The Human Genome Project provided information vital to a broad spectrum of research underlying human biology and medicine. As a next step, large-scale study of the variation of genetic information between individual humans will provide insight into the effect that natural variation in genome structure has on human health and susceptibility to disease.
Information about human variation has been used to construct a haplotype map of the human genome, HapMap, which will speed the ability to map genetic variantsassociated with disease, drug response, and other medically important phenotypes to an unprecedented degree.
However, we still do not completely understand the "normal" range of human variation present in populations to provide a basis for understanding the variations that result in disease.
The sequence-based Survey of Human Structural Variation aims to characterize common structural variants that are larger than 5 kb, such as multi-base insertions/deletions, inversions, translocations, and duplications. The approach entails sequencing the ends of fosmids and BACs from multiple individuals. This strategy can be efficiently scaled with current technology and is complementary to efforts to obtain human structural variation information by other technologies.
The initial implementation plan for this initiative calls for sequencing ~0.4X coverage in fosmid ends from up to 21 individuals, and BAC ends for a few additional individuals. End sequence will be compared to the reference sequence. Clones that are discrepant with the reference will be fully sequenced. In addition ~5 Mb worth of regions will be selected and fully sequenced from 48 individuals, in order to provide a standard for studies of structural variation. Clones that identify structural variants will be retained and provided as a community resource. In the longer term, the structural variants will be genotyped for integration into the HapMap.
However, this large multi-year initiative must remain flexible enough to take into account new information and analyses. In addition, new sequencing technologies may offer significant advantages towards pursuing the overall aims., NHGRI has thus assembled a steering group to help implement and guide this initiative (See: Group Rosters). The steering group is charged with monitoring progress, analyzing the data to ensure that the goals are being met, suggesting mid-course modifications where they are scientifically justified, selecting the regions for full sequencing, and consulting with NHGRI about which clone resources should be maintained for distribution.
A white paper (See: Human Genome Structural Variation ) provides a full project description.
As with all NHGRI initiatives and projects, data are made available immediately through the NCBI Trace Archive. [ncbi.nlm.nih.gov]
Samples are available through the Coriell Institute.
Table: Fosmid libraries used for the structural variation survey.
Last Updated: January 21, 2014