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>> PNAS:外显子变异检测&&全基因组测序比全外显子测序更强大
PNAS:外显子变异检测——全基因组测序比全外显子测序更强大
来源：生物谷
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日讯 /生物谷BIOON/ --目前，全外显子测序和全基因组测序技术在遗传分析和发现导致疾病发生的潜在基因突变方面应用越来越广泛，随着测序技术的不断迭代更新，越来越成熟，昂贵的价格会逐渐降低，那么在排除价格因素之后，全外显子测序和全基因组测序在检测外显子突变方面究竟谁更加强大呢？来自美国的科学家对这一问题进行了相关研究，其研究结果发表在著名国际学术期刊PNAS上。
研究人员指出，全外显子测序(WES)是对具有蛋白编码功能的外显子进行的测序技术，近年来全外显子测序在发现外显子基因突变方面逐渐得到广泛应用，但全基因组测序(WGS)也越来越成为发现外显子基因突变的一项非常具有吸引力的测序技术。目前，全基因组测序比全外显子测序价格昂贵，但全基因组测序的价格应该会比全外显子测序下降得更快。
研究人员利用6个无关联个体的基因组比较了全外显子测序和全基因组测序。他们对WES捕获的一段基因区域分别利用WES和WGS进行内单核苷酸突变（SNV）和小片段插入/缺失突变（indel）检测，结果显示WES检测到的SNV和小片段插入/缺失突变的平均数为84,192和13,325，而WGS检测到的平均数为84,968和12,702。研究人员对SNV和indel的coverage depth，genotype quality和minor read ratio等参数的分布进行了评估，结果发现全基因组测序的结果更加均一。研究人员发现WGS和WES两种技术能检测出绝大多数SNV和indel，但利用WGS能够检测出大约650个高质量编码基因SNV（占编码基因突变的3%左右），而利用WES则错失了这些SNV。最后，研究人员还发现利用WES检测拷贝数突变（CNV）得到的结果并不可靠。
这项研究表明，虽然目前全基因组测序的价格高于全外显子测序，但全基因组测序在检测导致疾病发生的潜在基因突变方面更加强大，尤其是SNV检测方面。（生物谷）
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Whole-genome sequencing is more powerful than whole-exome sequencing for detecting exome variants
Aziz Belkadia,b,1, Alexandre Bolzec,1,2, Yuval Itanc, Aurélie Cobata,b, Quentin B. Vincenta,b, Alexander Antipenkoc, Lei Shangc, Bertrand Boissonc, Jean-Laurent Casanovaa, and Laurent Abel
We compared whole-exome sequencing (WES) and whole-genome sequencing (WGS) in six unrelated individuals. In the regions targeted by WES capture (81.5% of the consensus coding genome), the mean numbers of single-nucleotide variants (SNVs) and small insertions/deletions (indels) detected per sample were 84,192 and 13,325, respectively, for WES, and 84,968 and 12,702, respectively, for WGS. For both SNVs and indels, the distributions of coverage depth, genotype quality, and minor read ratio were more uniform for WGS than for WES. After filtering, a mean of 74,398 (95.3%) high-quality (HQ) SNVs and 9,033 (70.6%) HQ indels were called by both platforms. A mean of 105 coding HQ SNVs and 32 indels was identified exclusively by WES whereas 692 HQ SNVs and 105 indels were identified exclusively by WGS. We Sanger-sequenced a random selection of these exclusive variants. For SNVs, the proportion of false-positive variants was higher for WES (78%) than for WGS (17%). The estimated mean number of real coding SNVs (656 variants, ?3% of all coding HQ SNVs) identified by WGS and missed by WES was greater than the number of SNVs identified by WES and missed by WGS (26 variants). For indels, the proportions of false-positive variants were similar for WES (44%) and WGS (46%). Finally, WES was not reliable for the detection of copy-number variations, almost all of which extended beyond the targeted regions. Although currently more expensive, WGS is more powerful than WES for detecting potential disease-causing mutations within WES regions, particularly those due to SNVs.
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Copyright&2001- 版权所有 不得转载.三岱测庄拉本狸处显王撞菝拉本查遗笾痘；基因途断史．盥座用砑究；论文作者签名：魏越．；指导教师签名：兰Ｅ堡：；沦文评阅人１：扬月红∑副教授∑浙江太堂医堂院；评阅入２：王剑勇∑副圭焦医瘟∑泣江太堂隘属簋二匡；评阅人３：盆红∑副主鱼医垣∑拉划ｉ土生委指昱堑；答辩委员会主席：；委员１：；委员２：金扭∑数控∑浙江太堂隘屉妇亡叠医院吕吐丝；浙江大学研究生学位论文独创性声
三岱测庄拉本狸处显王撞菝拉本查遗笾痘
基因途断史．盥座用砑究
论文作者签名：魏越．
指导教师签名：兰Ｅ堡：
沦文评阅人１：扬月红∑副教授∑浙江太堂医堂院
评阅入２：王剑勇∑副圭焦医瘟∑泣江太堂隘属簋二匡院
评阅人３：盆红∑副主鱼医垣∑拉划ｉ土生委指昱堑
答辩委员会主席：
委员２：金扭∑数控∑浙江太堂隘屉妇亡叠医院吕吐丝∑敛授∑浙江太堂附属妲亡型医院芒庆主∑教授∑浙江太堂生佥叠堂堂院
浙江大学研究生学位论文独创性声明
本人声明所呈交的学位论文是本人在导师指导下进行的研究工作及取得的研究成果。除了文中特别加以标注和致谢的地方外，论文中不包含其他人已经发表或撰写过的研究成果，也不包含为获得滥姿态堂或其他教育机构的学位或证书而使用过的材料。与我一同工作的同志对本研究所做的任何贡献均已在论文中作了明确的说明并表示谢意。
学位论文作者签名：趣吹鞭签字日期：妣年弓月歹日
学位论文版权使用授权书
本学位论文作者完全了解．盥婆太堂有权保留并向国家有关部门或机构送交本论文的复印件和磁盘，允许论文被查阅和借阅。本人授权浙姿盘鲎可以将学位论文的全部或部分内容编入有关数据库进行检索和传播，可以采用影印、缩印或扫描等复制手段保存、汇编学位论文。
（保密的学位论文在解密后适用本授权书）
学位论文作者签名：爱蚕乏缎
签字日期：导师签名：∥ｒ≮≥新签名：咖岱签字日期：２护膨年３月３＂－日加摩年乡月夕日
浙江太生殛±堂位论文兹进
时光匆匆，转眼即逝，两年半的硕士研究生生涯很快就要结束。在我的毕业论文即将完成之际，我的心情十分复杂，想起在我读研期间给予我莫大帮助的老师、同学和朋友们，我想由衷的对他们表示我的感激之情。
首先，我要感谢我的导师祁鸣教授，祁老师在学术上一丝不苟的作风，求是创新的态度，以及博大精深的知识都给了我深远的影响。祁老师不仅仅教给了我大量的遗传学知识，也教给了我为人处世的经验，是值得我学习的好榜样。
感谢俞萍老师，这篇论文里每个实验过程，每一组实验数据都离不开俞老师手把手的悉心教导，是俞老师让我从一个什么都不懂的新生变成了一个掌握了多项实验技术的硕士研究生。在生活上，俞老师也给了我很大的关心，让我在实验室的时光里充满了欢乐，感受到了像家一样的温馨融洽。
感谢李晨老师，谢谢李老师这两年对我的关心和鼓励。李老师不仅是我的老师，更像是我的知心朋友，在各个方面都给了我很大的鼓励，真的很开心有这样一位老师。
另外，我还要感谢实验室的师兄、师姐、师弟、师妹，丛培宽、张婷、周忠位、陈姣、杨玲琳、吴谦、翁琛、ＳａｎｔａｓｒｅｅＢａｎｅｒｊｅｅ、ＪｏｓｅｐｈＫａｇｕｎｄａ、乐芳、王丽雅、潘佩佩、郑英明。谢谢大家平时对我的关心和鼓励，陪伴我度过了这短暂的研究生时光。还有实验室的工作人员，卢玲萍、雍晶和沈晴虹，谢谢你们给我的指导和帮助。
最后，我要感谢我的爸爸妈妈，是您们给了我生命，给了我现在的生活。您们的期望和支持是我不懈奋斗的动力，你们的健康快乐是我最大的心愿。
总之，没有你们的支持和帮助就没有今天的我，在此对你们表示我最真挚的感谢，谢谢你们！
逝翌太堂亟±望位论塞生塞摘墨二代测序技术和外显子捕获技术在遗传病基因诊断中
的应用研究
浙江大学医学院遗传学
硕士研究生魏天颖
导师祁鸣教授
引起遗传性疾病的分子机制有多种，常见的有点突变、小片段插入／缺失突变、拼接位点突变、外显子缺失／重复突变、基因重复和复杂重排及基因拷贝数异常等。作为一种重要的分子生物学分析方法，ＤＮＡ测序技术也被广泛应用于基因检测和遗传病诊断等方面。临床上通过ＤＮＡ测序技术，可以检测出大部分的点突变及部分小片段的插入／缺失突变．但由于遗传病的遗传异质性和较大片段的基因，传统的Ｓａｎｇｅｒ测序技术已经远远不能满足医学研究及临床应用的需要。新一代测序技术应运而生，由于其费用更低、速度更快，并且可以同时分析大量样本而得到广泛的应用。
外显子捕获（ｅｘｏｎｔｒａｐｐｉｎｇ）技术是遗传病剪接位点突变实验验证的有效工具。对可能引起可变剪接的突变，通过外显子捕获技术，不仅可以获得准确的诊断结果，并且可以对致病机制进一步研究。虽然目前已经有多种预测软件可以对突变位点进行剪接改变预测，但预测结果是否准确还需要进一步证实。因此，在进行临床诊断时，对可能引起剪接改变的突变同时应用外显子捕获技术及软件预测分析可以取得更准确的检测结果。
本研究对１６ｐｌ１．２微缺失综合征，Ｌｅｂｅｒ先天性黑蒙症（Ｌｅｂｅｒ’ｓ
ＩＩｃｏｎｇｅｎｉｔａｌ
逝江太堂亟±堂位ｉ金奎生文摘要ａｍａｕｒｏｓｉｓ，ＬＣＡ）和ｘ连锁无汗性外胚层发育不良（Ｘ．１ｉｎｋｅｄｈｙｐｏｈｉｄｒｏｔｉｃｅｃｔｏｄｅｒｍａｌｄｙｓｐｌａｓｉａ，ＸＬＨＥＤ）的三例样本分别应用二代测序技术及外显子捕获技术进行了检测分析和研究，证实这两种技术在遗传病诊断中的应用价值及不足之处，在实际应用时还需其他技术手段进行辅助分析。
关键词：二代测序技术；外显子捕获技术；拼接位点突变；实时荧光定量ＰＣＲ；１６ｐｌ１．２微缺失综合征；Ｌｅｂｅｒ先天性黑蒙症；Ｘ连锁无汗性外胚层发育不良ＩＩＩ
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　外显子组测序(Exome sequencing)是指利用序列捕获 技术将全基因组外显子区域 ...确定孟德尔遗传疾病相关外显子 SNP 位点和基因; 3)在癌症研究过程中,检测癌症... 　我国基因测序技术研究报告 1 三代测序技术简介从 ...目前是 10G 左右,但非常适合小基因组和外显子验证...新一代测序技术结合序 列捕获技术,可以对上百种单... 　外显子组测序是指利用序列捕获技术将全基因组外显子区域 DNA 捕捉并富集后进行高通量 测序的基因组分析方法。 外显子测序相对于基因组重测序成本较低, 对研究... 　基因组学研究(测序和注释)以及功能基因组学 (基因...科学界也开始越来越多地应用 第二代测序技术来解决...和 Nimblegen ,应用最多的是人全外显子组捕获测序... 　测序技术临床应用试点单位, 此前两家获得二代测序 注册证的华大基因和达安基因...应用试点共分 3 个专业,分别为遗传病诊断、产前筛 查与诊断、植入前胚胎遗传... 　此类检测试剂涉及的 NGS 技术 包括靶向性测序和非靶向性测序: 靶向性测序法是指对样本中的基因 组进行部分测序,如靶基因测序、外显子(组)测序等;非靶向性测 ... 　二代测序技术:next generation sequencing(NGS)又称...外显子组测序:是指利用序列捕获技术将全基因组外显...Metagenome,指特定生活环境中全部微小生物遗传物质的... 　人们大量遗传信息的同时,却成为限制其广泛应用的一个...测序技术的短小 基因片段进行组合,形成基因组外显子...但是使用最新的纳米孔捕获及再捕获技术对长基因片段... 　第十三章 遗传病的诊断 遗传疾病的诊断是一项复杂的...7.了解基因诊断技术的应用。 二、习题 (一)选择题...外显子 9-10 C. DNA 测序 C. RFLP 连锁分析 ...全外显子测序
标准信息分析
去除接头污染和低质量数据
比对、数据统计
SNP 变异信息检测、注释、 分析和统计
InDel 变异信息检测、注释、分析和统计
高级信息分析（针对人类样本）
非编码区SNP注释分析（ENCODE注释）
分编码区InDel注释分析（ENCODE注释）
肿瘤高级分析
成对样本（normal-tumor）Somatic SNP/InDel检测、注释及统计
成对样品肿瘤外显子CNV检测（ExomeCNV）及注释
成对样本（normal-tumor）SNV检测、注释及预测
影响氨基酸改变的突变基因的CancerGeneCensus数据库注释分析
复杂疾病高级分析
群体SNP检测和Genotype分型检测
SNP注释与统计
群体SNP质控
基于单个SNP的关联分析
群体进化高级信息分析
群体SNP检测和Genotype分型检测
SNP注释与统计（包含OMIM 注释）
群体SNP质控
基于遗传数据的样本质控：亲缘关系检测，基于近交系数的样本污染检测
群体结构分析，主成分分析和系统发育树构建
选择分析、通路分析、单体型分析
单基因病高级分析
考察可能影响功能原件的变异
筛选出的突变与已知数据库的注释和过滤
Case共有的突变筛选
SIFT 保守性预测
筛选出的基因GO、KEGG代谢通路注释
注：4、5、6、7条原则上只提供给合作项目。
定制化信息分析（针对人类样本）
复杂疾病定制化分析
配对分析（尤其适合只有Case无Control的研究或群体内部有分层现象）
Gene-based的关联分析（cmc，skat-o，wss，kbac，collapse）
候选基因优化
候选SNP的条件分析
候选位点附近的LD分析及基于单体型域的单体型关联分析
GO功能分类，以及GO/KEGG功能富集分析
基于代谢通路的交互分析（2交互或者多交互）
ROC曲线与遗传方差解释
群体CNV检测，注释与统计
CNV关联分析(Merge & Split)
注：本定制化分析适用于大样本量，建议至少200对case & control以上
基于家系样本的de novo mutation分析
De novo SNV检测、注释与统计
De novo Indel检测、注释与统计
注：以下条款适用于多个家系，建议至少30 trios或10-20 quads以上
De novo SNV，Indel与疾病的关联分析
基因间的功能分析，包括GO分析，pathway分析，以及蛋白关联分析
De novo SNV突变父母来源判断
基因组特异区间突变率分析
基因碱基替换比例及特性分析
Far far away, behind the word mountains, far from the countries Vokalia and Consonantia, there live the blind texts. Separated they live in Bookmarksgrove right at the coast of the Semantics, a large language ocean. A small river named Duden flows by their place and supplies it with the necessary regelialia. It is a paradisematic country, in which roasted parts of sentences fly into your mouth.
WeHealthGene Co., Ltd.| All rights reserved.Immugendx 分子检测服务
高通量测序技术服务方案
生物芯片数据分析方案
蛋白质组数据分析方案
表观遗传学
宏基因组学
数据库网站
靶向捕获测序服务
靶向捕获测序服务
采用Hiseq2500高通量测序仪，准确高效产出基因组数据
外显子组测序主要用于识别和研究与疾病、种群进化相关的编码区及UTR区域内的结构变异。结合大量的公共数据库提供的外显子数据，有利于更好地解释所得
变异结构之间的关联和致病机理。目前，外显子组测序已广泛用于单基因病（孟德尔疾病）、癌症等复杂疾病的研究，成为鉴定致
高通量测序服务介绍
全外显子组重测序
显子组测序（exome&sequencing）是利用芯片或探针杂交富集外显子DNA序列，然后进行高通量测序的方法。由于疾病相关的突变大部分集中在
蛋白编码序列（开放读码框），且外显子只占基因组大小的1%，因此外显子组测序能够、较经济地、针对性地对基因区域进行扫描，鉴定外显子上与疾病相关的碱
基变异。该方法能够获得指定外显子捕获平台探针设计区域及侧翼200bp序列的遗传信息，极大地提高了人类基因组中外显子区域的研究效率，显著降低了研究
外显子组测序主要用于识别和研究与疾病、种群进化相关的编码区及UTR区域内的结构变异。结合大量的公共数据库
提供的外显子数据，有利于更好地解释所得变异结构之间的关联和致病机理。目前，外显子组测序已广泛用于单基因病（孟德尔疾病）、癌症等复杂疾病的研究，成
为鉴定致病突变、揭示疾病发生机制、提供诊断治疗参考的重要工具。&
我们的优势
拥有标准化操作实验室和高通量测序技术平台，实验周期短，质量可靠。
拥有Illumina HiSeq 2500、MiSeq等多种高通量测序平台。
技术人员经验丰富，可以根据合作伙伴要求提供实验方案、解决实验问题、分析实验结果。
拥有专业的生物信息团队和超算服务器，可为合作伙伴提供全面生物信息分析服务与技术支持。
外显子组重测序技术服务流程
1. 样品要求
总量：≥&2.5&µg&DNA，最低样本量低至1µg&DNA；
浓度：≥&37.5&ng/µL；
纯度：OD260/280=1.8-2.0。
2. 测序策略
(1)&HiSeq&测序平台，PE&2X101；
(2)&推荐每个样本测序深度≥&50~100X。
3. 项目执行周期
按标准流程（不包括高级信息分析），100个样本，平均深度50X的外显子测序项目，运转周期约为40个工作日；
样本数量更多时，项目的运转周期根据项目的规模而定。
4. 技术合格指标
有效平均测序深度不低于合同的规定。
AmpliconSeq 扩增子MiSeq测序
很多复杂性疾病与MHC区域有关。本方案针对MHC区域设计靶向捕获测序，结合生物信息分析解析复杂疾病关联位点，包括HLA单倍型分析和氨基酸等位基因关联分析
癌症基因组学
单基因遗传病
复杂性状与疾病
Ancestry and pharmacogenomics of relapse in acute lymphoblastic leukemia.
Nat Genet. ):237-41. doi: 10.1038/ng.763. Epub 2011 Feb 6.
Although five-year survival rates for childhood&acute
lymphoblastic leukemia&(ALL) are now over 80% in most industrialized
countries, not all children have benefited equally from this progress.
Ethnic differences in survival after childhood ALL have been reported in
many clinical studies, with poorer survival observed among African
Americans or those with Hispanic ethnicity when compared with European
Americans or Asians. The causes of ethnic differences remain uncertain,
although both genetic and non-genetic factors are likely important.
Interrogating genome-wide germline SNP genotypes in an unselected large
cohort of children with ALL, we observed that the component of genomic
variation that co-segregated with Native American&ancestry&was
associated with risk of&relapse&(P = 0.0029) even after adjusting for
known prognostic factors (P = 0.017).&Ancestry-related differences
in&relapse&risk were abrogated by the addition of a single extra phase
of chemotherapy, indicating that modifications to therapy can mitigate
the&ancestry-related risk of&relapse.
The genetic basis of early T-cell precursor acute lymphoblastic leukaemia.
Nature. 2012 Jan 11;481(. doi: 10.1038/nature10725.
Early T-cell precursor acute lymphoblastic leukaemia (ETP ALL) is
an aggressive malignancy of unknown genetic basis. We performed
whole-genome sequencing of 12 ETP ALL cases and assessed the frequency
of the identified somatic mutations in 94 T-cell acute lymphoblastic
leukaemia cases. ETP ALL was characterized by activating mutations
in&genes&regulating cytokine receptor and RAS signalling (67%
NRAS, KRAS, FLT3, IL7R, JAK3, JAK1, SH2B3 and BRAF), inactivating
lesions disrupting haematopoietic development (58%; GATA3, ETV6, RUNX1,
IKZF1 and EP300) and histone-modifying&genes&(48%; EZH2, EED, SUZ12,
SETD2 and EP300). We also identified new targets of recurrent mutation
including DNM2, ECT2L and RELN. The&mutational&spectrum is similar to
myeloid tumours, and moreover, the global transcriptional profile of ETP
ALL was similar to that of normal and myeloid leukaemia haematopoietic
stem cells. These findings suggest that addition of myeloid-directed
therapies might improve the poor outcome of ETP ALL.
急性骨髓性白血病（acute myeloid leukaemia）
Clonal evolution in relapsed acute myeloid leukaemia revealed by whole-genome sequencing.
Nature. 2012 Jan 11;481(. doi: 10.1038/nature10738.
Most patients with&acute myeloid leukaemia&(AML) die from
progressive disease after relapse, which is associated with&clonal
evolution&at the cytogenetic level. To determine the mutational spectrum
associated with relapse, we sequenced the primary tumour and relapse
genomes from eight AML patients, and validated hundreds of somatic
mutations using deep& this allowed us to define clonality
and&clonal evolution&patterns precisely at relapse. In addition to
discovering novel, recurrently mutated genes (for example, WAC, SMC3,
DIS3, DDX41 and DAXX) in AML, we also found two major&clonal
evolution&patterns during AML relapse: (1) the founding clone in the
primary tumour gained mutations and evolved into the relapse clone, or
(2) a subclone of the founding clone survived initial therapy, gained
additional mutations and expanded at relapse. In all cases, chemotherapy
failed to eradicate the founding clone. The comparison of
relapse-specific versus primary tumour mutations in all eight
cases&revealed&an increase in transversions, probably due to DNA damage
caused by cytotoxic chemotherapy. These data demonstrate that AML
relapse is associated with the addition of new mutations and&clonal
evolution, which is shaped, in part, by the chemotherapy that the
patients receive to establish and maintain remissions.
DNA sequencing of a cytogenetically normal acute myeloid leukaemia genome.
Nature. 2008 Nov 6;456(. doi: 10.1038/nature07485.
Acute myeloid leukaemia&is a highly malignant haematopoietic
tumour that affects about 13,000 adults in the United States each year.
The treatment of this disease has changed little in the past two
decades, because most of the genetic events that initiate the disease
remain undiscovered. Whole-genome sequencing&is now possible at a
reasonable cost and timeframe to use this approach for the unbiased
discovery of tumour-specific somatic mutations that alter the
protein-coding genes. Here we present the results obtained
from&sequencing&a typical&acute myeloid leukaemia&genome, and its
matched&normalcounterpart obtained from the same patient's skin. We
discovered ten genes wit two were previously
described mutations that are thought to contribute to tumour
progression, and eight were new mutations present in virtually all
tumour cells at presentation and relapse, the function of which is not
yet known. Our study establishes whole-genome&sequencing&as an unbiased
method for discovering cancer-initiating mutations in previously
unidentified genes that may respond to targeted therapies.
Recurring mutations found by sequencing an acute myeloid leukemia genome.
N Engl J Med. 2009 Sep 10;361(11):1058-66. doi: 10.1056/NEJMoa0903840. Epub 2009 Aug 5.
BACKGROUND:
The full complement of DNA mutations that are responsible for the
pathogenesis of acute myeloid leukemia (AML) is not yet known.
We used massively parallel DNA sequencing to obtain a very high
level of coverage (approximately 98%) of a primary, cytogenetically
normal, de novo genome for AML with minimal maturation (AML-M1) and a
matched normal skin genome.
We identified 12 acquired (somatic) mutations within the coding
sequences of genes and 52 somatic point mutations in conserved or
regulatory portions of the genome. All mutations appeared to be
heterozygous and present in nearly all cells in the tumor sample. Four
of the 64 mutations occurred in at least 1 additional AML sample in 188
samples that were tested. Mutations in NRAS and NPM1 had been identified
previously in patients with AML, but two other mutations had not been
identified. One of these mutations, in the IDH1 gene, was present in 15
of 187 additional AML genomes tested and was strongly associated with
norma it was present in 13 of 80 cytogenetically
normal samples (16%). The other was a nongenic mutation in a genomic
region with regulatory potential and conservati we
detected it in one additional AML tumor. The AML genome that we
sequenced contains approximately 750 point mutations, of which only a
small fraction are likely to be relevant to pathogenesis.
CONCLUSIONS:
By comparing the sequences of tumor and skin genomes of a patient
with AML-M1, we have identified recurring mutations that may be relevant
for pathogenesis.
乳腺癌（breast cancer）
Genome remodelling in a basal-like breast cancer metastasis and xenograft.
Nature. 2010 Apr 15;464(05. doi: 10.1038/nature08989.
Massively parallel DNA sequencing technologies provide an
unprecedented ability to screen entire genomes for genetic changes
associated with tumour progression. Here we describe the genomic
analyses of four DNA samples from an African-American patient
with&basal-like&breast&cancer: peripheral blood, the primary tumour, a
brain&metastasis&and a&xenograft&derived from the primary tumour.
The&metastasis&contained two de novo mutations and a large deletion not
present in the primary tumour, and was significantly enriched for 20
shared mutations. The&xenograft&retained all primary tumour mutations
and displayed a mutation enrichment pattern that resembled
the&metastasis. Two overlapping large deletions, encompassing CTNNA1,
were present in all three tumour samples. The differential mutation
frequencies and structural variation patterns
in&metastasis&and&xenograft&compared with the primary tumour indicate
that secondary tumours may arise from a minority of cells within the
primary tumour.
Inferring tumor progression from genomic heterogeneity.
Genome Res. ):68-80. doi: 10.1101/gr.. Epub 2009 Nov 10.
Cancer&progression&in humans is difficult to infer because we do
not routinely sample patients at multiple stages of their&disease.
However, heterogeneous breast tumors provide a unique opportunity to
study human&tumor&progression&because they still contain evidence of
early and intermediate subpopulations in the form of the phylogenetic
relationships. We have developed a method we call
Sector-Ploidy-Profiling (SPP) to study the clonal composition of breast
tumors. SPP involves macro-dissecting tumors,
flow-sorting&genomic&subpopulations by DNA content, and profiling
genomes using comparative&genomichybridization (CGH). Breast carcinomas
display two classes of&genomic&structural variation: (1) monogenomic and
(2) polygenomic. Monogenomic tumors appear to contain a single major
clonal subpopulation with a highly stable chromosome structure.
Polygenomic tumors contain multiple clonal&tumorsubpopulations, which
may occupy the same sectors, or separate anatomic locations. In
polygenomic tumors, we show that&heterogeneity&can be ascribed to a few
clonal subpopulations, rather than a series of gradual intermediates. By
comparing multiple subpopulations from different anatomic locations, we
have inferred pathways of cancer&progression&and the organization
of&tumor&growth.
The landscape of cancer genes and mutational processes in breast cancer.
Nature. 2012 May 16;486(. doi: 10.1038/nature11017.
All cancers carry somatic mutations in their genomes. A subset,
known as driver mutations, confer clonal selective advantage
on&cancer&cells and are causally implicated in oncogenesis, and the
remainder are passenger mutations. The driver mutations
and&mutational&processes&operative in&breast cancer&have not yet been
comprehensively explored. Here we examine the genomes of 100 tumours for
somatic copy number changes and mutations in the coding exons of
protein-coding&genes. The number of somatic mutations varied markedly
between individual tumours. We found strong correlations between
mutation number, age at which&cancer&was diagnosed
and&cancer&histological grade, and observed
multiple&mutationalsignatures, including one present in about ten per
cent of tumours characterized by numerous mutations of cytosine at TpC
dinucleotides. Driver mutations were identified in several new&cancer
genes&including AKT2, ARID1B, CASP8, CDKN1B, MAP3K1, MAP3K13, NCOR1,
SMARCD1 and TBX3. Among the 100 tumours, we found driver mutations in at
least 40&cancer genes&and 73 different combinations of mutated&cancer
genes. The results highlight the substantial genetic diversity
underlying this common disease.
软骨肉瘤（chondrosarcoma）
Frequent mutation of the major cartilage collagen gene COL2A1 in chondrosarcoma.
Nat Genet. ):923-6. doi: 10.1038/ng.2668. Epub 2013 Jun 16.
Chondrosarcoma&is a heterogeneous collection of malignant bone
tumors and is the second most common primary malignancy of bone after
osteosarcoma. Recent work has identified&frequent, recurrent mutations
in IDH1 or IDH2 in nearly half of central chondrosarcomas. However,
there has been little systematic genomic analysis of this tumor type,
and, thus, the contribution of other genes is unclear. Here we report
comprehensive genomic analyses of 49 individuals
with&chondrosarcoma&(cases). We identified hypermutability of
the&major&cartilage&collagen&gene&COL2A1, with insertions, deletions and
rearrangements identified in 37% of cases. The patterns
of&mutation&were consistent with selection for variants likely to impair
normal&collagen&biosynthesis. In addition, we identified mutations in
IDH1 or IDH2 (59%), TP53 (20%), the RB1 pathway (33%) and Hedgehog
signaling (18%).
子宫内膜癌 (endometrial carcinoma)
Integrated genomic characterization of endometrial carcinoma.
Nature. 2013 May 2;497(. doi: 10.1038/nature12113.
We performed an&integrated&genomic, transcriptomic and
proteomic&characterization&of 373&endometrial&carcinomas using array-
and sequencing-based technologies. Uterine serous tumours and ∼25% of
high-grade endometrioid tumours had extensive copy number alterations,
few DNA methylation changes, low oestrogen receptor/progesterone
receptor levels, and frequent TP53 mutations. Most endometrioid tumours
had few copy number alterations or TP53 mutations, but frequent
mutations in PTEN, CTNNB1, PIK3CA, ARID1A and KRAS and novel mutations
in the SWI/SNF chromatin remodelling complex gene ARID5B. A subset of
endometrioid tumours that we identified had a markedly increased
transversion mutation frequency and newly identified hotspot mutations
in POLE. Our results classified&endometrial&cancers into four
categories: POLE ultramutated, microsatellite instability hypermutated,
copy-number low, and copy-number high. Uterine serous carcinomas
share&genomic&features with ovarian serous and basal-like breast
carcinomas. We demonstrated that the&genomic&features
of&endometrial&carcinomas permit a reclassification that may affect
post-surgical adjuvant treatment for women with aggressive tumours.
胶质母细胞瘤(glioblastoma)
Hotspot mutations in H3F3A and IDH1 define distinct epigenetic and biological subgroups of glioblastoma.
Cancer Cell. 2012 Oct 16;22(4):425-37. doi: 10.1016/j.ccr..
Glioblastoma&(GBM) is a brain tumor that carries a dismal
prognosis and displays considerable heterogeneity. We have recently
identified recurrentH3F3A&mutations&affecting two critical amino acids
(K27 and G34) of histone H3.3 in one-third of pediatric GBM. Here, we
show that each&H3F3Amutation defines an&epigenetic&subgroup of GBM with
a&distinct&global methylation pattern, and that they are mutually
exclusive with&IDH1&mutations, which characterize a third
mutation-defined subgroup. Three further&epigenetic&subgroups&were
enriched for hallmark genetic events of adult GBM and/or established
transcriptomic signatures. We also demonstrate that the
two&H3F3A&mutations&give rise to GBMs in separate anatomic compartments,
with differential regulation of transcription factors OLIG1, OLIG2, and
FOXG1, possibly reflecting different cellular origins.
髓母细胞瘤(medulloblastoma)
Novel mutations target distinct subgroups of medulloblastoma.
Nature. 2012 Aug 2;488(. doi: 10.1038/nature11213.
Medulloblastoma&is a malignant childhood brain tumour comprising
four discrete&subgroups. Here, to identify&mutations&that
drive&medulloblastoma, we sequenced the entire genomes of 37 tumours and
matched normal blood. One-hundred and thirty-six genes harbouring
somatic&mutations&in this discovery set were sequenced in an additional
56 medulloblastomas. Recurrent&mutations&were detected in 41 genes not
yet implicat several&target&distinct&components of
the epigenetic machinery in different disease&subgroups, such as
regulators of H3K27 and H3K4 trimethylation in&subgroups&3 and 4 (for
example, KDM6A and ZMYM3), and CTNNB1-associated chromatin re-modellers
in WNT-subgroup tumours (for example, SMARCA4 and CREBBP). Modelling
of&mutations&in mouse lower rhombic lip progenitors that generate
WNT-subgroup tumours identified genes that maintain this cell lineage
(DDX3X), as well as mutated genes that initiate (CDH1) or cooperate
(PIK3CA) in tumorigenesis. These data provide important new insights
into the pathogenesis of&medulloblastoma&subgroups&and highlight targets
for therapeutic development.
The genetic landscape of the childhood cancer medulloblastoma.
Science. 2011 Jan 28;331(. doi: 10.1126/science.1198056. Epub 2010 Dec 16.
Medulloblastoma&(MB) is the most common malignant brain tumor of
children. To identify the&genetic&alterations in this tumor type, we
searched for copy number alterations using high-density microarrays and
sequenced all known protein-coding genes and microRNA genes using Sanger
sequencing in a set of 22 MBs. We found that, on average, each tumor
had 11 gene alterations, fewer by a factor of 5 to 10 than in the adult
solid tumors that have been sequenced to date. In addition to
alterations in the Hedgehog and Wnt pathways, our analysis led to the
discovery of genes not previously known to be altered in MBs. Most
notably, inactivating mutations of the histone-lysine
N-methyltransferase genes MLL2 or MLL3 were identified in 16% of MB
patients. These results demonstrate key differences between
the&genetic&landscapes of adult and&childhood&cancers, highlight
dysregulation of developmental pathways as an important mechanism
underlying MBs, and identify a role for a specific type of histone
methylation in human tumorigenesis.
Pancreatic cancer genomes reveal aberrations in axon guidance pathway genes.
Nature. 2012 Nov 15;491(5. doi: 10.1038/nature11547. Epub 2012 Oct 24.
Pancreatic cancer&is a highly lethal malignancy with few
effective therapies. We performed exome sequencing and copy number
analysis to define genomic&aberrations&in a prospectively accrued
clinical cohort (n = 142) of early (stage I and II)
sporadic&pancreatic&ductal adenocarcinoma. Detailed analysis of 99
informative tumours identified substantial heterogeneity with 2,016
non-silent mutations and 1,628 copy-number variations. We define 16
significantly mutated&genes, reaffirming known mutations (KRAS, TP53,
CDKN2A, SMAD4, MLL3, TGFBR2, ARID1A and SF3B1), and uncover novel
mutated&genes&including additional&genes&involved in chromatin
modification (EPC1 and ARID2), DNA damage repair (ATM) and other
mechanisms (ZIM2, MAP2K4, NALCN, SLC16A4 and MAGEA6). Integrative
analysis with in vitro functional data and animal models provided
supportive evidence for potential roles for these genetic&aberrations&in
carcinogenesis.&Pathway-based analysis of recurrently
mutated&genesrecapitulated clustering in core signalling pathways
in&pancreatic&ductal adenocarcinoma, and identified new mutated&genes&in
each&pathway. We also identified frequent and diverse
somatic&aberrations&in&genes&described traditionally as embryonic
regulators of axon guidance, particularly SLIT/ROBO signalling, which
was also evident in murine Sleeping Beauty transposon-mediated somatic
mutagenesis models of&pancreatic cancer, providing further supportive
evidence for the potential involvement of axon
guidance&genes&in&pancreatic&carcinogenesis.
Publications
Nat Genet. ):260-3. doi: 10.1038/ng.515. Epub 2010 Jan 24.
A powerful way to map functional genomic variation and reveal the
genetic basis of local adaptation is to associate allele frequency
across the genome with environmental conditions. Serpentine soils,
characterized by high heavy-metal content and low calcium-to-magnesium
ratios, are a classic context for studying adaptation of plants to local
soil conditions. To investigate whether Arabidopsis lyrata is locally
adapted to serpentine soil, and to map the polymorphisms responsible for
such adaptation, we pooled DNA from individuals from serpentine and
nonserpentine soils and sequenced each 'gene pool' with the Illumina
Genome Analyzer. The polymorphisms that are most strongly associated
with soil type are enriched at heavy-metal detoxification and calcium
and magnesium transport loci, providing numerous candidate mutations for
serpentine adaptation. Sequencing of three candidate loci in the
European subspecies of A. lyrata indicates parallel differentiation of
the same polymorphism at one locus, confirming ecological adaptation,
and different polymorphisms at two other loci, which may indicate
convergent evolution.
Nat Genet. ):159-62. doi: 10.1038/ng.746. Epub 2011 Jan 9.
US maize yield has increased eight-fold in the past 80 years, with
half of the gain attributed to selection by breeders. During this time,
changes in maize leaf angle and size have altered plant architecture,
allowing more efficient light capture as planting density has increased.
Through a genome-wide association study (GWAS) of the maize nested
association mapping panel, we determined the genetic basis of important
leaf architecture traits and identified some of the key genes. Overall,
we demonstrate that the genetic architecture of the leaf traits is
dominated by small effects, with little epistasis, environmental
interaction or pleiotropy. In particular, GWAS results show that
variations at the liguleless genes have contributed to more upright
leaves. These results demonstrate that the use of GWAS with specially
designed mapping populations is effective in uncovering the basis of key
agronomic traits.
Nat Genet. ):163-8. doi: 10.1038/ng.747. Epub 2011 Jan 9.
Nested association mapping (NAM) offers power to resolve complex,
quantitative traits to their causal loci. The maize NAM population,
consisting of 5,000 recombinant inbred lines (RILs) from 25 families
representing the global diversity of maize, was evaluated for resistance
to southern leaf blight (SLB) disease. Joint-linkage analysis
identified 32 quantitative trait loci (QTLs) with predominantly small,
additive effects on SLB resistance. Genome-wide association tests of
maize HapMap SNPs were conducted by imputing founder SNP genotypes onto
the NAM RILs. SNPs both within and outside of QTL intervals were
associated with variation for SLB resistance. Many of these SNPs were
within or near sequences homologous to genes previously shown to be
involved in plant disease resistance. Limited linkage disequilibrium was
observed around some SNPs associated with SLB resistance, indicating
that the maize NAM population enables high-resolution mapping of some
genome regions.
Nat Genet. ):1027-30. doi: 10.1038/ng.684. Epub 2010 Oct 24.
We have resequenced a group of six elite maize inbred lines,
including the parents of the most productive commercial hybrid in China.
This effort uncovered more than 1,000,000 SNPs, 30,000 indel
polymorphisms and 101 low-sequence-diversity chromosomal intervals in
the maize genome. We also identified several hundred complete genes that
show presence/absence variation among these resequenced lines. We
discuss the potential roles of complementation of presence/absence
variations and other deleterious mutations in contributing to heterosis.
High-density SNP and indel polymorphism markers reported here are
expected to be a valuable resource for future genetic studies and the
molecular breeding of this important crop.
Nat Genet. ):1053-9. doi: 10.1038/ng.715. Epub 2010 Nov 14.
We report a large-scale analysis of the patterns of genome-wide
genetic variation in soybeans. We re-sequenced a total of 17 wild and 14
cultivated soybean genomes to an average of approximately ×5 depth and
&90% coverage using the Illumina Genome Analyzer II platform. We
compared the patterns of genetic variation between wild and cultivated
soybeans and identified higher allelic diversity in wild soybeans. We
identified a high level of linkage disequilibrium in the soybean genome,
suggesting that marker-assisted breeding of soybean will be less
challenging than map-based cloning. We report linkage disequilibrium
block location and distribution, and we identified a set of 205,614 tag
SNPs that may be useful for QTL mapping and association studies. The
data here provide a valuable resource for the analysis of wild soybeans
and to facilitate future breeding and quantitative trait analysis.
Nature. 2012 Nov 29;491(. doi: 10.1038/nature11650.
Bread wheat (Triticum aestivum) is a globally important crop,
accounting for 20 per cent of the calories consumed by humans. Major
efforts are underway worldwide to increase wheat production by extending
genetic diversity and analysing key traits, and genomic resources can
accelerate progress. But so far the very large size and polyploid
complexity of the bread wheat genome have been substantial barriers to
genome analysis. Here we report the sequencing of its large,
17-gigabase-pair, hexaploid genome using 454?pyrosequencing, and
comparison of this with the sequences of diploid ancestral and
progenitor genomes. We identified between 94,000 and 96,000 genes, and
assigned two-thirds to the three component genomes (A, B and D) of
hexaploid wheat. High-resolution synteny maps identified many small
disruptions to conserved gene order. We show that the hexaploid genome
is highly dynamic, with significant loss of gene family members on
polyploidization and domestication, and an abundance of gene fragments.
Several classes of genes involved in energy harvesting, metabolism and
growth are among expanded gene families that could be associated with
crop productivity. Our analyses, coupled with the identification of
extensive genetic variation, provide a resource for accelerating gene
discovery and improving this major crop.
Publications
Arterioscler Thromb Vasc Biol. ):2909-14. doi: 10.1161/ATVBAHA.113.302426. Epub 2013 Sep 26.
OBJECTIVE: Autosomal recessive hypercholesterolemia is a rare
inherited disorder, characterized by extremely high total and
low-density lipoprotein cholesterol levels, that has been previously
linked to mutations in LDLRAP1. We identified a family with autosomal
recessive hypercholesterolemia not explained by mutations in LDLRAP1 or
other genes known to cause monogenic hypercholesterolemia. The aim of
this study was to identify the molecular pathogenesis of autosomal
recessive hypercholesterolemia in this family.
APPROACH AND RESULTS: We used exome sequencing to assess all
protein-coding regions of the genome in 3 family members and identified a
homozygous exon 8 splice junction mutation (c.894G&A, also known as
E8SJM) in LIPA that segregated with the diagnosis of
hypercholesterolemia. Because homozygosity for mutations in LIPA is
known to cause cholesterol ester storage disease, we performed directed
follow-up phenotyping by noninvasively measuring hepatic cholesterol
content. We observed abnormal hepatic accumulation of cholesterol in the
homozygote individuals, supporting the diagnosis of cholesterol ester
storage disease. Given previous suggestions of cardiovascular disease
risk in heterozygous LIPA mutation carriers, we genotyped E8SJM in
&27 000 individuals and found no association with plasma lipid levels
or risk of myocardial infarction, confirming a true recessive mode of
inheritance.
CONCLUSIONS: By integrating observations from Mendelian and
population genetics along with directed clinical phenotyping, we
diagnosed clinically unapparent cholesterol ester storage disease in the
affected individuals from this kindred and addressed an outstanding
question about risk of cardiovascular disease in LIPA E8SJM heterozygous
KEYWORDS: genetics, hypercholesterolemia, myocardial infarction
J Natl Cancer Inst. ):djt338. doi: 10.1093/jnci/djt338. Epub 2013 Dec 7.
We encountered a family of Japanese descent in which multiple
members developed lung cancer. Using whole-exome sequencing, we
identified a novel germline mutation in the transmembrane domain of the
human epidermal growth factor receptor 2 (HER2) gene (G660D). A novel
somatic mutation (V659E) was also detected in the transmembrane domain
of HER2 in one of 253 sporadic lung adenocarcinomas. Because the
transmembrane domain of HER2 is considered to be responsible for the
dimerization and subsequent activation of the HER family and downstream
signaling pathways, we performed functional analyses of these HER2
mutants. Mutant HER2 G660D and V659E proteins were more stable than
wild-type protein. Both the G660D and V659E mutants activated Akt. In
addition, they activated p38, which is thought to promote cell
proliferation in lung adenocarcinoma. Our findings strongly suggest that
mutations in the transmembrane domain of HER2 may be oncogenic, causing
hereditary and sporadic lung adenocarcinomas.
DNA and amino acid sequences in the transmembrane domain of&HER2.&A)
Direct Sanger sequencing of the proband (III-4), her affected mother
(II-4), and her unaffected sister (III-5). The results indicated that
G660D was a germline mutation.&B) Direct sequencing of a sporadic lung adenocarcinoma with a&HER2&V659E
mutation. V659E was found to be of somatic origin based on the
sequencing results of the peritumoral lung tissue from the same
specimen. All the sequence variants were confirmed by independent
polymerase chain reaction amplifications and were sequenced in both
directions.&C) Interspecies conservation of the transmembrane domain of&HER2&(UCSC Genome Browser,&, accessed September 12, 2013). The&yellow highlight&indicates the N-terminal glycine zipper motif Thr652-X3-Ser656-X3-Gly660, a tandem variant of a GG4-like motif of human&HER2. Codons 659 and 660 in human&HER2&are highly conserved among the listed vertebrate species (shown in&red).&X. tropicalis&=&Xenopus tropicalis.
Blood. 2013 Apr 25;121(17):3428-30. doi: 10.1182/blood-210. Epub 2013 Mar 1.
Primary mediastinal large B-cell lymphoma (PMBCL) is a subtype of
diffuse large B-cell lymphoma (DLBCL) accounting for 2% to 4% of all
non-Hodgkin lymphomas. We report a family of 3 siblings with PMBCL and
their cousin with extranodal DLBCL. The histopathological
characteristics of lymphomas of all 4 patients are similar, implying
post-germinal center differentiation and growth deregulation by other
mechanisms than BCL2-mediated inhibition of apoptosis and suggesting a
shared biological background. We aimed to identify the genetic defect
underlying lymphoma susceptibility in this family using exome sequencing
and linkage analysis. The only variant segregating in all 4 patients
and not reported in genetic databases was 5533C&A (His1845Asn) in the
MLL gene. To our knowledge, this is the first time when familial
clustering of PMBCL is reported. Although we propose MLL as a candidate
predisposition gene for this condition, this finding needs to be
validated in additional cases.
The pedigree of the Finnish family with 3 siblings affected by
PMBCL and their cousin with extranodal DLBCL. The age of lymphoma onset
is shown for all affected individuals. The MLL 5533C&A mutation
status is shown for all studied family members: plus indicates mutation,
and minus indicates the wild-type allele. Genome-wide genotype data
were available from individuals marked with an asterisk. The pedigree
has been modified for confidentiality.
Am J Hum Genet. 2013 Jun 6;92(6):974-80. doi: 10.1016/j.ajhg.. Epub 2013 May 16.
The genetic cause of some familial nonsyndromic renal cell
carcinomas (RCC) defined by at least two affected first-degree relatives
is unknown. By combining whole-exome sequencing and tumor profiling in a
family prone to cases of RCC, we identified a germline BAP1 mutation
c.277A&G (p.Thr93Ala) as the probable genetic basis of RCC
predisposition. This mutation segregated with all four RCC-affected
relatives. Furthermore, BAP1 was found to be inactivated in RCC-affected
individuals from this family. No BAP1 mutations were identified in 32
familial cases presenting with only RCC. We then screened for germline
BAP1 deleterious mutations in familial aggregations of cancers within
the spectrum of the recently described BAP1-associated tumor
predisposition syndrome, including uveal melanoma, malignant pleural
mesothelioma, and cutaneous melanoma. Among the 11 families that
included individuals identified as carrying germline deleterious BAP1
mutations, 6 families presented with 9 RCC-affected individuals,
demonstrating a significantly increased risk for RCC. This strongly
argues that RCC belongs to the BAP1 syndrome and that BAP1 is a
RCC-predisposition gene.
Figure 1. Clinical and Biological Characterization of Family A
Figure 2. Pedigree of the Families with Members Carrying BAP1 Mutations
Am J Hum Genet. 2012 Apr 6;90(4):734-9. doi: 10.1016/j.ajhg.. Epub 2012 Mar 29.
An exome-sequencing study of families with multiple
breast-cancer-affected individuals identified two families with XRCC2
mutations, one with a protein-truncating mutation and one with a
probably deleterious missense mutation. We performed a population-based
case-control mutation-screening study that identified six probably
pathogenic coding variants in 1,308 cases with early-onset breast cancer
and no variants in 1,120 controls (the severity grading was p &
0.02). We also performed additional mutation screening in 689
multiple-case families. We identified ten breast-cancer-affected
families with protein-truncating or probably deleterious rare missense
variants in XRCC2. Our identification of XRCC2 as a breast cancer
susceptibility gene thus increases the proportion of breast cancers that
are associated with homologous recombination-DNA-repair dysfunction and
Fanconi anemia and could therefore benefit from specific targeted
treatments such as PARP (poly ADP ribose polymerase) inhibitors. This
study demonstrates the power of massively parallel sequencing for
discovering susceptibility genes for common, complex diseases.
Figure 1. Pedigrees of Families Found to Carry XRCC2 Mutations
Mutation status is indicated for all family members for whom a DNA
sample was available. Cancer diagnosis and age of onset are indicated
for affected members. Asterisks indicate that DNA underwent exome
sequencing (libraries for 50 bp fragment reads were prepared according
to the SOLiD Baylor protocol 2.1 and the Nimblegen exome-capture
protocol v.1.2 with some variations). The following abbreviations are
used: BC, breast cancer (black filled symbols); PC,
BwC, UC, MM, UK,
BlC, OC, BCC, basal cell
L, (all gray-filled symbols); V, verified cancer
(via cancer registry or pathology report); and wt, wild-type. Some
symbols represent more than one person as indicated by a numeral.
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