title: Increased constraints on MC4R during primate and human evolution.
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.
authors.affiliation: Department of Evolutionary Genetics, Max Planck Institute for Evolutionary Anthropology, Leipzig, Germany. hughes@eva.mpg.de
authors.forename: David A
authors.initials: DA
authors.lastname: Hughes
authors.forename: Anke
authors.initials: A
authors.lastname: Hinney
authors.forename: Harald
authors.initials: H
authors.lastname: Brumm
authors.forename: Anne-Kathrin
authors.initials: AK
authors.lastname: Wermter
authors.forename: Heike
authors.initials: H
authors.lastname: Biebermann
authors.forename: Johannes
authors.initials: J
authors.lastname: Hebebrand
authors.forename: Mark
authors.initials: M
authors.lastname: Stoneking
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D001483:Base Sequence; D019556:COS Cells; D002522:Chlorocebus aethiops; D000242:Cyclic AMP / Q000378:metabolism; D004252:DNA Mutational Analysis; D017931:DNA Primers / Q000235:genetics; D019143:Evolution, Molecular; D014644:Genetic Variation; D006801:Humans; D008969:Molecular Sequence Data; D009154:Mutation; D009765:Obesity / Q000235:genetics; D010802:Phylogeny; D011323:Primates / Q000235:genetics*; D044105:Receptor, Melanocortin, Type 4 / Q000235:genetics* / Q000378:metabolism; D011994:Recombinant Proteins / Q000235:genetics / Q000378:metabolism; D012641:Selection, Genetic; D017386:Sequence Homology, Amino Acid; D013045:Species Specificity; D014162:Transfection
chemical_list: D017931:DNA Primers; C470072:MC4R protein, human; D044105:Receptor, Melanocortin, Type 4; D011994:Recombinant Proteins; D000242:Cyclic AMP