Skip to main content

Advertisement

SpringerLink
Log in

Thr92Ala polymorphism in the type 2 deiodinase gene: an evolutionary perspective

  • Original Article
  • Published:
Journal of Endocrinological Investigation Aims and scope Submit manuscript

Abstract

Purpose

In the past, a role of thyroid hormones in human evolution has been hypothesized. T3, the metabolically active form, derives from extrathyroidal conversion of T4 by deionidase 2 (D2) enzyme encoded by DIO2 gene. In thyroid-deficient patients, decreased levels of free T3 have been associated with the polymorphism rs225014 A/G in DIO2, which causes the substitution of Threonine with Alanine (p.Thr92Ala) at protein level.

Methods

We compared DNA and protein sequences of D2 from archaic human subspecies with those of contemporary humans.

Results

Neanderthals and Denisovans displayed only the G allele at the rs225014 polymorphism, which encodes for an Alanine on the amino acid level. These data suggest that these hominines were homozygous for the Ala amino acid. These arcaic humans often lived in condition of iodine deficiency and thus, defective mechanisms of T3 biosynthesis could be life threatining. A reduced D2 activity is likely to cause decreased T3 levels, which could be critical for those individuals. Neanderthals and Denisovans were hunters/gatherers, and their diet was mainly based on the consumption of meat, with a low intake of carbohydrates. The need for circulating T3 is reduced at such alimentary conditions. On the basis of our genome comparisons the A allele, corresponding to Threonine and associated with higher levels of circulating T3 in thyroid-deficient patients, appeared for the first time during evolution in Anatomically Modern Humans during the Upper Pleistocene and has been conserved during the Neolithic age. With the advent of agriculture and herding, individuals carrying A allele might have a higher probability for surviving and reproducing. Thus, the variant was positively selected during the evolution.

Conclusion

Here we present an evolutionary perspective for p.Thr92Ala variant of D2 from Neanderthals to Anatomically Modern Humans

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2

Similar content being viewed by others

References

  1. Mullur R, Liu YY, Brent GA (2014) Thyroid hormone regulation of metabolism. Physiol Rev 94:355–382. https://doi.org/10.1152/physrev.00030.2013

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  2. Salvatore D (2018) Deiodinases and stem cells: an intimate relationship. J Endocrinol Invest 41:59–66. https://doi.org/10.1007/s40618-017-0737-4

    Article  CAS  PubMed  Google Scholar 

  3. Bianco AC (2011) Minireview: cracking the metabolic code for thyroid hormone signaling. Endocrinology 152:3306–3311. https://doi.org/10.1210/en.2011-1104

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. Bianco AC, Salvatore D, Gereben B, Berry MJ, Larsen PR (2002) Biochemistry, cellular and molecular biology and physiological roles of the iodothyronine selenodeiodinases. Endocr Rev 23:38–89. https://doi.org/10.1210/edrv.23.1.0455

    Article  CAS  PubMed  Google Scholar 

  5. Maia AL, Kim BW, Huang SA, Harney JW, Larsen PR (2005) Type 2 iodothyronine deiodinase is the major source of plasma T3 in euthyroid humans. J Clin Invest 115:2524–2533. https://doi.org/10.1172/JCI25083

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Luongo C, Dentice M, Salvatore D (2019) Deiodinases and their intricate role in thyroid hormone homeostasis. Nat Rev Endocrinol 15:479–488. https://doi.org/10.1038/s41574-019-0218-2

    Article  PubMed  Google Scholar 

  7. He B, Li J, Wang G, Ju W, Lu Y, Shi Y, He L, Zhong N (2009) Association of genetic polymorphisms in the type II deiodinase gene with bipolar disorder in a subset of Chinese population. Prog Neuropsychopharmacol Biol Psychiatry 33:986–990. https://doi.org/10.1016/j.pnpbp.2009.05.003

    Article  CAS  PubMed  Google Scholar 

  8. Butler PW, Smith SM, Linderman JD, Brychta RJ, Alberobello AT, Dubaz OM, Luzon JA, Skarulis MC, Cochran CS, Wesley RA, Pucino F, Celi FS (2010) The Thr92Ala 5' type 2 deiodinase gene polymorphism is associated with a delayed triiodothyronine secretion in response to the thyrotropin-releasing hormone-stimulation test: a pharmacogenomic study. Thyroid 20:1407–1412. https://doi.org/10.1089/thy.2010.0244

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Dora JM, Machado WE, Rheinheimer J, Crispim D, Maia AL (2010) Association of the type 2 deiodinase Thr92Ala polymorphism with type 2 diabetes: case-control study and meta-analysis. Eur J Endocrinol 163:427–434. https://doi.org/10.1530/EJE-10-0419

    Article  CAS  PubMed  Google Scholar 

  10. Castagna MG, Dentice M, Cantara S, Ambrosio R, Maino F, Porcelli T, Marzocchi C, Garbi C, Pacini F, Salvatore D (2017) DIO2 Thr92Ala reduces deiodinase-2 activity and serum-T3 levels in thyroid-deficient patients. J Clin Endocrinol Metab 102:1623–1630. https://doi.org/10.1210/jc.2016-2587

    Article  PubMed  Google Scholar 

  11. Cantara S, Ricci C, Maino F, Marzocchi C, Pacini F, Castagna MG (2019) Variants in MCT10 protein do not affect FT3 levels in athyreotic patients. Endocrine 66:551–556. https://doi.org/10.1007/s12020-019-02001-z

    Article  CAS  PubMed  Google Scholar 

  12. Jo S, Fonseca TL, Bocco BMLC, Fernandes GW, McAninch EA, Bolin AP, Da Conceição RR, Werneck-de-Castro JP, Ignacio DL, Egri P, Németh D, Fekete C, Bernardi MM, Leitch VD, Mannan NS, Curry KF, Butterfield NC, Bassett JHD, Williams GR, Gereben B, Ribeiro MO, Bianco AC (2019) Type 2 deiodinase polymorphism causes ER stress and hypothyroidism in the brain. J Clin Invest 129:230–245

  13. Crockford SJ (2003) Thyroid rhythm phenotypes and hominid evolution: a new paradigm implicates pulsatile hormone secretion in speciation and adaptation changes. Comp Biochem Physiol A Mol Integr Physiol 135:105–129. https://doi.org/10.1016/s1095-6433(02)00259-3

    Article  PubMed  Google Scholar 

  14. Poinar HN, Stankiewicz BA (1999) Protein preservation and DNA retrieval from ancient tissues. Proc Natl Acad Sci USA 96:8426–8431. https://doi.org/10.1073/pnas.96.15.8426

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Poinar HN (1999) DNA from fossils: the past and the future. Acta Paediatr Suppl 88:133–140. https://doi.org/10.1111/j.1651-2227.1999.tb14423.x

    Article  CAS  PubMed  Google Scholar 

  16. Scholz M, Bachmann L, Nicholson GJ, Bachmann J, Giddings I, Rüschoff-Thale B, Czarnetzki A, Pusch CM (2000) Genomic differentiation of Neanderthals and anatomically modern man allows a fossil-DNA-based classification of morphologically indistinguishable hominid bones. Am J Hum Genet 66:1927–1932. https://doi.org/10.1086/302949

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Noonan JP, Coop G, Kudaravalli S, Smith D, Krause J, Alessi J, Chen F, Platt D, Pääbo S, Pritchard JK, Rubin EM (2006) Sequencing and analysis of Neanderthal genomic DNA. Science 314:1113–1118. https://doi.org/10.1126/science.1131412

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Green RE, Krause J, Ptak SE, Briggs AW, Ronan MT, Simons JF, Du L, Egholm M, Rothberg JM, Paunovic M, Pääbo S (2006) Analysis of one million base pairs of Neanderthal DNA. Nature 444:330–336. https://doi.org/10.1038/nature05336

    Article  CAS  PubMed  Google Scholar 

  19. Wakefield MJ (2006) Genomics from Neanderthals to high-throughput sequencing. Genome Biol 7:326. https://doi.org/10.1186/gb-2006-7-8-326

    Article  PubMed  PubMed Central  Google Scholar 

  20. Rogers R, Bohlender RJ, Huff CD (2017) Early history of Neanderthals and Denisovans. Proc Natl Acad Sci USA 114:9859–9863. https://doi.org/10.1073/pnas.1706426114

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Bermúdez de Castro JM, Martinón-Torres M, Martínez de Pinillos M, García-Campos C, Modesto-Mata M, Martín-Francés L, Arsuaga JL (2019) Metric and morphological comparison between the Arago (France) and Atapuerca-Sima de los Huesos (Spain) dental samples, and the origin of Neanderthals. Q Sci Rev 217:45–61. https://doi.org/10.1016/j.quascirev.2018.04.003

    Article  Google Scholar 

  22. Hublin JJ (2009) The origin of Neandertals. Proc Natl Acad USA 106:16022–16027. https://doi.org/10.1073/pnas.0904119106

    Article  Google Scholar 

  23. Green RE, Krause J, Briggs AW, Maricic T, Stenzel U, Kircher M, Patterson N, Li H, Zhai W, Fritz MH, Hansen NF, Durand EY, Malaspinas AS, Jensen JD, Marques-Bonet T, Alkan C, Prüfer K, Meyer M, Burbano HA, Good JM, Schultz R, Aximu-Petri A, Butthof A, Höber B, Höffner B, Siegemund M, Weihmann A, Nusbaum C, Lander ES, Russ C, Novod N, Affourtit J, Egholm M, Verna C, Rudan P, Brajkovic D, Kucan Ž, Gušic I, Doronichev VB, Golovanova LV, Lalueza-Fox C, de la Rasilla M, Fortea J, Rosas A, Schmitz RW, Johnson PLF, Eichler EE, Falush D, Birney E, Mullikin JC, Slatkin M, Nielsen R, Kelso J, Lachmann M, Reich D, Pääbo S (2010) A draft sequence of the Neandertal genome. Science 328:710–722. https://doi.org/10.1126/science.1188021

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Higham T, Douka K, Wood R, Bronk Ramsey C, Brock F, Basell L, Camps M, Arrizabalaga A, Baena J, Barroso-Ruíz C, Bergman C, Boitard C, Boscato P, Caparrós M (2014) The timing and spatiotemporal patterning of Neanderthal disappearance. Nature 512:306–309. https://doi.org/10.1038/nature13621

    Article  CAS  PubMed  Google Scholar 

  25. Reich D, Green RE, Kircher M, Krause J, Patterson N, Durand EY, Viola B, Briggs AW, Stenzel U, Johnson PL, Maricic T, Good JM, Marques-Bonet T, Alkan C, Fu Q, Mallick S, Li H, Meyer M, Eichler EE, Stoneking M, Richards M, Talamo S, Shunkov MV, Derevianko AP, Hublin JJ, Kelso J, Slatkin M, Pääbo S (2010) Genetic history of an archaic hominin group from Denisova Cave in Siberia. Nature 468:1053–1060. https://doi.org/10.1038/nature09710

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Chen F, Welker F, Shen CC, Bailey SE, Bergmann I, Davis S, Xia H, Wang H, Fischer R, Freidline SE, Yu TL, Skinner MM, Stelzer S, Dong G, Fu Q, Dong G, Wang J, Zhang D, Hublin JJ (2019) A late Middle Pleistocene Denisovan mandible from the Tibetan Plateau. Nature 569:409–412. https://doi.org/10.1038/s41586-019-1139-x

    Article  CAS  PubMed  Google Scholar 

  27. Slon V, Mafessoni F, Vernot B, de Filippo C, Grote S, Viola B, Hajdinjak M, Peyrégne S, Nagel S, Brown S, Douka K, Higham T, Kozlikin MB, Shunkov MV, Derevianko AP, Kelso J, Meyer M, Prüfer K, Pääbo S (2018) The genome of the offspring of a Neanderthal mother and a Denisovan father. Nature 561:113–116. https://doi.org/10.1038/s41586-018-0455-x

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Mednikova M (2011) A proximal pedal phalanx of a Paleolithic hominin from Denisova cave, Altai. Archaeol Ethnol Anthropol Eurasia 39:129–138. https://doi.org/10.1016/j.aeae.2011.06.017

    Article  Google Scholar 

  29. Meyer M, Kircher M, Gansauge MT, Li H, Racimo F, Mallick S, Schraiber JG, Jay F, Prufer K, de Filippo C, Sudmant PH, Alkan C, Fu Q, Do R, Rohland N, Tandon A, Siebauer M, Green RE, Bryc K, Briggs AW, Stenzel U, Dabney J, Shendure J, Kitzman J, Hammer MF, Shunkov MV, Derevianko AP, Patterson N, Andres AM, Eichler EE, Slatkin M, Reich D, Kelso J, Paabo S (2012) A high-coverage genome sequence from an archaic denisovan individual. Science 328:710–722. https://doi.org/10.1126/science.1224344

    Article  CAS  Google Scholar 

  30. van de Loosdrecht M, Bouzouggar A, Humphrey L, Posth C, Barton N, Aximu-Petri A, Nickel B, Nagel S, Talbi EH, El Hajraoui MA, Amzazi S, Hublin JJ, Pääbo S, Schiffels S, Meyer M, Haak W, Jeong C, Krause J (2018) Pleistocene North African genomes link Near Eastern and sub-Saharan African human populations. Science 360:548–552. https://doi.org/10.1126/science.aar8380

    Article  CAS  PubMed  Google Scholar 

  31. Sikora M, Seguin-Orlando A, Sousa VC (2017) Ancient genomes show social and reproductive behavior of early Upper Paleolithic foragers. Science 358:659–662. https://doi.org/10.1126/science.aao1807

    Article  CAS  PubMed  Google Scholar 

  32. Prendergast ME, Lipson M, Sawchuk EA, Olalde I, Ogola CA, Rohland N, Sirak KA, Adamski N, Bernardos R, Broomandkhoshbacht N, Callan K, Culleton BJ, Eccles L, Harper TK, Lawson AM, Mah M, Oppenheimer J, Stewardson K, Zalzala F, Ambrose SH, Ayodo G, Gates HL Jr, Gidna AO, Katongo M, Kwekason A, Mabulla AZP, Mudenda GS, Ndiema EK, Nelson C, Robertshaw P, Kennett DJ, Manthi FK, Reich D (2019) Ancient DNA reveals a multistep spread of the first herders into sub-Saharan Africa. Science 365:6448. https://doi.org/10.1126/science.aaw6275

    Article  CAS  Google Scholar 

  33. Leinonen R, Sugawara H, Shumway M (2011) International nucleotide sequence database collaboration. The sequence read archive. Nucleic Acids Res 39:D19–21. https://doi.org/10.1093/nar/gkq1019

    Article  CAS  PubMed  Google Scholar 

  34. Altschul SF, Gish W, Miller W, Myers EW, Lipman DJ (1990) Basic local alignment search tool. J Mol Biol 21:403–410. https://doi.org/10.1016/S0022-2836(05)80360-2

    Article  Google Scholar 

  35. Lobo I, Shaw K (2008) Phenotypic range of gene expression: environmental influence. Nature Education 1:12

    Google Scholar 

  36. Ralston A, Shaw K (2008) Environment controls gene expression: Sex determination and the onset of genetic disorders. Nature Education 1:203

    Google Scholar 

  37. Gereben B, McAninch EA, Ribeiro MO, Bianco AC (2015) Scope and limitations of iodothyronine deiodinases in hypothyroidism. Nat Rev Endocrinol 11:642–652. https://doi.org/10.1038/nrendo.2015.155

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Arrojo E, Drigo R, Fonseca TL, Werneck-de-Castro JP, Bianco AC (2013) Role of the type 2 iodothyronine deiodinase (D2) in the control of thyroid hormone signaling. Biochim Biophys Acta 1830:3956–3964. https://doi.org/10.1016/j.bbagen.2012.08.019

    Article  CAS  Google Scholar 

  39. Kopp W (2004) Nutrition, evolution and thyroid hormone levels a link to iodine deficiency disorders? Med Hypotheses 62:871–875. https://doi.org/10.1016/j.mehy.2004.02.033

    Article  CAS  PubMed  Google Scholar 

  40. Eaton SB (2006) The ancestral human diet: what was it and should it be a paradigm for contemporary nutrition? Proc Nutr Soc 65:1–6. https://doi.org/10.1079/pns2005471

    Article  CAS  PubMed  Google Scholar 

  41. Jaouen K, Richards MP, Le Cabec A, Welker F, Rendu W, Hublin JJ, Soressi M, Talamo S (2019) Exceptionally high δ(15)N values in collagen single amino acids confirm Neandertals as high-trophic level carnivores. Proc Natl Acad Sci USA 116:4928–4933. https://doi.org/10.1073/pnas.1814087116

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  42. Crockford S (2002) Commentary: thyroid hormone in neandertal evolution: a natural or a pathological role? Geogr Rev 92:73–88. https://doi.org/10.2307/4140952

    Article  Google Scholar 

  43. Mathieson RA, Walberg JL, Gwazdauskas FC, Hinkle DE, Gregg JM (1986) The effect of varying carbohydrate content of a very-low-caloric diet on resting metabolic rate and thyroid hormones. Metabolism 35:394–398. https://doi.org/10.1016/0026-0495(86)90126-5

    Article  CAS  PubMed  Google Scholar 

  44. Humphrey LT, De Groote I, Morales J, Barton N, Collcutt S, Bronk Ramsey C, Bouzouggar A (2014) Earliest evidence for caries and exploitation of starchy plant foods in Pleistocene hunter-gatherers from Morocco. Proc Natl Acad Sci USA 21(111):954–959. https://doi.org/10.1073/pnas.1318176111

    Article  CAS  Google Scholar 

  45. De Groote I, Humphrey LT (2016) Characterizing evulsion in the later stone age maghreb: age, sex and effects on mastication. Quatern Int 413:50–61

    Article  Google Scholar 

  46. Zhang X, Sun J, Han W, Jiang Y, Peng S, Shan Z, Teng W (2016) The type 2 deiodinase Thr92Ala polymorphism is associated with worse glycemic control in patients with type 2 diabetes mellitus: a systematic review and meta-analysis. J Diabetes Res 2016:5928726. https://doi.org/10.1155/2016/5928726

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  47. Bersaglieri T, Sabeti PC, Patterson N, Vanderploeg T, Schaffner SF, Drake JA, Rhodes M, Reich DE, Hirschhorn JN (2004) Genetic signatures of strong recent positive selection at the lactase gene. Am J Hum Genet 74:1111–1120. https://doi.org/10.1086/421051

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  48. Wildea S, Timpson A, Ka K, Kaiserd E, Kaysere Md, Unterländera M, Hollfeldera N, Potekhinaf ID, Schierd W, Thomas MG, Burgera J (2014) Direct evidence for positive selection of skin, hair, and eye pigmentation in Europeans during the last 5,000 y. Proc Natl Acad Sci USA 111:4832–4837. https://doi.org/10.1073/pnas.1316513111

    Article  CAS  Google Scholar 

  49. Jablonski NG, Chaplin G (2010) Human skin pigmentation as an adaptation to UV radiation. Proc Natl Acad Sci USA 107:8962–8968. https://doi.org/10.1073/pnas.0914628107

    Article  PubMed  PubMed Central  Google Scholar 

  50. Laland KN, Odling-Smee J, Myles S (2010) How culture shaped the human genome: bringing genetics and the human sciences together. Nature Rev Genet 11:137–148. https://doi.org/10.1016/j.quaint.2015.08.082

    Article  CAS  PubMed  Google Scholar 

  51. Haber M, Mezzavilla M, Xue Y, Tyler-Smith C (2016) Ancient DNA and the rewriting of human history: be sparing with Occam’s razor. Genome Biol 17:1. https://doi.org/10.1186/s13059-015-0866-z

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  52. Richards MP, Schulting RJ, Hedges RE (2003) Archaeology: sharp shift in diet at onset of Neolithic. Nature 425:366. https://doi.org/10.1038/425366a

    Article  CAS  PubMed  Google Scholar 

Download references

Funding

This work was supported in part by the German Research Council Ku961/13-1 and Ku961/14-1.

Author information

Author notes

  1. Claudia Ricci and Kumar Reddy Kakularam contributed equally to the work.

Authors and Affiliations

  1. Department of Medical, Surgical and Neurological Sciences, University of Siena, Viale Bracci 16, 53100, Siena, Italy

    C. Ricci, C. Marzocchi, G. Riolo, M. G. Castagna & S. Cantara

  2. Corporate Member of Freie Universität Berlin, Humboldt-Universität Zu Berlin, and Berlin Institute of Health, Institute of Biochemistry, Charité-Universitätsmedizin Berlin, Berlin, Germany

    K. R. Kakularam & H. Kuhn

  3. Department of Physical Sciences, Earth and Environment, University of Siena, Siena, Italy

    G. Capecchi & F. Boschin

Authors
  1. C. Ricci
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. K. R. Kakularam
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. C. Marzocchi
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. G. Capecchi
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. G. Riolo
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. F. Boschin
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. H. Kuhn
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. M. G. Castagna
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. S. Cantara
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to S. Cantara.

Ethics declarations

Conflict of interest

The authors declare that they have no conflict of interest.

Human and animal rights

This article does not contain any studies with human participants or animals performed by any of the authors.

Informed consent

For this type of study, formal consent is not required.

Additional information

Publisher's Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Ricci, C., Kakularam, K.R., Marzocchi, C. et al. Thr92Ala polymorphism in the type 2 deiodinase gene: an evolutionary perspective. J Endocrinol Invest 43, 1749–1757 (2020). https://doi.org/10.1007/s40618-020-01287-5

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s40618-020-01287-5

Keywords

Search

Navigation