biostudies-literatureUnknown6(3)Xu SNational Natural Science Foundation of ChinaMarine 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 <i>APPL1</i> ^P378L and <i>NEIL1</i> ^E71G 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., <i>NKX3-2</i>, <i>SOX9</i>, <i>HAND2</i>), shaping cetacean limb phenotypes. Additionally, convergent shifts in topologically associating domains (TADs) across cetaceans and pinnipeds were implicated in the regulation of <i>ASXL3</i> and <i>FAM43B</i> 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 <i>NUP153</i> and <i>ID4</i>, 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.Innovation (Cambridge (Mass.))100798https://www.ebi.ac.uk/biostudies/studies/S-EPMC11910941biostudies-literatureMulti-level genomic convergence of secondary aquatic adaptation in marine mammals.PMC11910941Zhou MRen WYang GZheng YShan LZhang QDeme LSun LZhang ZYin DTian RSun DXu SChen YLiang NChai SWu TYu ZSeim IXu ZfalseMulti-level genomic convergence of secondary aquatic adaptation in marine mammals.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 <i>APPL1</i> ^P378L and <i>NEIL1</i> ^E71G 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., <i>NKX3-2</i>, <i>SOX9</i>, <i>HAND2</i>), shaping cetacean limb phenotypes. Additionally, convergent shifts in topologically associating domains (TADs) across cetaceans and pinnipeds were implicated in the regulation of <i>ASXL3</i> and <i>FAM43B</i> 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 <i>NUP153</i> and <i>ID4</i>, 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.2025-01-01T00:00:00Z2025 Mar2026-06-01T06:04:58.506Z2025-04-03T23:26:47.036ZS-EPMC119109414009866410.1016/j.xinn.2025.100798