Submitted:
11 July 2025
Posted:
11 July 2025
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Abstract
High-altitude and marine mammals inhabit vastly different ecosystems yet share the selective pressure of chronic hypoxia. Convergent evolutionary adaptations, particularly in pulmonary architecture with increased elastic fibers, facilitate efficient oxygen use under hypoxia. This review synthesizes molecular insights into these adaptations, highlighting gene family dynamics, positive selection, and convergent amino acid substitutions. The findings from comparative genomic studies offer valuable insights for human pulmonary fibrosis research.
Keywords:
convergent evolution
; pulmonary fibrosis
; hypoxia
; high-altitude mammals
; marine mammals
; gene families
; positive selection
; elastic fibers
Introduction
Hypoxia imposes severe selective pressures, driving convergent evolution among mammals in high-altitude and marine habitats. Despite differing environments, these mammals exhibit parallel adaptations, particularly in lung structure and function, essential for survival in low-oxygen conditions¹⁻4 (see Figure 1).”
Phenotypic Adaptations: Pulmonary Elasticity
Enhanced pulmonary elasticity, characterized by abundant elastic fibers, represents a critical adaptation. High-altitude mammals such as wild yaks and Xizang antelopes exhibit extensive elastic fibers in their alveolar septa, optimizing gas exchange efficiency5⁻7. Marine mammals, including whales and seals, similarly possess elastic-rich alveolar walls enabling lung collapse during deep dives, mitigating decompression sickness risks8.
Gene Family Expansion and Contraction
Comparative genomic analyses reveal significant expansions and contractions of gene families involved in cell morphogenesis, protein folding, and stress responses (see Figure 2). Notably, contractions in the keratin gene family are consistently observed, correlating with increased pulmonary elasticity and reduced fibrosis susceptibility9.
Genes Under Positive Selection and Accelerated Evolution
Genes undergoing positive selection and accelerated evolution, such as ZFP36L1, FN1, and NEDD9, are critical to pulmonary fibrosis pathways and lung morphogenesis. These genetic modifications are instrumental in developing enhanced elastic fiber networks crucial for pulmonary adaptation to chronic hypoxia10.
Convergent Amino Acid Substitutions
Convergent amino acid substitutions, exemplified by the leucine-to-isoleucine mutation in the SLC26A3 gene, influence pulmonary cellular adhesion and vascular development. These changes likely contribute to improved pulmonary functionality under prolonged hypoxic stress11.
Convergent Gene Loss
Gene loss analyses reveal convergent pseudogenization of CFAP47, vital in sperm morphology, in hypoxia-tolerant mammals. This relaxation in selective pressure highlights indirect reproductive adaptations potentially related to hypoxia tolerance mechanisms (see Figure 3).
Implications for Human Health
These evolutionary insights offer novel perspectives on human pulmonary disorders such as pulmonary fibrosis. In addition to the structural and genomic adaptations discussed above, recent advances in transcriptomic and multi-omics studies have highlighted the importance of regulatory networks—especially those involving non-coding RNAs—in pulmonary fibrosis and hypoxic adaptation. For example, competing endogenous RNA (ceRNA) networks and cross-talks among RNAs play crucial roles in regulating lung tissue remodeling, fibrosis, and cell survival under hypoxic stress, as shown in integrative studies of lung adenocarcinoma and other disease models12,13. Identifying these molecular pathways from comparative genomics and network-based research can inform new therapeutic strategies for managing human pulmonary fibrosis and related diseases.
Conclusion and Future Directions
Convergent pulmonary adaptations in hypoxia-adapted mammals involve complex genetic and molecular modifications, notably in lung elasticity and structure. Future studies focusing on functional validations and translational applications could significantly advance treatments for human pulmonary diseases.
Acknowledgments
Supported by the National Natural Science Foundation of China (Grant No. 32270442, 31872219, 31370401, 32030011, 31630071, 31772448) and the Postgraduate Research & Practice Innovation Program of Jiangsu Province (Grant No. KYCX23_1747, KYCX23_1740).
Conflict of Interest Statement
The author declares no conflicts of interest related to this manuscript.
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Figure 1.
Phylogenetic tree and divergence times based on fourfold degenerate sites of 5,243 one-to-one orthologous genes. Red font and “yes” represent species living in low-oxygen environments; black font and “no” represent closely related species. Adapted from the original article11.
Figure 1.
Phylogenetic tree and divergence times based on fourfold degenerate sites of 5,243 one-to-one orthologous genes. Red font and “yes” represent species living in low-oxygen environments; black font and “no” represent closely related species. Adapted from the original article11.
Figure 2.
Gene family expansion and contraction in 23 mammalian species. (A) Phylogenetic tree showing expansions (blue) and contractions (green). (B) Significant gene family expansions in hypoxia-tolerant mammals. (C) Functional annotation of significantly expanded gene families. Adapted from original article11.
Figure 2.
Gene family expansion and contraction in 23 mammalian species. (A) Phylogenetic tree showing expansions (blue) and contractions (green). (B) Significant gene family expansions in hypoxia-tolerant mammals. (C) Functional annotation of significantly expanded gene families. Adapted from original article11.
Figure 3.
Convergent gene loss and GO term enrichment analysis in whales, marine mammals, and high-altitude mammals. (A) Numbers of gene losses by lineage. (B) Venn diagram of commonly lost genes. (C) GO term enrichment of lost genes. Adapted from original article11.
Figure 3.
Convergent gene loss and GO term enrichment analysis in whales, marine mammals, and high-altitude mammals. (A) Numbers of gene losses by lineage. (B) Venn diagram of commonly lost genes. (C) GO term enrichment of lost genes. Adapted from original article11.
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