Polyadenylation-related isoform switching in human evolution revealed by full-length transcript structure.

Area of Science:

• Genomics and Transcriptomics
• Comparative Primate Biology
• Bioinformatics and Computational Biology

Background:

• Rhesus macaque is a vital nonhuman primate model for evolutionary and translational research.
• Existing macaque gene models are error-prone, limiting their utility in scientific studies.
• Accurate gene models are crucial for advancing comparative genomics and understanding primate evolution.

Purpose of the Study:

• To de novo define comprehensive, full-length rhesus macaque gene models.
• To enable accurate human-macaque comparative analysis of gene regulation, specifically polyadenylation (PA).
• To investigate the mechanisms driving human-specific transcriptome and phenotypic changes.

Main Methods:

• Utilized single-molecule, long-read transcriptome sequencing across four macaque tissues.
• Integrated RNA sequencing and cap analysis gene expression sequencing data for fine-scale structure refinement.
• Performed comparative genomics analysis between human and macaque, using mouse as an outgroup.

Main Results:

• Generated over 8.5 million long complementary DNA reads, defining 51,605 accurate macaque gene models.
• These models cover a high percentage of macaque (89.7%) and human (75.7%) orthologous genes.
• Identified 79 human-specific distal polyadenylation (PA) events, primarily driven by strengthening distal sites, impacting gene expression regulation.

Conclusions:

• The developed full-length macaque gene models provide an intact reference for primate research.
• Human-specific isoforms, regulated by PA, contribute to temporospatially specific gene expression reduction.
• Isoform switching represents an underappreciated regulatory mechanism in human-specific transcriptome and phenotypic evolution.