravinda Chakravarti2
4. 1National Human Genome Research Institute, National Institutes of Health (NIH), Bethesda, Maryland 20892 USA;2Department of Genetics and Center for Human Genetics, Case Western Reserve University and University Hospitals of Cleveland, Cleveland, Ohio 44106 USA

Identifying the genes conferring susceptibility or resistance to common human diseases should become increasingly feasible with improved methods for finding DNA sequence variants on a genome-wide scale (Collins et al. 1997; Landegren et al. 1998; Wang et al. 1998). To facilitate the discovery of DNA sequence variants, the National Human Genome Research Institute (NHGRI) of NIH, working with the Centers for Disease Control and Prevention, the National Institute of Environmental Health Sciences, and several individual investigators, has assembled a DNA Polymorphism Discovery Resource of samples from 450 U.S. residents with ancestry from all the major regions of the world. This DNA Polymorphism Discovery Resource will be immensely valuable for the discovery of human genetic variation, which other follow-up studies can relate to health and disease.

Most successes so far in finding genes that contribute to disease risk have been for highly penetrant diseases caused by single genes, such as cystic fibrosis (Kerem et al. 1989; Rommens et al. 1989). To locate genes affecting these rare disorders, researchers perform linkage analysis on families, which requires 300–500 highly informative genetic markers spanning the entire human genome. However, it has been considerably harder to locate the genes contributing to the risk of common diseases such as diabetes, heart disease, cancers, and psychiatric disorders, because these phenotypes are affected by multiple genes, each with small effect; environmental contributions are also important. Instead of linkage analysis on families it may be much more efficient to perform association analysis on many affected and unaffected individuals, which would require hundreds of thousands of variants spread over the entire genome (Risch and Merikangas 1996). Such a large number of variants is currently not available. The DNA Polymorphism Discovery Resource is designed to promote their discovery.

About 90% of sequence variants in humans are differences …