Research ArticleEVOLUTIONARY BIOLOGY

Genes lost during the transition from land to water in cetaceans highlight genomic changes associated with aquatic adaptations

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Science Advances  25 Sep 2019:
Vol. 5, no. 9, eaaw6671
DOI: 10.1126/sciadv.aaw6671
  • Fig. 1 Key coagulation factors that promote thrombosis were lost in the cetacean stem lineage.

    (A) F12 (coagulation factor XII) and KLKB1 (kallikrein B1) were lost in the cetacean stem lineage, consistent with previous findings (6, 22, 25). Boxes illustrate coding exons superimposed with those gene-inactivating mutations that are shared among odontocetes and mysticetes (both lineages are labeled in the phylogenetic tree) and thus likely occurred before the split of these lineages. The inset shows one representative inactivating mutation. Shared breakpoints imply that the deletion of KLKB1 coding exons 6 to 12 occurred in the cetacean stem lineage (intronic bases adjacent to exons 5 and 13 are in lowercase letters). All inactivating mutations in both genes are shown in figs. S4 and S5. (B) Left: F12 encodes a zymogen that autoactivates by contact with a variety of surfaces, which likely include nitrogen microbubbles that form during breath-hold diving (27, 29). KLKB1 encodes another zymogen that can be activated to plasma kallikrein (PK) by either activated F12 or by the endothelial membrane–associated endopeptidase prolylcarboxypeptidase (PRCP) (26). PK, in turn, can activate F12. Both activated F12 and PK proteases promote thrombosis formation (26). Right: Gene knockouts in mice suggest that loss of F12 and KLKB1 has no major effect on wound sealing but protects from thrombus formation via different mechanisms. While loss of KLKB1 protects from thrombosis by reducing the expression of F3 (coagulation or tissue factor III) (30), loss of F12 prevents activation on nitrogen microbubbles during diving. Because a vasoconstriction-induced reduction in blood vessel diameters and nitrogen microbubble formation increase the risk of thrombosis for frequent divers, the loss of both genes was likely beneficial for cetaceans.

  • Fig. 2 Loss of an error-prone DNA repair polymerase could have improved tolerance of oxidative DNA damage in cetaceans.

    (A) POLM (DNA polymerase mu) was lost in the cetacean stem lineage, as shown by shared gene-inactivating mutations. Visualization as in Fig. 1A. All inactivating mutations are shown in fig. S6. (B) ROS (reactive oxygen species) induce DNA damage, which includes oxidation of guanine (8-oxodG) as one the most frequent lesions. POLM encodes the DNA repair polymerase Polμ, which often does not perform a correct translesion synthesis (left) but instead introduces errors (right). In particular, Polμ typically deletes bases (35) or erroneously incorporates deoxy-adenosine opposite to 8-oxodG (instead of the correct deoxy-cytosine), which results in a C:G to A:T transversion mutation (34). In contrast to Polμ, another DNA repair polymerase Polλ is much less error prone (36). Loss of POLM in cetaceans may have reduced the mutagenic potential of diving-induced oxidative stress by increasing the utilization of the more precise Polλ and accurate homology-directed DNA repair.

  • Fig. 3 Loss of lung-related and renal transporter genes in the cetacean stem lineage.

    (A and B) The loss of MAP3K19 (mitogen-activated protein kinase 19) and SEC14L3 (SEC14-like lipid binding 3), which are specifically expressed in cell types of the lung, may relate to the high-performance respiratory system of cetaceans. (C) The loss of the renal amino acid transporter SLC6A18 (solute carrier family 6 member 18) offers an explanation for the low plasma arginine levels in cetaceans and may have contributed to stronger vasoconstriction during the diving response. Visualization as in Fig. 1A. A shared donor (gt ➔ at) and acceptor (ag ➔ aa) splice site disrupting mutation is indicated in (B). All inactivating mutations are shown in figs. S7 to S9.

  • Fig. 4 Loss of a pleiotropic ion transporter in cetaceans relates to the dispensability of saliva secretion.

    (A) Several shared inactivating mutations indicate that SLC4A9 (solute carrier family 4 member 9) was lost in the cetacean stem lineage. Visualization as in Fig. 1A. All inactivating mutations are shown in fig. S10. (B) Simplified illustration of saliva secretion. SLC4A9 encodes an ion transporter. (1) In the submandibular salivary gland, SLC4A9 participates in creating a transepithelial chloride anion flux into the acinar lumen, together with another transporter SLC12A2 and chloride channels (52). (2) This first evokes a passive movement of cations across the tight junctions into the acinar lumen. (3) The resulting osmotic gradient induces a flow of water, which constitutes fluid secretion into the acinar lumen, the initial site of saliva secretion. SLC4A9 knockout in mice leads to a 35% reduction in saliva secretion (52). The remaining saliva secretion potential in SLC4A9 knockout mice is maintained by SLC12A2 (52). However, SLC12A2 lacks inactivating mutations in cetaceans; these mutations lead to severe phenotypes in humans and mice (55), suggesting that gene essentiality maintained this gene in cetaceans. In addition to saliva secretion, SLC4A9 is also involved in transepithelial sodium ion flux in the kidney (not shown here) and participates in sodium chloride reabsorption (56), a process that is less important in hyperosmotic marine environments.

  • Fig. 5 Complete loss of melatonin synthesis and reception may have been a precondition to exclusively adopt unihemispheric sleep in cetaceans.

    (A) Shared inactivating mutations indicate that AANAT (aralkylamine N-acetyltransferase), the first enzyme required to synthesize melatonin, and MTNR1B, one of the two melatonin receptors, were lost in the cetacean stem lineage. Subsequently, the second enzyme ASMT (acetylserotonin O-methyltransferase) and the second receptor MTNR1A were probably independently lost in cetaceans after the split of odontocetes and mysticetes; however, overlapping deletions of the last ASMT coding exon and MTNR1A exon 2 do not exclude the possibility of ancestral gene losses. Visualization as in Fig. 1A. All inactivating mutations are shown in figs. S11 to S14. (B) Pathway to synthesize melatonin from serotonin and the main sites of expression of the two melatonin transmembrane receptors.

Supplementary Materials

  • Supplementary material for this article is available at http://advances.sciencemag.org/cgi/content/full/5/9/eaaw6671/DC1

    Fig. S1. Workflow for identifying gene losses that are lost in the cetacean stem lineage.

    Fig. S2. Raw DNA sequencing read validation of shared inactivating mutations.

    Fig. S3. Expression of the remnants of genes lost in cetaceans.

    Fig. S4. Inactivating mutations in F12 in cetaceans.

    Fig. S5. Inactivating mutations in KLKB1.

    Fig. S6. Inactivating mutations in POLM.

    Fig. S7. Inactivating mutations in MAP3K19.

    Fig. S8. Inactivating mutations in SEC14L3.

    Fig. S9. Inactivating mutations in SLC6A18.

    Fig. S10. Inactivating mutations in SLC4A9.

    Fig. S11. Inactivating mutations in AANAT.

    Fig. S12. Inactivating mutations in MTNR1B.

    Fig. S13. Inactivating mutations in ASMT.

    Fig. S14. Inactivating mutations in MTNR1A.

    Fig. S15. Inactivating mutations in TRIM14.

    Fig. S16. Inactivating mutations in TREM1.

    Fig. S17. Inactivating mutations in PGLYRP1.

    Fig. S18. Inactivating mutations in PGLYRP3.

    Fig. S19. Inactivating mutations in PGLYRP4.

    Fig. S20. Inactivating mutations in MSS51.

    Fig. S21. Inactivating mutations in ACSM3.

    Fig. S22. Inactivating mutations in ADH4.

    Fig. S23. Inactivating mutations in SPINK7.

    Fig. S24. Inactivating mutations in FABP12.

    Fig. S25. Inactivating mutations in ASIC5.

    Fig. S26. Inactivating mutations in C10orf82.

    Fig. S27. Convergent gene losses between any of the three aquatic or semi-aquatic mammalian lineages.

    Table S1. Species and genome assemblies used in this study.

    Table S2. Genes lost in the cetacean stem lineage.

    Table S3. Validation of all smaller inactivating mutations with raw DNA sequencing reads.

    Table S4. Analysis of relaxed selection.

    Table S5. Convergently inactivated genes between (semi-) aquatic mammalian clades, represented by killer whale, manatee, and Pacific walrus.

    References (7184)

  • Supplementary Materials

    The PDF file includes:

    • Fig. S1. Workflow for identifying gene losses that are lost in the cetacean stem lineage.
    • Fig. S2. Raw DNA sequencing read validation of shared inactivating mutations.
    • Fig. S3. Expression of the remnants of genes lost in cetaceans.
    • Fig. S4. Inactivating mutations in F12 in cetaceans.
    • Fig. S5. Inactivating mutations in KLKB1.
    • Fig. S6. Inactivating mutations in POLM.
    • Fig. S7. Inactivating mutations in MAP3K19.
    • Fig. S8. Inactivating mutations in SEC14L3.
    • Fig. S9. Inactivating mutations in SLC6A18.
    • Fig. S10. Inactivating mutations in SLC4A9.
    • Fig. S11. Inactivating mutations in AANAT.
    • Fig. S12. Inactivating mutations in MTNR1B.
    • Fig. S13. Inactivating mutations in ASMT.
    • Fig. S14. Inactivating mutations in MTNR1A.
    • Fig. S15. Inactivating mutations in TRIM14.
    • Fig. S16. Inactivating mutations in TREM1.
    • Fig. S17. Inactivating mutations in PGLYRP1.
    • Fig. S18. Inactivating mutations in PGLYRP3.
    • Fig. S19. Inactivating mutations in PGLYRP4.
    • Fig. S20. Inactivating mutations in MSS51.
    • Fig. S21. Inactivating mutations in ACSM3.
    • Fig. S22. Inactivating mutations in ADH4.
    • Fig. S23. Inactivating mutations in SPINK7.
    • Fig. S24. Inactivating mutations in FABP12.
    • Fig. S25. Inactivating mutations in ASIC5.
    • Fig. S26. Inactivating mutations in C10orf82.
    • Fig. S27. Convergent gene losses between any of the three aquatic or semi-aquatic mammalian lineages.
    • References (7184)

    Download PDF

    Other Supplementary Material for this manuscript includes the following:

    • Table S1 (Microsoft Excel format). Species and genome assemblies used in this study.
    • Table S2 (Microsoft Excel format). Genes lost in the cetacean stem lineage.
    • Table S3 (Microsoft Excel format). Validation of all smaller inactivating mutations with raw DNA sequencing reads.
    • Table S4 (Microsoft Excel format). Analysis of relaxed selection.
    • Table S5 (Microsoft Excel format). Convergently inactivated genes between (semi-) aquatic mammalian clades, represented by killer whale, manatee, and Pacific walrus.

    Files in this Data Supplement:

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