基于标签单核苷酸多态性单倍型和单倍域的构建及其在关联研究中的应用

人类基因组中单倍型(haplotype)和单倍域(haplotype block)的结构提供了人类进化的宝贵信息,并成为发现人类复杂疾病易感基因的有效策略。一个单倍域可分割成多个具有有限单倍型多样性的离散的区域,代表每个区域结构特征的少量标签单核苷酸多态性(tag single nucleotide polymorphism,tSNP)可使绝大部分单倍型相互区分开来。因此,标签SNP在单倍型和单倍域的构建和关联研究中具有重要地位。构建单倍型和单倍域的方法分为两类,分别是基于大家系中基因分型数据和基于统计学的算法。通过系统回顾几种单倍型和单倍域的构建方法,了解它们在不同的疾病模型或根据不同的分割标准,进行关联研究的检验效能,客观评价每种方法的优、缺点、应用前景及其在关联研究中的应用。随着国际人类基因组单倍型图的完成和单倍型构建统计学运算规则的完善,融合数学、物理学、计算机科学等学科的单倍型构建方法将对人类遗传学、复杂疾病易感基因的定位和克隆鉴定等生命科学的相关领域产生深远的影响。

Construction of haplotype and haplotype block based on tag single nucleotide polymorphisms and their applications in association studies

Human genome has structures of haplotype and haplotype block which provide valuable information on human evolutionary history and may lead to the development of more efficient strategies to identify genetic variants that increase susceptibility to complex diseases.Haplotype block can be divided into discrete blocks of limited haplotype diversity.In each block,a small fraction of "tag SNPs" can be used to distinguish a large fraction of the haplotypes.These tag SNPs can be potentially useful for construction of haplotype and haplotype block,and association studies in complex diseases.There are two general classes of methods to construct haplotype and haplotype blocks based on genotypes on large pedigrees and statistical algorithms respectively.The author evaluate several construction methods to assess the power of different association tests with a variety of disease models and block-partitioning criteria.The advantages,limitations and applications of each method and the application in the association studies are discussed equitably.With the completion of the HapMap and development of statistical algorithms for addressing haplotype reconstruction,ideas of construction of haplotype based on combination of mathematics,physics,and computer science etc will have profound impacts on population genetics,location and cloning for susceptible genes in complex diseases,and related domain with life science etc.