TNF receptor 1 genetic risk mirrors outcome of anti-TNF therapy in multiple sclerosis

Although there has been much success in identifying genetic variants associated with common diseases using genome-wide association studies (GWAS), it has been difficult to demonstrate which variants are causal and what role they have in disease. Moreover, the modest contribution that these variants make to disease risk has raised questions regarding their medical relevance. Here we have investigated a single nucleotide polymorphism (SNP) in the TNFRSF1A gene, that encodes tumour necrosis factor receptor 1 (TNFR1), which was discovered through GWAS to be associated with multiple sclerosis (MS), but not with other autoimmune conditions such as rheumatoid arthritis, psoriasis and Crohn’s disease. By analysing MS GWAS data in conjunction with the 1000 Genomes Project data we provide genetic evidence that strongly implicates this SNP, rs1800693, as the causal variant in the TNFRSF1A region. We further substantiate this through functional studies showing that the MS risk allele directs expression of a novel, soluble form of TNFR1 that can block TNF. Importantly, TNF-blocking drugs can promote onset or exacerbation of MS, but they have proven highly efficacious in the treatment of autoimmune diseases for which there is no association with rs1800693. This indicates that the clinical experience with these drugs parallels the disease association of rs1800693, and that the MS-associated TNFR1 variant mimics the effect of TNF-blocking drugs. Hence, our study demonstrates that clinical practice can be informed by comparing GWAS across common autoimmune diseases and by investigating the functional consequences of the disease-associated genetic variation.     

Sequence-based characterization of structural variation in the mouse genome

Structural variation is widespread in mammalian genomes and is an important cause of disease, but just how abundant and important structural variants (SVs) are in shaping phenotypic variation remains unclear. Without knowing how many SVs there are, and how they arise, it is difficult to discover what they do. Combining experimental with automated analyses, we identified 711,920 SVs at 281,243 sites in the genomes of thirteen classical and four wild-derived inbred mouse strains. The majority of SVs are less than 1?kilobase in size and 98% are deletions or insertions. The breakpoints of 160,000 SVs were mapped to base pair resolution, allowing us to infer that insertion of retrotransposons causes more than half of SVs. Yet, despite their prevalence, SVs are less likely than other sequence variants to cause gene expression or quantitative phenotypic variation. We identified 24 SVs that disrupt coding exons, acting as rare variants of large effect on gene function. One-third of the genes so affected have immunological functions.     

An SNP map of human chromosome 22

The human genome sequence will provide a reference for measuring DNA sequence variation in human populations. Sequence variants are responsible for the genetic component of individuality, including complex characteristics such as disease susceptibility and drug response. Most sequence variants are single nucleotide polymorphisms (SNPs), where two alternate bases occur at one position. Comparison of any two genomes reveals around 1 SNP per kilobase. A sufficiently dense map of SNPs would allow the detection of sequence variants responsible for particular characteristics on the basis that they are associated with a specific SNP allele. Here we have evaluated large-scale sequencing approaches to obtaining SNPs, and have constructed a map of 2,730 SNPs on human chromosome 22. Most of the SNPs are within 25 kilobases of a transcribed exon, and are valuable for association studies. We have scaled up the process, detecting over 65,000 SNPs in the genome as part of The SNP Consortium programme, which is on target to build a map of 1 SNP every 5 kilobases that is integrated with the human genome sequence and that is freely available in the public domain.     

Hundreds of variants clustered in genomic loci and biological pathways affect human height

Most common human traits and diseases have a polygenic pattern of inheritance: DNA sequence variants at many genetic loci influence the phenotype. Genome-wide association (GWA) studies have identified more than 600 variants associated with human traits, but these typically explain small fractions of phenotypic variation, raising questions about the use of further studies. Here, using 183,727 individuals, we show that hundreds of genetic variants, in at least 180 loci, influence adult height, a highly heritable and classic polygenic trait. The large number of loci reveals patterns with important implications for genetic studies of common human diseases and traits. First, the 180 loci are not random, but instead are enriched for genes that are connected in biological pathways (P = 0.016) and that underlie skeletal growth defects (P?相似文献   

A first-generation linkage disequilibrium map of human chromosome 22

DNA sequence variants in specific genes or regions of the human genome are responsible for a variety of phenotypes such as disease risk or variable drug response. These variants can be investigated directly, or through their non-random associations with neighbouring markers (called linkage disequilibrium (LD)). Here we report measurement of LD along the complete sequence of human chromosome 22. Duplicate genotyping and analysis of 1,504 markers in Centre d'Etude du Polymorphisme Humain (CEPH) reference families at a median spacing of 15 kilobases (kb) reveals a highly variable pattern of LD along the chromosome, in which extensive regions of nearly complete LD up to 804 kb in length are interspersed with regions of little or no detectable LD. The LD patterns are replicated in a panel of unrelated UK Caucasians. There is a strong correlation between high LD and low recombination frequency in the extant genetic map, suggesting that historical and contemporary recombination rates are similar. This study demonstrates the feasibility of developing genome-wide maps of LD.     

Cellular and genetic mechanisms of self tolerance and autoimmunity

The mammalian immune system has an extraordinary potential for making receptors that sense and neutralize any chemical entity entering the body. Inevitably, some of these receptors recognize components of our own body, and so cellular mechanisms have evolved to control the activity of these 'forbidden' receptors and achieve immunological self tolerance. Many of the genes and proteins involved are conserved between humans and other mammals. This provides the bridge between clinical studies and mechanisms defined in experimental animals to understand how sets of gene products coordinate self-tolerance mechanisms and how defects in these controls lead to autoimmune disease.     

Strain-resolved community proteomics reveals recombining genomes of acidophilic bacteria

Microbes comprise the majority of extant organisms, yet much remains to be learned about the nature and driving forces of microbial diversification. Our understanding of how microorganisms adapt and evolve can be advanced by genome-wide documentation of the patterns of genetic exchange, particularly if analyses target coexisting members of natural communities. Here we use community genomic data sets to identify, with strain specificity, expressed proteins from the dominant member of a genomically uncharacterized, natural, acidophilic biofilm. Proteomics results reveal a genome shaped by recombination involving chromosomal regions of tens to hundreds of kilobases long that are derived from two closely related bacterial populations. Inter-population genetic exchange was confirmed by multilocus sequence typing of isolates and of uncultivated natural consortia. The findings suggest that exchange of large blocks of gene variants is crucial for the adaptation to specific ecological niches within the very acidic, metal-rich environment. Mass-spectrometry-based discrimination of expressed protein products that differ by as little as a single amino acid enables us to distinguish the behaviour of closely related coexisting organisms. This is important, given that microorganisms grouped together as a single species may have quite distinct roles in natural systems and their interactions might be key to ecosystem optimization. Because proteomic data simultaneously convey information about genome type and activity, strain-resolved community proteomics is an important complement to cultivation-independent genomic (metagenomic) analysis of microorganisms in the natural environment.     

A map of human genome variation from population-scale sequencing

The 1000 Genomes Project aims to provide a deep characterization of human genome sequence variation as a foundation for investigating the relationship between genotype and phenotype. Here we present results of the pilot phase of the project, designed to develop and compare different strategies for genome-wide sequencing with high-throughput platforms. We undertook three projects: low-coverage whole-genome sequencing of 179 individuals from four populations; high-coverage sequencing of two mother-father-child trios; and exon-targeted sequencing of 697 individuals from seven populations. We describe the location, allele frequency and local haplotype structure of approximately 15 million single nucleotide polymorphisms, 1 million short insertions and deletions, and 20,000 structural variants, most of which were previously undescribed. We show that, because we have catalogued the vast majority of common variation, over 95% of the currently accessible variants found in any individual are present in this data set. On average, each person is found to carry approximately 250 to 300 loss-of-function variants in annotated genes and 50 to 100 variants previously implicated in inherited disorders. We demonstrate how these results can be used to inform association and functional studies. From the two trios, we directly estimate the rate of de novo germline base substitution mutations to be approximately 10(-8) per base pair per generation. We explore the data with regard to signatures of natural selection, and identify a marked reduction of genetic variation in the neighbourhood of genes, due to selection at linked sites. These methods and public data will support the next phase of human genetic research.     

Methods for Population-Based eQTL Analysis in Human Genetics

Gene expression is a critical process in biological system that is influenced and modulated by many factors including genetic variation. Expression Quantitative Trait Loci（e QTL） analysis provides a powerful way to understand how genetic variants affect gene expression. For genome wide e QTL analysis, the number of genetic variants and that of genes are large and thus the search space is tremendous. Therefore, e QTL analysis brings about computational and statistical challenges. In this paper, we provide a comprehensive review of recent advances in methods for e QTL analysis in population-based studies. We first present traditional pairwise association methods, which are widely used in human genetics. To account for expression heterogeneity, we investigate the methods for correcting confounding factors. Next, we discuss newly developed statistical learning methods including Lasso-based models. In the conclusion, we provide an overview of future method development in analyzing e QTL associations. Although we focus on human genetics in this review, the methods are applicable to many other organisms.     

Accurate whole human genome sequencing using reversible terminator chemistry

DNA sequence information underpins genetic research, enabling discoveries of important biological or medical benefit. Sequencing projects have traditionally used long (400-800 base pair) reads, but the existence of reference sequences for the human and many other genomes makes it possible to develop new, fast approaches to re-sequencing, whereby shorter reads are compared to a reference to identify intraspecies genetic variation. Here we report an approach that generates several billion bases of accurate nucleotide sequence per experiment at low cost. Single molecules of DNA are attached to a flat surface, amplified in situ and used as templates for synthetic sequencing with fluorescent reversible terminator deoxyribonucleotides. Images of the surface are analysed to generate high-quality sequence. We demonstrate application of this approach to human genome sequencing on flow-sorted X chromosomes and then scale the approach to determine the genome sequence of a male Yoruba from Ibadan, Nigeria. We build an accurate consensus sequence from >30x average depth of paired 35-base reads. We characterize four million single-nucleotide polymorphisms and four hundred thousand structural variants, many of which were previously unknown. Our approach is effective for accurate, rapid and economical whole-genome re-sequencing and many other biomedical applications.     

Spontaneous shuffling of domains between introns of phage T4

The three self-splicing introns in phage T4 (in the td, sunY and nrdB genes) (Fig. 1a) each have the conserved group I catalytic RNA core structure (Fig. 1b), out of which is looped an open reading frame. Although the core sequences are very similar (approximately 60% identity), the open reading frames seem to be unrelated. Single crossover recombination events between homologous core sequences in the closely linked td and nrdB introns have led to 'exon shuffling. Here we describe spontaneous double crossovers between the unlinked td and sun Y introns that result in shuffling of an intron structure element, P7.1 (refs 3 and 4). The intron domain-switch variants were isolated as genetic suppressors of a splicing-defective P7.1 deletion in the td intron. This unprecedented example of suppression through inter-intron sequence substitution indicates that the introns are in a state of genetic flux and implies the functional interchangeability of the two analogous but nonidentical P7.1 elements. The implications of such recombination events are discussed in the light of the evolution of the introns themselves as well as that of their host genomes.     

Rate of turnover of structural variants in the rDNA gene family of Drosophila melanogaster

A high degree of polymorphism for the length and copy number of rDNA spacers, in both the X and Y chromosome clusters, has been found in a wild population of Drosophila melanogaster. The genetic behaviour of rDNA structural variants in separate and mixed populations derived from isofemale lines suggest that they are not subject to strong selection and are stable for over 1,000 generations. The high structural variability suggests an evolutionary rapid process of turnover in the family which could partly explain widespread sequence homogeneity (concerted evolution) of rDNA within a species.     

表观遗传学研究进展

 概述了表观遗传调节模式、表观遗传调节的效应、植物表观遗传学的研究进展等。在每种细胞中,都会发生一部分特异基因激活、另一部分基因抑制的现象,形成多种基因表达模式。表观遗传指DNA序列不发生变化,而基因表达发生可遗传改变的现象。表观遗传学改变包括DNA甲基化、组蛋白修饰、非编码RNA作用等,产生基因组印记、母性影响、基因沉默、核仁显性、休眠转座子激活等效应。表观遗传变异是环境因素和细胞内遗传物质间交互作用的结果,其效应通过调节基因表达,控制生物学表型来实现。正是因为表观修饰对于维持生物体内环境和各器官系统功能的重要性,表观遗传的异常会引发疾病,这也成为药物和治疗方案设计的着眼点。     

豇豆SSR标记在豌豆中的可转移性与应用初探

利用豇豆SSR引物筛选在豌豆具通用性的SSR引物。13对豇豆SSR引物中检测出8对引物在豌豆中可扩增,其中5对SSR引物表现出多态性,进而分析11个豌豆品种和5个豇豆品种的遗传多样性与遗传关系。结果表明:平均等位基因数、平均有效等位基因数、平均Shannon指数,在豌豆品种群中分别为2.00、1.64、0.55,豇豆品种群中分别为2.00、1.80、0.53,上述遗传参数反映出供试豌豆品种和豇豆品种具有中等水平的遗传多样性;利用UPGMA聚类分析,能将豌豆品种群和豇豆品种群分为两类,且每个品种群内的各个体之间能进行区分,尤其是两个豌豆品种亚群的聚类结果与其地理来源基本一致。     

An array of possibilities for the study of autoimmunity

Since the completion of the sequencing of the human genome, scientific focus has shifted from studying genes to analysing the much larger number of proteins encoded by them. Several proteins can be generated from a single gene depending on how the genetic information is read (transcribed) and how the resultant protein is modified following translation (post-translational modification). Genomic and proteomic technologies are already providing useful information about autoimmune disease, and they are likely to lead to important discoveries within the next decade.     

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.     

Genome sequence and analysis of the tuber crop potato

Potato (Solanum tuberosum L.) is the world's most important non-grain food crop and is central to global food security. It is clonally propagated, highly heterozygous, autotetraploid, and suffers acute inbreeding depression. Here we use a homozygous doubled-monoploid potato clone to sequence and assemble 86% of the 844-megabase genome. We predict 39,031 protein-coding genes and present evidence for at least two genome duplication events indicative of a palaeopolyploid origin. As the first genome sequence of an asterid, the potato genome reveals 2,642 genes specific to this large angiosperm clade. We also sequenced a heterozygous diploid clone and show that gene presence/absence variants and other potentially deleterious mutations occur frequently and are a likely cause of inbreeding depression. Gene family expansion, tissue-specific expression and recruitment of genes to new pathways contributed to the evolution of tuber development. The potato genome sequence provides a platform for genetic improvement of this vital crop.     

Variants conferring risk of atrial fibrillation on chromosome 4q25

Atrial fibrillation (AF) is the most common sustained cardiac arrhythmia in humans and is characterized by chaotic electrical activity of the atria. It affects one in ten individuals over the age of 80 years, causes significant morbidity and is an independent predictor of mortality. Recent studies have provided evidence of a genetic contribution to AF. Mutations in potassium-channel genes have been associated with familial AF but account for only a small fraction of all cases of AF. We have performed a genome-wide association scan, followed by replication studies in three populations of European descent and a Chinese population from Hong Kong and find a strong association between two sequence variants on chromosome 4q25 and AF. Here we show that about 35% of individuals of European descent have at least one of the variants and that the risk of AF increases by 1.72 and 1.39 per copy. The association with the stronger variant is replicated in the Chinese population, where it is carried by 75% of individuals and the risk of AF is increased by 1.42 per copy. A stronger association was observed in individuals with typical atrial flutter. Both variants are adjacent to PITX2, which is known to have a critical function in left-right asymmetry of the heart.     

A common sex-dependent mutation in a RET enhancer underlies Hirschsprung disease risk

The identification of common variants that contribute to the genesis of human inherited disorders remains a significant challenge. Hirschsprung disease (HSCR) is a multifactorial, non-mendelian disorder in which rare high-penetrance coding sequence mutations in the receptor tyrosine kinase RET contribute to risk in combination with mutations at other genes. We have used family-based association studies to identify a disease interval, and integrated this with comparative and functional genomic analysis to prioritize conserved and functional elements within which mutations can be sought. We now show that a common non-coding RET variant within a conserved enhancer-like sequence in intron 1 is significantly associated with HSCR susceptibility and makes a 20-fold greater contribution to risk than rare alleles do. This mutation reduces in vitro enhancer activity markedly, has low penetrance, has different genetic effects in males and females, and explains several features of the complex inheritance pattern of HSCR. Thus, common low-penetrance variants, identified by association studies, can underlie both common and rare diseases.