PT  - JOURNAL ARTICLE
AU  - Xudong Zou
AU  - Bernhard Schaefke
AU  - Yisheng Li
AU  - Fujian Jia
AU  - Wei Sun
AU  - Guipeng Li
AU  - Weizheng Liang
AU  - Tristan Reif
AU  - Florian Heyd
AU  - Qingsong Gao
AU  - Shuye Tian
AU  - Yanping Li
AU  - Yisen Tang
AU  - Liang Fang
AU  - Yuhui Hu
AU  - Wei Chen
TI  - Mammalian splicing divergence is shaped by drift, buffering in <em>trans</em>, and a scaling law
AID  - 10.26508/lsa.202101333
DP  - 2022 Apr 01
TA  - Life Science Alliance
PG  - e202101333
VI  - 5
IP  - 4
4099  - https://www.life-science-alliance.org/content/5/4/e202101333.short
4100  - https://www.life-science-alliance.org/content/5/4/e202101333.full
SO  - Life Sci. Alliance2022 Apr 01; 5
AB  - Alternative splicing is ubiquitous, but the mechanisms underlying its pattern of evolutionary divergence across mammalian tissues are still underexplored. Here, we investigated the cis-regulatory divergences and their relationship with tissue-dependent trans-regulation in multiple tissues of an F1 hybrid between two mouse species. Large splicing changes between tissues are highly conserved and likely reflect functional tissue-dependent regulation. In particular, micro-exons frequently exhibit this pattern with high inclusion levels in the brain. Cis-divergence of splicing appears to be largely non-adaptive. Although divergence is in general associated with higher densities of sequence variants in regulatory regions, events with high usage of the dominant isoform apparently tolerate more mutations, explaining why their exon sequences are highly conserved but their intronic splicing site flanking regions are not. Moreover, we demonstrate that non-adaptive mutations are often masked in tissues where accurate splicing likely is more important, and experimentally attribute such buffering effect to trans-regulatory splicing efficiency.