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Discovery of Large-Scale Copy Number Polymorphism and Chromosomal Inversions as Common Variants in the Human Genome
Summary: Stephen Scherer's group uses experimental and computational genomic approaches to understand the structure and function of the human genome, with special emphasis on structural variation along chromosomes as well as the molecular genetics of autism.
Recently, our group (Nature Genetics, 2004) and others discovered that large-scale copy number gains or losses, often encompassing hundreds of thousands of nucleotides of DNA (called large-scale copy number variants, or LCVs), exist in the human genome. Moreover, we have found that chromosomal inversions are also a more common feature along chromosomes than realized previously (Nature Genetics, 2001; Science, 2003). Our current project aims to catalogue the full extent of LCVs and inversions in the human genome and their potential role in disease susceptibility and genome evolution. We are using “tiling-path‿ array comparative genomic hybridization (CGH) and Affymetrix 500k single nucleotide polymorphism (SNP) arrays to scan the genomes of 1800 “phenotypically normal control‿ samples (the entire HapMap plus Human Diversity samples) for their LCV content. To identify new chromosomal inversions, we are using comparative DNA sequence analysis (human vs. human and human vs. chimp) followed by confirmatory polymerase chain reaction and fluorescent in situ hybridization analysis. To date, we have found 334 LCVs or inversions across the human genome, and individuals appear to differ by, at a minimum, 12 large-scale variants (data available at http://projects.tcag.ca/variation/). Approximately 238 genes have been found to overlap with the variable intervals, including some involved in neurological function, cell growth, and metabolism. In 14 cases, the LCVs or inversions encompassed known disease loci, and 26 of the 102 recurring variants mapped to low-copy repeat regions that are known to be susceptible to rearrangements, particularly by nonallelic homologous recombination. Therefore, these newly defined variants could be generated by illegitimate recombination, suggesting that there may be a common mechanism underlying disease-associated and normal copy-number/ inversion variation. If this is true, the LCVs and inversions themselves may point to unstable regions of the genome, where new disease-associated rearrangements will be identified.
Abstract from 2005 International Research Scholars Meeting
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