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Finding Variants in the Human Genome: HapMap 3 Points the Way Forward for Human Genetics Studies

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.



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./releases/2010/09/100901132201.htm

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Finding Variants in the Human Genome: HapMap 3 Points the Way Forward for Human Genetics Studies

基因组变异体的发现：HapMap 3为人类遗传研究导向
译者：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.

《每日科学》2010年9月2日报道 —— 国际人类基因组单体型图计划（简称HapMap计划）的最新阶段研究喜获进展：新的发现既显示了跨人群遗传研究的价值、也显示了用于探测遗传变异的最新DNA测序技术的价值。本研究结果已发表于《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)

一国际联合组织今天发表了第三代人类遗传变异图谱（HapMap），其中包括来自全球的另外七个人群的数据，使人群总数提高到11个。优化后的新图谱将有助于研究者解读目前的旨在发现与复杂性疾病相关的普通与罕见遗传变异的基因组研究。（照片来源：美国国立人类基因组研究所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.

研究者对多人群的遗传变异的广泛研究将为未来的变异与疾病的遗传学研究提供原则性框架：他们的发现突出了两点：一：为找出最大的遗传变体群落，检查不同人群是必要的；二：为发现尽可能多的变异，也需要有效利用测序技术。

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计划试图确认人类基因组中的路标，从而使寻找重要遗传变体的过程简化。在HapMap最新研究阶段中，研究者从来自11个人群的1184个样本的全基因组范围内搜索变异体。

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.

他们选择了大样本集合以及范围广泛的人群， 使他们能够捕获的遗传变异最大化。该计划同时包括单字母差异（“单字母多态性” single-letter polymorphism，或SNPs；也即“单核苷酸多态性” single nucleotide polymorphism —— 译者）与由区域丧失、获得或复制导致的大型差异（挎贝数多态性，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.

美国贝勒医学院德州休斯敦分院分子与人类遗传学教授、BCM人类基因组研究中心主任Richard Gibbs 说：“继人类基因组计划之后，尽管取得了引人注目的成就，我们对于人类遗传变异的知识仍然有限。我们现在已经研究了更多的人群，能够在全基因组研究中将挎贝数多态性即CNPs的研究包括在内。”

"These results tell us more about human genetic variation and about how to study variation successfully."

“这些结果告诉我们更多有关人类遗传变异的知识， 以及有关成功研究变异的方法与步骤。”

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.

本研究结果显示：越罕见的变体，其在人群中的分布也越不均衡。这可能在预料之中 —— 进化论表明，一般的变异体通常就是年代更久的那些变型，因为它们有更多的时间在一个人群中传播 —— 但该结果也警示我们， 遗传研究应该包括范围广泛的人群，从而发现更多新的、仅在特定人群中存在的变体。

"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.

“我们对人类遗传变异的观察越接近，粒度也就越大。遗传学中的一个很重要的任务是：区分出对健康有重大影响的变异体与那些只扮演部分背景角色的变异体。”日内瓦大学教授、本计划协调人之一、前卫尔康信托桑格研究院成员的 Manolis Dermitzakis说。

"This new version of the HapMap will help us design ways to do that -- to sort the wheat from the chaff."

“这个HapMap新版本将帮助我们设计相关实施方案，以去粗取精、去芜存菁。”

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.

除了以上所说的基因型分型研究，HapMap 3 也对来自人类基因组的定性清楚的区域上的有着十万个碱基对的十个片段进行测序。与利用DNA芯片的发现不同（迄今为止大多数研究都利用了芯片），直接测序并非偏向于（发现）更多的普通变异体，而是对变异体的出现率给出直接的估计。

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.

研究者发现大多数的变异体是相对不常见的（十个人中不超过一个人有该变异体），但他们也发现大量罕见的变异体（100个人中不超过1人），或者“私人”变异体（只是某个人有）。有个人群，并且只是这个人群，十个变体中几乎有八个是新的；并且，那些在一百个人只有一个人中出现的变异体，10个（变体）里面就有4个（变体）仅在该人群内才有。

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.

从这些结果出发，研究者建议应使某些基因（包括与免疫系统、伤口愈合与嗅觉相关的基因）中存在的变体在不同的人群中处于可供选择（研究）状态。现在可以研究这些基因，以了解这些系统的工作原理并了解有关抗病性（问题）。这些发现显示了拥有大型研究的价值（与意义）。大型研究是指拥有多人群、大样本，以此来达成对人类变异的全面理解（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.

“一些人说过去的十年里来自人类基因组计划（的收获）少得可怜， 但是他们也许忘记了：当时我们对基因组的了解少得多么的可怜。令人称羡的是：我们已经从完成程度少于90%的基因组中脱身而出，转而关注二百人中只有一人（或少于一人）才存在的遗传变化上。几年前，我们根本不知道结构性变异的范围，或不知道怎样才能对以低频率出现的变异进行取样。”波士顿麻省总医院、麻省理工学院布劳德研究院以及哈佛大学麻省剑桥分校的David Altshuler教授说，

"The HapMap and other large-scale projects have transformed our understanding of the human genome and its relation to health and disease."

“HapMap以及其它大规模计划已经使我们对人类基因组、 基因组与健康与疾病关系的理解焕然一新。”

The HapMap 3/ENCODE 3 data set is publicly available at http://www.hapmap.org.

HapMap 3/ENCODE 3数据集公开发表于：
http://www.hapmap.org.

（Docofsoul 译于2010-09-03）