Researchers Uncover Surprising Degree Of Large-scale Variation In The Human Genome

The study, which appears this week in the journal Science, used a powerful new DNA profiling technique, originally developed by Wigler's group, called ROMA (representational oligonucleotide microarray analysis). The technique was initially developed to detect the genetic differences between normal cells and cancer cells. This application of ROMA has revealed several chromosomal amplifications (excess copies of DNA segments) and deletions (missing DNA segments) associated with a variety of human cancers in individual patients (see http://www.cshl.edu/public/releases/revealing.html ).

However, in the course of that work, the researchers were greatly surprised to have detected several large-scale, previously unidentified differences in human DNA when they carried out "normal to normal" control comparisons of DNA from different individuals.

In the new study, Wigler's group created an extensive profile of such genetic variation in normal human DNA. The researchers sampled blood and multiple tissues from 20 individuals from a variety of geographic backgrounds. Differences in the chromosomal DNA purified from these samples were detected by ROMA.

The researchers detected 76 large-scale "copy number polymorphisms" or CNPs. Among the 70 genes associated with the newly-identified CNPs were those involved in Cohen syndrome and neurological development, and others implicated in leukemia and drug resistant forms of breast cancer. In addition, some CNPs identified genes with known influence on 'normal' human phenotypes including one—neuropeptide-Y4 receptor—that is directly involved in the regulation of food intake and body weight.

According to the study, a relationship between CNPs and susceptibility to health problems such as neurological disease, cancer, and obesity is an intriguing possibility. The study revealed considerable structural variation in the human genome, most of which was not previously apparent by other methods of genomic analysis.

Previous studies by others using different methods had identified only a handful of such large-scale copy number polymorphisms in human DNA. The increased CNP detection frequency in the new study stems from the greater resolving power of the ROMA technology (which currently employs one probe every 35 kb) relative to other methods. Moreover, several features of ROMA result in a signal-to-background ratio superior to that which can be obtained by hybridization of total genomic DNA to an array of BACs. Further refinements of ROMA, which promise to reveal more information about large-scale polymorphisms in the human genome, are underway.

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Among Wigler's colleagues from Cold Spring Harbor Laboratory, Columbia University, the Broad Institute, the Karolinska Institute, the Fred Hutchinson Cancer Research Center, and Stony Brook University, Jonathan Sebat was the first author of the study.