Mental Retardation and Cancer CNVs Polymorphisms Germ-line Mutations/ Paternal Age?

Researchers Determine Genetic Causes of Mental Retardation
Marco Marra of the University of British Columbia and Lisa Lit of the University of California, Davis, discuss chromosome copy number in mental retardation.

VANCOUVER, Canada, December 11, 2006 — University of British Columbia scientists, led by Marco Marra and Jan Friedman, have identified chromosomal abnormalities—genetic duplications and deletions as small as 37.6 kb—that are responsible for the development of mental retardation in children. Using whole-genome sampling analysis (WGSA) with Affymetrix Mapping 100K Arrays, the researchers pinpointed the probable genetic causes of mental retardation in at least twice as many children as conventional cytogenetic analysis, and were able to detect smaller abnormalities than can be detected using BAC-tiling-path arrays.

The researchers examined 100 children and their unaffected parents; each of the children had been assessed by clinical geneticists who were unable to identify the cause of the child’s mental retardation. The team found that 11 children harbored genetic alterations, including eight deletions, two duplications and one with additional copies of chromosome nine in approximately 20 percent of cells. Some deletions were not unique—they appeared in more than one individual
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deletions and you’ll see associations of haplotypes of amplifications. In other words, we will begin to see how germ-line polymorphic alleles might be contributing to the cancer that develops. I think that’s one very exciting area which can really only be looked at using the SNP array platform.
Maris: Yes, I agree with that completely. The 500K especially is going to open up a whole new world in terms of doing classic genetic association studies as well as pretty novel cancer-specific genomics. So we’re excited about that as well.

For mainly technological reasons, we have had a very, uni-focal, looking-under-the-lamppost type of approach, and prognostic biomarkers have been assessed one at a time, a deletion here, or an amplification there by itself and correlated with corollary measures, clinical
factors. And it is very clear that it’s the pattern of DNA aberrations across the genome that really gives you a much more refined picture of the phenotype. There are cooperating loci and associations that if you can consider those together, may be more powerful than the uni-focal approach that we have now. So that’s one of the big areas of interest in our lab, what is the pattern of aberrations and can you learn more from the entire profile than you can from the region-by-region approach, considering things one at a time.

The only downside I see is as we’ve gotten higher and higher resolution, we’ve really run into this problem of how complex the human genome is in terms of copy number polymorphisms, and separating out the real signal from the noise is still a bit of a challenge.

Sellers: Some of that will be offset by the scale of
some of the germ-line studies that are planned by the medical population geneticists using the 500K. With researchers running 10,000 normal germ-line DNAs on the 500K, you’re going to have a pretty good map of polymorphisms pretty soon. It’ll never find the ones that are less than one in a thousand, but I think we can count on our medical population genetics colleagues to identify many of these, and that will help us just simply subtract these by database searches.

Maris: I agree. In the meantime, we are going to be scratching our heads until there is a big database of these copy number polymorphisms