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One-letter switches in the DNA code occur much more frequently inhuman genomes than anticipated, but are often only found in one ora few individuals. The abundance of rare variations across the human genome isconsistent with the population explosion of the past few thousandyears, medical geneticists and evolutionary biologists report inthe advanced online edition of Science. "This is a dramatic example of how recent human history hasprofoundly shaped patterns of genetic variation," said Joshua Akey,University of Washington associate professor of genome sciences anda senior author of the study. His lab studies the geneticarchitecture behind differences among humans (as well as amongother species) and the mechanisms of evolutionary change. Although so-called single nucleotide variants are rare, they mayinfluence a person's resistance or susceptibility to commondiseases, like heart or lung trouble or blood problems. The rarityof each specific variation means that scientists will often need tostudy DNA samples from very large numbers of people to draw anygenetic links to these disorders. Researchers already realize that commonly occurring gene variantshave only a modest role in the complex medical conditions with themost public health repercussions. In this week's paper, "Evolution and Functional Impact of RareCoding Variations from Deep Sequencing of Exomes," investigatorsdescribed their study of the protein-coding sections of genomesfrom almost 2,440 individuals. The participants were 1,351 peopleof European extraction and 1,088 of African ancestry. The study is a first step toward understanding how rare geneticvariants contribute to some of the leading chronic illness causesof death in the world. It was conducted as part of the mission of the Seattle GO at theUniversity of Washington and the Broad GO at Harvard University andMIT, both funded by the National Institute of Health's NationalHeart Lung and Blood Institute Exome Sequencing Project. The exomeconsists of the protein-coding regions of the genome. The overall project encompasses a great many individuals who havedistinct traits, such as heart attacks before old age, strokes , or a high body mass index, to discover the genes and molecularmechanisms behind these conditions. Low cost, rapid sequencing of whole genomes is on its way tobecoming clinically feasible. The information gleaned would be moreuseful if statistical and experimental methods could moreaccurately identify gene variations that regulate biologicalprocesses and produce functionally significant proteins. Such methods would link gene variations to disease causes andprovide information for preventing and treating diseases. The other senior author of the paper from the Exome SequencingProject is Michael J. Bamshad, University of Washington professorof pediatrics in the Division of Genetic Medicine. Researchers fromeight institutions across the nation collaborated. The group sequenced and compared 15,585 human protein-coding genes.They located more than a half-million single-letter DNA codevariations in their sample populations. The majority of these variations arose recently in humanevolutionary history and so were rare, novel, and specific eitherto the African or the European study populations, the researchersdiscovered. The researchers went on to pick just thosesingle-letter variations in the DNA that might affect the functionsof proteins. Alterations in protein functions are among the keyways genetic differences spin into disease traits. They estimated that a little more than 2 percent of theapproximately 13,600 single nucleotide variations each personcarried, on average, influenced the function of about 313 genes pergenome. More than 95 percent of the single-letter code changespredicted to be functionally important were rare in the overallstudy population. How did so many rare variations affecting protein function arise inthe human genetic code? The researchers suggest that this excess ofrare variations is due to a combination of demographic andevolutionary forces. Both European and African populations grew exponentially beginningaround 10,000 years ago, but in the past 5,000 years growth ratesaccelerated leading to the billions of people living today. Thedramatic recent increase in population size has thereforeprofoundly influenced the spectrum of protein-coding variationpresent in humans. The scientists calculated the mean average of novel, single-lettercode variations in their study subjects: 549 per individualoverall. People of African descent had about twice the number ofnew variations compared to those of European descent, or 762 versus382. The researchers measured the effects of natural selection on rarecoding variation. To do so, they also brought in genetic detailsfrom genes highly specific to humans relative to chimps andmacaques to look for what are called "selective sweeps." A selective sweep occurs when natural selection increases thefrequency of a beneficial variant in a population. The beneficialvariant doesn't travel alone. Nearby genetic material is sweptalong with it. Included among the genes the scientists culled outas affected by positive selection were those related to the senseof smell and to the use of energy. The researchers also learned that most of the protein-codingvariations identified in their study were predicted to be harmful.Rare variation contributes not simply to each individual'suniqueness, but also to their risk for life-shortening illnesses. What are the implications of these findings for understandingdisease and advancing personalized medicine? Before answering, theresearchers pointed to present limitations in robustly identifyingfunctional important gene variation. "Nevertheless," they said, "there was considerable rare geneticvariation among individuals that is predicted to be functional,which could explain variability in disease risk and in drugresponse." The researchers would like more powerful tests to detect theeffects of rare genetic variations on human health. They suggestthat accounting gene-by-gene might improve research methods. They added that the population-specific nature of most of thesingle-letter code changes will make it challenging to replicatedisease associations with a variant across the world's people. Additional References Citations. We are high quality suppliers, our products such as Rack Mount Fiber Enclosure , Fiber Optic Adapter Manufacturer for oversee buyer. To know more, please visits Fiber Optic Patch Cord.
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