Lack of direct evidence for natural selection at the candidate thrifty gene locus, PPARGC1A

Cadzow, Murray, Merriman, Tony R., Boocock, James, Dalbeth, Nicola, Stamp, Lisa K., Black, Michael A., Visscher, Peter M. and Wilcox, Phillip L. (2016) Lack of direct evidence for natural selection at the candidate thrifty gene locus, PPARGC1A. BMC Medical Genetics, 17 1: . doi:10.1186/s12881-016-0341-z

Author Cadzow, Murray
Merriman, Tony R.
Boocock, James
Dalbeth, Nicola
Stamp, Lisa K.
Black, Michael A.
Visscher, Peter M.
Wilcox, Phillip L.
Title Lack of direct evidence for natural selection at the candidate thrifty gene locus, PPARGC1A
Journal name BMC Medical Genetics   Check publisher's open access policy
ISSN 1471-2350
Publication date 2016-11-15
Sub-type Article (original research)
DOI 10.1186/s12881-016-0341-z
Open Access Status DOI
Volume 17
Issue 1
Total pages 13
Place of publication London, United Kingdom
Publisher BioMed Central
Language eng
Formatted 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, Maori, 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 Maori≤0.35, Samoan≤0.20). When compared to European (New Zealand Maori≤0.40, Samoan≤0.25) or African populations (New Zealand Maori≤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.

Conclusion: 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.
Keyword BMI
Natural selection
Selective sweeps
Thrifty gene
Type 2 diabetes
Q-Index Code C1
Q-Index Status Provisional Code
Institutional Status UQ

Document type: Journal Article
Sub-type: Article (original research)
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