Mesh : Humans Alternative Splicing Protein Isoforms / genetics metabolism Quantitative Trait Loci Genome-Wide Association Study 3' Untranslated Regions / genetics Alzheimer Disease / genetics immunology Genome, Human Mitochondrial Precursor Protein Import Complex Proteins

来  源:   DOI:10.1038/s41467-024-48615-4   PDF(Pubmed)

Abstract:
Alternative splicing events are a major causal mechanism for complex traits, but they have been understudied due to the limitation of short-read sequencing. Here, we generate a full-length isoform annotation of human immune cells from an individual by long-read sequencing for 29 cell subsets. This contains a number of unannotated transcripts and isoforms such as a read-through transcript of TOMM40-APOE in the Alzheimer\'s disease locus. We profile characteristics of isoforms and show that repetitive elements significantly explain the diversity of unannotated isoforms, providing insight into the human genome evolution. In addition, some of the isoforms are expressed in a cell-type specific manner, whose alternative 3\'-UTRs usage contributes to their specificity. Further, we identify disease-associated isoforms by isoform switch analysis and by integration of several quantitative trait loci analyses with genome-wide association study data. Our findings will promote the elucidation of the mechanism of complex diseases via alternative splicing.
摘要:
可变剪接事件是复杂性状的主要因果机制,但由于短读测序的局限性,它们的研究不足。这里,我们通过29个细胞亚群的长读数测序,从个体中产生人免疫细胞的全长同工型注释.这包含许多未注释的转录物和同种型,例如阿尔茨海默氏病基因座中TOMM40-APOE的通读转录物。我们描述了同工型的特征,并表明重复元素显着解释了未注释的同工型的多样性,提供对人类基因组进化的洞察。此外,一些同种型以细胞类型特异性方式表达,其替代3'-UTR的使用有助于其特异性。Further,我们通过同种型开关分析以及将几个数量性状基因座分析与全基因组关联研究数据整合来鉴定疾病相关同种型.我们的发现将通过可变剪接促进复杂疾病机制的阐明。
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