Novel, Low-cost Method Of Sifting Genome's High-value Regions Devised

A team led by CSHL's Gregory Hannon, Ph.D. a molecular and cell biologist, and W. Richard McCombie, Ph.D., a molecular biologist who heads the Laboratory's gene sequencing center, sought an efficient way of separating what's most valuable in the genome from less important stretches of genomic "code." In all, there are over 3 billion "letters" of code in the human genome, only 2 percent of which actually instructs cells to produce proteins, the workhorses of all life processes.

CSHL's new method is innovative because it enables genome scientists to save significant time and labor by capturing and then sequencing, or "spelling out," genomic code culled from relatively small, focused areas - as opposed to sequencing the entire genome and only afterward honing in on areas of interest.

"In practical terms, this means that a new world of discovery is opening to scientists interested in studying the genomes of large groups of people on a comparative basis - which is a prime basis for our insights about gene mutations that cause disease," said Dr. Hannon.

Dr. McCombie added: "By enabling scientists to target a small fraction of the genome, our method makes it possible for people with interesting ideas, to do significant work, on a modest budget. This will afford researchers the opportunity to include enough samples to conduct truly meaningful genome-wide comparative studies."

The CSHL team's innovation is demonstrated in a paper appearing in the November 4, 2007 online edition of Nature Genetics. A set of seven flexible, high-density microarrays, or gene-chips, were used to extract from a DNA sample only those stretches of genomic sequence that code for the manufacture of proteins.  These segments, called exons, following their capture on the arrays were enriched and then sent to a state-of-the-art sequencing machine. The technique is called selective resequencing because it compares the newly obtained targeted sequences - in this case, of exons - with those of a "reference" version of the whole genome produced by the Human Genome Project.

The authors of "Genome-wide in situ exon capture for selective resequencing" include: Emily Hodges, Zhenyu Xuan, Vivekanand Balija, Melissa Kramer, Michael N. Molla, Steven W. Smith, Christina M. Middle, Matthew J. Rodesch, Thomas J. Albert, Gregory J. Hannon, and W. Richard McCombie.  An advance version of the paper is available online.

The work was performed in cooperation with NimbleGen Systems, Inc., a genomics company based in Madison, Wisconsin.

CSHL is a private, non-profit research and education institution dedicated to exploring molecular biology and genetics in order to advance the understanding and ability to diagnose and treat cancers, neurological diseases, and other causes of human suffering.