中国6个民族群体HLA区域内TNF基因簇的核苷酸变异和单体型多态性
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摘要
随着人类基因组(测序)计划的完成和测序技术的日臻成熟,许多研究组织对世界各地人群实施了大量的、有针对性的测序计划和分型计划。亚洲人群在世界人群中占有相当的比重,且中国不同民族群体的亲缘关系和疾病易感性的差异成为众多研究人员关注的焦点。在长期与环境相适应的进化过程中,种群动态、迁徙历史和选择压力等使中国人群形成了独特的亚群体。在核苷酸水平上研究群体的多态性,有助于了解中国民族群体的遗传结构,探测不同环境下群体所受的自然选择压力,以揭示不同民族群体对疾病易感性和药物反应的差异。我们选取了和人类免疫应答和免疫调控密切相关的HLA区域内TNF基因簇周围32kb片段,采用测序的方法检测了中国6个民族群体(1、山东汉族,2、黎族,3、广东汉族,4、彝族,5、藏族,6、蒙古族)在该区域内的SNP多态性,为中国人群和该区域相关疾病基因的定位、诊断、治疗和预防提供了基本的遗传信息。
该32kb区域包含了5个重要的基因即:LTA、TNF、LTB、LST1和NCR3,其中LTA、TNF、LTB基因为TNF超家族成员。它们和许多人类免疫系统疾病相关,如心肌梗死、血脂症、远端结肠炎、麻疯病、强直性脊柱炎、银屑病关节炎、脑型疟、阿尔茨海默病等。另外,这5个基因,特别是TNF基因在调节免疫系统、抑制癌细胞、脂代谢、凝血、胰岛素抵抗等系统中发挥着重要功能。通过测序得到的多态位点中有8个SNP为上述某些疾病的致病突变位点,另外还有许多位点和上述疾病相关联。rs1041981与心肌梗死发病相关,在彝族中致病等位基因频率明显小于其它5个民族群体。rs2239704与麻风病的发病相关,我们所研究的北方群体(山东汉族、蒙古族)的致病等位基因频率略高于南方群体(广东汉族、黎族)。rs1800629与胰岛素抵抗相关,其致病等位基因在广东汉族和黎族代表的南方群体中频率较高。阿尔茨海默病的两个致病等位基因分别为TNF-850T和TNF-863A,前者在广东汉族中的频率较低,而后者在彝族和藏族群体中频率却较高。致病等位基因频率的差异反映了这6个群体疾病易感性的不同,清楚的了解中国不同民族群体的致病等位基因的频率差异将为疾病的研究提供帮助。
我们一共找到了273个多态位点,包括242个碱基替换,3个STR和28个Indel。其中133个是新发现的多态位点,有13个为常见多态位点。在所有的多态位点中低频位点占73%,平均每117bp便存在一个多态位点,大量低频位点预示着种群扩展和自然选择的发生。依据总SNP位点、民族群体特有SNP位点的频率分布可以看出,来自北方的群体的遗传多态性要高于来自南方的群体。大量新的SNP位点表明中国人群中仍旧有较多的SNP位点未被检出,特别是那些能够反映群体差异的SNP位点和低频SNP位点。如果仅选用目前dbSNP数据库所提供的SNP来预测群体差异、种群动态和自然选择时势必存在较大偏差。在32kb区域内,基因间区、5'UTR的核苷酸多态性(π)较高,这些基因表达调控区域的高度多态性势必增加基因表达的差异性,有利于提高人群对环境的适应能力。编码区的核苷酸多态性较低,反映了这些基因具有重要功能,以及自然选择对编码区突变的严格控制。
大量研究和证据表明中国人群经历了快速扩展的过程。歧点分布图近似钟形分布,Fs检验为显著的负值,Tajiama's D检验和Fu和Li的D以及F检验为负值提示:所研究的人群在历史上存在种群扩展过程。同样单体型进化树成放射状分布也证明人群扩展的发生。6个民族群体的种群扩展程度以来自北方群体的蒙古族和山东汉族较明显,而独居于海南岛上的黎族却未检测到种群扩展过程。
该区域高度的核苷酸多态性提示了较高的染色体重组率和这5个基因在人群对环境适应过程中发挥的重要作用。HLA区域存在大量和免疫防御相关的基因,因此高度多态性是发挥防御功能的必要前提,染色体重组则有利于增加该区域多态性。在短短32kb区域内发现了大量单体型,单体型块被较多重组事件打断。相对于背景而言,某些区域的重组率较高,尽管6个群体的重组率变化的趋势相似但却各不相同。北方群体的染色体重组率要高于南方群体,但西南地区藏族的重组率最高,黎族的染色体重组率最低。在32kb区域内,所有群体在LTA基因和它前面的基因间区有一明显的单体型块,但其它区域的单体型块都被重组事件打断,重组事件打破了原有位点间的连锁不平衡,而使得关联分析难以用少量标签SNP覆盖大部分的多态位点。然而,染色体重组大大增加了基因组的多样性,从而增加了人群适应性。
大量低频位点存在预示着自然选择的发生,多种检测方法均发现该区域受到了自然选择的作用。但是6个群体受到选择方式和强度并不相同,说明这6个群体在适应环境过程中逐渐产生了差异。LTA基因及前方基因间区可能受到了平衡选择作用,但只有黎族和彝族的显著,其它基因的基因区和启动子区可能受到了正或者负选择作用,但黎族和彝族却不明显。Fay和Wu的H检验发现所有群体在LTB、LSTl以及它们的启动子区都发生了选择扫荡,且广东汉族和蒙古族相对于其它4个群体要显著的多。染色体重组导致自然选择所产生的单体型模式快速的被破坏,而种群扩展、迁徙、亚群体、瓶颈效应同样也会使自然选择的检测出现显著的负值,因而检测的结果只能说明我们所研究的区域可能受到了自然选择的作用。
HapMap为高精度高效率的全基因组关联分析提供基础,已经有众多的组织使用其数据进行疾病的关联研究。但由于HapMap样本代表性有限以及SNP的选择存在群体偏差,再加上亚洲群体结构的复杂性,而使得亚洲人群的疾病关联分析可能存在系统偏颇。染色体重组使得重组热点区成为关联分析的难点,而要覆盖重组高发区域的所有常见SNP,就必须增加标签SNP的量。HapMap在该区域检测了93个多态位点,并提供了关联分析时选用的标签SNP。但是,该区域较高的重组率和中国人群较多的常见SNP位点HapMap并未检测,而使得HapMap提供的标签SNP难以覆盖该区域中国人群的常见SNP,甚至丢失了约1/3的常见SNP。故在关联分析时需要更多的标签SNP来覆盖该区域的单体型信息,甚至需要全测序的方法才能准确探知与疾病关联的多态位点。我们的研究结果表明在使用SNP进行关联分析时,除考虑HapMap所提供的标签SNP外,应结合目标区域的染色体重组模式来调整标签SNP的分布。采用测序的方法,结合中国的人群结构,构建详尽的单体型图将为疾病基因的定位研究提供可靠的遗传基础。
After the release of the first draft of Human Genome,the advent of high throughput sequencing and genotyping methods push forward a various genomics projects and lead to portray the human genome in populations scale.Asian population takes a considerable proportion in the world's population,and lots of researchers are engaged in exploring the relationship and diseases susceptibility of different Chinese populations.Population dynamics,migration history and the pressure of natural selection has driven Chinese population into specific sub-groups on the long-term course of human evolution.To specifically investigate the genetic structure and polymorphism in major Chinese populations,we sequenced a 32-kb genomic region from the human Major Histocompatibility Complex with Shandong Han(SH), Guangdong Han(GH),Li(LI),Yi(YI),Tibetan(ZH),and Inner-Mongolian(MG). This will facilitate the researches not only disease mapping,but also in health care-related areas such as prevention,diagnosis,and treatment of disease.
The 32-kb region comprises 5 important immune-related genes(LTA,TNF,LTB, LST1,and NCR3) which have relationship with a large number of human immune system diseases,such as myocardial infarction,dyslipidemia,distal colitis,leprosy, ankylosing spondylitis,rheumatoid arthritis,cerebral malaria and Alzheimer disease. In particular,tumor necrosis factor(TNF),a pre-inflammatory cytokine,plays important roles in lipid metabolism,blood coagulation,insulin resistance,and endothelial function.We also estimate the allele frequency of 8 polymorphic sites which are disease-causing mutations of some of those diseases.LTA,+804C-A (rs1041981) in the LTA gene that caused a threonine-to-asparagine substitution at codon 26 is significantly associated with increased risk for myocardial infarction.The LTA+804A allele's MAF of YI is much lower than that of other 5 populations.The low-producing LTA+80A allele is significantly associated with an increase in leprosy risk and LTA+80A's MAF is a little lower in southern Chinese population(GH,LI) than in northern Chinese population(SH,MG).TNF,-308G-A(rs1800629) genetic variants is associated with features of the insulin resistance syndrome and TNF-308A allele's MAF is higher in SH,LI than in GH,YI,ZH.TNF-850T and TNF-863A are associated with Alzheimer disease,TNF-850T allele's MAF is smaller in GH and TNF-863A allele is higher in YI,ZH which come from South-West of China.The different frequency of risk alleles in 6 Chinese populations indicates that various diseases susceptibility of them.
From the 6 Chinese populations,273 polymorphic sites,including 242 SNPs,3 STRs,and 28 indels,are identified.133 sites among these are newly-discovered and not present in the dbSNP database(v.127),and 13 newly-discovered SNPs are common SNPs.Rare SNP take the proportion of 73%and there is one SNP per 117bp in the 32-kb region.The allele distributions of polymorphic site in 6 Chinese populations indicate that the northern Chinese are more polymorphic than southern Chinese in the studied region,population expansion in northern Chinese is more severely than that of southern Chinese.Lots of new SNPs was detected indicate that there in Chinese populations the human genome,especially for those rare SNPs and polymorphic sites which represent the differentiation between populations.Thus, using the SNPs from dbSNP to investigate population differentiation,population dynamics and natural selection,the results will lead to deviate from reality.High polymorphism in gene regulatory region,such as promoter,5'UTR and intron will increase the discrepancy of gene expression and improve the adaptation of human. Low polymorphism in coding region agree with the functional constrain of genes and high pressure of natural selection on mutation.
Lots of evidences show that Chinese populations experience an expansion in history.A smooth,approximate bell-shaped mismatch distribution,significant negative value of Fs test and radial branches of minimum spanning network for haplotypes indicate expansion of 6 Chinese populations.Northern Chinese population represented by Inner-Mongolian and Shandong Han expand more severely than other
4 populations.We don't detect population expansion of LI who lives alone on the Hainan Island.A large number of low-frequency SNPs also predict the occurrence of natural selection,high DNA polymorphism indicate not only that 5 genes play an important role in human adaptation to environment changes,but also high recombination rate of 32-kb region.
Lots of genes in the HLA region participate in immune defense.High polymorphism of these genes will help for immune defense and high chromosome recombination will increase the gene polymorphism.The 32-kb region contains a rather loosely-formed linkage disequilibrium(LD) block and 2 to 3 genomic spots at elevated recombination rate.These lead to the observation of a high number of haplotypes.The recombination rate of some regions is higher relative to the background.Similar trend of recombination rate alone the 32-kb region in 6 Chinese populations,but there is a little different between them.Tibetan's recombination rate is highest and Li's recombination rate is lowest.Recombination rate of northern Chinese population is higher than southern Chinese population.There is only one distinct haplotype-block at LTA gene and intergenic region before it,but in the rest region no distinct haplotype-block exists because of recombination.Recombination events break the LD between loci and make it is difficult to predict the most of common SNPs by tag SNPs through the association study.
Many tests have used for detecting natural selection on the 32-kb region,and we found that the pattern and intensity of selection are different in 6 Chinese populations. Balancing selection maybe has acted on LTA gene and intergenic region before it,but only significant in Li and Yi.Negative/positive selection maybe has acted on almost all of other genes and their promoter region,the value is significant in all populations except Li and Yi.Selective sweep has acted on LTB,LST1 and their promoter region in 6 Chinese populations,the Fay and Wu' H statistic is more significant in Guangdong Han,Inner-Mongolian than in other 4 populations.Recombination will decay the pattern constructed by natural selection and population expansion, migration,subpopulation,bottleneck can also cause many selection statistics to be significant negative,thus the natural selection maybe act on the region under study.
The International HapMap Project has been instrumental in making well-powered, large-scale,genome-wide association studies a reality.It is now clear that the HapMap can be a useful resource for the design and analysis of disease association studies in populations across the world.The Asian population structure is complex and many populations specific common SNPs are still not identified.Disease association studies in Asian population will deviate from the reality when using tag SNPs from HapMap, because of inherent and intentional bias in sampling and rules used for SNP selection in HapMap project.It's also difficult for association studies to detect common SNPs in the region of recombination hotspot.One must increase the number of tag SNPs if he wants to cover the common SNPs in high recombination rate region when doing association study.In the 32-kb region,HapMap project select 93 SNPs and give 15 tag SNPs for association study.It would loss 1/3 common SNPs information when use these 15 tag SNPs because of high recombination rate of this region and lots of Chinese population specific common SNPs are not identified.A comprehensive search for genetic influences on disease would involve examining all genetic differences in a large number of affected individuals and controls.It may eventually become possible to accomplish this by complete genome resequencing.Finally, comparing to the data of the latest HapMap release in the 32-kb region,our resequencing effort captures more rare and Chinese-specific polymorphic sites.This shows that the Han data from HapMap database is not without problems of ascertainment bias.Extending the resequencing effort in larger genomic regions with Chinese populations will facilitate the researches not only in disease mapping,but also in health care-related areas such as prevention,diagnosis,and treatment of disease.
该32kb区域包含了5个重要的基因即:LTA、TNF、LTB、LST1和NCR3,其中LTA、TNF、LTB基因为TNF超家族成员。它们和许多人类免疫系统疾病相关,如心肌梗死、血脂症、远端结肠炎、麻疯病、强直性脊柱炎、银屑病关节炎、脑型疟、阿尔茨海默病等。另外,这5个基因,特别是TNF基因在调节免疫系统、抑制癌细胞、脂代谢、凝血、胰岛素抵抗等系统中发挥着重要功能。通过测序得到的多态位点中有8个SNP为上述某些疾病的致病突变位点,另外还有许多位点和上述疾病相关联。rs1041981与心肌梗死发病相关,在彝族中致病等位基因频率明显小于其它5个民族群体。rs2239704与麻风病的发病相关,我们所研究的北方群体(山东汉族、蒙古族)的致病等位基因频率略高于南方群体(广东汉族、黎族)。rs1800629与胰岛素抵抗相关,其致病等位基因在广东汉族和黎族代表的南方群体中频率较高。阿尔茨海默病的两个致病等位基因分别为TNF-850T和TNF-863A,前者在广东汉族中的频率较低,而后者在彝族和藏族群体中频率却较高。致病等位基因频率的差异反映了这6个群体疾病易感性的不同,清楚的了解中国不同民族群体的致病等位基因的频率差异将为疾病的研究提供帮助。
我们一共找到了273个多态位点,包括242个碱基替换,3个STR和28个Indel。其中133个是新发现的多态位点,有13个为常见多态位点。在所有的多态位点中低频位点占73%,平均每117bp便存在一个多态位点,大量低频位点预示着种群扩展和自然选择的发生。依据总SNP位点、民族群体特有SNP位点的频率分布可以看出,来自北方的群体的遗传多态性要高于来自南方的群体。大量新的SNP位点表明中国人群中仍旧有较多的SNP位点未被检出,特别是那些能够反映群体差异的SNP位点和低频SNP位点。如果仅选用目前dbSNP数据库所提供的SNP来预测群体差异、种群动态和自然选择时势必存在较大偏差。在32kb区域内,基因间区、5'UTR的核苷酸多态性(π)较高,这些基因表达调控区域的高度多态性势必增加基因表达的差异性,有利于提高人群对环境的适应能力。编码区的核苷酸多态性较低,反映了这些基因具有重要功能,以及自然选择对编码区突变的严格控制。
大量研究和证据表明中国人群经历了快速扩展的过程。歧点分布图近似钟形分布,Fs检验为显著的负值,Tajiama's D检验和Fu和Li的D以及F检验为负值提示:所研究的人群在历史上存在种群扩展过程。同样单体型进化树成放射状分布也证明人群扩展的发生。6个民族群体的种群扩展程度以来自北方群体的蒙古族和山东汉族较明显,而独居于海南岛上的黎族却未检测到种群扩展过程。
该区域高度的核苷酸多态性提示了较高的染色体重组率和这5个基因在人群对环境适应过程中发挥的重要作用。HLA区域存在大量和免疫防御相关的基因,因此高度多态性是发挥防御功能的必要前提,染色体重组则有利于增加该区域多态性。在短短32kb区域内发现了大量单体型,单体型块被较多重组事件打断。相对于背景而言,某些区域的重组率较高,尽管6个群体的重组率变化的趋势相似但却各不相同。北方群体的染色体重组率要高于南方群体,但西南地区藏族的重组率最高,黎族的染色体重组率最低。在32kb区域内,所有群体在LTA基因和它前面的基因间区有一明显的单体型块,但其它区域的单体型块都被重组事件打断,重组事件打破了原有位点间的连锁不平衡,而使得关联分析难以用少量标签SNP覆盖大部分的多态位点。然而,染色体重组大大增加了基因组的多样性,从而增加了人群适应性。
大量低频位点存在预示着自然选择的发生,多种检测方法均发现该区域受到了自然选择的作用。但是6个群体受到选择方式和强度并不相同,说明这6个群体在适应环境过程中逐渐产生了差异。LTA基因及前方基因间区可能受到了平衡选择作用,但只有黎族和彝族的显著,其它基因的基因区和启动子区可能受到了正或者负选择作用,但黎族和彝族却不明显。Fay和Wu的H检验发现所有群体在LTB、LSTl以及它们的启动子区都发生了选择扫荡,且广东汉族和蒙古族相对于其它4个群体要显著的多。染色体重组导致自然选择所产生的单体型模式快速的被破坏,而种群扩展、迁徙、亚群体、瓶颈效应同样也会使自然选择的检测出现显著的负值,因而检测的结果只能说明我们所研究的区域可能受到了自然选择的作用。
HapMap为高精度高效率的全基因组关联分析提供基础,已经有众多的组织使用其数据进行疾病的关联研究。但由于HapMap样本代表性有限以及SNP的选择存在群体偏差,再加上亚洲群体结构的复杂性,而使得亚洲人群的疾病关联分析可能存在系统偏颇。染色体重组使得重组热点区成为关联分析的难点,而要覆盖重组高发区域的所有常见SNP,就必须增加标签SNP的量。HapMap在该区域检测了93个多态位点,并提供了关联分析时选用的标签SNP。但是,该区域较高的重组率和中国人群较多的常见SNP位点HapMap并未检测,而使得HapMap提供的标签SNP难以覆盖该区域中国人群的常见SNP,甚至丢失了约1/3的常见SNP。故在关联分析时需要更多的标签SNP来覆盖该区域的单体型信息,甚至需要全测序的方法才能准确探知与疾病关联的多态位点。我们的研究结果表明在使用SNP进行关联分析时,除考虑HapMap所提供的标签SNP外,应结合目标区域的染色体重组模式来调整标签SNP的分布。采用测序的方法,结合中国的人群结构,构建详尽的单体型图将为疾病基因的定位研究提供可靠的遗传基础。
After the release of the first draft of Human Genome,the advent of high throughput sequencing and genotyping methods push forward a various genomics projects and lead to portray the human genome in populations scale.Asian population takes a considerable proportion in the world's population,and lots of researchers are engaged in exploring the relationship and diseases susceptibility of different Chinese populations.Population dynamics,migration history and the pressure of natural selection has driven Chinese population into specific sub-groups on the long-term course of human evolution.To specifically investigate the genetic structure and polymorphism in major Chinese populations,we sequenced a 32-kb genomic region from the human Major Histocompatibility Complex with Shandong Han(SH), Guangdong Han(GH),Li(LI),Yi(YI),Tibetan(ZH),and Inner-Mongolian(MG). This will facilitate the researches not only disease mapping,but also in health care-related areas such as prevention,diagnosis,and treatment of disease.
The 32-kb region comprises 5 important immune-related genes(LTA,TNF,LTB, LST1,and NCR3) which have relationship with a large number of human immune system diseases,such as myocardial infarction,dyslipidemia,distal colitis,leprosy, ankylosing spondylitis,rheumatoid arthritis,cerebral malaria and Alzheimer disease. In particular,tumor necrosis factor(TNF),a pre-inflammatory cytokine,plays important roles in lipid metabolism,blood coagulation,insulin resistance,and endothelial function.We also estimate the allele frequency of 8 polymorphic sites which are disease-causing mutations of some of those diseases.LTA,+804C-A (rs1041981) in the LTA gene that caused a threonine-to-asparagine substitution at codon 26 is significantly associated with increased risk for myocardial infarction.The LTA+804A allele's MAF of YI is much lower than that of other 5 populations.The low-producing LTA+80A allele is significantly associated with an increase in leprosy risk and LTA+80A's MAF is a little lower in southern Chinese population(GH,LI) than in northern Chinese population(SH,MG).TNF,-308G-A(rs1800629) genetic variants is associated with features of the insulin resistance syndrome and TNF-308A allele's MAF is higher in SH,LI than in GH,YI,ZH.TNF-850T and TNF-863A are associated with Alzheimer disease,TNF-850T allele's MAF is smaller in GH and TNF-863A allele is higher in YI,ZH which come from South-West of China.The different frequency of risk alleles in 6 Chinese populations indicates that various diseases susceptibility of them.
From the 6 Chinese populations,273 polymorphic sites,including 242 SNPs,3 STRs,and 28 indels,are identified.133 sites among these are newly-discovered and not present in the dbSNP database(v.127),and 13 newly-discovered SNPs are common SNPs.Rare SNP take the proportion of 73%and there is one SNP per 117bp in the 32-kb region.The allele distributions of polymorphic site in 6 Chinese populations indicate that the northern Chinese are more polymorphic than southern Chinese in the studied region,population expansion in northern Chinese is more severely than that of southern Chinese.Lots of new SNPs was detected indicate that there in Chinese populations the human genome,especially for those rare SNPs and polymorphic sites which represent the differentiation between populations.Thus, using the SNPs from dbSNP to investigate population differentiation,population dynamics and natural selection,the results will lead to deviate from reality.High polymorphism in gene regulatory region,such as promoter,5'UTR and intron will increase the discrepancy of gene expression and improve the adaptation of human. Low polymorphism in coding region agree with the functional constrain of genes and high pressure of natural selection on mutation.
Lots of evidences show that Chinese populations experience an expansion in history.A smooth,approximate bell-shaped mismatch distribution,significant negative value of Fs test and radial branches of minimum spanning network for haplotypes indicate expansion of 6 Chinese populations.Northern Chinese population represented by Inner-Mongolian and Shandong Han expand more severely than other
4 populations.We don't detect population expansion of LI who lives alone on the Hainan Island.A large number of low-frequency SNPs also predict the occurrence of natural selection,high DNA polymorphism indicate not only that 5 genes play an important role in human adaptation to environment changes,but also high recombination rate of 32-kb region.
Lots of genes in the HLA region participate in immune defense.High polymorphism of these genes will help for immune defense and high chromosome recombination will increase the gene polymorphism.The 32-kb region contains a rather loosely-formed linkage disequilibrium(LD) block and 2 to 3 genomic spots at elevated recombination rate.These lead to the observation of a high number of haplotypes.The recombination rate of some regions is higher relative to the background.Similar trend of recombination rate alone the 32-kb region in 6 Chinese populations,but there is a little different between them.Tibetan's recombination rate is highest and Li's recombination rate is lowest.Recombination rate of northern Chinese population is higher than southern Chinese population.There is only one distinct haplotype-block at LTA gene and intergenic region before it,but in the rest region no distinct haplotype-block exists because of recombination.Recombination events break the LD between loci and make it is difficult to predict the most of common SNPs by tag SNPs through the association study.
Many tests have used for detecting natural selection on the 32-kb region,and we found that the pattern and intensity of selection are different in 6 Chinese populations. Balancing selection maybe has acted on LTA gene and intergenic region before it,but only significant in Li and Yi.Negative/positive selection maybe has acted on almost all of other genes and their promoter region,the value is significant in all populations except Li and Yi.Selective sweep has acted on LTB,LST1 and their promoter region in 6 Chinese populations,the Fay and Wu' H statistic is more significant in Guangdong Han,Inner-Mongolian than in other 4 populations.Recombination will decay the pattern constructed by natural selection and population expansion, migration,subpopulation,bottleneck can also cause many selection statistics to be significant negative,thus the natural selection maybe act on the region under study.
The International HapMap Project has been instrumental in making well-powered, large-scale,genome-wide association studies a reality.It is now clear that the HapMap can be a useful resource for the design and analysis of disease association studies in populations across the world.The Asian population structure is complex and many populations specific common SNPs are still not identified.Disease association studies in Asian population will deviate from the reality when using tag SNPs from HapMap, because of inherent and intentional bias in sampling and rules used for SNP selection in HapMap project.It's also difficult for association studies to detect common SNPs in the region of recombination hotspot.One must increase the number of tag SNPs if he wants to cover the common SNPs in high recombination rate region when doing association study.In the 32-kb region,HapMap project select 93 SNPs and give 15 tag SNPs for association study.It would loss 1/3 common SNPs information when use these 15 tag SNPs because of high recombination rate of this region and lots of Chinese population specific common SNPs are not identified.A comprehensive search for genetic influences on disease would involve examining all genetic differences in a large number of affected individuals and controls.It may eventually become possible to accomplish this by complete genome resequencing.Finally, comparing to the data of the latest HapMap release in the 32-kb region,our resequencing effort captures more rare and Chinese-specific polymorphic sites.This shows that the Han data from HapMap database is not without problems of ascertainment bias.Extending the resequencing effort in larger genomic regions with Chinese populations will facilitate the researches not only in disease mapping,but also in health care-related areas such as prevention,diagnosis,and treatment of disease.
引文
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