Heinzen Erin L, Ge Dongliang, Cronin Kenneth D, Maia Jessica M, Shianna Kevin V, Gabriel Willow N, Welsh-Bohmer Kathleen A, Hulette Christine M, Denny Thomas N, Goldstein David B
Institute for Genome Sciences & Policy, Center for Human Genome Variation, Duke University, Durham, North Carolina, USA.
PLoS Biol. 2008 Dec 23;6(12):e1. doi: 10.1371/journal.pbio.1000001.
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.
众多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及剪接的相关性仍不明确。据我们所知，我们首次在人类原代细胞中进行了全基因组筛选，以寻找与可变剪接和基因表达相关的单核苷酸多态性（SNP），评估了93份来自无明确神经精神疾病的尸检皮质脑组织样本以及80份从健康活体供体采集的外周血单核细胞样本。我们确定了23个与总表达具有高度置信度的关联以及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在两种组织类型中均显示出效应，这有力地证明了两种组织类型中剪接和表达存在不同的遗传控制。此处生成的数据还表明，在84个已报道的与人类性状的全基因组显著关联中，多达13个关联可能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大的表型意义。
