Species-Specific Exon Loss in Human Transcriptomes

• Published in: Molecular biology and evolution Vol. 32; no. 2; pp. 481 - 494
• Main Authors: Wang, Jinkai, Lu, Zhi-xiang, Tokheim, Collin J., Miller, Sara E., Xing, Yi
• Format: Journal Article
• Language: English
• Published: United States Oxford University Press 01.02.2015
• Subjects: 5' Untranslated regions; Amino Acid Transport Systems, Basic - genetics; Amino acids; Animals; Annotations; Biological evolution; Deoxyribonucleic acid; Discoveries; DNA; Evolution; Evolution, Molecular; Evolutionary biology; Exons; Exons - genetics; Gene sequencing; Genomics; Human subjects; Human tissues; Humans; Molecular modelling; Monkeys & apes; Nucleotide sequence; Nucleotides; Pan troglodytes; Phylogenetics; Phylogeny; Primates; Primates - genetics; Regulatory sequences; Ribonucleic acid; RNA; Splicing; Transcriptome - genetics; Transcriptomes; primate; exon loss; evolution; splicing; RNA-seq
• ISSN: 0737-4038; 1537-1719; 1537-1719
• DOI: 10.1093/molbev/msu317

Changes in exon–intron structures and splicing patterns represent an important mechanism for the evolution of gene functions and species-specific regulatory networks. Although exon creation is widespread during primate and human evolution and has been studied extensively, much less is known about the scope and potential impact of human-specific exon loss events. Historically, transcriptome data and exon annotations are significantly biased toward humans over nonhuman primates. This ascertainment bias makes it challenging to discover human-specific exon loss events. We carried out a transcriptome-wide search of human-specific exon loss events, by taking advantage of RNA sequencing (RNA-seq) as a powerful and unbiased tool for exon discovery and annotation. Using RNA-seq data of humans, chimpanzees, and other primates, we reconstructed and compared transcript structures across the primate phylogeny. We discovered 33 candidate human-specific exon loss events, among which six exons passed stringent experimental filters for the complete loss of splicing activities in diverse human tissues. These events may result from human-specific deletion of genomic DNA, or small-scale sequence changes that inactivated splicing signals. The impact of human-specific exon loss events is predominantly regulatory. Three of the six events occurred in the 5′ untranslated region (5′-UTR) and affected cis-regulatory elements of mRNA translation. In SLC7A6, a gene encoding an amino acid transporter, luciferase reporter assays suggested that both a human-specific exon loss event and an independent human-specific single nucleotide substitution in the 5′-UTR increased mRNA translational efficiency. Our study provides novel insights into the molecular mechanisms and evolutionary consequences of exon loss during human evolution.