"Using new genome scanning technologies, we serendipitously found stretches of DNA sometimes hundreds of thousands of chemical bases (nucleotides) long that were present or absent in the genomes of healthy individuals. These large-scale copy variations, or LCVs, frequently overlap with genes and could explain why people are different," said Dr. Stephen Scherer, co-principal investigator of the study, a Sick Kids senior scientist, and an associate professor in the Department of Molecular and Medical Genetics at the University of Toronto.
"At first we were astonished and didn't believe our results because for years we had been taught that most variation in DNA was limited to very small changes. Then we heard the Harvard group was making similar observations and ultimately we combined our data and came to the same conclusion," added Dr. Scherer.
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 nucleotide changes scattered amongst the chromosomes. The new data from the Sick Kids and Harvard groups revealed 255 regions (comprising more than 0.1 per cent) of the genome where large chunks of DNA are present in different copy numbers between individuals. Over 50 per cent of these alterations lead to changes in gene numbers and at least 14 regions overlapped with known sites associated with human disease.
"Because these newly discovered variants exist in the genomes of healthy individuals, their presence could lead to subtle differences affecting physical or behavioural traits by influencing the expression of specific genes, but they could also predispose to future disease," said BWH's Dr. Charles Lee, co-principal investigator and assistant professor at HMS. "For example, the most common LCV involves amylase genes. Our study shows that some people may have 10 copies of this gene while others may have as much as 24 copies of this same gene. It would be really exciting if we found that an increased copy number of these genes was associated with increased susceptibility to pancreatic diseases or cancer. This would allow us to use these LCVs as disease markers."
The information on identified LCVs has been collated into a publicly accessible database called the Genome Variation Database (http://projects.tcag.ca/variation) that will be a valuable resource for clinical genetic studies.
Other members of the research team include co-lead authors Dr. Lars Feuk, a Sick Kids postdoctoral fellow and Dr. A. John Iafrate, a postdoctoral fellow at BWH and HMS, and Miguel L. Listewnik (BWH), Patricia K. Donahoe (Massachusetts General Hospital and HMS), and Ying Qi (Sick Kids).
At Sick Kids, the research was supported by Genome Canada through the Ontario Genomics Institute, the McLaughlin Centre for Molecular Medicine, The Centre for Applied Genomics at Sick Kids, and the Sick Kids Foundation. Dr. Feuk is supported by the Swedish Medical Research Council. Dr. Scherer is an Investigator of the Canadian Institutes of Health Research and International Scholar of the Howard Hughes Medical Institute.
At BMH/HMS, the research was supported by the Department of Pathology at Brigham and Women's Hospital, the Friends of the Dana-Farber Cancer Institute, a Brigham and Women's Hospital Pathology Department training grant, and the National Institutes of Health.
The Hospital for Sick Children, 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. Its mission is to provide the best in family-centred, compassionate care, to lead in scientific and clinical advancement, and to prepare the next generation of leaders in child health.