Different mRNAs encoding identical proteins: how and why?

Abstract

Alternative splicing (AS) produces various forms of mRNAs and protein isoforms and contributes to biodiversity. However, different mRNAs might have identical CDS and encode the same protein sequence. It is unclear why organisms need these distinct mRNAs if they encode the same protein? We propose two complementary hypotheses, namely adaptive hypothesis and error hypothesis, and tested these ideas using genomes of four representative organisms, human, mouse, fruitfly, and Arabidopsis. We found that only the fruitfly meets most predictions made by the adaptive hypothesis, while the other species generally align with the error hypothesis. Fruitfly exhibits a surprisingly high fraction (> 70%) of protein-coding genes (PCGs) having multiple mRNAs encoding identical proteins. These mRNAs have long CDS, variable UTR lengths, and highly conserved protein sequences. In contrast, opposite or insignificant trends are observed in human, mouse, and Arabidopsis. While molecular errors are common in cell systems, in species like the fruitfly with large effective population size, the strong natural selection might maintain those mRNAs with potentially adaptive regulatory roles. Although encoding identical proteins, different mRNAs can be regulated in a condition-specific manner, facilitating adaptive evolution. Our work provides novel perspectives in genomics and evolutionary biology.