Bioinformatics Interdepartmental Graduate Program, University of California, Los Angeles, Los Angeles, CA 90095, USA; Center for Computational and Genomic Medicine, The Children's Hospital of Philadelphia, Philadelphia, PA 19104, USA.
Bioinformatics Interdepartmental Graduate Program, University of California, Los Angeles, Los Angeles, CA 90095, USA.
Am J Hum Genet. 2020 Aug 6;107(2):196-210. doi: 10.1016/j.ajhg.2020.06.002. Epub 2020 Jun 25.
A major question in human genetics is how sequence variants of broadly expressed genes produce tissue- and cell type-specific molecular phenotypes. Genetic variation of alternative splicing is a prevalent source of transcriptomic and proteomic diversity in human populations. We investigated splicing quantitative trait loci (sQTLs) in 1,209 samples from 13 human brain regions, using RNA sequencing (RNA-seq) and genotype data from the Genotype-Tissue Expression (GTEx) project. Hundreds of sQTLs were identified in each brain region. Some sQTLs were shared across brain regions, whereas others displayed regional specificity. These "regionally ubiquitous" and "regionally specific" sQTLs showed distinct positional distributions of single-nucleotide polymorphisms (SNPs) within and outside essential splice sites, respectively, suggesting their regulation by distinct molecular mechanisms. Integrating the binding motifs and expression patterns of RNA binding proteins with exon splicing profiles, we uncovered likely causal variants underlying brain region-specific sQTLs. Notably, SNP rs17651213 created a putative binding site for the splicing factor RBFOX2 and was associated with increased splicing of MAPT exon 3 in cerebellar tissues, where RBFOX2 was highly expressed. Overall, our study reveals a more comprehensive spectrum and regional variation of sQTLs in human brain and demonstrates that such regional variation can be used to fine map potential causal variants of sQTLs and their associated neurological diseases.
人类遗传学中的一个主要问题是，广泛表达的基因的序列变异如何产生组织和细胞类型特异性的分子表型。可变剪接的遗传变异是人类群体中转录组和蛋白质组多样性的一个普遍来源。我们使用来自基因型-组织表达（GTEx）项目的 RNA 测序（RNA-seq）和基因型数据，研究了 13 个人脑区域的 1209 个样本中的剪接数量性状基因座（sQTL）。在每个脑区都鉴定到了数百个 sQTL。一些 sQTL 在脑区之间共享，而另一些则显示出区域特异性。这些“区域普遍存在”和“区域特异性”的 sQTL 在其内含子和外显子剪接位点内和周围的单核苷酸多态性（SNP）的位置分布上表现出不同，这表明它们受到不同分子机制的调控。整合 RNA 结合蛋白的结合基序和表达模式与外显子剪接谱，我们发现了可能导致脑区特异性 sQTL 的潜在因果变异。值得注意的是，SNP rs17651213 创造了一个剪接因子 RBFOX2 的假定结合位点，并且与小脑组织中 MAPT 外显子 3 的剪接增加相关，而 RBFOX2 在小脑组织中高度表达。总的来说，我们的研究揭示了人类大脑中更全面的 sQTL 谱和区域变异，并表明这种区域变异可用于精细映射 sQTL 及其相关神经疾病的潜在因果变异。
