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About SickKids

September 4, 2007

First individual human diploid human genome published by international research group

( TORONTO ) - Researchers at the J. Craig Venter Institute (JCVI), along with collaborators at The Hospital for Sick Children (SickKids) in Toronto and the University of California, San Diego (UCSD), have published a genome sequence of an individual, J. Craig Venter, PhD, that covers both of his chromosome pairs (or diploid genome), one set being inherited from each of his parents.

Two other versions of the human genome currently exist—one published in 2001 by Dr. Venter and colleagues at privately-funded Celera Genomics, and another at the same time by a consortium of government and foundation-funded researchers. These genomes were not of any single individual, but rather were a mosaic of DNA sequences from various donors. In the case of Celera it was a consensus assembly from five individuals, while the publicly-funded version was based on patching together sequences from over 100 anonymous human sources. Both versions greatly underestimated human genetic diversity.

This new genome represents the first time a true diploid genome from one individual—Dr. Venter, has been published. The research is available in September issue of the open assess public journal, PLoS Biology.

Researchers at the JCVI have been sequencing this version of Dr. Venter's genome since 2003. Building on reanalyzed data from Dr. Venter's genome that constituted 60 per cent of the previously published Celera genome, the team had the goal of constructing a definitive reference human genome based on one individual.

The Toronto group, led by Stephen Scherer, PhD, senior scientist in Genetics & Genome Biology at SickKids and professor of Molecular and Medical Genetics at the University of Toronto , assisted in decoding the genetic variants found in Dr. Venter's DNA sequence, as well as in the clinical genetic studies. In particular, they catalogued the copy number variation (CNV) regions, a new form of genetic variation that Scherer's team co-discovered with Charles Lee, PhD at Brigham and Women's Hospital, Harvard Medical School , in 2004.

From the combined data of more than 20 billion base pairs of DNA, the international team assembled the majority of Dr. Venter's genetic blueprint. Since this genome assembly uniquely catalogues the contributions of each of the parental chromosomes, for the first time the total amount of variation existing between the two could be determined. Surprisingly, a higher than expected amount of genetic variation was found.

“Each time we peer deeper into the human genome we uncover more valuable insight into our intricate biology,” said Dr. Venter. “With this publication we have shown that human to human variation is more than five fold greater than earlier estimates proving that we are in fact more unique at the individual genetic level than we knew about before.” He added, “It is clear however that we are still at the earliest stages of discovery about ourselves and only with continued sequencing of more individual genomes will we be able to garner a full understanding of how our genes influence our lives.”

Within the human genome there are several different kinds of DNA variants. The most studied type is single nucleotide polymorphisms or SNPs and some 3.2 million were found in Dr. Venter's genome. This is a typical number expected to be found in any other human genome but at least 1.2 million of these SNPs had not been described before.

The team also found an abundance of other important variants. In fact, hundreds of thousands of CNV or smaller CNV-like variants were discovered. While the SNP events outnumbered the non-SNP variants, the latter class involved a larger portion (74 per cent) of the variable component of Dr. Venter's genome. The combined data suggests that human-to-human variation is much greater than the 0.1 per cent difference found in earlier genome sequencing experiments. The new estimate reveals that genomes between individuals have at least 0.5 per cent total genetic variation (or are 99.5 per cent similar).

According to Samuel Levy, PhD, lead author and senior scientist at JCVI, “The ability to use unbiased, high throughput, sequencing methods coupled with advanced computational analytic methods, enables us to characterize more comprehensively the wide variety of individual genetic variation. This offers us an unprecedented opportunity to study the prevalence and impact of these DNA variants on traits and diseases in human populations.”

Another important feature that is made possible by having an individual, diploid genome is the ability to generate more informed haplotype assemblies. Haplotypes are groups of linked variations along the chromosomes. Other studies have generated many common haplotypes, however, these are based on averages of large ethnogeographic populations rather than individuals. Individual haplotypes enable scientists to study rare or 'private' variants that might explain and help predict traits and diseases in that particular person—allowing an individualized approach in genomic applications.

“In the future it will be possible to know the parental origin of DNA that contributes, either alone or in combination, to various traits or disease,” said Dr. Scherer. “This landmark study discovered that in an individual genome upwards of 44 per cent of genes were variable in sequence, a number that geneticists have wondered about for 50 years.”

“With this type of knowledge now in hand, the stage is set for an era of personalized medicine where genome sequence information becomes a critical reference to assist with health-related decisions.” concluded Scherer.

This research was funded by J. Craig Venter Institute, Genome Canada/Ontario Genomics Institute, the McLaughlin Centre for Molecular Medicine, the Canada Foundation for Innovation, Canadian Institutes of Health Research, the Canadian Institute for Advance Research 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.

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