Finding Variants in the Human Genome: HapMap 3 Points the Way Forward for Human Genetics StudiesScienceDaily (Sep. 2, 2010) — New findings show the value of genetic studies across human populations and the value of the latest DNA sequencing technologies to interrogate genetic variation. The results, from the latest phase of the international HapMap Project, are reported in Nature.
An international consortium today published a third-generation map of human genetic variation, called the HapMap, which includes data from an additional seven global populations, increasing the total number to 11 populations. The improved resolution will help researchers interpret current genome studies aimed at finding common and rarer genetic variants associated with complex diseases. (Credit: Jane Ades , NHGRI)
The researchers' extensive study of genetic variation in multiple populations will form a framework for future genetic studies of variation and disease: their findings highlight the need to examine various populations in order to tease out the widest collection of genetic variants, as well as the requirement to deploy sequencing technologies to find as many variants as possible.
The HapMap Project seeks to identify signposts on the human genome that will simplify the search for important genetic variants. In the latest phase -- HapMap 3 -- the researchers looked for variants across the genome in 1184 samples from 11 populations. They chose the large sample set and the wide range of populations to maximize the variation they could capture. The project includes both single-letter differences (single-letter polymorphisms, or SNPs) as well as large differences from the loss, gain or duplication of regions, called copy-number polymorphisms, or CNPs.
"Despite the remarkable achievements following from the Human Genome Project, our knowledge of human genetic variation remains limited," says Professor Richard Gibbs, professor of molecular and human genetics at Baylor College of Medicine in Houston, Texas, and director of the BCM Human Genome Research Center. "Here we have studied more populations and were able to include CNPs in genomewide studies.
"These results tell us more about human genetic variation and about how to study variation successfully."
The results show that rarer variants are distributed more unevenly among populations. This might be expected -- evolutionary theory implies that the common variants are generally the older ones, having had greater time to spread through a population -- but also cautions that genetic studies should include a wide range of population groups to maximise discovery of more recent, population-specific variants.
"The closer we look at human genetic variation, the greater the granularity," explains Professor Manolis Dermitzakis, from the University of Geneva and one of the project coordinators, and formerly at the Wellcome Trust Sanger Institute. "An important task in genetics is to discriminate between the variants that are important for health and those that are part of the background.
"This new version of the HapMap will help us design ways to do that -- to sort the wheat from the chaff."
In addition to the genotyping studies described above, HapMap 3 also sequenced ten segments of 100,000 bases from well-characterized regions of the human genome. Unlike discovery using DNA chips -- as used in most studies to date -- direct sequencing is not biased towards more common variants, but gives a direct estimate of the frequencies of variants.
The researchers found that most variants were relatively uncommon (found in less than one person in ten), but they also found a large number of rare variants (each found in less than one in 100 people) or 'private' variants (found in only one person). Almost eight of ten variants were new and almost four of ten of those seen in less than one in 100 people were found in only one population.
From the results, the researchers suggest that variants in some genes, including genes involved in the immune system, wound healing and sense of smell, are under selection in different populations. These genes can now be studied to learn about how these systems work and about disease resistance. These findings show the value of having large studies that include many populations and samples to achieve comprehensive understanding of human variation.
"Some have talked about how little has come from the Human Genome Project over the past ten years, but perhaps they forget how little we knew then," says Professor David Altshuler of Massachusetts General Hospital in Boston and the Broad Institute of Massachusetts Institute of Technology (MIT) and Harvard University in Cambridge, Mass. "It is amazing that we have gone from a genome less than 90 per cent completed to looking at genetic changes in one in 200 people or rarer. A few years ago, we had no idea of the extent of structural variation or how we might sample variants present at low frequency.
"The HapMap and other large-scale projects have transformed our understanding of the human genome and its relation to health and disease."
The HapMap 3/ENCODE 3 data set is publicly available at
http://www.hapmap.org.http://www.sciencedaily.com/releases/2010/09/100901132201.htm============================================
Finding Variants in the Human Genome: HapMap 3 Points the Way Forward for Human Genetics Studies
基因組變異體的發(fā)現(xiàn)：HapMap 3為人類遺傳研究導(dǎo)向
譯者：Docofsoul ScienceDaily (Sep. 2, 2010) — New findings show the value of genetic studies across human populations and the value of the latest DNA sequencing technologies to interrogate genetic variation. The results, from the latest phase of the international HapMap Project, are reported in Nature.
《每日科學(xué)》2010年9月2日?qǐng)?bào)道 —— 國(guó)際人類基因組單體型圖計(jì)劃（簡(jiǎn)稱HapMap計(jì)劃）的最新階段研究喜獲進(jìn)展：新的發(fā)現(xiàn)既顯示了跨人群遺傳研究的價(jià)值、也顯示了用于探測(cè)遺傳變異的最新DNA測(cè)序技術(shù)的價(jià)值。本研究結(jié)果已發(fā)表于《Nature》。
An international consortium today published a third-generation map of human genetic variation, called the HapMap, which includes data from an additional seven global populations, increasing the total number to 11 populations. The improved resolution will help researchers interpret current genome studies aimed at finding common and rarer genetic variants associated with complex diseases. (Credit: Jane Ades , NHGRI)
一國(guó)際聯(lián)合組織今天發(fā)表了第三代人類遺傳變異圖譜（HapMap），其中包括來(lái)自全球的另外七個(gè)人群的數(shù)據(jù)，使人群總數(shù)提高到11個(gè)。優(yōu)化后的新圖譜將有助于研究者解讀目前的旨在發(fā)現(xiàn)與復(fù)雜性疾病相關(guān)的普通與罕見(jiàn)遺傳變異的基因組研究。（照片來(lái)源：美國(guó)國(guó)立人類基因組研究所Jane Ades)The researchers' extensive study of genetic variation in multiple populations will form a framework for future genetic studies of variation and disease: their findings highlight the need to examine various populations in order to tease out the widest collection of genetic variants, as well as the requirement to deploy sequencing technologies to find as many variants as possible.
研究者對(duì)多人群的遺傳變異的廣泛研究將為未來(lái)的變異與疾病的遺傳學(xué)研究提供原則性框架：他們的發(fā)現(xiàn)突出了兩點(diǎn)：一：為找出最大的遺傳變體群落，檢查不同人群是必要的；二：為發(fā)現(xiàn)盡可能多的變異，也需要有效利用測(cè)序技術(shù)。
The HapMap Project seeks to identify signposts on the human genome that will simplify the search for important genetic variants. In the latest phase -- HapMap 3 -- the researchers looked for variants across the genome in 1184 samples from 11 populations.
HapMap計(jì)劃試圖確認(rèn)人類基因組中的路標(biāo)，從而使尋找重要遺傳變體的過(guò)程簡(jiǎn)化。在HapMap最新研究階段中，研究者從來(lái)自11個(gè)人群的1184個(gè)樣本的全基因組范圍內(nèi)搜索變異體。
They chose the large sample set and the wide range of populations to maximize the variation they could capture. The project includes both single-letter differences (single-letter polymorphisms, or SNPs) as well as large differences from the loss, gain or duplication of regions, called copy-number polymorphisms, or CNPs.
他們選擇了大樣本集合以及范圍廣泛的人群， 使他們能夠捕獲的遺傳變異最大化。該計(jì)劃同時(shí)包括單字母差異（“單字母多態(tài)性” single-letter polymorphism，或SNPs；也即“單核苷酸多態(tài)性” single nucleotide polymorphism —— 譯者）與由區(qū)域喪失、獲得或復(fù)制導(dǎo)致的大型差異（挎貝數(shù)多態(tài)性，或CNPs）。
"Despite the remarkable achievements following from the Human Genome Project, our knowledge of human genetic variation remains limited," says Professor Richard Gibbs, professor of molecular and human genetics at Baylor College of Medicine in Houston, Texas, and director of the BCM Human Genome Research Center. "Here we have studied more populations and were able to include CNPs in genomewide studies.
美國(guó)貝勒醫(yī)學(xué)院德州休斯敦分院分子與人類遺傳學(xué)教授、BCM人類基因組研究中心主任Richard Gibbs 說(shuō)：“繼人類基因組計(jì)劃之后，盡管取得了引人注目的成就，我們對(duì)于人類遺傳變異的知識(shí)仍然有限。我們現(xiàn)在已經(jīng)研究了更多的人群，能夠在全基因組研究中將挎貝數(shù)多態(tài)性即CNPs的研究包括在內(nèi)?！?br>
"These results tell us more about human genetic variation and about how to study variation successfully."
“這些結(jié)果告訴我們更多有關(guān)人類遺傳變異的知識(shí)， 以及有關(guān)成功研究變異的方法與步驟?！?br>
The results show that rarer variants are distributed more unevenly among populations. This might be expected -- evolutionary theory implies that the common variants are generally the older ones, having had greater time to spread through a population -- but also cautions that genetic studies should include a wide range of population groups to maximise discovery of more recent, population-specific variants.
本研究結(jié)果顯示：越罕見(jiàn)的變體，其在人群中的分布也越不均衡。這可能在預(yù)料之中 —— 進(jìn)化論表明，一般的變異體通常就是年代更久的那些變型，因?yàn)樗鼈冇懈嗟臅r(shí)間在一個(gè)人群中傳播 —— 但該結(jié)果也警示我們， 遺傳研究應(yīng)該包括范圍廣泛的人群，從而發(fā)現(xiàn)更多新的、僅在特定人群中存在的變體。
"The closer we look at human genetic variation, the greater the granularity," explains Professor Manolis Dermitzakis, from the University of Geneva and one of the project coordinators, and formerly at the Wellcome Trust Sanger Institute. "An important task in genetics is to discriminate between the variants that are important for health and those that are part of the background.
“我們對(duì)人類遺傳變異的觀察越接近，粒度也就越大。遺傳學(xué)中的一個(gè)很重要的任務(wù)是：區(qū)分出對(duì)健康有重大影響的變異體與那些只扮演部分背景角色的變異體?！比諆?nèi)瓦大學(xué)教授、本計(jì)劃協(xié)調(diào)人之一、前衛(wèi)爾康信托桑格研究院成員的 Manolis Dermitzakis說(shuō)。
"This new version of the HapMap will help us design ways to do that -- to sort the wheat from the chaff."
“這個(gè)HapMap新版本將幫助我們?cè)O(shè)計(jì)相關(guān)實(shí)施方案，以去粗取精、去蕪存菁。”
In addition to the genotyping studies described above, HapMap 3 also sequenced ten segments of 100,000 bases from well-characterized regions of the human genome. Unlike discovery using DNA chips -- as used in most studies to date -- direct sequencing is not biased towards more common variants, but gives a direct estimate of the frequencies of variants.
除了以上所說(shuō)的基因型分型研究，HapMap 3 也對(duì)來(lái)自人類基因組的定性清楚的區(qū)域上的有著十萬(wàn)個(gè)堿基對(duì)的十個(gè)片段進(jìn)行測(cè)序。與利用DNA芯片的發(fā)現(xiàn)不同（迄今為止大多數(shù)研究都利用了芯片），直接測(cè)序并非偏向于（發(fā)現(xiàn)）更多的普通變異體，而是對(duì)變異體的出現(xiàn)率給出直接的估計(jì)。
The researchers found that most variants were relatively uncommon (found in less than one person in ten), but they also found a large number of rare variants (each found in less than one in 100 people) or 'private' variants (found in only one person). Almost eight of ten variants were new and almost four of ten of those seen in less than one in 100 people were found in only one population.
研究者發(fā)現(xiàn)大多數(shù)的變異體是相對(duì)不常見(jiàn)的（十個(gè)人中不超過(guò)一個(gè)人有該變異體），但他們也發(fā)現(xiàn)大量罕見(jiàn)的變異體（100個(gè)人中不超過(guò)1人），或者“私人”變異體（只是某個(gè)人有）。有個(gè)人群，并且只是這個(gè)人群，十個(gè)變體中幾乎有八個(gè)是新的；并且，那些在一百個(gè)人只有一個(gè)人中出現(xiàn)的變異體，10個(gè)（變體）里面就有4個(gè)（變體）僅在該人群內(nèi)才有。
From the results, the researchers suggest that variants in some genes, including genes involved in the immune system, wound healing and sense of smell, are under selection in different populations. These genes can now be studied to learn about how these systems work and about disease resistance. These findings show the value of having large studies that include many populations and samples to achieve comprehensive understanding of human variation.
從這些結(jié)果出發(fā)，研究者建議應(yīng)使某些基因（包括與免疫系統(tǒng)、傷口愈合與嗅覺(jué)相關(guān)的基因）中存在的變體在不同的人群中處于可供選擇（研究）狀態(tài)?，F(xiàn)在可以研究這些基因，以了解這些系統(tǒng)的工作原理并了解有關(guān)抗病性（問(wèn)題）。這些發(fā)現(xiàn)顯示了擁有大型研究的價(jià)值（與意義）。大型研究是指擁有多人群、大樣本，以此來(lái)達(dá)成對(duì)人類變異的全面理解（的目的）。
"Some have talked about how little has come from the Human Genome Project over the past ten years, but perhaps they forget how little we knew then," says Professor David Altshuler of Massachusetts General Hospital in Boston and the Broad Institute of Massachusetts Institute of Technology (MIT) and Harvard University in Cambridge, Mass. "It is amazing that we have gone from a genome less than 90 per cent completed to looking at genetic changes in one in 200 people or rarer. A few years ago, we had no idea of the extent of structural variation or how we might sample variants present at low frequency.
“一些人說(shuō)過(guò)去的十年里來(lái)自人類基因組計(jì)劃（的收獲）少得可憐， 但是他們也許忘記了：當(dāng)時(shí)我們對(duì)基因組的了解少得多么的可憐。令人稱羨的是：我們已經(jīng)從完成程度少于90%的基因組中脫身而出，轉(zhuǎn)而關(guān)注二百人中只有一人（或少于一人）才存在的遺傳變化上。幾年前，我們根本不知道結(jié)構(gòu)性變異的范圍，或不知道怎樣才能對(duì)以低頻率出現(xiàn)的變異進(jìn)行取樣?！辈ㄊ款D麻省總醫(yī)院、麻省理工學(xué)院布勞德研究院以及哈佛大學(xué)麻省劍橋分校的David Altshuler教授說(shuō)，
"The HapMap and other large-scale projects have transformed our understanding of the human genome and its relation to health and disease."
“HapMap以及其它大規(guī)模計(jì)劃已經(jīng)使我們對(duì)人類基因組、 基因組與健康與疾病關(guān)系的理解煥然一新?！?br>
The HapMap 3/ENCODE 3 data set is publicly available at
http://www.hapmap.org. HapMap 3/ENCODE 3數(shù)據(jù)集公開發(fā)表于：
http://www.hapmap.org. （Docofsoul 譯于2010-09-03）
