Pedigree transmission disequilibrium test for QTL mapping of threshold trait

With biological and economic importance,threshold traits are discrete in phenotype but have the same polygenic genetic basis as quantitative traits. The traditional linkage analysis for quantitative traits is invalid for threshold traits due to their special characters. The transmission disequilibrium test (TDT) has received great attention recently in localizing human disease genes due to its simplicity and powerfulness. But TDT only deals with data from independent nuclear families and it will lose information about extended pedigree that incorporates information not only from parents and siblings but also from other relatives. The pedigree disequilibrium test (PDT) proposed by Martin in 2001 can be used to analyze the extended pedigree in human.In this study, PDT was introduced into the QTL mapping of threshold traits for farm animals, and was modified in order to accommodate the pedigree structures of farm animals.The modified PDT was renamed pedigree transmission disequilibrium test (PTDT) and its power and type I error were investigated and compared with that of PDT by Monte Carlo simulation. It was shown that PTDT is a robust and valid approach to mapping QTL of threshold trait. When the parental information is complete, PTDT and PDT are almost the same in terms of power and type I error. However, if the parental information is missing to a certain extent, PTDT is higher in power and lower in type I error than PDT. These results imply that PTDT can be a novel approach to QTL fine mapping of threshold traits based on the existing coarse mapping information.     

LOD score exclusion analyses for candidate disease susceptibility genes using case-parents design

The focus of almost all the association studies of candidate genes is to test for their importance. We recently developed a LOD score approach that can be used to test against the importance of candidate genes for complex diseases and quantitative traits in random samples. As a complementary method to regular association analyses, our LOD score approach is powerful but still affected by the population admixture, though it is more conservative. To control the confounding effect of population heterogeneity, we develop here a LOD score exclusion analysis using case?parents design, the basic design of the transmission disequilibrium test (TDT) approach that is immune to population admixture. In the analysis, specific genetic effects and inheritance models at candidate genes can be analyzed and if a LOD score is ≤-2.0, the locus can be excluded from having an effect larger than that specified. Simulations show that this approach has reasonable power to exclude a candidate gene having small genetic effects if it is not a disease susceptibility locus (DSL) with sample size often employed in TDT studies. Similar to association analyses with the TDT in nuclear families, our exclusion analyses are generally not affected by population admixture. The exclusion analyses may be implemented to rule out candidate genes with no or minor genetic effects as supplemental analyses for the TDT. The utility of the approach is illustrated with an application to test the importance of vitamin D receptor (VDR) gene underlying the differential risk to osteoporosis.     

基于单体型重构的传递不平衡检验

传递不平衡检验是基于家系检测疾病位点与标记位点之间连锁与连锁不平衡的经典分析方法。论文针对紧密连锁位点,提出了单体型的传递不平衡检验方法,并把此方法用于分析IgA肾病的两紧密连锁位点的基因定位数据。首先在估计核心家系的单体型频率的基础上,重构单体型的传递/未传递的交叉分类表格,然后通过检验此表格的对称性与边缘齐性进行传递不平衡检验,同时,自编Excel宏命令VBA程序,用于家系数据单体型频率估计与重构。此方法充分利用所有家系信息,并能处理缺失数据。C2093T-C2081T的单体型多态性与IgA肾病关联。此方法推广了已有单体型传递不平衡检验。     

A method for haplotype inference in general pedigrees without recombination

The abundance of single nucleotide polymorphisms (SNPs) makes the haplotype-based method instead of single-maker-oriented method the main approach to association studies on QTL mapping. The key problem in haploptype-based method is how to reconstruct haplotypes from genotype data. Directly assaying haplotypes in diploid individuals by experimental methods is too expensive, therefore the in silico haplotyping-determination methods are the major choice at the present. This paper presents a rapid and reliable algorithm for haplotype reconstruction for tightly linked SNPs in general pedigrees. It is based on six rules and consists of three steps. First, the parental origins of alleles in offspring are assigned conditional on genotypes in parent-offspring trios; second, the redundant haplotypes are eliminated based on the six rules; and finally, the most likely haplotype combinations are chosen via maximum likelihood method. Our method was verified and compared with PEDPHASE by simulated data with different pedigree sizes, numbers of loci, and proportions of missing genotypes. The result shows that our algorithm was superior to PEDPHASE in terms of computing time and accuracy of haplotype estimation. The computing time for 100 runs was 10―15 times less and the accuracy was 4%―10% higher than PEDPHASE. The result also indicates that our method was very robust and was hardly affected by pedigree size, number of loci, and proportion of missing genotypes.     

A genome-wide association study identifies KIAA0350 as a type 1 diabetes gene

Type 1 diabetes (T1D) in children results from autoimmune destruction of pancreatic beta cells, leading to insufficient production of insulin. A number of genetic determinants of T1D have already been established through candidate gene studies, primarily within the major histocompatibility complex but also within other loci. To identify new genetic factors that increase the risk of T1D, we performed a genome-wide association study in a large paediatric cohort of European descent. In addition to confirming previously identified loci, we found that T1D was significantly associated with variation within a 233-kb linkage disequilibrium block on chromosome 16p13. This region contains KIAA0350, the gene product of which is predicted to be a sugar-binding, C-type lectin. Three common non-coding variants of the gene (rs2903692, rs725613 and rs17673553) in strong linkage disequilibrium reached genome-wide significance for association with T1D. A subsequent transmission disequilibrium test replication study in an independent cohort confirmed the association. These results indicate that KIAA0350 might be involved in the pathogenesis of T1D and demonstrate the utility of the genome-wide association approach in the identification of previously unsuspected genetic determinants of complex traits.     

A second generation human haplotype map of over 3.1 million SNPs

We describe the Phase II HapMap, which characterizes over 3.1 million human single nucleotide polymorphisms (SNPs) genotyped in 270 individuals from four geographically diverse populations and includes 25-35% of common SNP variation in the populations surveyed. The map is estimated to capture untyped common variation with an average maximum r2 of between 0.9 and 0.96 depending on population. We demonstrate that the current generation of commercial genome-wide genotyping products captures common Phase II SNPs with an average maximum r2 of up to 0.8 in African and up to 0.95 in non-African populations, and that potential gains in power in association studies can be obtained through imputation. These data also reveal novel aspects of the structure of linkage disequilibrium. We show that 10-30% of pairs of individuals within a population share at least one region of extended genetic identity arising from recent ancestry and that up to 1% of all common variants are untaggable, primarily because they lie within recombination hotspots. We show that recombination rates vary systematically around genes and between genes of different function. Finally, we demonstrate increased differentiation at non-synonymous, compared to synonymous, SNPs, resulting from systematic differences in the strength or efficacy of natural selection between populations.     

An evolutionarily stable strategy approach to indiscriminate spite

AN individual behaves spitefully when it harms itself in order to harm another individual more(1). Hamilton(1,2) predicted that spite may evolve if it is expressed only in those encounters that occur between individuals of less than average relatedness. More recently Verner(3) suggested that territory size may become super-optimal because of a selective advantage arising from the spiteful exclusion of others from limited resources. His model is essentially different from Hamilton's in that spite is directed at individuals indiscriminately with respect to relatedness. Recently Rothstein(4) has shown analytically that the initial spread of spiteful traits will be very slow in all but the smallest populations. He also argued verbally that indiscriminate spite can never be evolutionarily stable even if it should spread (see also Davies(5)). The question of evolutionary stability is clearly important, but its resolution requires an analytical approach. We report here an approach based on Maynard Smith's(6) concept of the evolutionarily stable strategy (ESS), a strategy which, when common, does better than any alternative strategy played by a rare mutant. We show that spite can be an ESS, but that the magnitude of spite will be small in large populations.     

从输电阻塞角度建立的风电场容量可信度模型

风电并网时既要考虑系统的可靠性又要考虑输电阻塞。目前风电场容量可信度仅从可靠性单一角度提出。为此从输电阻塞角度提出了风电场容量可信度的定义;通过Monte Carlo法建立计及元件故障(发电机、线路和变压器)的风电场容量可信度模型,并提出该模型的二分法求解算法;同时还提出了风电阻塞指标以描述风电场并入电力系统对缓解系统输电阻塞的贡献。通过对修改的IEEE-RTS进行算例分析,验证了方法的正确性和实用性。结果表明:系统阻塞状况的缓解程度与并入风电场的位置有关,风电场容量可信度和风电阻塞指标相结合可以评价风电场并网对系统阻塞状况改善的有效性和经济性。     

女贞家系种子播种品质性状的变异及相关性

试验测定了13个女贞家系种子的千粒重、生活力、发芽率等播种品质指标，进行了差异显著性分析和相关性分析，探讨了不同家系种子发芽进程的变化规律。     

Genes mirror geography within Europe

Understanding the genetic structure of human populations is of fundamental interest to medical, forensic and anthropological sciences. Advances in high-throughput genotyping technology have markedly improved our understanding of global patterns of human genetic variation and suggest the potential to use large samples to uncover variation among closely spaced populations. Here we characterize genetic variation in a sample of 3,000 European individuals genotyped at over half a million variable DNA sites in the human genome. Despite low average levels of genetic differentiation among Europeans, we find a close correspondence between genetic and geographic distances; indeed, a geographical map of Europe arises naturally as an efficient two-dimensional summary of genetic variation in Europeans. The results emphasize that when mapping the genetic basis of a disease phenotype, spurious associations can arise if genetic structure is not properly accounted for. In addition, the results are relevant to the prospects of genetic ancestry testing; an individual's DNA can be used to infer their geographic origin with surprising accuracy-often to within a few hundred kilometres.     

Undesirable evolutionary consequences of trophy hunting

Phenotype-based selective harvests, including trophy hunting, can have important implications for sustainable wildlife management if they target heritable traits. Here we show that in an evolutionary response to sport hunting of bighorn trophy rams (Ovis canadensis) body weight and horn size have declined significantly over time. We used quantitative genetic analyses, based on a partly genetically reconstructed pedigree from a 30-year study of a wild population in which trophy hunting targeted rams with rapidly growing horns, to explore the evolutionary response to hunter selection on ram weight and horn size. Both traits were highly heritable, and trophy-harvested rams were of significantly higher genetic 'breeding value' for weight and horn size than rams that were not harvested. Rams of high breeding value were also shot at an early age, and thus did not achieve high reproductive success. Declines in mean breeding values for weight and horn size therefore occurred in response to unrestricted trophy hunting, resulting in the production of smaller-horned, lighter rams, and fewer trophies.     

Ecology: avoidance of disease by social lobsters

Transmissible pathogens are the bane of social animals, so they have evolved behaviours to decrease the probability of infection. There is no record, however, of social animals avoiding diseased individuals of their own species in the wild. Here we show how healthy, normally gregarious Caribbean spiny lobsters (Panulirus argus) avoid conspecifics that are infected with a lethal virus. Early detection and avoidance of infected, though not yet infectious, individuals by healthy lobsters confers a selective advantage and highlights the importance of host behaviour in disease transmission among natural populations.     

Close linkage of c-Harvey-ras-1 and the insulin gene to affective disorder is ruled out in three North American pedigrees

Affective disorder (AD) is one of the major forms of functional psychoses. Although the mode of transmission is uncertain, family, twin and adoption studies strongly suggest a genetic involvement. Because a basic biochemical abnormality is not known, direct analysis of the disease using a probe for the defective gene is not possible. However, a specific locus can be tested for its relevance to the aetiology of AD by genetic linkage, using restriction fragment length polymorphisms (RFLPs). Using probes for the c-Ha-ras-1 oncogene and the insulin gene, Gerhard et al. and Egeland et al. found convincing evidence for close linkage between these markers and a locus for AD in a large Old Order Amish pedigree. In an attempt to confirm this finding, we examined three bipolar pedigrees outside the Amish population. Our results indicate the absence of linkage from 0 to 15% recombination frequency between AD and the insulin gene-HRAS1 region in these pedigrees.     

A genome-wide association study identifies novel risk loci for type 2 diabetes

Type 2 diabetes mellitus results from the interaction of environmental factors with a combination of genetic variants, most of which were hitherto unknown. A systematic search for these variants was recently made possible by the development of high-density arrays that permit the genotyping of hundreds of thousands of polymorphisms. We tested 392,935 single-nucleotide polymorphisms in a French case-control cohort. Markers with the most significant difference in genotype frequencies between cases of type 2 diabetes and controls were fast-tracked for testing in a second cohort. This identified four loci containing variants that confer type 2 diabetes risk, in addition to confirming the known association with the TCF7L2 gene. These loci include a non-synonymous polymorphism in the zinc transporter SLC30A8, which is expressed exclusively in insulin-producing beta-cells, and two linkage disequilibrium blocks that contain genes potentially involved in beta-cell development or function (IDE-KIF11-HHEX and EXT2-ALX4). These associations explain a substantial portion of disease risk and constitute proof of principle for the genome-wide approach to the elucidation of complex genetic traits.     

Statistical approaches in QTL mapping and molecular breeding for complex traits

Most of the important agronomic traits in crops,such as yield and quality,are complex traits affected by multiple genes with gene × gene interaction as well as gene × environment interaction.Understanding the genetic architecture of complex traits is a long-term task for quantitative geneticists and plant breeders who wish to design efficient breeding programs.Conventionally,the genetic properties of traits can be revealed by partitioning the total variation into variation components caused by specific genetic effects.With recent advances in molecular genotyping and high-throughput technology,the unraveling of the genetic architecture of complex traits by analyzing quantitative trait locus (QTL) has become possible.The improvement of complex traits has also been achieved by pyramiding individual QTL.In this review,we describe some statistical methods for QTL mapping that can be used to analyze QTL × QTL interaction and QTL × environment interaction,and discuss their applications in crop breeding for complex traits.     

Genetic mechanisms of floral trait correlations in a natural population

Genetic correlations among traits are important in evolution, as they can constrain evolutionary change or reflect past selection for combinations of traits. Constraints and integration depend on whether the correlations are caused by pleiotropy or linkage disequilibrium, but these genetic mechanisms underlying correlations remain largely unknown in natural populations. Quantitative trait locus (QTL) mapping studies do not adequately address the mechanisms of within-population genetic correlations because they rely on crosses between distinct species, inbred lines or selected lines (see ref. 5), and they cannot distinguish moderate linkage disequilibrium from pleiotropy because they commonly rely on only one or two episodes of recombination. Here I report that after nine generations of enforced random mating (nine episodes of recombination), correlations between six floral traits in wild radish plants are unchanged, showing that pleiotropy generates the correlations. There is no evidence for linkage disequilibrium despite previous correlational selection acting on one functionally integrated pair of traits. This study provides direct evidence of the genetic mechanisms underlying correlations between quantitative traits in a natural population and suggests that there may be constraints on the independent evolution of pairs of highly correlated traits.     

二棱大麦数量性状相关遗传力和选择指数分析

以15个二棱大麦品种(系)为材料,用相关遗传力研究大麦数量性状的相关遗传,并计算分析籽粒产量和产量构成性状所组合的各种选择指数。结果表明:各性状与单株粒重的相关遗传力均低于单株粒重的遗传力,因而仅利用一个性状作间接选择的效率比对单株粒重作直接选择的效率低,在构成大麦产量的三要素中,着重提高单株穗数对产量的选择效率为最大;高产育种同时考虑与产量显著相关的性状比单纯对产量选择的效果好,其中以单株穗数、每穗粒数和籽粒产量结合起来选择的效果最佳。本文并对相关遗传力在相关遗传变异分析中的应用进行了讨论。     

Composite interval mapping of QTL for dynamic traits

The theoretical foundation for mapping quantitative trait loci (QTL) was laid by Sax[1] who discovered the association between the segregation pattern of pigment markers with seed size of bean. However, statistical methods were not well developed until th…     

A general integrative model for scaling plant growth, carbon flux, and functional trait spectra

Linking functional traits to plant growth is critical for scaling attributes of organisms to the dynamics of ecosystems and for understanding how selection shapes integrated botanical phenotypes. However, a general mechanistic theory showing how traits specifically influence carbon and biomass flux within and across plants is needed. Building on foundational work on relative growth rate, recent work on functional trait spectra, and metabolic scaling theory, here we derive a generalized trait-based model of plant growth. In agreement with a wide variety of empirical data, our model uniquely predicts how key functional traits interact to regulate variation in relative growth rate, the allometric growth normalizations for both angiosperms and gymnosperms, and the quantitative form of several functional trait spectra relationships. The model also provides a general quantitative framework to incorporate additional leaf-level trait scaling relationships and hence to unite functional trait spectra with theories of relative growth rate, and metabolic scaling. We apply the model to calculate carbon use efficiency. This often ignored trait, which may influence variation in relative growth rate, appears to vary directionally across geographic gradients. Together, our results show how both quantitative plant traits and the geometry of vascular transport networks can be merged into a common scaling theory. Our model provides a framework for predicting not only how traits covary within an integrated allometric phenotype but also how trait variation mechanistically influences plant growth and carbon flux within and across diverse ecosystems.