人类基因组中的连锁不平衡方式

连锁不平衡(linkagedisequilibrium,LD)伴随突变的多态性出现,由于位点间重组,LD程度逐渐下降。对于一个特定群体而言影响LD的因素很多,一系列人口历史因素起着重要的作用。LD程度的度量,目前常用的两种配对检验方法为D′和r2。在染色体的部分区域存在一系列重组热点分割的单倍型块。目前LD主要应用于关联研究中以定位复杂的疾病基因。     

基因型错误对定位QTL的LD指数效应

连锁不平衡(LD)在基因定位中起着关键作用，因而是现代遗传研究中的一个重要工具。但是，连锁不平衡背景的估计受多种因素的影响，其中之一就是基因型错误。已经有研究考察了基因型错误对四个常用LD 指数D, r, Q, 和d的影响。而基因型错误对于定位数量性状位点(QTL)的LD 指数的效应还没有得到研究。本文从分析的角度调查了基因型错误存在时LD 指数lx 的性质。结果表明，指数lx 因依赖于基因型错误率因而值变小了，当基因型错误率达到0.03， lx值的改变量(减小值)将超过50％，特别是在标记基因频率比较高的时候。基因型错误的影响也通过基于血管紧张肽转化酶(ACE)基因的10个SNPs单体型频率的模拟研究得到了证实。     

基因型错误对定位QTL的LD指数的效应

连锁不平衡(LD)在基因定位中起着关键作用,因而是现代遗传研究中的一个重要工具。但是,连锁不平衡背景的估计受多种因素的影响,其中之一就是基因型错误。已经有研究考察了基因型错误对四个常用LD 指数D, r, Q, 和d的影响。而基因型错误对于定位数量性状位点(QTL)的LD 指数的效应还没有得到研究。本文从分析的角度调查了基因型错误存在时LD 指数lx 的性质。结果表明,指数lx 因依赖于基因型错误率因而值变小了,当基因型错误率达到0.03, lx值的改变量(减小值)将超过50％,特别是在标记基因频率比较高的时候。基因型错误的影响也通过基于血管紧张肽转化酶(ACE)基因的10个SNPs单体型频率的模拟研究得到了证实。     

单核苷酸多态性与连锁不平衡研究进展

单核苷酸多态性(single nucleotide polymorphism,SNP)是人类基因组中最广泛的多态性现象,也是造成个体差异的最主要的遗传原因,发现和研究SNP的工作在目前人类基因组研究中倍受关注。连锁不平衡是不同遗传标记问存在着的非随机组合现象,SNP作为极具优势的遗传标记为深入研究连锁不平衡、以及利用连锁不平衡进行群体遗传学的参数估计、基因精细定位、关联分析等提供了良好的先决条件。最近,在SNP研究及连锁不平衡的度量和连锁不平衡性质的研究方面取得的一系列进展为遗传学在将来发展奠定了基础。     

应用连锁不平衡检验法进行单纯性先天性心脏病易感基因 …

将人类单纯性先天性心脏病（ｃｏｎｇｅｎｉｔａｌｈｅａｒｔｄｅｆｅｃｔ，ＣＨＤ）易感基因初步定位，为进一步对其克隆奠定基础，方法在胚胎心脏发育调控相关基因－ＨＯＸ基因Ａ簇、Ｂ簇所在在的染色体区域７ｐ１４－１５、１７ｑ２１内选择３个微卫星ＤＮＡ标记Ｄ７Ｓ１８０８、Ｄ７Ｓ６７３、Ｄ１７Ｓ７９１，应用荧光标记聚合酶边反应技术扩增微卫星征 段，对３９个单纯性ＣＨＤ核心家系的１１２名成员进行基因型，并进行遗传     

复杂性状疾病基因定位的策略和手段

复杂性状疾病包括的范围很广，由于外显不全和遗传异质性等原因，这一类性状的基因克隆难度较大。本文概述了寻找复杂性状（疾病）相关基因的一般步骤，并简要介绍遗传分析中的连锁分析、同胞及亲属对分析、关联分析及其应用。     

应用连锁不平衡图谱的关联研究分析方法

目的提出一种对高通量单核苷酸多态位点(single nucleotide polymorphism,SNP)关联研究的数据分析方法。方法在160名上海地区中国人中进行754个SNP的基因型检测,分别构建病例组和对照组的连锁不平衡(linkage disequilibrium,LD)图谱,通过比较两组间染色体区域LD图谱随物理距离的变化趋势寻找与疾病相关的位点,并与传统LD分析以及SNP单点、单倍型分析进行比较。结果LD图谱的分析能判断出两组间LD存在差异的染色体区域,并且该区域SNP等位基因频率和单倍型频率在两组间分布存在统计学差异或差异趋势。结论可应用该方法对高通量SNP的关联研究进行数据分析。     

小家鼠群体基因组连锁不平衡研究

模式动物小鼠是复杂性状相关疾病遗传研究的重要资源.连锁不平衡(linkage disequilib-rium,LD)是群体基因组遗传的重要信息.如果群体LD程度高,相关连锁区段大,有助于用少量遗传位标来对目标基因进行初步定位;反之,如果群体LD程度低,相关连锁区段小,则利用高密度的遗传位标可以对目标基因进行精细定位.本文介绍了实验小鼠群体和野生小鼠群体相关的LD、与LD相关的部分遗传参数以及利用LD进行相关基因定位研究.并提示实验小鼠和野生小鼠各具优势,都是复杂性状基因定位的重要遗传资源.     

6号染色体微卫星标记与精神分裂症的连锁不平衡研究

目的 探索6号染色体的有关微卫星标记与精神分裂症的关系。方法 对115个精神分裂症同胞及核心家系，按照不同的诊断分类，以分布于6号染色体的28个微卫星标记，进行连锁不平衡研究，并分别按照阳性和阴性症状量表及发病年龄分成不同的亚组，在不同的亚组中进行连锁不平衡分析。以XDT和MAPMAKER／SIBS软件系统完成所有连锁不平衡关系具有显著性意义，P值均小于0.005。在以各项PANSS量表和不同发病年龄所分亚组的分析中表明，只有D6S1960位点与精神分裂症的连锁不平衡关系值始终具有显著性意义（P＜0.05）。结论 6号染色体短臂D6S1960附近可能存在精神分裂症的易感基因。     

单核苷酸多态性的研究进展及其应用

本文系统地介绍了单核苷酸多态性的理论基础、相关研究和最新进展，为进行这方面的研究提供线索。     

CHROMSCAN: genome-wide association using a linkage disequilibrium map

CHROMSCAN implements a composite likelihood model for the analysis of association data. Disease-gene localisation is on a linkage disequilibrium unit (LDU) map, and locations and standard errors, for putatively causal polymorphisms, are determined by the programme. Distortions of the probability distribution created by auto-correlation are avoided by implementation of a permutation test. We evaluated the relative efficiency of the LDU map by simulating pseudo-phenotypes in real genotype samples. We observed that multi-locus mapping on an underlying LDU map reduces location error by ∼46%. Furthermore, there is a small, but significant, increase in power of ∼5%. Effective meta-analysis across multiple samples, increasingly important to combine evidence from genome-wide and other association data, is achieved through the weighted combination of location evidence provided by the programme. Electronic supplementary material The online version of this article (doi:) contains supplementary material, which is available to authorised users.     

Akaike's information criterion for a measure of linkage disequilibrium

 The extent and distribution of linkage disequilibrium (LD) in humans is a current topic especially for gene mapping of complex diseases. Akaike's information criterion (AIC) was applied to estimate LD and compared with other standard LD measures, D′ and r ². By comparison of an independent model (IM; linkage equilibrium) and a dependent model (DM; linkage disequilibrium), the parsimonious model is the one with the smaller AIC score. Therefore, the extent of LD by AIC is expressed as AIC(IM) — AIC(DM)(AIC(LD)). A total of 39 single-nucleotide polymorphisms on a 1.6-Mb region of chromosome 21q22 were identified, and genotyped in 192 Japanese individuals. All possible pairs were analyzed to estimate LD and the analyses were compared. AIC(LD) became highly positive as the D′ value increased and was negative at D′ values of around 0.2. Because a negative value of AIC(LD) implies linkage equilibrium, D′ values below 0.2 should be regarded as linkage equilibrium. The LD estimate by AIC yielded results similar to those obtained by r ², indicating that AIC(LD) would be useful for fine gene mapping. Received: July 3, 2002 / Accepted: October 2, 2002     

Discovery of genetic difference between asthmatic children with high IgE level and normal IgE level by whole genome linkage disequilibrium mapping using 763 autosomal STR markers

The genome-wide linkage disequilibrium screen for loci associated with genetic difference between allergic and nonallergic asthma was conducted with 763 autosomal STR markers and included 190 asthmatic children. Evidence for association with differences between the two forms of asthma was observed for 36 STR markers. Marker-to-marker synergetic effect and by simulation resampling tests revealed D5S2011, D6S305, and D9S286 were important loci in allergic asthma while D6S1574, D8S1769, and D19S226 were important in nonallergic asthma. Our results show strong genetic evidence that these markers play an important role in defining allergic and nonallergic asthma and provides important candidates of susceptible genes in these two categories of asthma. This study further shows that asthma is, indeed, a heterogeneous group of underlying diseases and, although with similar clinical phenotypes, may have different clinical severities, outcomes, and need more tailor-made management.     

Detecting linkage disequilibrium in the presence of locus heterogeneity

Locus heterogeneity is a common phenomenon in complex diseases and is one of the most important factors that affect the power of either linkage or linkage disequilibrium (LD) analysis. In linkage analysis, the heterogeneity LOD score (HLOD) rather than LOD itself is often used. However, the existing methods for detecting linkage disequilibrium, such as the TDT and many of its variants, do not take into account locus heterogeneity. We propose two novel likelihood-based methods, an LD-Het likelihood and an LD-multinomial likelihood, to test linkage disequilibrium (LD) that explicitly incorporate locus heterogeneity in the analysis. The LD-Het is applicable to general nuclear family data but requires a working penetrance model. The LD-multinomial is only applicable to affected sib-pair data but does not require specification of a trait model. For affected sib-pair data, both methods have similar power to detect LD under the recessive model, but the LD-multinomial model has greater power when the underlying model is dominant or additive.     

Comparison between various strategies for the disease-gene mapping using linkage disequilibrium analyses: studies on adenine phosphoribosyltransferase deficiency used as an example

Recently, linkage disequilibrium analyses have been used to detect disease-causing loci based on the common disease-common variant hypothesis. To see what methods can effectively identify the genes, we have to apply them to the practical data obtained from the human population. We extensively performed linkage disequilibrium and haplotype analyses on adenine phosphoribosyltransferase (APRT) genes in both control and deficient subjects. To examine the power to detect disease-causing loci, we analyzed SNPs, STRPs, and VNTR within and around the APRT gene. When only SNPs were used, P values did not necessarily show significant difference, even at loci close to the mutation site for APRT*J that is exclusively observed among Japanese. However, the examination of the same samples with haplotypes based on the haplotype block data gave sufficient significance. In the case of STRP and VNTR, some single-marker loci showed significant difference. Our study suggested that the use of haplotype analysis based on the haplotype-block structure is more powerful than single-marker locus analysis for the detection of disease-related loci.     

Analysis of linkage disequilibrium between different cystic fibrosis mutations and three intragenic microsatellites in the Italian population

Three intragenic microsatellites of the CFTR gene, a TA and a CA repeats, namely IVSl7bTA and IVSl7bCA, located in intron 17b and a CA repcat (IVS8CA) located in intron 8 of the CFTR gene, were analyzed in a large sample of Italian cystic fibrosis (CF) and normal chromosomes. Linkage disequilibrium was evaluated between each marker and different CF mutations on a total of 377 CF and 358 normal chromosomes. Our results are consistent with the hypothesis that all AF508 chromosomes derive from a single mutational event. The same hypothesis is valid for mutations G542X, N1303K, 1717-1IG→, which might have been originated more recently than δF508. © 1995 Wiley- Liss, Inc.