Progress and promise in understanding the genetic basis of common diseases

Susceptibility to common human diseases is influenced by both genetic and environmental factors. The explosive growth of genetic data, and the knowledge that it is generating, are transforming our biological understanding of these diseases. In this review, we describe the technological and analytical advances that have enabled genome-wide association studies to be successful in identifying a large number of genetic variants robustly associated with common disease. We examine the biological insights that these genetic associations are beginning to produce, from functional mechanisms involving individual genes to biological pathways linking associated genes, and the identification of functional annotations, some of which are cell-type-specific, enriched in disease associations. Although most efforts have focused on identifying and interpreting genetic variants that are irrefutably associated with disease, it is increasingly clear that—even at large sample sizes—these represent only the tip of the iceberg of genetic signal, motivating polygenic analyses that consider the effects of genetic variants throughout the genome, including modest effects that are not individually statistically significant. As data from an increasingly large number of diseases and traits are analysed, pleiotropic effects (defined as genetic loci affecting multiple phenotypes) can help integrate our biological understanding. Looking forward, the next generation of population-scale data resources, linking genomic information with health outcomes, will lead to another step-change in our ability to understand, and treat, common diseases.     

多基因遗传病基因研究的策略和方法

基因在决定个体表型方面起着决定性的作用。虽然单基因疾病的致病基因的克隆工作取得了显著的进展,但对于多基因疾病来说,仍然存在许多问题,同时也是巨大的挑战。本文综述了多基因疾病的遗传特点和多基因疾病易感基因识别、分离和克隆的一般步骤和存在的问题,介绍了人类基因组计划在此过程中的作用和单核苷酸多态性的应用前景,提出 了最有可能克隆出多基因疾病易感基因的策略和方法。     

奶牛重要经济性状全基因组关联分析研究进展

产奶性状是奶牛最重要的生产性状,随着平衡育种理念的提出和发展,繁殖性状、体型性状、健康性状和长寿性等功能性状也逐渐被重视并纳入育种规划中。鉴定产奶性状和功能性状主效基因或遗传标记并将之应用于奶牛标记辅助选择可望加快遗传进展。随着高密度SNP标记的高通量检测技术的发展,全基因组关联分析已成为鉴定畜禽重要经济性状基因的重要途径。文章对奶牛产奶性状和功能性状全基因组关联分析研究进展进行综述。     

奶牛重要经济性状全基因组关联分析研究进展

产奶性状是奶牛最重要的生产性状, 随着平衡育种理念的提出和发展, 繁殖性状、体型性状、健康性状和长寿性等功能性状也逐渐被重视并纳入育种规划中。鉴定产奶性状和功能性状主效基因或遗传标记并将之应用于奶牛标记辅助选择可望加快遗传进展。随着高密度SNP标记的高通量检测技术的发展, 全基因组关联分析已成为鉴定畜禽重要经济性状基因的重要途径。文章对奶牛产奶性状和功能性状全基因组关联分析研究进展进行综述。     

Association analysis of candidate genes for neuropsychiatric disease: the perpetual campaign

Association studies have been proposed to identify the genetic determinants of complex neuropsychiatric traits. Although such studies of candidate genes offer great potential to identify genetic variants that contribute to the expression of psychiatric disease, no consistent associations have been identified. Studies to date have focused on candidate genes that are selected for analysis on the basis of incomplete information about gene function in the brain, therefore the majority of genes expressed in the brain have been ignored. Additionally, most genetic determinants of psychiatric disease will probably be of modest effect and therefore require association studies of large samples. As genomic technologies advance, massive genotyping of large samples should allow identification of alleles that contribute to psychopathology.     

Complex adaptive system models and the genetic analysis of plasma HDL-cholesterol concentration

Despite remarkable advances in diagnosis and therapy, ischemic heart disease (IHD) remains a leading cause of morbidity and mortality in industrialized countries. Recent efforts to estimate the influence of genetic variation on IHD risk have focused on predicting individual plasma high-density lipoprotein cholesterol (HDL-C) concentration. Plasma HDL-C concentration (mg/dl), a quantitative risk factor for IHD, has a complex multifactorial etiology that involves the actions of many genes. Single gene variations may be necessary but are not individually sufficient to predict a statistically significant increase in risk of disease. The complexity of phenotype-genotype-environment relationships involved in determining plasma HDL-C concentration has challenged commonly held assumptions about genetic causation and has led to the question of which combination of variations, in which subset of genes, in which environmental strata of a particular population significantly improves our ability to predict high or low risk phenotypes. We document the limitations of inferences from genetic research based on commonly accepted biological models, consider how evidence for real-world dynamical interactions between HDL-C determinants challenges the simplifying assumptions implicit in traditional linear statistical genetic models, and conclude by considering research options for evaluating the utility of genetic information in predicting traits with complex etiologies.     

Genetics and genomics of behavioral and psychiatric disorders

Psychiatric conditions are to some degree under genetic influences. Despite the application of advanced genetic and molecular biological technologies, the genetic bases of the human behavioral traits and psychiatric diseases remains largely unresolved. Conventional genetic linkage approaches have not yielded definitive results, possibly because of the absence of objective diagnostic tests, the complex nature of human behavior or the incomplete penetrance of psychiatric traits. However, recent studies have revealed some genes of interest using multifaceted approaches to overcome these challenges. The approaches include using families in which specific behaviors segregate as a mendelian trait, utilization of endophenotypes as biological intermediate traits, identification of psychiatric disease phenotypes in genomic disorders, and the establishment of mouse models.     

绵羊基因组研究进展

过去几年中,家畜基因组计划取得了巨大进展。已经构建了猪、鸡、牛、绵羊、马、鹿的遗传图谱,其遗传标记间距在5～20cM。这些图谱对于家畜中与重要经济性状相关的基因或遗传标记的鉴定非常重要。该文从绵羊的基因图谱、比较图谱、重要经济性状基因及QTL定位方面对绵羊基因组的研究进展作了简要阐述。 Abstract:During the last few years,advances in livestock genome projects have been remarkable.Species-specific genetic maps exist for pig,chicken,cattle,sheep,horse,and deer with marker intervals of 5 to 20 cM.These maps have been essential for the identification of genes and genetic markers associated with importantly economic traits in livestock.In this paper,advances of gene map,comparative map,the genes for importantly economic traits and quantitative trait loci (QTL) mapping were briefly introduced in sheep.     

Manipulation of hormone biosynthetic genes in transgenic plants

Modification of plant hormone biosynthesis through the introduction of bacterial genes is a natural form of genetic engineering, which has been exploited in numerous studies on hormone function. Recently, biosynthetic pathways have been largely elucidated for most of the plant hormone classes, and genes encoding many of the enzymes have been cloned. These advances offer new opportunities to manipulate hormone content in order to study their mode of action and the regulation of their biosynthesis. Furthermore, this technology is providing the means to introduce agriculturally useful traits into crops.     

Beyond Mendel: an evolving view of human genetic disease transmission

Methodological and conceptual advances in human genetics have led to the identification of an impressive number of human disease genes. This wealth of information has also revealed that the traditional distinction between Mendelian and complex disorders might sometimes be blurred. Genetic and mutational data on an increasing number of disorders have illustrated how phenotypic effects can result from the combined action of alleles in many genes. In this review, we discuss how an improved understanding of the genetic basis of multilocus inheritance is catalysing the transition from a segmented view of human genetic disease to a conceptual continuum between Mendelian and complex traits.     

A novel knowledge-driven systems biology approach for phenotype prediction upon genetic intervention

Deciphering the biological networks underlying complex phenotypic traits, e.g., human disease is undoubtedly crucial to understand the underlying molecular mechanisms and to develop effective therapeutics. Due to the network complexity and the relatively small number of available experiments, data-driven modeling is a great challenge for deducing the functions of genes/proteins in the network and in phenotype formation. We propose a novel knowledge-driven systems biology method that utilizes qualitative knowledge to construct a Dynamic Bayesian network (DBN) to represent the biological network underlying a specific phenotype. Edges in this network depict physical interactions between genes and/or proteins. A qualitative knowledge model first translates typical molecular interactions into constraints when resolving the DBN structure and parameters. Therefore, the uncertainty of the network is restricted to a subset of models which are consistent with the qualitative knowledge. All models satisfying the constraints are considered as candidates for the underlying network. These consistent models are used to perform quantitative inference. By in silico inference, we can predict phenotypic traits upon genetic interventions and perturbing in the network. We applied our method to analyze the puzzling mechanism of breast cancer cell proliferation network and we accurately predicted cancer cell growth rate upon manipulating (anti)cancerous marker genes/proteins.     

Advances in QTL mapping in pigs

Over the past 15 years advances in the porcine genetic linkage map and discovery of useful candidate genes have led to valuable gene and trait information being discovered. Early use of exotic breed crosses and now commercial breed crosses for quantitative trait loci (QTL) scans and candidate gene analyses have led to 110 publications which have identified 1,675 QTL. Additionally, these studies continue to identify genes associated with economically important traits such as growth rate, leanness, feed intake, meat quality, litter size, and disease resistance. A well developed QTL database called PigQTLdb is now as a valuable tool for summarizing and pinpointing in silico regions of interest to researchers. The commercial pig industry is actively incorporating these markers in marker-assisted selection along with traditional performance information to improve traits of economic performance. The long awaited sequencing efforts are also now beginning to provide sequence available for both comparative genomics and large scale single nucleotide polymorphism (SNP) association studies. While these advances are all positive, development of useful new trait families and measurement of new or underlying traits still limits future discoveries. A review of these developments is presented.     

Genetic mapping of determinants in drug resistance,virulence, disease susceptibility,and interaction of host-rodent malaria parasites

Genetic mapping has been widely employed to search for genes linked to phenotypes/traits of interest. Because of the ease of maintaining rodent malaria parasites in laboratory mice, many genetic crosses of rodent malaria parasites have been performed to map the parasite genes contributing to malaria parasite development, drug resistance, host immune response, and disease pathogenesis. Drs. Richard Carter, David Walliker, and colleagues at the University of Edinburgh, UK, were the pioneers in developing the systems for genetic mapping of malaria parasite traits, including characterization of genetic markers to follow the inheritance and recombination of parasite chromosomes and performing the first genetic cross using rodent malaria parasites. Additionally, many genetic crosses of inbred mice have been performed to link mouse chromosomal loci to the susceptibility to malaria parasite infections. In this chapter, we review and discuss past and recent advances in genetic marker development, performing genetic crosses, and genetic mapping of both parasite and host genes. Genetic mappings using models of rodent malaria parasites and inbred mice have contributed greatly to our understanding of malaria, including parasite development within their hosts, mechanism of drug resistance, and host-parasite interaction.     

Multivariate genome-wide association studies on tenderness of Berkshire and Duroc pig breeds

Genome-wide association studies (GWAS) have been steadily used for identification of genomic links to disease and various economical traits. Of those traits, a tenderness of pork is one of the most important factors in quality evaluation of consumers. In this study, we use two pig breed populations; Berkshire is known for its excellent meat quality and Duroc which is known for its high intramuscular fat content in meat. Multivariate genome-wide association studies (MV-GWAS) was executed to compare SNPs of two pigs to find out what genetic variants occur the tenderness of pork. Through MV-GWAS, we have identified candidate genes and the association of biological pathways involved in the tenderness of pork. From these direct and indirect associations, we displayed the usefulness of simple statistical models and their potential contribution to improving the meat quality of pork. We identified a candidate gene related to the tenderness in only Berkshire. Furthermore, several of the biological pathways involved in tenderness in both Berkshire and Duroc were found. The candidate genes identified in this study will be helpful to use them in breeding programs for improving pork quality.     

Butterfly genomics eclosing

Technological and conceptual advances of the last decade have led to an explosion of genomic data and the emergence of new research avenues. Evolutionary and ecological functional genomics, with its focus on the genes that affect ecological success and adaptation in natural populations, benefits immensely from a phylogenetically widespread sampling of biological patterns and processes. Among those organisms outside established model systems, butterflies offer exceptional opportunities for multidisciplinary research on the processes generating and maintaining variation in ecologically relevant traits. Here we highlight research on wing color pattern variation in two groups of Nymphalid butterflies, the African species Bicyclus anynana (subfamily Satyrinae) and species of the South American genus Heliconius (subfamily Heliconiinae), which are emerging as important systems for studying the nature and origins of functional diversity. Growing genomic resources including genomic and cDNA libraries, dense genetic maps, high-density gene arrays, and genetic transformation techniques are extending current gene mapping and expression profiling analysis and enabling the next generation of research questions linking genes, development, form, and fitness. Efforts to develop such resources in Bicyclus and Heliconius underscore the general challenges facing the larger research community and highlight the need for a community-wide effort to extend ongoing functional genomic research on butterflies.     

Domestication and crop evolution of wheat andbarley: Genes,genomics, and future directions

Wheat and barley are two of the founder crops of the agricultural revolution that took place 10,000 years ago in the Fertile Crescent and both crops remain among the world's most important crops. Domestication of these crops from their wild ancestors required the evolution of traits useful to humans, rather than survival in their natural environment. Of these traits, grain retention and threshability, yield improvement, changes to photoperiod sensitivity and nutritional value are most pronounced between wild and domesticated forms. Knowledge about the geographical origins of these crops and the genes responsible for domestication traits largely pre-dates the era of nextgeneration sequencing, although sequencing will lead to new insights. Molecular markers were initially used to calculate distance(relatedness), genetic diversity and to generate genetic maps which were useful in cloning major domestication genes. Both crops are characterized by large,complex genomes which were long thought to be beyond the scope of whole-genome sequencing. However, advances in sequencing technologies have improved the state of genomic resources for both wheat and barley. The availability of reference genomes for wheat and some of its progenitors,as well as for barley, sets the stage for answering unresolved questions in domestication genomics of wheat and barley.     

Microdiversity of extracellular enzyme genes among sequenced prokaryotic genomes

Understanding the relationship between prokaryotic traits and phylogeny is important for predicting and modeling ecological processes. Microbial extracellular enzymes have a pivotal role in nutrient cycling and the decomposition of organic matter, yet little is known about the phylogenetic distribution of genes encoding these enzymes. In this study, we analyzed 3058 annotated prokaryotic genomes to determine which taxa have the genetic potential to produce alkaline phosphatase, chitinase and β-N-acetyl-glucosaminidase enzymes. We then evaluated the relationship between the genetic potential for enzyme production and 16S rRNA phylogeny using the consenTRAIT algorithm, which calculated the phylogenetic depth and corresponding 16S rRNA sequence identity of clades of potential enzyme producers. Nearly half (49.2%) of the genomes analyzed were found to be capable of extracellular enzyme production, and these were non-randomly distributed across most prokaryotic phyla. On average, clades of potential enzyme-producing organisms had a maximum phylogenetic depth of 0.008004–0.009780, though individual clades varied broadly in both size and depth. These values correspond to a minimum 16S rRNA sequence identity of 98.04–98.40%. The distribution pattern we found is an indication of microdiversity, the occurrence of ecologically or physiologically distinct populations within phylogenetically related groups. Additionally, we found positive correlations among the genes encoding different extracellular enzymes. Our results suggest that the capacity to produce extracellular enzymes varies at relatively fine-scale phylogenetic resolution. This variation is consistent with other traits that require a small number of genes and provides insight into the relationship between taxonomy and traits that may be useful for predicting ecological function.