title: Lack of direct evidence for natural selection at the candidate thrifty gene locus, PPARGC1A.
abstract: BACKGROUND
  The gene PPARGC1A, in particular the Gly482Ser variant (rs8192678), had been proposed to be subject to natural selection, particularly in recent progenitors of extant Polynesian populations. Reasons include high levels of population differentiation and increased frequencies of the derived type 2 diabetes (T2D) risk 482Ser allele, and association with body mass index (BMI) in a small Tongan population. However, no direct statistical tests for selection have been applied.
  
  
  METHODS
  Using a range of Polynesian populations (Tongan, Māori, Samoan) we re-examined evidence for association between Gly482Ser with T2D and BMI as well as gout. Using also Asian, European, and African 1000 Genome Project samples a range of statistical tests for selection (FST, integrated haplotype score (iHS), cross population extended haplotype homozygosity (XP-EHH), Tajima's D and Fay and Wu's H) were conducted on the PPARGC1A locus.
  
  
  RESULTS
  No statistically significant evidence for association between Gly482Ser and any of BMI, T2D or gout was found. Population differentiation (FST) was smallest between Asian and Pacific populations (New Zealand Māori ≤ 0.35, Samoan ≤ 0.20). When compared to European (New Zealand Māori ≤ 0.40, Samoan ≤ 0.25) or African populations (New Zealand Māori ≤ 0.80, Samoan ≤ 0.66) this differentiation was larger. We did not find any strong evidence for departure from neutral evolution at this locus when applying any of the other statistical tests for selection. However, using the same analytical methods, we found evidence for selection in specific populations at previously identified loci, indicating that lack of selection was the most likely explanation for the lack of evidence of selection in PPARGC1A.
  
  
  CONCLUSIONS
  We conclude that there is no compelling evidence for selection at this locus, and that this gene should not be considered a candidate thrifty gene locus in Pacific populations. High levels of population differentiation at this locus and the reported absence of the derived 482Ser allele in some Melanesian populations, can alternatively be explained by multiple out-of-Africa migrations by ancestral progenitors, and subsequent genetic drift during colonisation of Polynesia. Intermediate 482Ser allele frequencies in extant Western Polynesian populations could therefore be due to recent admixture with Melanesian progenitors.
authors.affiliation: Department of Biochemistry, University of Otago, Dunedin, New Zealand.|Virtual Institute of Statistical Genetics (www.visg.co.nz), Dunedin, New Zealand.
authors.forename: Murray
authors.initials: M
authors.lastname: Cadzow
authors.affiliation: Department of Biochemistry, University of Otago, Dunedin, New Zealand.|Virtual Institute of Statistical Genetics (www.visg.co.nz), Dunedin, New Zealand.
authors.forename: Tony R
authors.initials: TR
authors.lastname: Merriman
authors.affiliation: Department of Biochemistry, University of Otago, Dunedin, New Zealand.|Virtual Institute of Statistical Genetics (www.visg.co.nz), Dunedin, New Zealand.
authors.forename: James
authors.initials: J
authors.lastname: Boocock
authors.affiliation: Department of Medicine, University of Auckland, Auckland, New Zealand.
authors.forename: Nicola
authors.initials: N
authors.lastname: Dalbeth
authors.affiliation: Department of Medicine, University of Otago, Christchurch, New Zealand.
authors.forename: Lisa K
authors.initials: LK
authors.lastname: Stamp
authors.affiliation: Department of Biochemistry, University of Otago, Dunedin, New Zealand.|Virtual Institute of Statistical Genetics (www.visg.co.nz), Dunedin, New Zealand.
authors.forename: Michael A
authors.initials: MA
authors.lastname: Black
authors.affiliation: Virtual Institute of Statistical Genetics (www.visg.co.nz), Dunedin, New Zealand.|The Queensland Brain Institute, University of Queensland, Brisbane, Australia.|University of Queensland Diamantina Institute, University of Queensland, Translational Research Institute (TRI), Brisbane, Australia.
authors.forename: Peter M
authors.initials: PM
authors.lastname: Visscher
authors.affiliation: Department of Biochemistry, University of Otago, Dunedin, New Zealand. phillip.wilcox@otago.ac.nz.|Virtual Institute of Statistical Genetics (www.visg.co.nz), Dunedin, New Zealand. phillip.wilcox@otago.ac.nz.|formerly Scion (New Zealand Forest Research Institute Ltd), 49 Sala Street, Rotorua, New Zealand. phillip.wilcox@otago.ac.nz.|Department of Mathematics and Statistics, University of Otago, Science III Building, 730 Cumberland St, Dunedin, 9016, New Zealand. phillip.wilcox@otago.ac.nz.
authors.forename: Phillip L
authors.initials: PL
authors.lastname: Wilcox
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D055815:Young Adult; D000483:Alleles; D015992:Body Mass Index; D003924:Diabetes Mellitus, Type 2 / Q000235:genetics / Q000473:pathology; D005838:Genotype; D006073:Gout / Q000235:genetics / Q000473:pathology; D006239:Haplotypes; D016014:Linear Models; D016015:Logistic Models; D016017:Odds Ratio; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha / Q000235:genetics; D020641:Polymorphism, Single Nucleotide; D018947:Samoa; D012641:Selection, Genetic; D014058:Tonga
chemical_list: D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; C486497:PPARGC1A protein, human
keywords: BMI; Gout; Natural selection; Selective sweeps; Thrifty gene; Type 2 diabetes