Multi-level genomic convergence of secondary aquatic adaptation in marine mammals

Public summary

*High-quality chromosome-level genome assemblies were produced for two marine mammals and one terrestrial relative.

*Convergent evolution of secondary aquatic adaptation is evident in marine mammals.

*Convergent amino acid changes in P378L (APPL1) and E71G (NEIL1) enhance lipid accumulation and reduce cervical cancer cell proliferation.

*Genetic variations in non-coding elements contribute to cancer suppression, blubber thickening, and neuronal traits.

Abstract

Marine mammals provide a valuable model for studying the molecular basis of convergent evolution during secondary aquatic adaptation. Using multi-omics data and functional experiments, including CRISPR-Cas9 mouse models and luciferase reporter assays, this study explored the molecular mechanisms driving this transition across coding regions, regulatory elements, and genomic architecture. Convergent amino acid substitutions in APPL1P378L and NEIL1E71G were found to promote lipid accumulation and suppress cancer cell proliferation, likely contributing to the evolution of extensive blubber layers and cancer resistance. Convergently evolved conserved non-exonic elements (CNEs) and lineage-specific regulatory variations were shown to influence the activity of nearby genes (e.g., NKX3-2, SOX9, HAND2), shaping cetacean limb phenotypes. Additionally, convergent shifts in topologically associating domains (TADs) across cetaceans and pinnipeds were implicated in the regulation of ASXL3 and FAM43B expression, playing a role in the formation of thickened blubber layers and mitigating cancer susceptibility. Structural variations within conserved TADs were associated with the expression of neuronal genes, including NUP153 and ID4, potentially driving cognitive and social adaptations. These findings provide novel insights into the molecular foundations of the convergent evolution of secondary aquatic adaptations in mammals.