JAX researchers, collaborators report on variations in human genome

Farmington, Conn. – A consortium of international researchers, including Charles Lee, Ph.D., professor and scientific director at The Jackson Laboratory for Genomic Medicine and a distinguished professor of Ewha Womans University have reported findings from a massive research project exploring variations in the human genome, including structural variations.

The 1000 Genomes Project, launched in 2008, is a global initiative to sequence the genomes of large numbers of people. Lee and members of his lab, including Ankit Malhotra and Chengsheng Zhang, were among the authors of the two back-to-back papers published this week in Nature, reporting the completion of the project.

“With the 1000 Genomes Project, we are providing a truly global and comprehensive resource on human genetic variation and critical insights for the scientific community regarding genetic associations to disease.” Says Lee.

The genomes of 2,504 individuals from 26 populations—in Africa, East Asia, Europe, South Asia and the Americas—were reconstructed using a combination of sequencing techniques. The resulting dataset is now publicly available to the research community.

The most common type of genetic variation is the SNP (pronounced “snip”) or single nucleotide polymorphism—a difference in a single DNA building block, called a nucleotide (replacing cytosine with thymine, for example).

Beyond SNPs, Lee was the first to identify widespread structural variation in the human genome, in the form of copy number variants—repetitions or deletions of genes that may have a role in health and disease. Since then, other kinds of structural variants (SVs) have been identified, including insertions and deletions of DNA segments (indels) and inversions (sections where the sequence is correct but the order is reversed).

The researchers in these papers, report that a “typical” genome differs from the reference human genome—the result of the Human Genome Sequencing Project—at between 4.1 million and 5.0 million sites. More than 99.9 percent of the variants consist of SNPs and short indels, but the 2,100-2,500 structural variants they found affect more DNA throughout the human genome.

As one of the lead principal investigators for the 1000 Genomes Project’s structural variation subgroup, Lee is also the senior author of the second paper published in Nature that focuses specifically on structural variations. The research team mapped 68,818 structural variants into the largest reference panel of its kind, a valuable resource for population and disease genetics research.

The findings underscore the significant role of structural variants in determining gene expression. Structural variants are also frequently involved in the gene-disease connections identified in genome-wide association studies (GWAS).

Malhotra comments, “These results underscore the importance of structural variants in disease genetics and indicate that our integrated SV map, which comprises numerous SVs not captured in earlier studies linking SVs to common disease, may serve as a valuable resource for future association studies.”

The Jackson Laboratory is an independent, nonprofit biomedical research institution and National Cancer Institute-designated Cancer Center based in Bar Harbor, Maine, with a facility in Sacramento, Calif., and The Jackson Laboratory for Genomic Medicine in Farmington, Conn. It employs 1,700 staff, and its mission is to discover precise genomic solutions for disease and empower the global biomedical community in the shared quest to improve human health.

Ewha Womans University was founded in 1886 as Korea’s first educational institute for women. It is currently the world's largest female educational institute and is one of the most prestigious universities in South Korea, with nearly 20,000 students across 15 graduate schools, 11 colleges and 67 departments.

Read a JAX blog post about structural variants