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。     

Unified views on variant impact across many diseases

Genomic studies of human disorders are often performed by distinct research communities (i.e., focused on rare diseases, common diseases, or cancer). Despite underlying differences in the mechanistic origin of different disease categories, these studies share the goal of identifying causal genomic events that are critical for the clinical manifestation of the disease phenotype. Moreover, these studies face common challenges, including understanding the complex genetic architecture of the disease, deciphering the impact of variants on multiple scales, and interpreting noncoding mutations. Here, we highlight these challenges in depth and argue that properly addressing them will require a more unified vocabulary and approach across disease communities. Toward this goal, we present a unified perspective on relating variant impact to various genomic disorders.     

Human molecular genetics: from monogenic to polygenic or complex disorders

Human molecular genetics has successfully identified the genes involved in several monogenic disorders. It now aims at pinpointing the genetic determinants of polygenic or complex traits with a strong genetic component. This constitutes a new challenge. We discuss the methodological and practical aspects of identifying such genes as well as the challenges facing physicians that will have to use efficiently these new diagnostic tools.     

The genetic architecture of autism spectrum disorders(ASDs) and the potential importance of common regulatory genetic variants

Currently, there is great interest in identifying genetic variants that contribute to the risk of developing autism spectrum disorders(ASDs), due in part to recent increases in the frequency of diagnosis of these disorders worldwide. While there is nearly universal agreement that ASDs are complex diseases, with multiple genetic and environmental contributing factors, there is less agreement concerning the relative importance of common vs rare genetic variants in ASD liability. Recent observations that rare mutations and copy number variants(CNVs) are frequently associated with ASDs, combined with reduced fecundity of individuals with these disorders, has led to the hypothesis that ASDs are caused primarily by de novo or rare genetic mutations. Based on this model, large-scale whole-genome DNA sequencing has been proposed as the most appropriate method for discovering ASD liability genes. While this approach will undoubtedly identify many novel candidate genes and produce important new insights concerning the genetic causes of these disorders, a full accounting of the genetics of ASDs will be incomplete absent an understanding of the contributions of common regulatory variants, which are likely to influence ASD liability by modifying the effects of rare variants or, by assuming unfavorable combinations, directly produce these disorders. Because it is not yet possible to identify regulatory genetic variants by examination of DNA sequences alone, their identification will require experimentation. In this essay, I discuss these issues and describe the advantages of measurements of allelic expression imbalance(AEI) of m RNA expression for identifying cis-acting regulatory variants that contribute to ASDs.     

Will family studies return to prominence in human genetics and genomics? Rare variants and linkage analysis of complex traits

A major focus of modern human genetics has been the search for genetic variations that contribute to human disease. These studies originated in families and used linkage methods as a primary analytical tool. With continued technical improvements, these family-based linkage studies have been very powerful in identifying genes contributing to monogenic disorders. When these methods were applied to disorders with complex, non-Mendelian patterns of inheritance they largely failed. The development of effective capabilities for Genome Wide Association Studies (GWAS) relegated family-based studies to a peripheral role in human genetics research. Despite the remarkable record of GWAS discoveries, common variations identified in GWAS account for a limited (frequently less than 10%) proportion of the heritable risk of qualitative traits or variance of quantitative traits. Next generation sequencing is facilitating a re-examination of family-based methods with surprising and intriguing results. We propose that rare variants of large effect underlie many linkage peaks, including complex quantitative phenotypes, and review the issues underlying this proposed basis for complex traits.     

Drosophila as a Model Organism for Investigating Molecular and Cellular Etiologies Underlying Complex Neurological Disorders in Humans

The fruit fly Drosophila has been utilized as a powerful biological system to address fundamental questions concerning neurological disorders in humans, since the related basic molecular components and signal transduction pathways in humans are mostly conserved in Drosophila. In addition, Drosophila offers great experimental advantages in genetics, behavioral analysis and cell and molecular biology. Pathogenesis and etiologies underlying several monogenic neurological disorders including familial Parkinson disease, Alzheimer's disease, or ataxia have been faithfully replicated in Drosophila system when causative mutations of those disorders were transgenically introduced or loss of function mutations of endogenous homologues were made. However, more than 90% of reported cases of neurological disorders are complex forms whose inheritance patterns do not follow a monogenic inheritance. Nevertheless, complex disorders are more often observed among the families or relatives of affected patients, strongly suggesting that they are most likely to be caused by interaction of multiple genetic mutations or combinations of genetic and environmental risk factors. Complex neurological disorders are include sporadic forms of Parkinson disease, Alzheimer's disease, amyotrophic lateral sclerosis (ALS), dystonia, epilepsy, and mental retardation, etc. Our understanding of the genetic defects and environmental risk factors involved in the onset and progression of complex neurological disorders are, however, still rudimentary. Thus identifying unknown factors involved in the onset and progression of complex neurological disorders in humans is one of the major challenges in medical sciences.     

The pleiotropic effects of fibroblast growth factor receptors in mammalian development

In recent years the study of fibroblast growth factor receptors (FGFRs) in normal development and human genetic disorders has increased our understanding of some complex cellular processes. At least fifteen genetic disorders result from mutations within FGFR genes including skeletal dysplasias such as Apert syndrome and achondroplasia. In vitro experiments and the generation of animal models indicate that these mutations result in activation of the receptors and that FGFRs act as negative regulators of bone growth. FGFRs also play a role in wound healing and cancer. In this article, we review the expression of FGFRs in human development, the phenotypes resulting from FGFR mutations, and recent data identifying pathways downstream of the activated receptors.     

全基因组关联研究现状

在过去的5年中, 全基因组关联研究(Genome-wide association study, GWAS)方法已被证明是研究复杂疾病和性状遗传易感变异的一种有效手段。目前, 各国科学家在多种复杂疾病和性状中开展了大量的GWAS, 对肿瘤、糖尿病、心脏病、神经精神疾病、自身免疫及免疫相关疾病等复杂疾病以及一些常见性状(如身高、体重、血脂、色素等)的遗传易感基因研究取得了重大成果。截止到2010年9月11日, 运用GWAS开展了对近200种复杂疾病/性状的研究, 发现了3 000多个疾病相关的遗传变异。文章就GWAS的发展及其在复杂疾病/性状中的应用做一综述。     

A sibling-pair based approach for mapping genetic loci that influence quantitative measures of reading disability

Family and twin studies consistently demonstrate a significant role for genetic factors in the aetiology of the reading disorder dyslexia. However, dyslexia is complex at both the genetic and phenotypic levels, and currently the nature of the core deficit or deficits remains uncertain. Traditional approaches for mapping disease genes, originally developed for single-gene disorders, have limited success when there is not a simple relationship between genotype and phenotype. Recent advances in high-throughput genotyping technology and quantitative statistical methods have made a new approach to identifying genes involved in complex disorders possible. The method involves assessing the genetic similarity of many sibling pairs along the lengths of all their chromosomes and attempting to correlate this similarity with that of their phenotypic scores. We are adopting this approach in an ongoing genome-wide search for genes involved in dyslexia susceptibility, and have already successfully applied the method by replicating results from previous studies suggesting that a quantitative trait locus at 6p21.3 influences reading disability.     

Genetic approaches to identify disease genes for birth defects with cleft lip/palate as a model

BACKGROUND: Understanding the etiology of birth defects is an important step toward developing improved treatment and preventive strategies. Most birth defects have an underlying genetic basis, ranging from single genes playing dominant or recessive roles in Mendelian disorders to a mixture of contributions from multiple genes and environmental triggers in complex traits. The purpose of this article is to provide an overview of genetic approaches to identifying disease genes for genetically complex birth defects. METHODS: A review of the literature describing successes and limitations for identifying disease genes for complex traits was conducted. RESULTS: Cleft lip and cleft palate are common congenital anomalies with significant medical, psychological, social, and economic ramifications. The Online Mendelian Inheritance in Man catalog (OMIM; http://www3.ncbi.nlm.nih.gov/Omim) lists more than 400 single-gene causes of clefts of the lip and/or palate. Genetic causes of clefting also include chromosomal rearrangements, genetic susceptibility to teratogenic exposures, and complex genetic contributions of multiple genes. CONCLUSIONS: Genetic causes of birth defects can be identified using an increasingly powerful combination of careful sample collection, molecular analytic methods, and statistical evaluations. We will describe a range of approaches to search for genetic factors of birth defects and use our own work with cleft lip and palate as a model.     

Identifying genetic risk factors for osteoporosis

Over the past decades epidemiological research of so-called "complex" diseases, i.e., common age-related disorders such as cancer, cardiovascular disease, diabetes, and osteoporosis, has identified anthropometric, behavioural, and serum parameters as risk factors. Recently, genetic polymorphisms have gained considerable interest, propelled by the Human Genome Project and its sequela that have identified most genes and uncovered a plethora of polymorphic variants, some of which embody the genetic risk factors. In all fields of complex disease genetics (including osteoporosis) progress in identifying these genetic factors has been hampered by often controversial results. Because of the small effect size for each individual risk polymorphism, this is mostly due to low statistical power and limitations of analytical methods. Genome-wide scanning approaches can be used to find the responsible genes. It is by now clear that linkage analysis is not suitable for this, but genome-wide association analysis has much better possibilities, as is illustrated by successful identification of risk alleles for several complex diseases. Candidate gene association analysis followed by replication and prospective multi-centred meta-analysis, is currently the best way forward to identify genetic markers for complex traits, such as osteoporosis. To accomplish this, we need large (global) collaborative studies using standardized methodology and definitions, to quantify by meta-analysis the subtle effects of the responsible gene variants.     

复杂疾病靶基因识别与网络重建的计算系统生物研究

复杂疾病相关靶基因的识别、构建疾病驱使相关基因网络及进行疾病机制研究,是功能基因组学研究中非常重要的科学问题。文章以计算系统生物学的观点和三维的角度,综述了基于生物谱（SNP遗传谱、芯片表达谱和2D-PAGE蛋白质谱等）的复杂疾病靶基因识别、多水平（SNPs虚拟网络、基因调控网络、蛋白质互作网络等）遗传网络逆向重构方法,及不同水平的网络之间在生物学和拓扑学上的纵向映射关系,并给出复杂疾病靶基因识别与网络关系的计算系统生物方法研究的未来展望。     

Development and function of the midbrain dopamine system: what we know and what we need to

The past two decades have seen an explosion in our understanding of the origin and development of the midbrain dopamine system. Much of this work has been focused on the aspects of dopamine neuron development related to the onset of movement disorders such as Parkinson's disease, with the intent of hopefully delaying, preventing or fixing symptoms. While midbrain dopamine degeneration is a major focus for treatment and research, many other human disorders are impacted by abnormal dopamine, including drug addiction, autism and schizophrenia. Understanding dopamine neuron ontogeny and how dopamine connections and circuitry develops may provide us with key insights into potentially important avenues of research for other dopamine‐related disorders. This review will provide a brief overview of the major molecular and genetic players throughout the development of midbrain dopamine neurons and what we know about the behavioral‐ and disease‐related implications associated with perturbations to midbrain dopamine neuron development. We intend to combine the knowledge of two broad fields of neuroscience, both developmental and behavioral, with the intent on fostering greater discussion between branches of neuroscience in the service of addressing complex cognitive questions from a developmental perspective and identifying important gaps in our knowledge for future study.     

Empowering international canine inherited disorder management

The mapping of the canine genome and the study of canine breed genomic architecture has revolutionized the discovery of genetic tests for inherited disorders in dogs. As the genetics underlying complex disorders are revealed, canine breeders and their registering organisations will be required to understand genetics in a much more sophisticated way. To facilitate the management of genetic disorders in the era of new complex information, we consider how best to apply the results of new research and analytical techniques to benefit the wider canine breeding community with the aims of improving canine health and maintaining benevolent genetic diversity. If this is not done, there is a serious risk that expensive and valuable genetic research will remain unused or be misused to the detriment of breeds. In this review, we make a case for the formation of an international organisation that will exist as a central repository for breed-based genetic analysis and information sharing. This organisation ("Inter-Dog") could be modelled on a similar organisation that is monitoring genetic improvement of dairy cattle. The formation of such an organisation will require the collaboration of international kennel management organisations, researchers, and agencies offering genetic testing services.     

New perspectives for the elucidation of genetic disorders

For almost 15 years, genome research has focused on the search for major risk factors in common diseases, with disappointing results. Only recently, whole-genome association studies have begun to deliver because of the introduction of high-density single-nucleotide-polymorphism arrays and massive enlargement of cohort sizes, but most of the risk factors detected account for only a small proportion of the total genetic risk, and their diagnostic value is negligible. There is reason to believe that the complexity of many "multifactorial" disorders is primarily due to genetic heterogeneity, with defects of different genes causing the same disease. Moreover, de novo copy-number variation has been identified as a major cause of mental retardation and other complex disorders, suggesting that new mutations are an important, previously overlooked factor in the etiology of complex diseases. These observations support the notion that research into the previously neglected monogenic disorders should become a priority of genome research. Because of the introduction of novel high-throughput, low-cost sequencing methods, sequencing and genotyping will soon converge, with far-reaching implications for the elucidation of genetic disease and health care.     

Substance abuse vulnerability loci: converging genome scanning data

Classical genetic studies suggest strong complex genetic contributions to a predisposition to abuse multiple addictive substances. Until recently, there were no reproducible genome scanning data identifying chromosomal positions likely to contain allelic variants that predispose the carrier to illegal substance addiction. Nominal results of linkage-based genome scanning studies for ethanol and nicotine addictions failed to display much agreement. Our recent data from association-based genome scans for illegal addictions, and reanalyses of previous results now provide a substantial body of converging results. The 15 reproducible chromosomal loci identified here are good candidates to harbor allelic variants that alter human substance abuse vulnerabilities. We discuss several approaches to identifying the specific gene variants that underlie these convergent association and linkage observations, and the impact that these convergent observations should have on understanding important human addictive disorders.     

Genetic and Environmental Factors in Complex Neurodevelopmental Disorders

Complex neurodevelopmental disorders, such as schizophrenia, autism, attention deficit (hyperactivity) disorder, (manic) depressive illness and addiction, are thought to result from an interaction between genetic and environmental factors. Association studies on candidate genes and genome-wide linkage analyses have identified many susceptibility chromosomal regions and genes, but considerable efforts to replicate association have been surprisingly often disappointing. Here, we summarize the current knowledge of the genetic contribution to complex neurodevelopmental disorders, focusing on the findings from association and linkage studies. Furthermore, the contribution of the interaction of the genetic with environmental and epigenetic factors to the aetiology of complex neurodevelopmental disorders as well as suggestions for future research are discussed.Key Words: Neurodevelopmental disorders, susceptibility genes, environmental factors, gene-environment interactions, association studies, linkage analysis.     

Candidate genes for panic disorder: insight from human and mouse genetic studies

Panic disorder is a major cause of medical attention with substantial social and health service cost. Based on pharmacological studies, research on its etiopathogenesis has been focused on the possible dysfunction of specific neurotransmitter systems. However, recent work has related the genes involved in development, synaptic plasticity and synaptic remodeling to anxiety disorders. This implies that learning processes and changes in perception, interpretation and behavioral responses to environmental stimuli are essential for development of complex anxiety responses secondary to the building of specific brain neural circuits and to adult plasticity. The focus of this review is on progress achieved in identifying genes that confer increased risk for panic disorder through genetic epidemiology and the use of genetically modified mouse models. The integration of human and animal studies targeting behavioral, systems-level, cellular and molecular levels will most probably help identify new molecules with potential impact on the pathogenetic aspects of the disease.     

Human behavioural genetics of cognitive abilities and disabilities

Although neither the genome nor the environment can be manipulated in research on human behaviour, some of the new tools of molecular genetics can be brought to bear on human behavioural disorders (e.g. cognitive disabilities) and quantitative traits (e.g. cognitive abilities). The inability to manipulate the human genome experimentally has had the positive effect of focusing attention on naturally occuring genetic variation responsible for behavioural differences among individuals in all their complex multifactorial splendour. Genes in such complex multiple-gene systems are called quantitative trait loci (QTLs), which merge the two worlds of genetic research, quantitative genetics and molecular genetics. Although most genetic research on complex human behaviour has focused on severe mental disorders, cognitive abilities and disabilities may be even more immediately relevant to neuroscience. For example, verbal ability and spatial ability are two of the most heritable cognitive abilities, and reading disability is the first behavioural disability for which replicated QTL linkage has been found. The purpose of this essay is to provide an overview of the genetics of cognitive abilities and disabilities as an example of the impending merger of quantitative genetics and molecular genetics in QTL analysis of complex traits.