CoChat
Sign Up
Cited by 15

The DOI matches its Crossref record; 3 of the 3 references it cites were found in a registry or an index.

Evolutionary genetics of flipper forelimb and hindlimb loss from limb development-related genes in cetaceans

Sun, Linxia, Rong, Xinghua, Liu, Xing, Yu, Zhenpeng, Zhang, Qian, Ren, Wenhua, Yang, Guang, Xu, Shixia·2022·BMC Genomics
DOI 10.1186/s12864-022-09024-3PMC PMC9719152
Open this paper in CoChat — free account

Abstract

Background: Cetacean hindlimbs were lost and their forelimb changed into flippers characterized by webbed digits and hyperphalangy, thus allowing them to adapt to a completely aquatic environment. However, the underlying molecular mechanism behind cetacean limb development remains poorly understood. Results: In the present study, we explored the evolution of 16 limb-related genes and their cis-regulatory elements in cetaceans and compared them with that of other mammals. TBX5, a forelimb specific expression gene, was identified to have been under accelerated evolution in the ancestral branches of cetaceans. In addition, 32 cetacean-specific changes were examined in the SHH signaling network (SHH, PTCH1, TBX5, BMPs and SMO), within which mutations could yield webbed digits or an additional phalange. These findings thus suggest that the SHH signaling network regulates cetacean flipper formation. By contrast, the regulatory activity of the SHH gene enhancer—ZRS in cetaceans—was significantly lower than in mice, which is consistent with the cessation of SHH gene expression in the hindlimb bud during cetacean embryonic development. It was suggested that the decreased SHH activity regulated by enhancer ZRS might be one of the reasons for hindlimb degeneration in cetaceans. Interestingly, a parallel / convergent site (D42G) and a rapidly evolving CNE were identified in marine mammals in FGF10 and GREM1, respectively, and shown to be essential to restrict limb bud size; this is molecular evidence explaining the convergence of flipper-forelimb and shortening or degeneration of hindlimbs in marine mammals. Conclusions: We did evolutionary analyses of 16 limb-related genes and their cis-regulatory elements in cetaceans and compared them with those of other mammals to provide novel insights into the molecular basis of flipper forelimb and hindlimb loss in cetaceans.

Overview

The claims and statistics of this paper haven’t been checked yet.

Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.

A few free checks a day · papers already verified open instantly · results are public

Integrity signals

Registry

Crossref · 10.1186/s12864-022-09024-3

Cites

3 of 3 references verified0 citation errors · 0 not checkable

Statistics

Verification

Claims the paper makes

The claims and statistics of this paper haven’t been checked yet.

Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.

A few free checks a day · papers already verified open instantly · results are public

Claims other papers make about this one

Each is checked against this paper’s own text: does it say what the citing paper says it does?

  • The first applications of PhyloAcc to genomewide datasets are beginning to appear.

    “Inde e d , the fir st a pplica tio ns o f PhyloAcc to geno mew ide d ata sets are beginning to appear ( Sun et al. 2022 ;Xu et al. 2022 ;Cicconardi et al. 2023 ;Eastment et al. 2024 )”

    From Practical Guidance and Workflows for Identifying Fast Evolving Non-Coding Genomic Elements Using PhyloAcc (2024) · cites this paper as Sun et al. 2022

    The Methods section (‘Evolution analysis of regulatory elements in 16 limb-related genes’) says the authors used PhyloAcc on alignments built from mammalian genomes. But they screened candidate regions near 16 limb-related genes, and the Results (‘Analysis of cis-regulatory elements’) report 26 CNEs in those regions. This supports an application to genomic data, not a genomewide analysis. (LLM, conf=0.86)

    Experimental — accuracy not yet measured

  • PhyloAcc and its descendants are already being used in a variety of contexts and animal clades.

    “PhyloAcc an d its descendants provide a n importa nt adva nce towa rd re alizing t he f u l l potent ia l of PhyloG2P a nd a r e alr eady being used in a variety of contexts and animal clades ( Sac kt on et al . 2019 ;Sun et al . 2022 ;Wuit c hik et al . 2022 ;Xu et al. 2022 ;Cicconardi et a l. 2023 ;East ment et al. 2024 ).”

    From Practical Guidance and Workflows for Identifying Fast Evolving Non-Coding Genomic Elements Using PhyloAcc (2024) · cites this paper as Sun et al. 2022

Self-check

Percentages, sums and reported differences re-computed from the paper’s own numbers.

The self-check needs the paper’s full text.

Citations

Cites

Flagged first, then by citations

Research works printed but not linked: 58

  1. Cooper LN, Dawson SD, Reidenberg JS, Berta A. Neuromuscular anatomy and evolution of the cetacean forelimb. Anat Rec. 2007;290:1121–37. · DOI
  2. Reidenberg JS. Anatomical adaptations of aquatic mammals. Anat Rec. 2007;290:507–13. · DOI
  3. Cooper LN, Berta A, Dawson SD, Reidenberg JS. Evolution of hyperphalangy and digit reduction in the cetacean Manus. Anat Rec. 2007;290(6):654–72. · DOI
  4. Richardson MK, Oelschläger HH. Time, pattern, and heterochrony: a study of hyperphalangy in the dolphin embryo flipper. Evol Dev. 2002;4(6):435–44. · DOI
  5. Fedak TJ, Hall BK. Perspectives on hyperphalangy: patterns and processes. J Anat. 2004;204(3):151–63. · DOI
  6. Richardson MK, Chipman AD. Developmental constraints in a comparative framework: a test case using variations in phalanx number during amniote evolution. Mol Dev Evol. 2003;296(1):8–22. · DOI
  7. Hartmann C, Tabin CJ. Wnt-14 plays a pivotal role in inducing synovial joint formation in the developing appendicular skeleton. Cell. 2001;104(3):341–51. · DOI
  8. Cooper LN, Sears KE, Armfield BA, Kala B, Hubler M, Thewissen J. Review and experimental evaluation of the embryonic development and evolutionary history of flipper development and hyperphalangy in dolphins (Cetacea: Mammalia). Genesis. 2018;56(1):e23076. · DOI
  9. Javier LR. The many lives of SHH in limb development and evolution. Semin Cell Dev Biol. 2016;49:116–24. · DOI
  10. Zhu J, Mackem S. John Saunders' ZPA, sonic hedgehog and digit identity-how does it really all work? Dev Biol. 2017;429(2):391–400. · DOI
  11. Wada N, Kawakami Y, Nohno T. Sonic hedgehog signaling during digit pattern duplication after application of recombinant protein and expressing cells. Develop Growth Differ. 1999;41(5):567–74. · DOI
  12. Litingtung Y, Dahn RD, Li Y, Fallon JF, Chiang C. Shh and Gli3 are dispensable for limb skeleton formation but regulate digit number and identity. Nature. 2002;418(6901):979–83. · DOI
  13. Ros MA, Dahn RD, Fernandez-Teran M, Rashka K, Caruccio NC, Hasso SM, et al. The chick oligozeugodactyly (ozd) mutant lacks sonic hedgehog function in the limb. Development. 2003;130(3):527–37. · DOI
  14. Murgai A, Altmeyer S, Wiegand S, Tylzanowski P, Stricker S. Cooperation of BMP and IHH signaling in interdigital cell fate determination. PLoS One. 2018;13(5):e0197535. · DOI
  15. Kaltcheva MM, Anderson MJ, Harfe BD, Lewandoski M. BMPs are direct triggers of interdigital programmed cell death. Dev Biol. 2006;411(2):266–76. · DOI
  16. Montero JA, Gañan Y, Macias D, Rodriguez-Leon J, Sanz-Ezquerro JJ, Merino R, et al. Role of FGFs in the control of programmed cell death during limb development. Development. 2001;128(11):2075–84. · DOI
  17. Hernández-Martínez R, Covarrubias L. Interdigital cell death function and regulation: new insights on an old programmed cell death model. Develop Growth Differ. 2011;53(2):245–58. · DOI
  18. Itoh N. FGF10: a multifunctional mesenchymal-epithelial signaling growth factor in development, health, and disease. Cytokine Growth F R. 2016;28:63–9. · DOI
  19. Rallis C, Bruneau BG, Del Buono J, Seidman CE, Seidman J, Nissim S, et al. Tbx5 is required for forelimb bud formation and continued outgrowth. Development. 2003;130:2741–51. · DOI
  20. Kariminejad A, Szenker-Ravi E, Lekszas C, Tajsharghi H, Moslemi A-R, Naert T, et al. Homozygous null TBX4 mutations lead to posterior amelia with pelvic and pulmonary hypoplasia. Am J Hum Genet. 2019;105(6):1294–301. · DOI
  21. Klopocki E, Kähler C, Foulds N, Shah H, Joseph B, Vogel H, et al. Deletions in PITX1 cause a spectrum of lower-limb malformations including mirror-image polydactyly. Eur J Hum Genet. 2012;20(6):705–8. · DOI
  22. Kvon EZ, Kamneva OK, Melo US, Barozzi I, Osterwalder M, Mannion BJ, et al. Progressive loss of function in a limb enhancer during snake evolution. Cell. 2016;167(3):633–42. · DOI
  23. Leal F, Cohn MJ. Loss and re-emergence of legs in snakes by modular evolution of sonic hedgehog and HOXD enhancers. Curr Biol. 2016;26(21):2966–73. · DOI
  24. Potuijt JW, Baas M, Sukenik-Halevy R, Douben H, Nguyen P, Venter DJ, et al. A point mutation in the pre-ZRS disrupts sonic hedgehog expression in the limb bud and results in triphalangeal thumb-polysyndactyly syndrome. Genet Med. 2018;20(11):1405–13. · DOI
  25. Infante CR, Mihala AG, Park S, Wang JS, Johnson KK, Lauderdale JD, et al. Shared enhancer activity in the limbs and phallus and functional divergence of a limb-genital cis-regulatory element in snakes. Dev Cell. 2015;35(1):107–19. · DOI
  26. Chan YF, Marks ME, Jones FC, Villarreal G, Shapiro MD, Brady SD, et al. Adaptive evolution of pelvic reduction in sticklebacks by recurrent deletion of a Pitx1 enhancer. Science. 2010;327(5963):302–5. · DOI · Paper page
  27. Osterwalder M, Speziale D, Shoukry M, Mohan R, Ivanek R, Kohler M, et al. HAND2 targets define a network of transcriptional regulators that compartmentalize the early limb bud mesenchyme. Dev Cell. 2014;31(3):345–57. · DOI
  28. Tokita M, Matsushita H, Asakura Y. Developmental mechanisms underlying webbed foot morphological diversity in waterbirds. Sci Rep. 2020;10(1):1–11. · DOI
  29. Lin Q, Fan S, Zhang Y, Xu M, Zhang H, Yang Y, et al. The seahorse genome and the evolution of its specialized morphology. Nature. 2016;540(7633):395–9. · DOI
  30. Koyano-Nakagawa N, Gong W, Das S, Theisen JWM, Swanholm TB, Van Ly D, et al. Etv2 regulates enhancer chromatin status to initiate Shh expression in the limb bud. Nat Commun. 2022;13(1):4221. · DOI
  31. Peluso S, Douglas A, Hill A, De Angelis C, Moore BL, Grimes G, et al. Fibroblast growth factors (FGFs) prime the limb specific Shh enhancer for chromatin changes that balance histone acetylation mediated by E26 transformation-specific (ETS) factors. eLife. 2017;6:e28590. · DOI
  32. Tickle C, Towers M. Sonic hedgehog signaling in limb development. Front Cell Dev Biol. 2017;5:14. · DOI
  33. Sanz-Ezquerro JJ, Tickle C. Fgf signaling controls the number of phalanges and tip formation in developing digits. Curr Biol. 2003;13(20):1830–6. · DOI
  34. Resh MD. Palmitoylation of hedgehog proteins by hedgehog acyltransferase: roles in signalling and disease. Open Biol. 2021;11(3):200414. · DOI
  35. Feng W, Choi I, Clouthier DE, Niswander L, Williams T. The Ptch1DL mouse: a new model to study lambdoid craniosynostosis and basal cell nevus syndrome-associated skeletal defects. Genesis. 2013;51(10):677–89. · DOI
  36. Duprez D, Bell EJ, Richardson MK, Archer CW, Wolpert L, Brickell PM, et al. Overexpression of BMP-2 and BMP-4 alters the size and shape of developing skeletal elements in the chick limb. Mech Dev. 1996;57(2):145–57. · DOI
  37. Macias D, Gañan Y, Sampath TK, Piedra ME, Ros MA, Hurle JM. Role of BMP-2 and OP-1 (BMP-7) in programmed cell death and skeletogenesis during chick limb development. Development. 1997;124(6):1109–17. · DOI
  38. Satoh A, Suzuki M, Amano T, Tamura K, Ide H. Joint development in Xenopus laevis and induction of segmentations in regenerating froglet limb (spike). Dev Dyn. 2005;233(4):1444–53. · DOI
  39. Cunningham TJ, Lancman JJ, Berenguer M, Dong PDS, Duester G. Genomic knockout of two presumed forelimb Tbx5 enhancers reveals they are nonessential for limb development. Cell Rep. 2018;23(11):3146–51. · DOI
  40. Cooper KL, Sears KE, Uygur A, Maier J, Baczkowski KS, Brosnahan M, et al. Patterning and post-patterning modes of evolutionary digit loss in mammals. Nature. 2014;511(7507):41–5. · DOI
  41. Lopez-Rios J, Duchesne A, Speziale D, Andrey G, Peterson KA, Germann P, et al. Attenuated sensing of SHH by Ptch1 underlies evolution of bovine limbs. Nature. 2014;511(7507):46–51. · DOI
  42. Galis F, Vanalphen JJM, Metz JAJ. Why five fingers? Evolutionary constraints on digit numbers. Am Zool. 2001;41(6):1448–9.
  43. Xu J, Wu J, Teng X, Cai L, Yuan H, Chen X, et al. Large duplication in LMBR1 gene in a large Chinese pedigree with triphalangeal thumb polysyndactyly syndrome. Am J Med Genet A. 2020;182(9):2117–23. · DOI
  44. Thewissen J, Cohn M, Stevens L, Bajpai S, Heyning J, Horton W. Developmental basis for hind-limb loss in dolphins and origin of the cetacean bodyplan. Proc Natl Acad Sci U S A. 2006;103(22):8414–8. · DOI
  45. Booker BM, Friedrich T, Mason MK, VanderMeer JE, Zhao J, Eckalbar WL, et al. Bat accelerated regions identify a bat forelimb specific enhancer in the HoxD locus. PLoS Genet. 2016;12(3):e1005738. · DOI · Paper page
  46. Weber PW, Howle LE, Murray MM, Fish FE. Lift and drag performance of odontocete cetacean flippers. J Exp Biol. 2009;212(14):2149–58. · DOI
  47. Pajni-Underwood S, Wilson CP, Elder C, Mishina Y, Lewandoski M. BMP signals control limb bud interdigital programmed cell death by regulating FGF signaling. Development. 2007;134(12):2359–68. · DOI
  48. Weatherbee SD, Behringer RR, Rasweiler JJ, Niswander LA. Interdigital webbing retention in bat wings illustrates genetic changes underlying amniote limb diversification. Proc Natl Acad Sci U S A. 2006;103(41):15103–7. · DOI
  49. Löytynoja A. Phylogeny-aware alignment with PRANK in multiple sequence alignment methods. Methods Mol Biol. 2014;1079:155–70. · DOI
  50. Castresana J. Selection of conserved blocks from multiple alignments for their use in phylogenetic analysis. Mol Biol Evol. 2000;17(4):540–52. · DOI
  51. Lalitha S. Primer premier 5. Biotech Softw Inter Rep. 2000;1(6):270–2. · DOI
  52. Yang Z. PAML 4: phylogenetic analysis by maximum likelihood. Mol Biol Evol. 2007;24(8):1586–91. · DOI · Paper page
  53. Kumar S, Stecher G, Suleski M, Hedges SB. TimeTree: a resource for timelines, timetrees, and divergence times. Mol Biol Evol. 2017;34(7):1812–9. · DOI
  54. Huang X, Sun D, Wu T, Liu X, Xu S, Yang G. Genomic insights into body size evolution in Carnivora support Peto's paradox. BMC Genomics. 2021;22(1):429. · DOI
  55. Kent WJ, Baertsch R, Hinrichs A, Miller W, Haussler D. Evolution's cauldron: duplication, deletion, and rearrangement in the mouse and human genomes. Proc Natl Acad Sci U S A. 2003;100(20):11484–9. · DOI · Paper page
  56. Blanchette M, Kent WJ, Riemer C, Elnitski L, Smit AF, Roskin KM, et al. Aligning multiple genomic sequences with the threaded blockset aligner. Genome Res. 2004;14(4):708–15. · DOI · Paper page
  57. Sun Y. FasParser2: a graphical platform for batch manipulation of tremendous amount of sequence data. Bioinformatics. 2018;34(14):2493–5. · DOI
  58. Liang N, Deme L, Kong Q, Sun L, Cao Y, Wu T, et al. Divergence of Tbx4 hindlimb enhancer HLEA underlies the hindlimb loss during cetacean evolution. Genomics. 2022;114(2):110292. · DOI

Cited by

Sorted by citations

Metadata

Authors
Sun, L., Rong, X., Liu, X., Yu, Z., Zhang, Q., Ren, W., Yang, G., & Xu, S.
Venue
BMC Genomics
Publisher
Springer Science and Business Media LLC
Published
2022-12-02
Volume
23
Issue
1
ISSN
1471-2164
DOI
10.1186/s12864-022-09024-3
PMC
PMC9719152
Cited by
15
References
3
Language
en
Licence

About these checks

Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.

Statistics and arithmetic are recomputed, not judged.

Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.

What counts as a claim ›How we measure confidence ›How we check this ›

Are you an author, or do you see a problem with this page? Request a review