A likelihood-based framework for variant calling and de novo mutati...
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):e1002944. doi: 10.1371/journal.pgen.1002944. Epub
2012 Oct 4.A likelihood-based framework for variant calling and de novo mutation detection in families.1, , , , , , , , .1Center for Human Genetics Research, Department of Physiology and Biophysics, Vanderbilt University, Nashville, TN, USA. bingshan.li@vanderbilt.eduAbstractFamily samples, which can be enriched for rare causal variants by focusing on families with multiple extreme individuals and which facilitate detection of de novo mutation events, provide an attractive resource for next-generation sequencing studies. Here, we describe, implement, and evaluate a likelihood-based framework for analysis of next generation sequence data in family samples. Our framework is able to identify variant sites accurately and to assign individual genotypes, and can handle de novo mutation events, increasing the sensitivity and specificity of variant calling and de novo mutation detection. Through simulations we show explicit modeling of family relationships is especially useful for analyses of low-frequency variants and that genotype accuracy increases with the number of individuals sequenced per family. Compared with the standard approach of ignoring relatedness, our methods identify and accurately genotype more variants, and have high specificity for detecting de novo mutation events. The improvement in accuracy using our methods over the standard approach is particularly pronounced for low-frequency variants. Furthermore the family-aware calling framework dramatically reduces Mendelian inconsistencies and is beneficial for family-based analysis. We hope our framework and software will facilitate continuing efforts to identify genetic factors underlying human diseases.PMID:
[PubMed - indexed for MEDLINE] PMCID: PMC3464213 A) is a 3-generation extended pedigree with numbers labeling the individual heterozygous genotype mismatch rates (%) at coverage of 15× with base quality of Q20 without mapping error and panel B) labels the corresponding mismatch rates for the standard approach of ignoring relatedness. Panel C) and D) display the heterozygous mismatch rates (%) when a fixed sequencing effort of 150× is allocated differently to family members: Panel C) is for the situation where the founders are allocated 30× while non-founders have 5× and in Panel D) founders and non-founders have coverage of 6× and 21× respectively.PLoS Genet. ):e1002944.The 4 categories are (A) overall genotypes, (B) homozygous alternative allele, (C) heterozygotes and (D) homozygous reference allele.PLoS Genet. ):e1002944.Panel A) shows the power for trios with base quality Q20 and Q30 and panel B) shows the power comparisons of trios, nuclear families with 2 and 3 siblings, and 3-generation extended pedigrees (shown in Figure 1) for base quality Q20 without mapping error.PLoS Genet. ):e1002944.PolyMutt (ignoring relatedness) and GATK calls were obtained by jointly calling a trio assuming individuals in a trio are unrelated using Polymutt and GATK respectively.PLoS Genet. ):e1002944.PLoS Genet. ):e1002944.Publication TypesMeSH TermsGrant SupportFull Text SourcesOther Literature SourcesMedical
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External link. Please review our .Whole-genome sequencing in autism identifies hot spots for de novo ...
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2012 Dec 21;151(7):1431-42. doi: 10.1016/j.cell..Whole-genome sequencing in autism identifies hot spots for de novo germline mutation.1, , , , , , , , , , , , , , , , , , , , , , , , , , , .1Beyster Center for Genomics of Psychiatric Diseases, University of California, San Diego, La Jolla, CA 92093, USA.AbstractDe novo mutation plays an important role in autism spectrum disorders (ASDs). Notably, pathogenic copy number variants (CNVs) are characterized by high mutation rates. We hypothesize that hypermutability is a property of ASD genes and may also include nucleotide-substitution hot spots. We investigated global patterns of germline mutation by whole-genome sequencing of monozygotic twins concordant for ASD and their parents. Mutation rates varied widely throughout the genome (by 100-fold) and could be explained by intrinsic characteristics of DNA sequence and chromatin structure. Dense clusters of mutations within individual genomes were attributable to compound mutation or gene conversion. Hypermutability was a characteristic of genes involved in ASD and other diseases. In addition, genes impacted by mutations in this study were associated with ASD in independent exome-sequencing data sets. Our findings suggest that regional hypermutation is a significant factor shaping patterns of genetic variation and disease risk in humans.Copyright (C) 2012 Elsevier Inc. All rights reserved.Comment inPMID:
[PubMed - indexed for MEDLINE] PMCID: PMC3712641 Data points represent the total number of autosomal DNMs detected in offspring. See also Supplemental Figure 1 and Supplemental Table 1.Cell. ;151(7):.Quantile-quantile plots of the observed distribution of inter-DNM distances within and between individuals and the expected distribution based on a random mutation model. Differences are statistically significant at α=0.05 by the KS test. See also Supplemental Figure 4 and Supplemental Table 2.Cell. ;151(7):.Predisposition to de novo mutation is influenced by sequence and chromatin characteristics. A variety of quantitative genome data were tested for associations with de novo mutation sites, including conservation, DNase hypersensitivity, GC content, histone marks, lamin B1 association, nucleosome occupancy, recombination rate, replication timing, transcription in human embryonic stem cells, simple repeats at the site of DNM, and the particular trinucleotide sequence centered at the site of DNM. The data were tested for association at different scales (i.e. window sizes at which the genome data were averaged), indicated on the x-axis. The strength and direction of association between the features and DNM are indicated by logistic regression coefficients (y-axis), which are shown with their standard errors. Significant associations (FDR & 0.10) are indicated in bold type. A summary of the relationship between these features and the principal components used in the predictive model is provided in Supplemental Figure 6. A detailed legend of the feature names and their descriptions is provided in Supplemental Table 6, and further details relating to the origin and construction of the features can be found in methods.Cell. ;151(7):.Mutability index at the site level (1 bp) is highly predictive of the mutation rate in (A) ASD genomes in this study, (B) Control genomes in Conrad et al., 2011, and in ASD cases (C) and controls (D) of previous exome studies (combined data from O’Roak et al. 2011 and 2012, Iossifov et al., 2012, Sanders et al., 2012, and Neale et al., 2012). Mutability index explains a majority of the variability in site specific mutation rates, and the degree of mutation rate variation was similar in cases and controls. CpG sites and non-CpG sites varied widely in their mutability and the range of CpG mutability overlapped considerably with the range for non-CpG sites (Supplemental Fig. 2). Mutability index was also predictive of regional mutation rates (Supplemental Fig. 3).Cell. ;151(7):.(A) The 1 kb average mutability index (MI) across a 20 Mb genomic region of chromosome 8p21–23 indicates the existence of extended regions of hypermutability. “Hotspots” (red), “warm spots” (orange) as well as “cold spots” were defined by segmenting the MI scores using a 5 state HMM (see Supplemental Table 7). Predicted mutation rates (y-axis) were computed by multiplying the arithmetic mean MI by the baseline mutation rate of 10-8, then transforming to the log10 scale. The genome- and exome-wide distributions of MI are depicted in Supplemental Figure 7. The locations of DNMs are also shown and include a dense cluster of DNMs from individual 74–0355 (red, DNMs & 100 kb apart marked by asterisk). (B) The lower panel displays segmentation results for a second genomic region at 15q11–13. This region is notable for having a high rate of recurrent structural mutation. In the same region, the predicted rate of nucleotide substitutions is highly elevated.Cell. ;151(7):.(A) Throughout the genome, we observe a correlation of hypermutability, hyperdivergence and hyperdiversity, consistent with previous studies. By contrast, in highly conserved regions the opposite trend is evident. MI and conservation were averaged in 1kb windows genome-wide. Windows were then binned according to percentiles of conservation. (B) Specifically within exons, there is a strong positive correlation of mutability and evolutionary conservation (also binned by percentiles of conservation). (C) The positive correlation between mutation rate and average exon conservation was confirmed by data from exome studies. Note that the positive relationship exists for both cases and controls. Under the null hypothesis, in which exons are hit with probability proportional to their length, this relationship is not observed.Cell. ;151(7):.Disease genes are more mutable than non-disease genes (A) within genes and (B) within exons. In both cases, mutability is highest for genes involved in dominant disorders and mutability is increased to a lesser extent for genes involved recessive and polygenic traits. Mutability is significantly elevated for genes preferentially expressed in the brain (C- D) as well as genes involved in ASD (see methods for details). An asterisk indicates a significant difference compared to the respective background set (at α=0.01 by a two-sided t-test). See also Supplemental Table 3 and Supplemental Table 4 for the mean mutability index of exons and genes, respectively.Cell. ;151(7):.Publication TypesMeSH TermsGrant SupportFull Text SourcesOther Literature SourcesMedicalMiscellaneous
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单基因杂合新生突变（heterozyous de novo mutation）引起的显性遗传疾病。 Alexander Hoischen等用Agilent Sureselect human exome kits结合SOLiD测序技术（1/4 slide）分别对无血缘关系的4名Schinzel-Giedion综合症患者的外显子组序列进行了测序，发现这4个样本在SETBP1位点均存在杂合新生突变（heterozyous de novo mutation），用Sanger法对另外8个患儿的SETBP1位点进行测序验证，亦发现该位点同时出现了突变，而所有的点突变集中于高度保守的11nt的外显子区域。 随后的研究表明Schinzel-Giedion综合症的发病机理是：SETBP1基因外显子区段高度保守的11个核苷酸（染色体位置85915bp，核苷酸）发生了杂合新生突变，该突变产生了功能获得效应（gain-of-function effect）或者说具有显性负效应（dominant-negative effective），从而引发Schinzel-Giedion综合症。而SETBP1基因突变及与Schinzel-Giedion综合症临床表型也有一定的关联。 结论： 本文首次阐明了外显子组测序技术用于检测显性孟德尔遗传病是可行的，尤其是在没有全基因组序列作为参考的时候，外显子测序技术检测这类通过功能获得效应或者显性负效应而致病的突变更为有效。而全外显子组测序能够有效发现致病基因已成功应用于隐性孟德尔遗传病Miller综合症的研究中。当然，外显子测序技术的局限在于不能检测染色体结构变异，所以作者建议将外显子测序技术与芯片检测拷贝数相结合寻找致病基因。
图1 Schinzel-Giedion综合症患儿面部特征 部分结果： 1. 全外显子组序列捕获后测序数据 2. 数据筛选 为寻找到致病SNPs突变，作者首先将上述外显子测序数据进行了筛选，随后又将测序所得SNPs结果与 NCBI dbSNP、其他研究单位最新公布的SNP数据、内部SNP数据进行了比对分析，结果发现：测序所得的&95%的SNPs已被前人报道过且不能解释该显性遗传病。接着，作者将寻找致病SNPs突变范围缩小到4个测序个体同时发生突变的12个候选基因上；最终，只有2个候选基因在4个个体的不同基因组位置上均显示出变异。这2个候选基因分别是CTBP2和SETBP1。 3. 候选基因验证 随后的研究排除了CTBP2是致病基因的可能性，因为有高度同源序列的干扰，在不同的in-house 外显子组测序中该基因显示出大量的变异。另一个候选基因是SETBP1（编码SET结合蛋白1），随后的Sanger法测序验证表明：这4个患者该基因位点均存在杂合新生突变，而这4个患者的双亲DNA均出现了该基因新生突变。 此外，作者又选取了9个临床上表现为Schinzel-Giedion综合症的个体用Sanger法进行验证，8个检测出了SETBP1基因突变，而对这8个患者的双亲DNA检测有6个亦显示出了相同的突变（作者选取的13个患者均满足Schinzel-Giedion综合症临床标准，7个来自欧洲，3个来自新西兰，1个来自澳大利亚，1个来自美国）。 4. SETBP1基因突变及其产生的效应 所有个体的突变集中于SETBP1基因高度保守的11个连续核苷酸区段（染色体位置85915bp，核苷酸），影响了4个连续氨基酸中的3个（868~871：aspartate、serine、glycine、 isoleucine）。位于cDNA上G2602A和T2612C突变分别重复4次和5次（如下表）。 SETBP1基因的突变可能产生功能获得效应（gain-of-function effect）或者说具有显性负效应（dominant-negative effective）。所谓功能获得效应（gain-of-function effect）是指基因突变使得基因产物获得了新的非正常功能。显性负效应（dominant-negative effective）是指突变型蛋白和相关蛋白形成无功能的二聚体，抑制正常蛋白（野生型蛋白）的功能。 作者得出上述结论基于以下2点：①PTPN11和SOS1基因发生了类似的突变，产生了功能获得效应并引发Noonan综合症已被报道；FGFR3基因突变产生了功能获得效应并引起软骨发育不全也已被报道。②18号染色体长臂部分缺失（影响SETBP1蛋白形成）个体的表型与Schinzel-Giedion综合症不相似。 图2 突变涉及的氨基酸残基在进化中的保守性（Asp868, Gly870, Ile871） 图3 已知及预测的SETBP1蛋白质结构域及12个Schinzel-Giedion综合症患者突变位点（星号表示）示意图 SETBP1蛋白的第815~818位氨基酸（serine、glycine、isoleucine、glycine）残基被预测是一个糖胺聚糖结合位点，而角质硫酸盐（keratan sulates）作为糖胺聚糖的一种已被报道在骨骼发育中起着重要的作用；同时注意到，骨骼畸形是Schinzel-Giedion综合症的主要特征之一。但是，SETBP1蛋白的第815~818位氨基酸残基是否发生突变及与Schinzel-Giedion综合症骨骼畸形表型之间的关系，作者未做相关讨论。 突变区同一个与致癌基因SKI同源的区域（氨基酸残基：706~917位）有重叠，这就意味着SETBP1基因可能参与调控Ski-Ski同型二聚体及/或Ski-SnoN异型二聚体的形成，而这2类二聚体参与了细胞转化过程。 在癌细胞系中曾报道过SETBP1基因表达水平高，亦有报道SETBP1基因在特异性小儿急性T细胞淋巴白血病中作为NUP98染色体易位伴侣。对于Schinzel-Giedion综合症患者来说，这是否与神经上皮瘤和骶尾部畸胎瘤高危险性相关，将有待进一步验证。 原文出处： Alexander Hoischen, Bregje W M van Bon, Christian Gilissen et al.. De novo mutations of SETBP1 cause Schinzel-Giedion syndrome, NATURE GENETICS, 2010, doi:10.1038/ng.581.扫扫二维码，随身浏览文档
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denovo[di:'n&#601;uv&#601;u]denovo 基本解释 重新, 再一次denovo 网络解释1. 重新& & 白芝浩在一个多世纪之前所指出的)与猛长一样,货币体制也在发展,它们无法也不可能重新(denovo)构建一次. 但是,正如&1873年之罪行&这一例证所说明的那样,我们可以通过不同的方式,用审慎的行动来改变或影响它,2. 断想笔记本电脑& & 猜想笔记本电脑,Cenovo | 断想笔记本电脑,Denovo | 恶想笔记本电脑,Eenovo3. 从头,再& & Deintegro,重新 | Denovo,从头,再 | Deprofundia,深处,心底的(绝望)denovo 网络例句1. Denovo has been accredited for the ISO9001 international quality system. & &本公司已通过ISO9001国际质量体系认证。2. These services include Research, Market Entry, acquisitions, denovo startups, joint ventures and comprehensive distribution capabilities. & &这些服务包括研究/调研、市场进入、并购、再次重建、合资和综合分销能力的建设等。3. Objective To evaluate and compare the outcome of patients with denovo AML in CR1 undergone Auto-HSCT or HLA-identical Allo-HSCT. & &目的对AML-CR1患者Auto-HSCT和Allo-HSCT的治疗效果进行比较。4. To better meet the needs of the broad domestic and foreign markets, provide perfect service, safeguard the rights and interests of customers and provide them with more novel and high-quality products, Denovo established a large product exhibition center at the HQs of the factory. & &为了更好地配合广阔的国内外市场需要，提供完善的服务，维护广大客户的权益，及时将更多新颖、优质的产品推介于客户，本公司在厂部设立大型的产品陈列中心。5. satisfactory curative effect can be obtained with both ta and ma regimens in denovo acute myelogenic leukemia. & &对初治的急性髓性白血病，thp为主的联合化疗方案和mit为主的联合化疗方案均可取得满意的疗效，ta方案较ma方案更为安全。6. Denovo has always kept its commitment to trend, quality, originality and service in its production of each piece of office furniture that is up to standard and high quality for its customers in the spirit of never-ending improvement. & &潮流、品质、创意、服务是帝诺一贯的承诺，精益求精的精神，为广大客户生产每一件标准优质的办公家具。7. Equipped with CAD system, Denovo can provide professional interior space planning free of charge so that customers can feel more satisfied when they arrange the partition and layout of their office space. & &本公司配备CAD电脑辅助设计，免费提供专业的室内空间规划，令客户在布置办公室空间的间隔和摆设时更感称心。从 denovo 开始单词接龙选择难度小学英语初中英语高中英语大学英语出国英语考试英语denovo是什么意思,denovo在线翻译,denovo什么意思,denovo的意思,denovo的翻译,denovo的解释,denovo的发音,denovo的同义词,denovo的反义词,denovo的例句,denovo的相关词组,denovo意思是什么,denovo怎么翻译,单词denovo是什么意思常用英语教材考试英语单词大全 (7本教材)
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