Marine mammals provide a valuable model for studying the molecular basis of convergent evolution during secondary aquatic adaptation.Using multiomics data and functional experiments,including CRISPR-Cas9 mouse models ...Marine mammals provide a valuable model for studying the molecular basis of convergent evolution during secondary aquatic adaptation.Using multiomics 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.展开更多
Long-lived mammals are reported to have rare or considerably fewer instances of spontaneous tumors,suggesting they might have evolved specific or convergent mechanisms of cancer resistance to extend lifespan;however,t...Long-lived mammals are reported to have rare or considerably fewer instances of spontaneous tumors,suggesting they might have evolved specific or convergent mechanisms of cancer resistance to extend lifespan;however,the underlying mechanisms remain insufficiently explored.Here,we conducted comparative analysis across 60 mammalian genomes to investigate the genomic features associated with natural cancer resistance.We identified 296 strongly selected genes unique to long-lived species and associated with immune response,DNA repair,and cancer,which might contribute to cancer resistance and lifespan extension in long-lived species.Further,229 convergent cancer-related genes were detected in the four extremely long-lived species and in-vitro assays confirmed a convergent mutation of LZTS1,shared by bowhead whales and naked mole rats,could suppress cancer development.Importantly,16 genes were significantly related to both body weight and cancer,defined as candidate genes of Peto's paradox.Of them,the YAP1 gene,harboring the A214S mutation,was identified as a key gene that upregulated tumor suppression genes by localizing to the cytoplasm,which might prohibit cancer development in the large and long-lived cetaceans.These findings provide novel insights into the molecular mechanisms underlying natural cancer resistance in long-lived mammals and the biological basis of Peto's paradox.展开更多
基金supported by the National Key Programme of Research and Development,Ministry of Science and Technology(2022YFF1301600)to G.Y.the Key Project of the Na tional Natural Science Foundation of China(32030011)to G.Y.+5 种基金the National Natural Science Foundation of China(32070409,32270453,32270442,32070408,and 32270441)to S.X.,W.R.,L.S.,and R.T.the Priority Academic Program Development of Jiangsu Higher Education Institutions(PAPD),Qinglan Project of Jiangsu Province to S.X.the Specially-Appointed Professor Program of Jiangsu Province to I.S.the Jiangsu Foreign Expert Bureau to I.S.the Jiangsu Provincial Department of Technology(JSSCTD202142)to I.S.the PI Project of Southern Marine Science and Engineering Guangdong Laboratory(Guangzhou)(GML2021GD0805)to G.Y.
文摘Marine mammals provide a valuable model for studying the molecular basis of convergent evolution during secondary aquatic adaptation.Using multiomics 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.
基金supported by the National Natural Science Foundation of China(NSFC)(32270453,32070409)the National Key Programme of Research and Development,Ministry of Science and Technology(2022YFF1301602,2022YFF1301600)+1 种基金the Key Project of the NSFC(32030011)the Postdoctoral Fellowship Program of China Postdoctoral Science Foundation(CPSF,GZC20240729)。
文摘Long-lived mammals are reported to have rare or considerably fewer instances of spontaneous tumors,suggesting they might have evolved specific or convergent mechanisms of cancer resistance to extend lifespan;however,the underlying mechanisms remain insufficiently explored.Here,we conducted comparative analysis across 60 mammalian genomes to investigate the genomic features associated with natural cancer resistance.We identified 296 strongly selected genes unique to long-lived species and associated with immune response,DNA repair,and cancer,which might contribute to cancer resistance and lifespan extension in long-lived species.Further,229 convergent cancer-related genes were detected in the four extremely long-lived species and in-vitro assays confirmed a convergent mutation of LZTS1,shared by bowhead whales and naked mole rats,could suppress cancer development.Importantly,16 genes were significantly related to both body weight and cancer,defined as candidate genes of Peto's paradox.Of them,the YAP1 gene,harboring the A214S mutation,was identified as a key gene that upregulated tumor suppression genes by localizing to the cytoplasm,which might prohibit cancer development in the large and long-lived cetaceans.These findings provide novel insights into the molecular mechanisms underlying natural cancer resistance in long-lived mammals and the biological basis of Peto's paradox.
