A map of human genome sequence variation containing 1.42 million single nucleotide polymorphisms

We describe a map of 1.42 million single nucleotide polymorphisms (SNPs) distributed throughout the human genome, providing an average density on available sequence of one SNP every 1.9 kilobases. These SNPs were primarily discovered by two projects: The SNP Consortium and the analysis of clone overlaps by the International Human Genome Sequencing Consortium. The map integrates all publicly available SNPs with described genes and other genomic features. We estimate that 60,000 SNPs fall within exon (coding and untranslated regions), and 85% of exons are within 5 kb of the nearest SNP. Nucleotide diversity varies greatly across the genome, in a manner broadly consistent with a standard population genetic model of human history. This high-density SNP map provides a public resource for defining haplotype variation across the genome, and should help to identify biomedically important genes for diagnosis and therapy.     

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.     

A physical map of the human genome

The human genome is by far the largest genome to be sequenced, and its size and complexity present many challenges for sequence assembly. The International Human Genome Sequencing Consortium constructed a map of the whole genome to enable the selection of clones for sequencing and for the accurate assembly of the genome sequence. Here we report the construction of the whole-genome bacterial artificial chromosome (BAC) map and its integration with previous landmark maps and information from mapping efforts focused on specific chromosomal regions. We also describe the integration of sequence data with the map.     

Genome sequence, comparative analysis and haplotype structure of the domestic dog

Here we report a high-quality draft genome sequence of the domestic dog (Canis familiaris), together with a dense map of single nucleotide polymorphisms (SNPs) across breeds. The dog is of particular interest because it provides important evolutionary information and because existing breeds show great phenotypic diversity for morphological, physiological and behavioural traits. We use sequence comparison with the primate and rodent lineages to shed light on the structure and evolution of genomes and genes. Notably, the majority of the most highly conserved non-coding sequences in mammalian genomes are clustered near a small subset of genes with important roles in development. Analysis of SNPs reveals long-range haplotypes across the entire dog genome, and defines the nature of genetic diversity within and across breeds. The current SNP map now makes it possible for genome-wide association studies to identify genes responsible for diseases and traits, with important consequences for human and companion animal health.     

单核苷酸多态性与肺癌关系的研究进展

癌症是严重威胁人类生存与健康的恶性疾病之一,而肺癌是癌症中发病率最高的一种。由于癌症难于治愈,死亡率极高,因此,预防是目前应对癌症的一个有效途径。单核苷酸多态性(SNP)广泛存在于人类基因组中,可作为检测癌易感基因的一个有效遗传标记。通过检查病例-对照人群的SNP差异来确定易感癌症的高危人群,起到预防癌症的作用。     

Global variation in copy number in the human genome

Copy number variation (CNV) of DNA sequences is functionally significant but has yet to be fully ascertained. We have constructed a first-generation CNV map of the human genome through the study of 270 individuals from four populations with ancestry in Europe, Africa or Asia (the HapMap collection). DNA from these individuals was screened for CNV using two complementary technologies: single-nucleotide polymorphism (SNP) genotyping arrays, and clone-based comparative genomic hybridization. A total of 1,447 copy number variable regions (CNVRs), which can encompass overlapping or adjacent gains or losses, covering 360 megabases (12% of the genome) were identified in these populations. These CNVRs contained hundreds of genes, disease loci, functional elements and segmental duplications. Notably, the CNVRs encompassed more nucleotide content per genome than SNPs, underscoring the importance of CNV in genetic diversity and evolution. The data obtained delineate linkage disequilibrium patterns for many CNVs, and reveal marked variation in copy number among populations. We also demonstrate the utility of this resource for genetic disease studies.     

A physical map of the mouse genome

A physical map of a genome is an essential guide for navigation, allowing the location of any gene or other landmark in the chromosomal DNA. We have constructed a physical map of the mouse genome that contains 296 contigs of overlapping bacterial clones and 16,992 unique markers. The mouse contigs were aligned to the human genome sequence on the basis of 51,486 homology matches, thus enabling use of the conserved synteny (correspondence between chromosome blocks) of the two genomes to accelerate construction of the mouse map. The map provides a framework for assembly of whole-genome shotgun sequence data, and a tile path of clones for generation of the reference sequence. Definition of the human-mouse alignment at this level of resolution enables identification of a mouse clone that corresponds to almost any position in the human genome. The human sequence may be used to facilitate construction of other mammalian genome maps using the same strategy.     

High resolution linkage disequilibrium and haplotype maps for the genes in the centromeric region of chromosome 15 in Tibetans and comparisons with Han population

WITH THE SUCCESSFUL COMPLETION OF THE HUMAN GE- NOME PROJECT, ONE OF THE SCIENTIFIC MILESTONES, GENETIC VARIATIONS AND THEIR FUNCTIONAL IMPLICATIONS, HAVE BE- COME ONE OF THE FOCUSES IN GENOME RESEARCH. IT HAS BEEN KNOWN THAT GENETIC VARIATIONS, TOGETHER WITH ENVI- RONMENT, ARE RESPONSIBLE FOR THE DIFFERENCES IN COMPLEX TRAITS IN INDIVIDUALS: PHYSICAL CHARACTERISTICS, DISE…     

基于RAD-seq技术的鹅掌楸基因组SNP标记开发

【目的】开发大量可靠的SNP标记,为鹅掌楸高密度遗传连锁图谱的构建和基于基因组的林木选择育种提供分子基础。【方法】从北美鹅掌楸NK基因型为母本、鹅掌楸LS基因型为父本的F1代杂交群体中,选取198株个体为作图群体。用限制性内切酶EcoR I对包括2个亲本和198个子代在内的200个单株的基因组DNA进行酶切,构建RAD(restriction-site associated DNA)文库并进行RAD-seq测序。采用读长为91 bp的双末端测序。2个亲本的平均测序深度为2×,198个子代的平均测序深度为0.8×,平均产量为1.94 Gb,共获得约387.21 Gb数据。用Stacks软件将每个样品的RAD-reads作生物信息学分析,对候选位点进行卡方检验和缺失率检验,再将符合孟德尔遗传的标记及与之相对应的RAD-tag序列和鹅掌楸参考基因组序列进行比对。最后,从本研究开发的SNP标记中选取27个候选SNP位点,设计引物,对随机挑选的16个F1代进行PCR扩增并将结果进行测序,同时验证SNP的有效性。【结果】从候选群体中共鉴定到22 019个SNP位点,符合孟德尔遗传规律的标记为4 233个,最终获得3 501个候选SNP标记。SNP验证中,共有293个SNP标记完成测序并能判读结果,所有位点都为SNP位点,共有194(66.2%)个SNP变异类型得到了验证。 【结论】基于RAD-seq技术和鹅掌楸参考基因组序列为基础的策略,能够作为一种快速有效的手段,实现大规模的分子标记开发,可用于鹅掌楸等林木的高密度遗传图谱的构建。     

Construction of fine SNP haplotypes and haplotype blocks in 5 genes in the centromere of chromosome 15 in Chinese Han subjects

Recent advances have shown that the majorityof the nucleotide variation in human genome is single nucleo-tide polymorphisms (SNPs). Using SNPs each chromosomecan be divided into different haplotype blocks, and there arelimited common haplotypes in each block. This provides apowerful approach for whole genome scan for disease-asso-ciated genes/variants. However, most data available todayare based on the large-scale genomic analyses, data concern-ing individual genes for fine mapping with high density SNPsare relatively lacking. We have sequenced 7 genes and theirflanking regions, identified 34 novel SNPs, constructed highdensity SNP haplotypes and haplotype blocks in 5 genes inthe centromeric region of chromosome 15 in I00 ChineseHart subjects. Our results show that there is a great hetero-geneity in the haplotypes and haplotype block structureswithin and between these genes, which are in close physicalproximity. Data obtained in this study provide a useful toolfor candidate gene approach at the fine scale for identifyingdisease contributing variants in the genes/regions.     

计算机清绘地质图件的方法及其应用

介绍了利用计算机清绘地质图件的基本原理和方法。该方法是将人工编制的草图,经过图形数字化输入、数值处理、线条光滑连接及加宽等步骤,将其还原为原图的内容,并从指定的外部设备上快速输出。由计算机清绘的图件精度高、国幅美观、缩放灵活,在实际应用中取得了满意的效果。     

人类基因组计划及研究

近年来,采用ＤＮＡ序列测定、基因克隆、基因组文库的构建等方法对人类基因组进行了研究,完成了大部分人类基因组的物理图谱、转录图谱及单核苷酸多态性图谱的分析。进而发现、克隆和研究了许多新基因,如青光眼基因、肿瘤抑制基因等,这些结果使人类第一次在分子水平上认识自我,并有助于从人灰基因组中去除有害基因。最后本文探讨了人类基因组研究可能带来的问题。     

A physical map of the chicken genome

Strategies for assembling large, complex genomes have evolved to include a combination of whole-genome shotgun sequencing and hierarchal map-assisted sequencing. Whole-genome maps of all types can aid genome assemblies, generally starting with low-resolution cytogenetic maps and ending with the highest resolution of sequence. Fingerprint clone maps are based upon complete restriction enzyme digests of clones representative of the target genome, and ultimately comprise a near-contiguous path of clones across the genome. Such clone-based maps are used to validate sequence assembly order, supply long-range linking information for assembled sequences, anchor sequences to the genetic map and provide templates for closing gaps. Fingerprint maps are also a critical resource for subsequent functional genomic studies, because they provide a redundant and ordered sampling of the genome with clones. In an accompanying paper we describe the draft genome sequence of the chicken, Gallus gallus, the first species sequenced that is both a model organism and a global food source. Here we present a clone-based physical map of the chicken genome at 20-fold coverage, containing 260 contigs of overlapping clones. This map represents approximately 91% of the chicken genome and enables identification of chicken clones aligned to positions in other sequenced genomes.     

Chromosome sorting and its applications in common wheat (Triticum aestivum) genome sequencing

The large genome size (～17000 Mb) and complicated DNA structures of common wheat (Triticum aestivum) hamper its genome sequencing.By means of flow cytometry,systematic investigations on individual chromosome sorting have been carried out to construct chromosome-specific bacterial artificial chromosome (BAC) libraries since the 1980s.Several wheat chromosome-specific BAC libraries,such as chromosome 3B,three D genome chromosomes (1D,4D and 6D),and the short arm of chromosome 1B,have been developed,and the ph...     

应用SNaPshot技术对桉树SNP的检测

【目的】SNaPshot是一种单核苷酸多态性(SNP)检测的多重分析技术,具有检测速度快、准确性高、成本低廉等特点。利用多重PCR技术,结合SNaPshot分型方法,在桉树中构建SNP复合分型检测体系,促进SNP技术在桉树遗传图谱构建和无性系鉴定的应用。【方法】利用桉树已有的EST序列设计引物,通过PCR产物直接测序进行SNP标记位点的开发,利用多重PCR技术和SNaPshot分型方法建立SNP复合分型检测体系,并在尾叶桉和细叶桉作图群体的两亲本和6个F₁子代,以及16个国内常用的桉树无性系中进行分型检测。【结果】共设计合成12对SNP引物,分为3组(Ⅰ、Ⅱ、Ⅲ)建立了SNP复合分型检测体系,SNP分型情况与测序结果一致。对桉树作图群体的两个亲本和6个F₁子代的分型结果进行统计,发现12个SNP标记在6个子代中均发生了分离; 对桉树无性系进行多态性的分析,期望杂合度(H_e)为0.11～0.51、观测杂合度(H_o)为0.11～0.56,多态性信息含量(PIC)为0.10～0.37,表现为中度或低度多态性。【结论】利用多重PCR和SNaPshot技术可以快速地对桉树进行基因分型,其结果准确可靠,可以用于桉树遗传图谱的构建以及桉树无性系的鉴定等方面研究。     

Mapping and characterization of two relevance networks from SNP and gene levels

Variations of gene expression and DNA sequence are genetically associated. The goal of this study was to build genetic networks to map from SNPs to gene expressions and to characterize the two different kinds of networks. We employed mutual information to evaluate the strength of SNP–SNP and gene–gene associations based on SNPs identity by descent (IBD) data and differences of gene expressions. We applied the approach to one dataset of Genetics of Gene Expression in Humans, and discovered that both the SNP relevance network and the gene relevance network approximated the scale-free topology. We also found that 12.09% of SNP–SNP interactions matched 24.49% of gene–gene interactions, which was consistent with that of the previous studies. Finally, we identified 49 hub SNPs and 115 hub genes in their relevance networks, in which 27 hub SNPs were associated with 25 hub genes.     

The diploid genome sequence of an Asian individual

Here we present the first diploid genome sequence of an Asian individual. The genome was sequenced to 36-fold average coverage using massively parallel sequencing technology. We aligned the short reads onto the NCBI human reference genome to 99.97% coverage, and guided by the reference genome, we used uniquely mapped reads to assemble a high-quality consensus sequence for 92% of the Asian individual's genome. We identified approximately 3 million single-nucleotide polymorphisms (SNPs) inside this region, of which 13.6% were not in the dbSNP database. Genotyping analysis showed that SNP identification had high accuracy and consistency, indicating the high sequence quality of this assembly. We also carried out heterozygote phasing and haplotype prediction against HapMap CHB and JPT haplotypes (Chinese and Japanese, respectively), sequence comparison with the two available individual genomes (J. D. Watson and J. C. Venter), and structural variation identification. These variations were considered for their potential biological impact. Our sequence data and analyses demonstrate the potential usefulness of next-generation sequencing technologies for personal genomics.     

基于人行为地图的室内PIR定位方法

针对老人家庭看护中的室内定位问题,提出了一种基于人行为地图的室内热红外释电传感器(pyroelectric infrared sensor, PIR)定位方法.首先采集PIR传感器检测身体运动信号来确定人在室内的初步位置信息;利用惯性测量单元(inertial measurement unit, IMU)检测3D加速度信号识别人在室内的基本日常行为——躺、坐、站、走;利用IMU的3D加速度信号估计人的室内移动速度和方向;通过行为习惯观察,建立相应的躺、坐、站、走的行为地图;通过粒子滤波方法融合上述传感器信息,实现定位.实验结果表明,提出的方法在定位时,既保护人的隐私,也提高基于PIR传感器定位的精度及稳定性.     

Fine-scale recombination rate differences between sexes, populations and individuals

Meiotic recombinations contribute to genetic diversity by yielding new combinations of alleles. Recently, high-resolution recombination maps were inferred from high-density single-nucleotide polymorphism (SNP) data using linkage disequilibrium (LD) patterns that capture historical recombination events. The use of these maps has been demonstrated by the identification of recombination hotspots and associated motifs, and the discovery that the PRDM9 gene affects the proportion of recombinations occurring at hotspots. However, these maps provide no information about individual or sex differences. Moreover, locus-specific demographic factors like natural selection can bias LD-based estimates of recombination rate. Existing genetic maps based on family data avoid these shortcomings, but their resolution is limited by relatively few meioses and a low density of markers. Here we used genome-wide SNP data from 15,257 parent-offspring pairs to construct the first recombination maps based on directly observed recombinations with a resolution that is effective down to 10 kilobases (kb). Comparing male and female maps reveals that about 15% of hotspots in one sex are specific to that sex. Although male recombinations result in more shuffling of exons within genes, female recombinations generate more new combinations of nearby genes. We discover novel associations between recombination characteristics of individuals and variants in the PRDM9 gene and we identify new recombination hotspots. Comparisons of our maps with two LD-based maps inferred from data of HapMap populations of Utah residents with ancestry from northern and western Europe (CEU) and Yoruba in Ibadan, Nigeria (YRI) reveal population differences previously masked by noise and map differences at regions previously described as targets of natural selection.     

The physical maps for sequencing human chromosomes 1, 6, 9, 10, 13, 20 and X

We constructed maps for eight chromosomes (1, 6, 9, 10, 13, 20, X and (previously) 22), representing one-third of the genome, by building landmark maps, isolating bacterial clones and assembling contigs. By this approach, we could establish the long-range organization of the maps early in the project, and all contig extension, gap closure and problem-solving was simplified by containment within local regions. The maps currently represent more than 94% of the euchromatic (gene-containing) regions of these chromosomes in 176 contigs, and contain 96% of the chromosome-specific markers in the human gene map. By measuring the remaining gaps, we can assess chromosome length and coverage in sequenced clones.