Finding functional disease-associated non-coding variation using next-generation sequencing
Finding functional disease-associated non-coding variation using next-generation sequencing
复制标题
使用下一代测序寻找功能性疾病相关的非编码变异
DOI：
10.1101/060285
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发表时间：
2016
期刊：
影响因子：
--
通讯作者：
Devanna P
中科院分区：
文献类型：
--
作者：
Devanna P
下一代测序为在全外显子组或全基因组水平上大规模询问群组开辟了道路。目前，该领域主要集中在编码序列内的潜在致病变体上，并且被预测会引起蛋白质序列变化，通常丢弃非编码变体。然而，非编码DNA占基因组的约98%，并且包含控制蛋白质编码基因表达所必需的一系列序列。因此，潜在的致病性非编码变异目前被忽视。为了解决这个问题，我们设计了一种方法来评估一类非编码调控DNA的变异; 3′UTRome。基因的3 'UTR区域中的变体是特别感兴趣的，因为3' UTR负责通过它们与microRNA的相互作用来调节蛋白质表达水平。此外，由于3′ UTR-microRNA相互作用是基于互补碱基配对的，因此可以在全基因组水平上进行预测，因此它们适合于大规模分析。我们报告了一种用于识别和功能测试3 'UTRome内microRNA结合位点变体的策略，并证明了该管道在语言障碍儿童队列中的有效性。使用来自43个先证者的全外显子组序列数据，我们提取了位于3 'UTR microRNA结合位点内的变体。我们在microRNA结合位点中鉴定了一种常见变异（SNP），并发现该SNP与语言障碍（非单词重复）的内表型相关。我们发现，这种变异破坏了细胞中microRNA的调控，并与大脑中基因表达的改变有关，这表明它可能是导致SLI的一个危险因素。这项工作表明，尽管有丰富的下一代测序数据，但生物学相关的变体目前正在研究中，并提出了一种简单的策略来询问基因组的非编码区。我们建议，这种策略应常规应用于整个外显子组和全基因组序列数据，以扩大我们的理解，非编码遗传变异的基础复杂的表型，如神经发育障碍。
Next generation sequencing has opened the way for the large scale interrogation of cohorts at the whole exome, or whole genome level. Currently, the field largely focuses on potential disease causing variants that fall within coding sequences and that are predicted to cause protein sequence changes, generally discarding non-coding variants. However non-coding DNA makes up~98% of the genome and contains a range of sequences essential for controlling the expression of protein coding genes. Thus, potentially causative non-coding variation is currently being overlooked. To address this, we have designed an approach to assess variation in one class of non-coding regulatory DNA; the 3′UTRome. Variants in the 3'UTR region of genes are of particular interest because 3'UTRs are responsible for modulating protein expression levels via their interactions with microRNAs. Furthermore they are amenable to large scale analysis as 3′UTR-microRNA interactions are based on complementary base pairing and as such can be predictedin silicoat the genome-wide level. We report a strategy for identifying and functionally testing variants in microRNA binding sites within the 3'UTRome and demonstrate the efficacy of this pipeline in a cohort of language impaired children. Using whole exome sequence data from 43 probands, we extracted variants that lay within 3'UTR microRNA binding sites. We identified a common variant (SNP) in a microRNA binding site and found this SNP to be associated with an endophenotype of language impairment (non-word repetition). We showed that this variant disrupted microRNA regulation in cells and was linked to altered gene expression in the brain, suggesting it may represent a risk factor contributing to SLI. This work demonstrates that biologically relevant variants are currently being under-investigated despite the wealth of next-generation sequencing data available and presents a simple strategy for interrogating non-coding regions of the genome. We propose that this strategy should be routinely applied to whole exome and whole genome sequence data in order to broaden our understanding of how non-coding genetic variation underlies complex phenotypes such as neurodevelopmental disorders.
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来自1,092个人基因组的遗传变异的综合图。
影响因子：
64.8
作者：
通讯作者：
--
Explorer CMIP 和 ATP 2 C 2 调节语言障碍中的语音短期记忆
DOI：
--
发表时间：
2009
期刊：
影响因子：
--
作者：
D. Newbury;L. Winchester;L. Addis;S. Paracchini;Lyn;A. Clark;W. Cohen;H. Cowie;K. Dworzynski;A. Everitt;I. Goodyer;Elizabeth R. Hennessy;A. Kindley;L. Miller;J. Nasir;A. O'hare;Duncan J. Shaw;Z. Simkin;E. Simonoff;V. Slonims;J. Watson;J. Ragoussis;S. Fisher;J. Seckl;P. Helms;P. Bolton;A. Pickles;G. Conti;G. Baird;D. Bishop;A. Monaco
通讯作者：
A. Monaco
影响因子：
5.2
作者：
Jones, RW;Ring, S;Golding, J
通讯作者：
Golding, J
测试回顾：Wiig, E. H.、Semel, E. 和 Secord, W. A.（2013 年）语言基础临床评估 - 第五版 (CELF-5)。
DOI：
--
发表时间：
2015
期刊：
影响因子：
--
作者：
M. Coret;Adam Mccrimmon
通讯作者：
Adam Mccrimmon
影响因子：
9.8
作者：
Newbury DF;Winchester L;Addis L;Paracchini S;Buckingham LL;Clark A;Cohen W;Cowie H;Dworzynski K;Everitt A;Goodyer IM;Hennessy E;Kindley AD;Miller LL;Nasir J;O'Hare A;Shaw D;Simkin Z;Simonoff E;Slonims V;Watson J;Ragoussis J;Fisher SE;Seckl JR;Helms PJ;Bolton PF;Pickles A;Conti-Ramsden G;Baird G;Bishop DV;Monaco AP
通讯作者：
Monaco AP