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<p>Alternative isoform usage and RNA modifications are fundamental to transcriptome evolution. Among these, N6-methyladenosine (m6A), the most abundant internal mRNA modification, plays a key role in gene regulation. However, due to the limitations of short-read technology, the evolutionary conservation and phenotypic impact of transcript isoforms and m6A modifications remain incomplete. Here we present a comparative evolutionary analysis using direct-RNA long-read sequencing of six tissues from species representing three major clades within Mammalia, along with an avian outgroup. We find that although 71% of transcript isoforms are species-specific, they contribute less than 3% to total mRNA gene expression, whereas 18% of mammalian-conserved isoforms account for the majority of mRNA gene expression. We also identify that 14.2% of m6A modification sites, present in 39% of genes, are conserved across mammals, with enrichment in 3’-untranslated regions and stop codon-proximal regions. Notably, 27.3% of conserved m6A sites display isoform-specific deposition, supporting a role for epitranscriptomic regulation in maintaining functional transcript diversity. Finally, we uncover widespread conservation of coordinate splicing, in which exon co-regulation compensates for frameshift-inducing changes in individual exons, suggesting a buffering mechanism in isoform regulation. Together, these findings provide insight into how post-transcriptional regulation shapes phenotypic diversity and evolutionary adaptation in mammals.</p>

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Isoform-specific m6A deposition and coordinated splicing shape mammalian transcriptome evolution

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年4月21日

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  • Gabriela Santos-Rodriguez,
  • Akanksha Srivastava,
  • Agin Ravindran,
  • Favour O. Oyelami,
  • Chi Kin Ip,
  • Pallavi Gupta,
  • Jeanette Villanueva,
  • Helen E. King,
  • Abigail Grootveld,
  • Alexandra Sneddon,
  • James Blackburn,
  • Ishaan Gupta,
  • Helaine Graziele Santos Vieira,
  • Nikolay E. Shirokikh,
  • Eduardo Eyras,
  • Robert J. Weatheritt

摘要

Alternative isoform usage and RNA modifications are fundamental to transcriptome evolution. Among these, N6-methyladenosine (m6A), the most abundant internal mRNA modification, plays a key role in gene regulation. However, due to the limitations of short-read technology, the evolutionary conservation and phenotypic impact of transcript isoforms and m6A modifications remain incomplete. Here we present a comparative evolutionary analysis using direct-RNA long-read sequencing of six tissues from species representing three major clades within Mammalia, along with an avian outgroup. We find that although 71% of transcript isoforms are species-specific, they contribute less than 3% to total mRNA gene expression, whereas 18% of mammalian-conserved isoforms account for the majority of mRNA gene expression. We also identify that 14.2% of m6A modification sites, present in 39% of genes, are conserved across mammals, with enrichment in 3’-untranslated regions and stop codon-proximal regions. Notably, 27.3% of conserved m6A sites display isoform-specific deposition, supporting a role for epitranscriptomic regulation in maintaining functional transcript diversity. Finally, we uncover widespread conservation of coordinate splicing, in which exon co-regulation compensates for frameshift-inducing changes in individual exons, suggesting a buffering mechanism in isoform regulation. Together, these findings provide insight into how post-transcriptional regulation shapes phenotypic diversity and evolutionary adaptation in mammals.