Increased constraints on MC4R during primate and human evolution |
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Authors: | David A Hughes Anke Hinney Harald Brumm Anne-Kathrin Wermter Heike Biebermann Johannes Hebebrand Mark Stoneking |
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Institution: | 1.Department of Evolutionary Genetics,Max Planck Institute for Evolutionary Anthropology,Leipzig,Germany;2.Department of Child and Adolescent Psychiatry,University of Duisburg-Essen,Essen,Germany;3.Institute of Experimental Pediatric Endocrinology,Charité Universit?tsmedizin Berlin,Berlin,Germany;4.Department of Child and Adolescent Psychiatry,Philipps-University,Marburg,Germany |
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Abstract: | The melanocortin 4 receptor (MC4R) is routinely investigated for the role it plays in human obesity, as mutations in MC4R are the most common dominantly inherited form of the disease. As little is known about the evolutionary history of this locus,
we investigated patterns of variation at MC4R in a worldwide sample of 1,015 humans from 51 populations, and in 8 central chimpanzees. There is a significant paucity of
diversity at MC4R in humans, but not in chimpanzees. The spectrum of mutations in humans, combined with the overall low level of diversity,
suggests that most (if not all) of the observed non-synonymous polymorphisms are likely to be transient deleterious mutations.
The MC4R coding region was resequenced in 12 primate species and sequences from an additional 29 vertebrates were included in molecular
evolutionary analyses. MC4R is highly conserved throughout vertebrate evolution, and has apparently been subject to high levels of continuous purifying
selection that increased approximately threefold during primate evolution. Furthermore, the strong selection extends to codon
usage bias, where most silent mutations are expected to be either quickly fixed or removed from the population, which may
help explain the unusually low levels of silent polymorphisms in humans. Finally, there is a significant tendency for non-synonymous
mutations that impact MC4R function to occur preferentially at sites that are identified by evolutionary analyses as being subject to very strong purifying
selection. The information from this study should help inform future epidemiological investigations of MC4R.
Electronic supplementary material The online version of this article (doi:) contains supplementary material, which is available to authorized users. |
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