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Evidence for natural selection at the melanocortin-3 receptor gene in European and African populations

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Abstract

Aims

Obesity is increasing steadily in worldwide prevalence and is known to cause serious health problems in association with type 2 diabetes mellitus (T2DM), including hypertension, stroke, and cardiovascular diseases. According to the thrifty gene hypothesis, the natural selection of obesity-related genes is important during feast and famine because they control body weight and fat levels. Past human adaptations to environmental changes in food supply, lifestyle, and geography may have influenced the selection of genes associated with the metabolism of glucose, lipids, and energy. The melanocortin-3 receptor gene (MC3R) is associated with obesity, with MC3R-deficient mice showing increased fat mass. MC3R variations are also linked with childhood obesity and insulin resistance. Here, we aimed to uncover evidence of selection at MC3R.

Methods

We performed a three-step method to detect selection at MC3R using HapMap population data. We used Wright’s F statistics as a measure of population differentiation, the long-range haplotype test to identify extended haplotypes, and the integrated haplotype score (iHS) to detect selection at MC3R.

Results

We observed high population differentiation between European and African populations at two MC3R childhood obesity- and insulin resistance-associated single-nucleotide polymorphisms (rs3746619 and rs3827103) using Wright’s F statistics. The iHS revealed evidence of natural selection at MC3R.

Conclusions

These findings provide evidence for natural selection at MC3R. Further investigation is warranted into adaptive evolution at T2DM- and obesity-associated genes.

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References

  1. Stunkard AJ, Foch TT, Hrubec Z (1986) A twin study of human obesity. JAMA 256:51–54

    Article  CAS  PubMed  Google Scholar 

  2. Maes HH, Neale MC, Eaves LJ (1997) Genetic and environmental factors in relative body weight and human adiposity. Behav Genet 27:325–351

    Article  CAS  PubMed  Google Scholar 

  3. Yang J, Bakshi A, Zhu Z et al (2015) Genetic variance estimation with imputed variants finds negligible missing heritability for human height and body mass index. Nat Genet 47:1114–1120

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. Neel JV (1962) Diabetes mellitus: a “thrifty” genotype rendered detrimental by “progress”? Am J Hum Genet 14:353–362

    CAS  PubMed  PubMed Central  Google Scholar 

  5. Darwin C (1859) The origin of species by means of natural selection. Murray, London

    Google Scholar 

  6. Diamond J (2002) Evolution, consequences and future of plant and animal domestication. Nature 418:700–707

    Article  CAS  PubMed  Google Scholar 

  7. Yoshiuchi I (2013) Evidence of selection at insulin receptor substrate-1 gene loci. Acta Diabetol 50:775–779

    Article  CAS  PubMed  Google Scholar 

  8. Yoshiuchi I (2013) Two SNPs associated with type 2 diabetes and obesity at melanocortin-4 receptor gene loci exhibited high Fst values and natural selection. J Diabetes Metab S11:005. doi:10.4172/2155-6156.S11-005

    Google Scholar 

  9. Cooke GS, Campbell SJ, Bennett S et al (2008) Mapping of a novel susceptibility locus suggests a role for MC3R and CTSZ in human tuberculosis. Am J Respir Crit Care Med 178:203–207

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Chen AS, Marsh DJ, Trumbauer ME et al (2000) Inactivation of the mouse melanocortin-3 receptor results in increased fat mass and reduced lean body mass. Nat Genet 26:97–102

    Article  CAS  PubMed  Google Scholar 

  11. Feng N, Young SF, Aguilera G et al (2005) Co-occurrence of two partially inactivating polymorphisms of MC3R is associated with pediatric-onset obesity. Diabetes 54:2663–2667

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Rutanen J, Pihlajamäki J, Vänttinen M et al (2007) Single nucleotide polymorphisms of the melanocortin-3 receptor gene are associated with substrate oxidation and first-phase insulin secretion in offspring of type 2 diabetic subjects. J Clin Endocrinol Metab 92:1112–1117

    Article  CAS  PubMed  Google Scholar 

  13. Mencarelli M, Walker GE, Maestrini S et al (2008) Sporadic mutations in melanocortin receptor 3 in morbid obese individuals. Eur J Hum Genet 16:581–586

    Article  CAS  PubMed  Google Scholar 

  14. Mencarelli M, Dubern B, Alili R et al (2011) Rare melanocortin-3 receptor mutations with in vitro functional consequences are associated with human obesity. Hum Mol Genet 20:392–399

    Article  CAS  PubMed  Google Scholar 

  15. The International HapMap Consortium (2005) A haplotype map of the human genome. Nature 437:1299–1320

    Article  PubMed Central  Google Scholar 

  16. Novembre J, Di Rienzo A (2009) Spatial patterns of variation due to natural selection in humans. Nat Rev Genet 10:745–755

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Holsinger KE, Weir BS (2009) Genetics in geographically structured populations: defining, estimating and interpreting F (ST). Nat Rev Genet 10:639–650

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Sabeti PC, Reich DE, Higgins JM et al (2002) Detecting recent positive selection in the human genome from haplotype structure. Nature 419:832–837

    Article  CAS  PubMed  Google Scholar 

  19. Voight BF, Kudaravalli S, Wen X, Pritchard JK (2006) A map of recent positive selection in the human genome. PLoS Biol 4:446–458

    Article  CAS  Google Scholar 

  20. Excoffier L, Laval G, Schneider S (2005) Arlequin (version 3.0): an integrated software package for population genetics data analysis. Evol Bioinform Online 1:47–50

    CAS  Google Scholar 

  21. Southam L, Soranzo N, Montgomery SB et al (2009) Is the thrifty genotype hypothesis supported by evidence based on confirmed type 2 diabetes- and obesity-susceptibility variants? Diabetologia 52:1846–1851

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Pickrell JK, Coop G, Novembre J et al (2009) Signals of recent positive selection in a worldwide sample of human populations. Genome Res 19:826–837

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Caballero B (2007) The global epidemic of obesity: an overview. Epidemiol Rev 29:1–5. doi:10.1093/epirev/mxm012

    Article  PubMed  Google Scholar 

  24. Ng M, Fleming T, Robinson M et al (2014) Global, regional, and national prevalence of overweight and obesity in children and adults during 1980–2013: a systematic analysis for the Global Burden of Disease Study 2013. Lancet 384:766–781. doi:10.1016/S0140-6736(14)60460-8

    Article  PubMed  PubMed Central  Google Scholar 

  25. Ogden CL, Carroll MD, Kit BK, Flegal KM (2014) Prevalence of childhood and adult obesity in the United States, 2011–2012. JAMA 311:806–814. doi:10.1001/jama.2014.732

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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Acknowledgments

We want to thank Kyoko Yoshiuchi for secretarial assistance. Dr. Issei Yoshiuchi designed this project, analyzed data, wrote the manuscript, contributed to discussion, and reviewed and edited the manuscript.

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Authors and Affiliations

  1. Departments of Genetics, Diabetes Mellitus, and Medicine, Yoshiuchi Medical Diabetes Institute, 2-16-41 Kamakurayama, Kamakura City, Kanagawa, 248-0031, Japan

    Issei Yoshiuchi

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  1. Issei Yoshiuchi
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Correspondence to Issei Yoshiuchi.

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The author declares that there is no conflict of interests regarding the publication of this paper.

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The authors declare that there is no duality of interest associated with this manuscript.

Ethical standards

All procedures followed were in accordance with the ethical standards of the responsible committee on human experimentation and with the Helsinki Declaration, as revised in 2008 [5].

Human and Animal Rights

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

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Informed consent was obtained from all patients for being included in the study.

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Yoshiuchi, I. Evidence for natural selection at the melanocortin-3 receptor gene in European and African populations. Acta Diabetol 53, 583–587 (2016). https://doi.org/10.1007/s00592-016-0846-0

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  • DOI: https://doi.org/10.1007/s00592-016-0846-0

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