First author Jonathan Sebat and colleagues used representational oligonucleotide microarray analysis, or ROMA, to screen 20 “normal” individuals. ROMA is a comparative assay that can reveal differences in copy number between two samples. Sebat found 221 differences among the 20 samples, 76 of them unique CNPs. These polymorphisms can arise by somatic mutations. Indeed the authors have previously used the technique to detect differences between cancer cells and normal cells (see Lucito et al., 2003, but Sebat dismissed this possibility by measuring samples from several tissue types, confirming that the mutations are in the germline.

The results indicate how frequent CNPs are in the general population. They also implicate copy number in certain disorders. In one CNP, for example, the authors found a deletion carrying COH1. When inactivated, this gene causes a rare disease called Cohen syndrome that is characterized by mental retardation and developmental problems. Other CNPs may be related to neurologic disorders. GTF2H2, ATOH1, NCAM2, and several other genes, all involved in nervous system development, were found in CNPs. In all, Sebat found 70 genes with copy number variation in an average of 11 CNPs that occur between any two individuals. The CNPs had an average length of 465 Kb.

Though the authors did detect some known CNPs, their analysis failed to detect others, and they write that they expect more CNPs will be discovered. Their ROMA chips were designed to cover the genome at a resolution of 35 Kb using 85,000 probes, but a 380,000-probe analysis is planned. We may have much more to learn.—Tom Fagan.

Reference:
Sebat J, Lkshmi B, Troge J, Alexander J, Young J, Lundin P, Maner S, Massa H, Walker M, Chi M, Navin N, Lucito R, Healy J, Hicks J, Ye K, Reiner A, Gilliam TC, Trask B, Patterson N, Zetterberg A, Wigler M. Large-scale copy number polymorphism in the human genome. Science. 2004 July 23; 305:525-528. Abstract