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Study Finds Genetic Variation in Humans More Widespread Than Previously Thought; Around 10 Percent of Human Genes Exhibit Copy Number Changes

This article has been updated from a previous version to include information about the BAC tiling arrays that were used in the study.
NEW YORK (GenomeWeb News) – An international team of researchers has published a study showing that more than 10 percent of human genes vary in the number of copies of DNA sequences they contain – a finding that contradicts previous assumptions that the DNA of any two humans is 99.9 percent similar.
The discovery indicates that copy number variation could play a larger role in genetic disease than previously thought, with broad implications in disease association studies, genetic diagnostic testing, and cancer research.
The study was published in this week’s Nature and was conducted by researchers at Brigham and Women’s Hospital, Harvard Medical School, the Hospital for Sick Children, the Wellcome Trust Sanger Institute, the University of Tokyo, and Affymetrix.
The researchers used two methods -- Affymetrix Human Mapping 500K arrays and whole-genome tilepath arrays with 26,574 large-insert clones -- to study DNA samples from 270 participants in the International HapMap project. They found around 2,900 genes -- more than 10 percent of the genes in the human genome – that vary in copy number from the predicted two inherited copies. Previous research only looked at single-base-pair changes among this study group.
The study team found an average of 70 copy number variations averaging 250,000 nucleotides in size in each DNA sample. Overall, the researchers identified 1,447 different copy number variations covering around 12 percent of the human genome and six to 19 percent of any given chromosome.
Of the 2,900 copy number variations, 285 are already known to be associated with disease, including AIDS, inflammatory bowel disease, lupus, cataracts, arterial disease, and schizophrenia.
The findings could change the direction of future genetic disease research, which has primarily focused on SNPs. “Some diseases are caused by copy number variation rather than SNPs,” Stephen Scherer, a researcher at the Hospital for Sick Children, said in a statement.  
“I believe this paper will change forever the field of human genetics,” said James  Lupski, vice chair in the department of molecular and human genetics at Baylor College of Medicine. “One can no longer consider human traits as resulting primarily from single base-pair changes or influenced only by SNPs.”
In related research published in an advance online publication in Nature Genetics, the researchers propose that the thousands of differences found in comparisons of the human genome map assembled by Celera Genomics with that from the public Human Genome Project may be due to natural genetic variation rather than errors, as previously proposed.  
"Other people have [compared the two human genome sequences]," said Scherer, "but they found so many differences that they mostly attributed the results to error. They couldn't believe the alterations they found might be variants between the sources of DNA being analyzed."
Scherer said that this discovery could have implications for personalized genome sequencing, which will require reliable “reference” human genomes as a basis for comparison. "Our computer algorithms are smart, but it is hard to find something if it is not there in the reference you are comparing against," he said.

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