A bioinformatics workflow for detecting signatures of selection in genomic data

Cadzow, Murray; Boocock, James; Nguyen, Hoang; Wilcox, Phillip; Merriman, Tony R.; Black, Michael A.

doi:10.3389/fgene.2014.00293

Cited by 62 publications

(51 citation statements)

References 53 publications

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“…These ‘unrelated’ individuals were then haplotyped using SHAPEIT 49–53 and were annotated with ancestral allele information using the selectionTools pipeline 63 . Haplotype bifurcation diagrams and EHH plots were drawn using the rehh R package 64 .…”

Section: Methodsmentioning

confidence: 99%

A thrifty variant in CREBRF strongly influences body mass index in Samoans

et al. 2016

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Samoans are a unique founder population with a high prevalence of obesity1–3, making them well suited for identifying new genetic contributors to obesity4. We conducted a genome-wide association study (GWAS) in 3,072 Samoans, discovered a variant, rs12513649, strongly associated with body mass index (BMI) (P = 5.3 × 10−14), and replicated the association in 2,102 additional Samoans (P = 1.2 × 10−9). Targeted sequencing identified a strongly associated missense variant, rs373863828 (p.Arg457Gln), in CREBRF (meta P = 1.4 × 10−20). Although this variant is extremely rare in other populations, it is common in Samoans (frequency of 0.259), with an effect size much larger than that of any other known common BMI risk variant (1.36–1.45 kg/m2 per copy of the risk-associated allele). In comparison to wild-type CREBRF, the Arg457Gln variant when overexpressed selectively decreased energy use and increased fat storage in an adipocyte cell model. These data, in combination with evidence of positive selection of the allele encoding p.Arg457Gln, support a ‘thrifty’ variant hypothesis as a factor in human obesity.

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Section: Methodsmentioning

confidence: 99%

A thrifty variant in CREBRF strongly influences body mass index in Samoans

et al. 2016

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“…A region containing each gene, plus 100 kb upstream and 100 kb downstream, was retrieved in VCF format from the 1000 Genomes Project database, using tabix. Patterns of polymorphism at each gene and its surrounding region were analyzed for each population and each region (as defined by the 1000 Genomes Project), using the selectionTools pipeline and custom Perl scripts (74). Several statistical tests were evaluated: frequencybased methods (Tajima's D, Fay and Wu's H); linkage disequilibrium-based methods (Rsb, iHs); and population differentiation-based methods (F ST ).…”

Section: Methodsmentioning

confidence: 99%

Human-specific derived alleles of CD33 and other genes protect against postreproductive cognitive decline

Schwarz

Springer

Altheide

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

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The individuals of most vertebrate species die when they can no longer reproduce. Humans are a rare exception, having evolved a prolonged postreproductive lifespan. Elders contribute to cooperative offspring care, assist in foraging, and communicate important ecological and cultural knowledge, increasing the survival of younger individuals. Age-related deterioration of cognitive capacity in humans compromises these benefits and also burdens the group with socially costly members. We investigated the contribution of the immunoregulatory receptor CD33 to a uniquely human postreproductive disease, Alzheimer’s dementia. Surprisingly, even though selection at advanced age is expected to be weak, a CD33 allele protective against Alzheimer’s disease is derived and unique to humans and favors a functional molecular state of CD33 resembling that of the chimpanzee. Thus, derived alleles may be compensatory and restore interactions altered as a consequence of human-specific brain evolution. We found several other examples of derived alleles at other human loci that protect against age-related cognitive deterioration arising from neurodegenerative disease or cerebrovascular insufficiency. Selection by inclusive fitness may be strong enough to favor alleles protecting specifically against cognitive decline in postreproductive humans. Such selection would operate by maximizing the contributions of postreproductive individuals to the fitness of younger kin.

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“…In this study we combined association analyses between the Gly482Ser genotype and traits either directly (BMI) or indirectly (gout and T2D, which are correlated with BMI) to identify a potential functional role of Gly482Ser. To identify genomic evidence we used a recently-developed analytical pipeline to test selection by a combination of site frequency spectra based statistics, (Tajima’s D , Fay’s and Wu’s H ) as well as haplotype-length based measures that examine selection within populations (iHS) or between populations (XP-EHH, [10]). We also estimated population differentiation ( F ST ), which has also been used as an indicator of selection [25], as well as departure from expected HW equilibrium.…”

Section: Discussionmentioning

confidence: 99%

“…For populations where genome-wide genotypic data were available (i.e., the 1000 Genomes Project and Axiom/Omni-genotyped populations, Table 1), the following statistics were calculated: F ST between sample sets, Tajima’s D , Fay and Wu’s H , and integrated haplotype score (iHS, [18]) for individual populations, and cross population haplotype homozygosity (XP-EHH, [19]) to estimate selection between populations. To calculate these statistics we used a customized analytical pipeline [10]. For these analyses we assumed that the 482Ser allele was the derived allele, based on low frequencies of this allele in African populations [5].…”

Section: Methodsmentioning

confidence: 99%

“…Here, we tested for association between Gly482Ser rs8192678, BMI, T2D and gout in several Polynesian populations. We also examined evidence for recent positive selection at the derived 482Ser allele and in the region of PPARGC1A , by applying a recently developed analytical pipeline [10] to genomic data from the various Polynesian and 1000 Genomes Project world-wide populations.…”

Section: Introductionmentioning

confidence: 99%

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

et al. 2016

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BackgroundThe 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.MethodsUsing 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 (F ST, 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.ResultsNo statistically significant evidence for association between Gly482Ser and any of BMI, T2D or gout was found. Population differentiation (F ST) 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.ConclusionWe 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.Electronic supplementary materialThe online version of this article (doi:10.1186/s12881-016-0341-z) contains supplementary material, which is available to authorized users.

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A bioinformatics workflow for detecting signatures of selection in genomic data

Cited by 62 publications

References 53 publications

A thrifty variant in CREBRF strongly influences body mass index in Samoans

A thrifty variant in CREBRF strongly influences body mass index in Samoans

Human-specific derived alleles of CD33 and other genes protect against postreproductive cognitive decline

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

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