Tissue-specific genetic control of splicing: implications for the study of complex traits.
Tissue-specific genetic control of splicing: implications for the study of complex traits.
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剪接的组织特异性遗传控制：对复杂性状的研究的影响。
DOI：
10.1371/journal.pbio.1000001
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发表时间：
2008-12-23
期刊：
影响因子：
9.8
通讯作者：
Goldstein DB
中科院分区：
文献类型：
--
作者：
Heinzen EL;Ge D;Cronin KD;Maia JM;Shianna KV;Gabriel WN;Welsh-Bohmer KA;Hulette CM;Denny TN;Goldstein DB
多项针对影响基因表达的多态性进行的全基因组筛选，为转录的遗传控制提供了关键见解。尽管有这些工作，但特定多态性与体内表达和剪接的相关性仍不清楚。据我们所知，我们首次针对与人类原代细胞中的可变剪接和基因表达相关的单核苷酸多态性（SNP）进行了全基因组筛选，评估了93例无明确神经精神疾病的尸检采集的大脑皮质组织样本以及80例从健康活体捐赠者采集的外周血单核细胞样本。我们确定了23个与总表达高度相关的关联，以及80个与特定外显子表达水平所反映的可变剪接相关的关联。然而，不到50%的相关SNP在两种组织类型中都显示出影响，这反映了两种组织类型中剪接和表达存在不同遗传控制的有力证据。这里生成的数据还表明，在84个已报道的与人类性状具有全基因组显著关联中，可能有多达13个是由剪接效应导致的。这些结果强调了建立一个影响原代组织类型中剪接和表达的多态性数据库的重要性，并表明剪接效应可能比整体基因表达变化具有更重要的表型意义。
尽管人类的基因数量相对较少，但这些基因编码的蛋白质及其生物学功能要复杂得多。这种复杂性的增加部分是通过从同一基因序列产生不同信息（可变剪接）以及以组织特异性方式调节这些信息的表达等过程实现的。这些过程扩展了人类基因组的功能能力，但当这些过程出错时，也可能导致疾病易感性。在这项研究中，我们研究了单核苷酸多态性如何影响两种与人类疾病高度相关的重要细胞类型（大脑和血液）中的整体基因表达和可变剪接。在两种组织类型中观察到了广泛的且具有组织特异性的基因表达和可变剪接调控，并且其中一些多态性被证明与其他通过全基因组关联研究最近被认为与人类疾病相关的多态性有关。这些关联中的大多数似乎与可变剪接有关，而不是与整体表达变化有关，这表明剪接模式的变化可能比仅影响表达的变化对疾病的影响更大。这些数据强调了对所有人类组织类型中基因表达的遗传调控进行全面研究的重要性，以帮助理解遗传变异如何影响常见疾病的风险。
我们研究了人类原代细胞中基因表达和可变剪接的组织特异性遗传控制，并在此描述了其对理解遗传变异如何影响人类疾病的意义。
Numerous genome-wide screens for polymorphisms that influence gene expression have provided key insights into the genetic control of transcription. Despite this work, the relevance of specific polymorphisms to in vivo expression and splicing remains unclear. We carried out the first genome-wide screen, to our knowledge, for SNPs that associate with alternative splicing and gene expression in human primary cells, evaluating 93 autopsy-collected cortical brain tissue samples with no defined neuropsychiatric condition and 80 peripheral blood mononucleated cell samples collected from living healthy donors. We identified 23 high confidence associations with total expression and 80 with alternative splicing as reflected by expression levels of specific exons. Fewer than 50% of the implicated SNPs however show effects in both tissue types, reflecting strong evidence for distinct genetic control of splicing and expression in the two tissue types. The data generated here also suggest the possibility that splicing effects may be responsible for up to 13 out of 84 reported genome-wide significant associations with human traits. These results emphasize the importance of establishing a database of polymorphisms affecting splicing and expression in primary tissue types and suggest that splicing effects may be of more phenotypic significance than overall gene expression changes. Although humans have a relatively small complement of genes, the proteins encoded by those genes and their biologic function are far more complex. The increased complexity is achieved in part through processes that create different messages from the same gene sequence (alternative splicing) and that regulate the expression of those messages in a tissue-specific fashion. These processes expand the functional capacity of the human genome, but also can create predisposition to disease when these processes go awry. In this study, we investigated how single nucleotide polymorphisms influence both overall gene expression and alternative splicing in two important cell types (brain and blood) highly relevant to human disease. Extensive and tissue-specific regulation of gene expression and alternative splicing were observed in the two tissue types, and some of these polymorphisms were shown to be connected to other polymorphsims that have been recently implicated in human diseases through genome-wide association studies. Most of these connections appeared to relate to alternative splicing as opposed to overall expression changes, suggesting that changes in splicing patterns may be more consequential for disease than those affecting only expression. These data emphasize the importance of comprehensive studies into genetic regulation of gene expression in all human tissue types in order to help understand how genetic variation influences risk of common diseases. We investigated tissue-specific genetic control of gene expression and alternative splicing in primary human cells, and we describe here the implications for understanding how genetic variation influences human disease.
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影响因子：
9.8
作者：
Schadt EE;Molony C;Chudin E;Hao K;Yang X;Lum PY;Kasarskis A;Zhang B;Wang S;Suver C;Zhu J;Millstein J;Sieberts S;Lamb J;GuhaThakurta D;Derry J;Storey JD;Avila-Campillo I;Kruger MJ;Johnson JM;Rohl CA;van Nas A;Mehrabian M;Drake TA;Lusis AJ;Smith RC;Guengerich FP;Strom SC;Schuetz E;Rushmore TH;Ulrich R
通讯作者：
Ulrich R
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影响因子：
30.8
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4.5
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通讯作者：
Georges M
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通讯作者：
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