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Allele-specific down-regulation of RPTOR expression induced by retinoids contributes to climate adaptations.

Sun C, Southard C, Witonsky DB, Kittler R, Di Rienzo A - PLoS Genet. (2010)

Bottom Line: The regulatory associated protein of MTOR encoded by the RPTOR gene is a key component of this pathway.A previous survey of candidate genes found that RPTOR contains multiple SNPs with strong correlations between allele frequencies and climate variables, consistent with the action of selective pressures that vary across environments.Our results show that signatures of genetic adaptations can identify variants with functional effects, consistent with the idea that selection signals may be used for SNP annotation.

View Article: PubMed Central - PubMed

Affiliation: Department of Human Genetics, University of Chicago, Chicago, Illinois, United States of America.

ABSTRACT
The mechanistic target of rapamycin (MTOR) pathway regulates cell growth, energy homeostasis, apoptosis, and immune response. The regulatory associated protein of MTOR encoded by the RPTOR gene is a key component of this pathway. A previous survey of candidate genes found that RPTOR contains multiple SNPs with strong correlations between allele frequencies and climate variables, consistent with the action of selective pressures that vary across environments. Using data from a recent genome scan for selection signals, we honed in on a SNP (rs11868112) 26 kb upstream to the transcription start site of RPTOR that exhibits the strongest association with temperature variables. Transcription factor motif scanning and mining of recently mapped transcription factor binding sites identified a binding site for POU class 2 homeobox 1 (POU2F1) spanning the SNP and an adjacent retinoid acid receptor (RAR) binding site. Using expression quantification, chromatin immunoprecipitation (ChIP), and reporter gene assays, we demonstrate that POU2F1 and RARA do bind upstream of the RPTOR gene to regulate its expression in response to retinoids; this regulation is affected by the allele status at rs11868112 with the derived allele resulting in lower expression levels. We propose a model in which the derived allele influences thermogenesis or immune response by altering MTOR pathway activity and thereby increasing fitness in colder climates. Our results show that signatures of genetic adaptations can identify variants with functional effects, consistent with the idea that selection signals may be used for SNP annotation.

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Allele frequency for rs11868112 (ancestral and derived alleles are shown in white and black, respectively) in HGDP populations mapped onto a GIS map of Winter maximum temperature.
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pgen-1001178-g002: Allele frequency for rs11868112 (ancestral and derived alleles are shown in white and black, respectively) in HGDP populations mapped onto a GIS map of Winter maximum temperature.

Mentions: To refine the location of the polymorphism targeted by climate-related selective pressures, we mined the results of a recent genome-wide scan for signals of allele frequency correlation with climate variables (Hancock and Di Rienzo, personal communication). Allele frequencies for a total of 156 SNPs were obtained in the genomic region spanning the RPTOR gene and 100 kb upstream and downstream of the gene (See Table S1 for detailed information). The evidence for the action of selective pressures related to climate was assessed by means of a Bayesian method that yields a Bayes factor (BF), which is a measure of the support for a model in which a SNP allele frequency distribution is linearly dependent on a climate variable in addition to population structure, relative to a model in which the allele frequency distribution is dependent on population structure alone [27]. A transformed rank statistic (sometime referred to as an ‘empirical p-value’) was also calculated to determine whether the BF value of a SNP of interest is unusual relative to those of other SNPs matched by allele frequency; as with formal p-values, a low rank indicates strong evidence for a correlation (i.e. a large BF) [27]. We examined the following climate variables: mean, minimum and maximum temperature, precipitation rate, relative humidity and solar radiation; for all climate variables we considered the value in the winter and summer, respectively. Among the 156 SNPs tested, 56 had a rank lower that 5% for at least one climate variable. One SNP, rs11868112, had particularly large BFs with winter temperatures (rank statistic = 0.0082, 0.0064, and 0.0039 for minimum, mean and maximum winter temperature, respectively. See Figure 1 and Figure 2, Table S2 and Table S3for detail.). Therefore, this SNP, or one in strong LD with it, is a candidate target of selective pressures related to climate.


Allele-specific down-regulation of RPTOR expression induced by retinoids contributes to climate adaptations.

Sun C, Southard C, Witonsky DB, Kittler R, Di Rienzo A - PLoS Genet. (2010)

Allele frequency for rs11868112 (ancestral and derived alleles are shown in white and black, respectively) in HGDP populations mapped onto a GIS map of Winter maximum temperature.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC2965758&req=5

pgen-1001178-g002: Allele frequency for rs11868112 (ancestral and derived alleles are shown in white and black, respectively) in HGDP populations mapped onto a GIS map of Winter maximum temperature.
Mentions: To refine the location of the polymorphism targeted by climate-related selective pressures, we mined the results of a recent genome-wide scan for signals of allele frequency correlation with climate variables (Hancock and Di Rienzo, personal communication). Allele frequencies for a total of 156 SNPs were obtained in the genomic region spanning the RPTOR gene and 100 kb upstream and downstream of the gene (See Table S1 for detailed information). The evidence for the action of selective pressures related to climate was assessed by means of a Bayesian method that yields a Bayes factor (BF), which is a measure of the support for a model in which a SNP allele frequency distribution is linearly dependent on a climate variable in addition to population structure, relative to a model in which the allele frequency distribution is dependent on population structure alone [27]. A transformed rank statistic (sometime referred to as an ‘empirical p-value’) was also calculated to determine whether the BF value of a SNP of interest is unusual relative to those of other SNPs matched by allele frequency; as with formal p-values, a low rank indicates strong evidence for a correlation (i.e. a large BF) [27]. We examined the following climate variables: mean, minimum and maximum temperature, precipitation rate, relative humidity and solar radiation; for all climate variables we considered the value in the winter and summer, respectively. Among the 156 SNPs tested, 56 had a rank lower that 5% for at least one climate variable. One SNP, rs11868112, had particularly large BFs with winter temperatures (rank statistic = 0.0082, 0.0064, and 0.0039 for minimum, mean and maximum winter temperature, respectively. See Figure 1 and Figure 2, Table S2 and Table S3for detail.). Therefore, this SNP, or one in strong LD with it, is a candidate target of selective pressures related to climate.

Bottom Line: The regulatory associated protein of MTOR encoded by the RPTOR gene is a key component of this pathway.A previous survey of candidate genes found that RPTOR contains multiple SNPs with strong correlations between allele frequencies and climate variables, consistent with the action of selective pressures that vary across environments.Our results show that signatures of genetic adaptations can identify variants with functional effects, consistent with the idea that selection signals may be used for SNP annotation.

View Article: PubMed Central - PubMed

Affiliation: Department of Human Genetics, University of Chicago, Chicago, Illinois, United States of America.

ABSTRACT
The mechanistic target of rapamycin (MTOR) pathway regulates cell growth, energy homeostasis, apoptosis, and immune response. The regulatory associated protein of MTOR encoded by the RPTOR gene is a key component of this pathway. A previous survey of candidate genes found that RPTOR contains multiple SNPs with strong correlations between allele frequencies and climate variables, consistent with the action of selective pressures that vary across environments. Using data from a recent genome scan for selection signals, we honed in on a SNP (rs11868112) 26 kb upstream to the transcription start site of RPTOR that exhibits the strongest association with temperature variables. Transcription factor motif scanning and mining of recently mapped transcription factor binding sites identified a binding site for POU class 2 homeobox 1 (POU2F1) spanning the SNP and an adjacent retinoid acid receptor (RAR) binding site. Using expression quantification, chromatin immunoprecipitation (ChIP), and reporter gene assays, we demonstrate that POU2F1 and RARA do bind upstream of the RPTOR gene to regulate its expression in response to retinoids; this regulation is affected by the allele status at rs11868112 with the derived allele resulting in lower expression levels. We propose a model in which the derived allele influences thermogenesis or immune response by altering MTOR pathway activity and thereby increasing fitness in colder climates. Our results show that signatures of genetic adaptations can identify variants with functional effects, consistent with the idea that selection signals may be used for SNP annotation.

Show MeSH