Variations in DNA coding are more common than thought, according to new research.
One-letter switches in the DNA code occur much more frequently in human genomes than anticipated, but are often only found in one or a few individuals, according to new research published in the online edition of Science.
Researchers, including Gates alumnus Timothy O’Connor, found that the explosion in human population over the last 5,000 years has profoundly influenced genetic variation patterns.
Their paper, “Evolution and Functional Impact of Rare Coding Variations from Deep Sequencing of Exomes,” describes their study of the protein-coding sections of genomes from almost 2,440 individuals from European or African extraction.
The study is described as a first step towards understanding how rare genetic variants contribute to some of the leading chronic illnesses in the world.
It was conducted as part of the mission of the Seattle GO at the University of Washington and the Broad GO at Harvard University and MIT, both funded by the National Institute of Health’s National Heart Lung and Blood Institute Exome Sequencing Project.
The researchers sequenced and compared 15,585 human protein-coding genes. They found more than a half-million single-letter DNA code variations in their sample populations. The majority of these variations arose recently in human evolutionary history and so were rare, novel, and specific either to the African or European study populations.
They then focused on single-letter variations in the DNA that might affect the functions of proteins and be linked to specific diseases such as heart attacks before old age. They estimated that just over two per cent of the approximately 13,600 single nucleotide variations each person carried on average influenced the function of about 313 genes per genome. More than 95 percent of the single-letter code changes predicted to be functionally important were found to be rare.
The scientists calculated the average number of novel, single-letter code variations in their study subjects and found 549 per individual overall. People of African descent had about twice the number of new variations compared to those of European descent, or 762 versus 382.
The researchers also measured the effects of natural selection on rare coding variation.
They called for more powerful tests to detect the effects of rare genetic variations on human health and said that large sample sizes will be required to associate rare variants with complex traits.
Explaining the significance of the research, Tim O’Connor  said: “It shows that we must integrate evolutionary theory into our understanding of complex genetic diseases. For example, heart disease in one population may have a completely different genetic underpinning than in another population. We may need to re-evaluate some of the assumptions we make in population genetics analyses to better accommodate rare genetic variants as now we know they are abundant and potentially important.”
Tim did his PhD in Zoology with the support of a Gates Cambridge scholarship and is currently based at the University of Washington.
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