人类混血群体连锁不平衡的遗传学模型与基因定位

人类混血群体可以说是混合群体的一种特例．在无选择、无突变、无限随机交配群体的假定前提下,研究了亲本群体的基因频率对混血群体及其衍生后代群体连锁不平衡结构的影响,导出了各群体连锁不平衡值的表达式,建立了一个估计基因间重组率的简便方法;同时, 采用估算分子标记与QTL之间连锁不平衡系数的统计分析方法,分析了人类混血群体及其衍生后代群体QTL检测与估计的关系,建立了该关系的系列理论公式．研究结果表明,本方法不仅适用于人类疾病(包括复杂遗传疾病)基因定位,而且适合于人类正常基因的定位,同时也适用于人类普通多基因性状的QTL分析．     

以Lewontin连锁不平衡定位疾病基因

Lewontin连锁不平衡公式是定位疾病基因最好的方法之一（Q代表基因重组率,代表自从基因突变以来经历的世代数（,研究证明：在疾病基因比率高所情况下,Lewontin连锁不平衡公式的仍然通用,而其他类似方法则不通用;Lewontin连锁不平衡公式略加修正后,通用于显性,隐性,共显性及超显性遗传;以Lewontin公式为基础,推导出在有重复突变情况下仍然通用的公式,基于这些优越性,Lewontin公式应受到重视和发展,使其应用于定位常见病基因上。     

TNFR2基因的CA重复多态性在两个独立的白人群体中与肥胖表型的连锁和关联

我们先前通过全基因组扫描发现lp36与体重指数显提示性连锁（LOD=2．09）。肿瘤坏死因子受体2（1NFR2）定位于lp36,是肥胖的一个极好的图位和功能侯选基因。本研究采用数量传递连锁不平衡检验在两个大的独立的白人样本中进行了TNFR2基因与肥胖表型的连锁与关联检验。第一组受试者由来自79个多代家系的1836个个体组成;第二组受试者由来自157个核心家庭的636个个体组成。所检测的肥胖表型包括体重指数、脂肪量和脂肪量百分数。在多代家系中我们发现TNFR2基因变异与BMI显著连锁（P=0．0056）。结果表明,TNFR2基因是影响白人BMI变异的一个数量性状位点。     

一种有效的复杂疾病基因定位的检测法

连锁不平衡（LD）应用于某些复杂疾病基因的定位,近年来发展了许多LD定位方法,除TDT外,大多数LD定位方法须先假定无人群混和,人群混合可增大在疾病基因定位时犯Ⅰ类错误的机率,产生无效结果。此方法利用LD来检测标记位点和疾病敏感位点（DSL）的连锁（有连锁不平衡）相关（有连锁）。分析时采用不相关样本,已知其父母基因型和至少父母之一为杂合子,再将随机样本依基因型不同分类,然后对来自不同类的数据应用有力的统计方法进行单独和联合分析。此LD定位法不仅适用于患病和正常个体,而且有效消除据父母基因分类的样本定位时人群混合的影响,分析结果和模拟结果也表明此方法解决了在检测标记位点和疾病敏感位点之间的连锁和相关时人群混和的问题,但与TDT比,此法在检测的位点为DSL时丙能有效和充分地利用矫正数据,检测位点不是DSL时,此法和TDT法可相互补充更有效地检测连锁的DSL。     

一个基于熵的指数精细定位人类复杂性状位点

近来,一个基于熵的指数被提出用来对人类复杂性状位点进行连锁不平衡定位．这个熵指数比较了患病个体与正常个体或极端样本之间标记基因频率的熵和条件熵．本文基于熵理论,提出了另一个备选指数．这个新的指数比较患病个体与正常个体之间标记基因型频率的熵和条件熵．计算机模拟结果表明本文提出的新指数平行于之前的熵指数．而基于遗传性血色病（hereditary haemochromatosis,HH）数据的分析表明了这个新指数能有效对人类复杂性状位点进行精细定位．     

豌豆种质表型性状SSR标记关联分析

关联分析是以连锁不平衡原理为基础,鉴定某一群体内表型性状与遗传标记或候选基因间关系的遗传分析方法。本研究利用59个多态性SSR标记,对192份豌豆种质进行全基因组扫描,以分析SSR位点遗传多样性,寻找其连锁不平衡位点;采用TASSEL软件的一般线性模型,利用59个SSR标记对19个形态性状进行关联分析。结果显示SSR位点间有较高的多态性和一定程度的连锁不平衡,共检测出32个SSR标记位点与14个表形性状相关联,一些SSR标记与2个或多个形态性状相关联。     

家畜近亲繁殖群体连锁不平衡的分析

本文分析了家畜近亲繁殖群体连锁位点基因遗传平衡的实现,推导出了配子型频率及基因型频率通用递推公式．研究证明,近交群体不同于随机交配大群体,其连锁不平衡值d（绝对值）随世代的下降速率不仅取决于重组率,而且也依赖于近交速率．近交越剧烈,则d下降越慢;达平衡态时,近交群体d值并不一定等于0．连锁越紧密,近交越剧烈,则平衡d值越大．最后讨论了研究结果在家畜育种中的应用．     

乳蛋白座位与泌乳性状座位连锁关系的研究

本文利用杂合度分析和连锁群分析对乳蛋白基因座位与产奶量及乳成分等数量性状基因间的连锁关系进行了探讨。结果表明,各乳蛋白基因均具有较高的纯合度,但３个酪蛋白基因同时考虑时纯合度较低。泌乳性状的变差对乳蛋白基因座位杂合度没有明显的回归关系。Ｋ－ＣＮ基因与乳脂率和乳蛋白率,α_（ｓ１）－ＣＮ基因与３０５无产奶量间有显著的连锁关系。     

关联分析及其在植物中的应用

关联分析是新近开始在植物数量性状研究和植物育种中应用的一种分析方法.它以连锁不平衡为基础鉴定某一群体内性状与遗传标记或候选基因间的关系,是对分子育种中QTL分析的补充和提高.本文在介绍连锁不平衡的定义和度量方法的基础上,讨论连锁不平衡程度和群体结构对关联分析的影响,综述了关联分析在植物方面的研究进展,并最后讨论了关联分析在植物数量性状和分子育种研究中可能的应用.     

应用关联分析鉴定大豆对斜纹夜蛾的抗性基因

用135个分布于全基因组的SSR（simple sequence repeat）标记分析196份大豆（Glycine max）地方品种的遗传变异、群体结构和连锁不平衡（linkage disequilibrium,LD）。在考虑群体结构的条件下,应用全基因组关联分析的方法鉴定与大豆抗斜纹夜蛾有关的数量性状位点,进而发掘各关联位点的优异等位基因及代表性载体材料。结果表明：（1）该群体不仅地理起源广,而且遗传变异丰富;（2）在整个群体内,有17.9%的标记对处于显著的连锁不平衡,而且在相同染色体上标记对间连锁不平衡延伸的平均距离约为6.61cM（D＇〉0,P〈0.05）;（3）通过关联分析发现,有7个SSR标记分别与3个大豆抗斜纹夜蛾性状关联（P〈0.01）,其中4个位点对性状的变异解释率超过了10%,6个位点所在的连锁群上存在已报道的食叶性害虫抗性位点;（4）各位点等位基因的效应分析显示,幼虫重相关位点的等位基因主要表现为减效作用,等位基因Sat_334-A208减效作用最大（43.9%）;单虫食叶量和蛹重相关位点的等位基因主要表现为增效作用;等位基因Satt199-A186对单虫食叶量增效作用最大（36.4%）;等位基因Sat_320-A286对蛹重增效作用最大（31.4%）。     

The Admixture Linkage Disequilibrium and Genetic Linkage Inference on the Gradual Admixture Population

Through the theoretical analysis of the admixture linkage disequilibrium (ALD) in the gradual admixture (GA) model, in which admixture occurs in every generation, the ALD is found to be proportional to the difference in marker allele frequencies, p₁-p₂, between two subpopulations. Based on this property, we can employ a strict monotonic function (Δ_ker=Δ/(p₁-p₂), where Δ denotes the linkage disequilibrium (LD)) of the recombination fraction between the marker locus and the disease locus to infer the true genetic linkage. We construct a quasi likelihood ratio test (LRT) for the case-only data utilizing the information of unlinked markers in the human genome. The simulation results show that our tests can be used to fine map a disease locus. The effects of parameter values in the ALD mapping are also discussed.     

Inferring Admixture Histories of Human Populations Using Linkage Disequilibrium

Long-range migrations and the resulting admixtures between populations have been important forces shaping human genetic diversity. Most existing methods for detecting and reconstructing historical admixture events are based on allele frequency divergences or patterns of ancestry segments in chromosomes of admixed individuals. An emerging new approach harnesses the exponential decay of admixture-induced linkage disequilibrium (LD) as a function of genetic distance. Here, we comprehensively develop LD-based inference into a versatile tool for investigating admixture. We present a new weighted LD statistic that can be used to infer mixture proportions as well as dates with fewer constraints on reference populations than previous methods. We define an LD-based three-population test for admixture and identify scenarios in which it can detect admixture events that previous formal tests cannot. We further show that we can uncover phylogenetic relationships among populations by comparing weighted LD curves obtained using a suite of references. Finally, we describe several improvements to the computation and fitting of weighted LD curves that greatly increase the robustness and speed of the calculations. We implement all of these advances in a software package, ALDER, which we validate in simulations and apply to test for admixture among all populations from the Human Genome Diversity Project (HGDP), highlighting insights into the admixture history of Central African Pygmies, Sardinians, and Japanese.     

Linkage disequilibrium fine mapping of quantitative trait loci: A simulation study

Recently, the use of linkage disequilibrium (LD) to locate genes which affect quantitative traits (QTL) has received an increasing interest, but the plausibility of fine mapping using linkage disequilibrium techniques for QTL has not been well studied. The main objectives of this work were to (1) measure the extent and pattern of LD between a putative QTL and nearby markers in finite populations and (2) investigate the usefulness of LD in fine mapping QTL in simulated populations using a dense map of multiallelic or biallelic marker loci. The test of association between a marker and QTL and the power of the test were calculated based on single-marker regression analysis. The results show the presence of substantial linkage disequilibrium with closely linked marker loci after 100 to 200 generations of random mating. Although the power to test the association with a frequent QTL of large effect was satisfactory, the power was low for the QTL with a small effect and/or low frequency. More powerful, multi-locus methods may be required to map low frequent QTL with small genetic effects, as well as combining both linkage and linkage disequilibrium information. The results also showed that multiallelic markers are more useful than biallelic markers to detect linkage disequilibrium and association at an equal distance.     

How Population Growth Affects Linkage Disequilibrium

The “LD curve” relates the linkage disequilibrium (LD) between pairs of nucleotide sites to the distance that separates them along the chromosome. The shape of this curve reflects natural selection, admixture between populations, and the history of population size. This article derives new results about the last of these effects. When a population expands in size, the LD curve grows steeper, and this effect is especially pronounced following a bottleneck in population size. When a population shrinks, the LD curve rises but remains relatively flat. As LD converges toward a new equilibrium, its time path may not be monotonic. Following an episode of growth, for example, it declines to a low value before rising toward the new equilibrium. These changes happen at different rates for different LD statistics. They are especially slow for estimates of σd2, which therefore allow inferences about ancient population history. For the human population of Europe, these results suggest a history of population growth.     

Associative overdominance: Evaluating the effects of inbreeding and linkage disequilibrium

Expressions are obtained for the expected phenotypic values of homozygous and heterozygous genotypes for a neutral marker locus linked to a locus segregating for a recessive deleterious gene. The phenotypic values are functions of the allele frequencies at the marker locus, the inbreeding coefficient and the degree of association of the deleterious gene with the marker alleles. The analysis is extended to more than two alleles at the marker locus. Either linkage disequilibrium or inbreeding alone can produce an apparent superiority of heterozygotes for the marker locus (unless specified otherwise, the terms ‘homozygote’ and ‘heterozygote’ will refer to the marker locus). The effect of linkage disequilibrium on the difference between the heterozygote and homozygote values can be positive (associative overdominance) or negative (associative underdominance), depending on the frequencies of the marker alleles and the degree of their association with the deleterious gene. Inbreeding has always a positive effect. In general, the expected value of a homozygote is a positive function of its allele frequency. When the various homozygous genotypes are combined into one class and the various heterozygous genotypes into another, the phenotypic difference of the two classes is a function of the evenness of the allelic frequency distribution. Inbreeding is a more likely explanation of associative overdominance if the frequency of the deleterious gene is low, but its effect on the character high. Conversely, linkage disequilibrium is more likely if the frequency is high and the effect low. The degrees of association between marker alleles and the deleterious gene can, in principle, be estimated from the observed phenotypic scores and used to calculate expected multi-locus genotype scores. This could provide the basis for statistical tests of the associative overdominance hypothesis as an explanation of observed correlations between multi-locus heterozygosity and phenotypic traits.     

Linkage disequilibrium in the North American Holstein population

Linkage disequilibrium was estimated using 7119 single nucleotide polymorphism markers across the genome and 200 animals from the North American Holstein cattle population. The analysis of maternally inherited haplotypes revealed strong linkage disequilibrium ( r ²   >   0.8) in genomic regions of ∼50 kb or less. While linkage disequilibrium decays as a function of genomic distance, genomic regions within genes showed greater linkage disequilibrium and greater variation in linkage disequilibrium compared with intergenic regions. Identification of haplotype blocks could characterize the most common haplotypes. Although maximum haplotype block size was over 1 Mb, mean block size was 26–113 kb by various definitions, which was larger than that observed in humans (∼10 kb). Effective population size of the dairy cattle population was estimated from linkage disequilibrium between single nucleotide polymorphism marker pairs in various haplotype ranges. Rapid reduction of effective population size of dairy cattle was inferred from linkage disequilibrium in recent generations. This result implies a loss of genetic diversity because of the high rate of inbreeding and high selection intensity in dairy cattle. The pattern observed in this study indicated linkage disequilibrium in the current dairy cattle population could be exploited to refine mapping resolution. Changes in effective population size during past generations imply a necessity of plans to maintain polymorphism in the Holstein population.     

人类复杂遗传疾病QTL分析方法的理论探讨

利用连锁不平衡理论,人类遗传学家已能把影响人类疾病的质量基因定位在小至1cM区域内,有些基因已被克隆出来。罗泽伟等进一步发展统计分析方法检测及估算分子标记与QTL之间的连锁不平衡系数,从而提出了人类复杂遗传病高解析度基因定位的理论策略。以此为基础,进一步探讨了供试群体在双亲基因频率存在差异时检测QTL和检测QTL互作的方法,给出了有关的理论结果。     

Patterns and Causes of Signed Linkage Disequilibria in Flies and Plants

Most empirical studies of linkage disequilibrium (LD) study its magnitude, ignoring its sign. Here, we examine patterns of signed LD in two population genomic data sets, one from Capsella grandiflora and one from Drosophila melanogaster. We consider how processes such as drift, admixture, Hill–Robertson interference, and epistasis may contribute to these patterns. We report that most types of mutations exhibit positive LD, particularly, if they are predicted to be less deleterious. We show with simulations that this pattern arises easily in a model of admixture or distance-biased mating, and that genome-wide differences across site types are generally expected due to differences in the strength of purifying selection even in the absence of epistasis. We further explore how signed LD decays on a finer scale, showing that loss of function mutations exhibit particularly positive LD across short distances, a pattern consistent with intragenic antagonistic epistasis. Controlling for genomic distance, signed LD in C. grandiflora decays faster within genes, compared with between genes, likely a by-product of frequent recombination in gene promoters known to occur in plant genomes. Finally, we use information from published biological networks to explore whether there is evidence for negative synergistic epistasis between interacting radical missense mutations. In D. melanogaster networks, we find a modest but significant enrichment of negative LD, consistent with the possibility of intranetwork negative synergistic epistasis.     

A Discordant-Sibship Test for Disequilibrium and Linkage: No Need for Parental Data

The sibship disequilibrium test (SDT) is designed to detect both linkage in the presence of association and association in the presence of linkage (linkage disequilibrium). The test does not require parental data but requires discordant sibships with at least one affected and one unaffected sibling. The SDT has many desirable properties: it uses all the siblings in the sibship; it remains valid if there are misclassifications of the affectation status; it does not detect spurious associations due to population stratification; asymptotically it has a chi2 distribution under the null hypothesis; and exact P values can be easily computed for a biallelic marker. We show how to extend the SDT to markers with multiple alleles and how to combine families with parents and data from discordant sibships. We discuss the power of the test by presenting sample-size calculations involving a complex disease model, and we present formulas for the asymptotic relative efficiency (which is approximately the ratio of sample sizes) between SDT and the transmission/disequilibrium test (TDT) for special family structures. For sib pairs, we compare the SDT to a test proposed both by Curtis and, independently, by Spielman and Ewens. We show that, for discordant sib pairs, the SDT has good power for testing linkage disequilibrium relative both to Curtis''s tests and to the TDT using trios comprising an affected sib and its parents. With additional sibs, we show that the SDT can be more powerful than the TDT for testing linkage disequilibrium, especially for disease prevalence >.3.