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论文题目: Transcription-Associated Mutation Promotes RNA Complexity in Highly Expressed Genes- A Major New Source of Selectable Variation
论文题目英文:
作者: 潘胜凯,#Michael W. Bruford,王昱淞,林蓁蓁,谷中如,Xian Hou,#Xue-Mei Deng,#Andrew Dixon,#Jennifer A. Marshall Graves,詹祥江*
论文出处:
年: 2018
卷:
期: DOI: 10.1093/molbev/msy017
页:
联系作者: 詹祥江
发表期刊: Molecular Biology and Evolution
ISSN:
第一作者所在部门:
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论文链接: https://academic.oup.com/mbe/advance-article/doi/10.1093/molbev/msy017/4840230?searchresult=1
影响因子:
摘要: Alternatively spliced transcript isoforms are thought to play a critical role for functional diversity. However, the mechanism generating the enormous diversity of spliced transcript isoforms remains unknown, and its biological significance remains unclear. We analyzed transcriptomes in saker falcons, chickens and mice to show that alternative splicing occurs more frequently, yielding more isoforms, in highly expressed genes. We focused on hemoglobin in the falcon, the most abundantly expressed genes in blood, finding that alternative splicing produces tenfold more isoforms than expected from the number of splice junctions in the genome. These isoforms were produced mainly by alternative use of de novo splice sites generated by transcription-associated mutation (TAM), not by the RNA editing mechanism normally invoked. We found that high expression of globin genes increases mutation frequencies during transcription, especially on non-transcribed DNA strands. After DNA replication, transcribed strands inherit these somatic mutations, creating de novo splice sites and generating multiple distinct isoforms in the cell clone. Bisulfate sequencing revealed that DNA methylation may counteract this process by suppressing TAM, suggesting DNA methylation can spatially regulate RNA complexity. RNA profiling showed that falcons living on the high Qinghai-Tibetan Plateau possess greater global gene expression levels and higher diversity of mean to high abundance isoforms (RPKM ≥18) than their low-altitude counterparts, and we speculate that this may enhance their oxygen transport capacity under low-oxygen environments. Thus, TAM-induced RNA diversity may be physiologically significant, providing an alternative strategy in lifestyle evolution.
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