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About Sickkids
About SickKids

November 22, 2006

Researchers redefine understanding of variation in the human genome

TORONTO - A consortium of scientists led by The Hospital for Sick Children (SickKids), the Wellcome Trust Sanger Institute (WTSI), Brigham and Women’s Hospital (BWH) and Harvard Medical School (HMS), Affymetrix Corporation, and the University of Tokyo has created the first map of DNA and gene copy number variation in the human genome. This new resource, which provides critical information for understanding human evolution and disease, was published as a compendium of four scientific manuscripts released November 23 in Nature, Nature Genetics and Genome Research.

Early information from the Human Genome Project indicated that the DNA in the genome of any two individuals is 99.9 per cent identical with the 0.1 per cent variation arising primarily from some three million single chemical base (nucleotide) changes scattered amongst the chromosomes. In 2004, Dr. Stephen Scherer, a senior scientist in Genetics and Genomic Biology at SickKids and professor of Molecular and Medical Genetics at the University of Toronto and Dr. Charles Lee at BWH-HMS co-discovered that large segments of gene-sized DNA can be present in different copy numbers in all individuals. Genes are usually present in two copies in a genome, one being inherited from each parent; the majority of biological traits including adverse ones such as disease onset, are a result of gene copy and expression levels in the cell.

“Far exceeding anyone's predictions, our latest studies describe that thousands of chunks of DNA, sometimes encompassing millions of nucleotides, can vary between individuals,” said Dr. Scherer, a senior corresponding author of the Nature and Nature Genetics papers. “Most surprising was that some 2900 genes, or 10 per cent of all of those known, varied from their normal copy number of two, pointing to possible new explanations for individual uniqueness, as well as why disease develops.”

In the Nature paper, genome-scanning experiments were used to assess DNA samples from 270 individuals from around the world. These samples (called the HapMap collection) were used previously to generate a map of single nucleotide changes, thereby allowing an integrated map of all genetic diversity to be assembled. The information is now freely accessible in a database housed by SickKids.

“We also found regions of the genome that never varied in copy number, indicating fixed dosage of this DNA is critical for life,” said Dr. Matthew Hurles of WTSI, an evolutionary geneticist and the Nature study’s co-senior author. “At the other end of the spectrum, in some individuals some genes were missing altogether begging the question if they are at all needed, or at the very least, what their function is.”

In the Nature Genetics study, Dr. Lars Feuk of Scherer's group used new computer algorithms to compare, for the first time, two human genomes and found thousands of smaller variants not detected in the Nature study. “These observations are critical to finalize a reference human genome sequence essential to all genetic studies including projects aiming to win the recently announced Archon X-Prize for personalized genome sequencing,” added Scherer.

The technical details of all of the experimental work were published in two papers in Genome Research. The Toronto team relied on The Centre for Applied Genomics, a provincially and federally supported facility at SickKids.

“These new results define an emerging discipline in genome research having broad ranging impact in pharmacology, forensics, clinical diagnostics, and even the basic sociology of what makes us human,” said Dr. Martin Godbout, President & CEO of Genome Canada, one of the principle funders of this research.

Other authors on the paper were Lars Feuk, Andrew R. Carson, Jeffrey R. MacDonald, Christian R. Marshall, Kohji Okamura and Junjun Zhang from SickKids; Richard Redon, T. Daniel Andrews, Heike Fiegler, Dimitrios Kalaitzopoulos, Matthew E. Hurles, Armand Valsesia, Cara Woodwark, Nigel P. Carter, Chris Tyler-Smith, Lyndal Montgomery, Fengtang Yang, and Tatiana Zerjal of the The Wellcome Trust Sanger Institute; Shumpei Ishikawa, Kunihiro Nishimura, Hiroyuki Aburatani and Daisuke Komura, of the University of Tokyo; Karen R. Fitch, Michael H. Shapero, Wenwei Chen, Jing Huang , Keith W. Jones, Rui Mei, Fan Shen and Jane Zhang of Affymetrix, Inc.; George H. Perry, Eun Kyung Cho, Stephanie Dallair, Jennifer Freeman, Joelle Tchinda and Charles Lee from Brigham and Women's Hospital, Boston; Juan R. Gonzalez, Monica Gratacos, Lluis Armengol and Xavier Estivill from Center for Genomic Regulation, Barcelona, Catalonia, Spain; Martin J. Somerville from the University of Alberta and Donald F. Conrad from University of Chicago.

This research was funded by Genome Canada/Ontario Genomics Institute, the Canadian Institutes of Health Research, the McLaughlin Centre for Molecular Medicine, the Canada Foundation of Innovation, the Howard Hughes Medical Institute, Ontario Innovation Trust, Ontario Ministry of Research and Innovation, the Core Research for Evolutional Science and Technology (CREST) from the Japan Science and Technology Agency, the Department of Pathology, Brigham and Women's Hospital, Genoma España, the Leukemia and Lymphoma Society, the Ministry of Education, Culture, Sports, Science and Technology of Japan, the Natural Science and Engineering Research Council, the Swedish Medical Research Council, the Wellcome Trust Sanger Institute and SickKids Foundation.

The Hospital for Sick Children (SickKids), affiliated with the University of Toronto, is Canada’s most research-intensive hospital and the largest centre dedicated to improving children’s health in the country. As innovators in child health, SickKids improves the health of children by integrating care, research and teaching. Our mission is to provide the best in complex and specialized care by creating scientific and clinical advancements, sharing our knowledge and expertise and championing the development of an accessible, comprehensive and sustainable child health system. For more information, please visit www.sickkids.ca. SickKids is committed to healthier children for a better world.

Copy Number Variation Frequently Asked Questions - in pdf format

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