First human DNA large-scale variation map is produced

Researchers in the US have produced the first sequence-based map of large-scale structural variation across the human genome.

The work, published late April in the prestigious journal Nature, provides a starting point to examine the role of such DNA variation in human health and disease.

Other recently created maps, such as the HapMap, have catalogued the patterns of small-scale variations in the genome involving single DNA bases. However, the scientific community has been eagerly awaiting the creation of large-scale variation maps — especially in light of findings that larger scale differences account for a great deal of the common genetic variation among individuals and between populations.

They may also account for a significant fraction of diseases.

Large-scale structural variations are differences in the genome that range from a few thousand to a few million DNA bases. Some are gains or losses of stretches of genome sequence, while others appear as rearrangements of stretches of sequence. Already, scientists have linked some structural variations to differences in susceptibility to the human immunodeficiency virus (HIV), coronary heart disease, schizophrenia and autism. Researchers hope the new map will help uncover the functions of large variants in even more conditions.

“It is important that we understand how changes in the human genome, both small and large, contribute to individual differences in susceptibility to diseases,” said Francis Collins, director of the US National Human Genome Research Institute (NHGRI).

“This map is a valuable starting point for researchers studying the normal patterns of structural variation and how differences in those patterns affect human health.”

Researchers constructed the map by partially sequencing the genomes of eight people: four people of African descent, two of Asian descent and two of European descent. The samples were collected as part of the International HapMap Project.

No medical or personal identifying information was obtained from the donors, but the samples were labelled by population groups.

Sequence data were collected from each end of roughly 1 million random small pieces of DNA from each individual’s genome. The end sequences were compared to the reference sequence of the human genome completed in 2003. Where precise matches did not occur, the scientists inferred that there was a structural difference between the volunteer’s sample and the reference sequence of the human genome.

In addition to revealing new variations, the map also provides a more detailed look at the locations of nearly 1700 structural variations — half of which had not been previously described.

About half of the structural variations were found in at least two of the eight genomes analysed.

The work also uncovered 525 new regions of large-scale structural variation in the human genome. The differences came in many forms, including deletions and out-of-place insertions of long stretches of DNA.

Almost half of the new variations consist of differences in copy number variant (which measures how many copies individuals have of a certain gene).

"The structural variation map will give us a much better picture of genetic variation between each individual, and help us better understand these areas of the genome that are prone to large-scale changes over time," said Evan Eichler of the University of Washington, who led the research.

Sequence data from the structural variation map are publicly available through the US National Institute of Health’s National Center for Biotechnology Information Trace Archive, www.ncbi.nlm.nih.gov/Traces. Mapping data are also freely available from the University of Washington, http://hgsv.washington.edu.