Department of Ecology and Evolutionary Biology, University of Michigan, Ann Arbor, MI.
Mol Biol Evol. 2020 Jul 1;37(7):2015-2028. doi: 10.1093/molbev/msaa063.
Alternative translation initiation (ATLI) refers to the existence of multiple translation initiation sites per gene and is a widespread phenomenon in eukaryotes. ATLI is commonly assumed to be advantageous through creating proteome diversity or regulating protein synthesis. We here propose an alternative hypothesis that ATLI arises primarily from nonadaptive initiation errors presumably due to the limited ability of ribosomes to distinguish sequence motifs truly signaling translation initiation from similar sequences. Our hypothesis, but not the adaptive hypothesis, predicts a series of global patterns of ATLI, all of which are confirmed at the genomic scale by quantitative translation initiation sequencing in multiple human and mouse cell lines and tissues. Similarly, although many codons differing from AUG by one nucleotide can serve as start codons, our analysis suggests that using non-AUG start codons is mostly disadvantageous. These and other findings strongly suggest that ATLI predominantly results from molecular error, requiring a major revision of our understanding of the precision and regulation of translation initiation.
选择性翻译起始（ATLI）是指每个基因存在多个翻译起始位点，这是真核生物中普遍存在的现象。通常认为 ATLI 通过产生蛋白质组多样性或调节蛋白质合成而具有优势。我们在这里提出了一个替代假设，即 ATLI 主要是由于核糖体区分真正信号翻译起始的序列基序与类似序列的能力有限而导致的起始错误所致。我们的假设（而不是适应性假设）预测了一系列 ATLI 的全局模式，这些模式都在多个人类和小鼠细胞系和组织的定量翻译起始测序的基因组范围内得到了证实。同样，尽管有许多与 AUG 相差一个核苷酸的密码子可以作为起始密码子，但我们的分析表明，使用非 AUG 起始密码子大多是不利的。这些和其他发现强烈表明，ATLI 主要是由分子错误引起的，这需要对我们对翻译起始的精确性和调控的理解进行重大修订。
