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Genes Regulated by Vitamin D in Bone Cells Are Positively Selected in East Asians.

Arciero E, Biagini SA, Chen Y, Xue Y, Luiselli D, Tyler-Smith C, Pagani L, Ayub Q - PLoS ONE (2015)

Bottom Line: Comparing allele frequency-spectrum-based summary statistics between these gene sets and matched control genes, we observed a selection signal specific to East Asians for a gene set associated with vitamin D action in bones.Examination of population differentiation and haplotypes allowed us to identify several candidate causal regulatory variants in each gene.We also observed haplotype sharing between East Asians, Finns and an extinct archaic human (Denisovan) sample at the CXXC1 locus, which is best explained by incomplete lineage sorting.

View Article: PubMed Central - PubMed

Affiliation: The Wellcome Trust Sanger Institute, Wellcome Genome Campus, Hinxton, CB10 1SA, United Kingdom.

ABSTRACT
Vitamin D and folate are activated and degraded by sunlight, respectively, and the physiological processes they control are likely to have been targets of selection as humans expanded from Africa into Eurasia. We investigated signals of positive selection in gene sets involved in the metabolism, regulation and action of these two vitamins in worldwide populations sequenced by Phase I of the 1000 Genomes Project. Comparing allele frequency-spectrum-based summary statistics between these gene sets and matched control genes, we observed a selection signal specific to East Asians for a gene set associated with vitamin D action in bones. The selection signal was mainly driven by three genes CXXC finger protein 1 (CXXC1), low density lipoprotein receptor-related protein 5 (LRP5) and runt-related transcription factor 2 (RUNX2). Examination of population differentiation and haplotypes allowed us to identify several candidate causal regulatory variants in each gene. Four of these candidate variants (one each in CXXC1 and RUNX2 and two in LRP5) had a >70% derived allele frequency in East Asians, but were present at lower (20-60%) frequency in Europeans as well, suggesting that the adaptation might have been part of a common response to climatic and dietary changes as humans expanded out of Africa, with implications for their role in vitamin D-dependent bone mineralization and osteoporosis insurgence. We also observed haplotype sharing between East Asians, Finns and an extinct archaic human (Denisovan) sample at the CXXC1 locus, which is best explained by incomplete lineage sorting.

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Related in: MedlinePlus

Vitamin D and folate acquisition, metabolism and gene sets analyzed in this study.The upper part shows metabolism of vitamin D (yellow arrows) and folate (black arrows). Vitamin D3 can be obtained from the diet, but it is mainly synthesised in the skin from 7-dehydrocholesterol (7-DHC) in response to light. It is then transported into the liver where it is hydroxylated to produce 25-hydroxyvitamin D3 which is subsequently converted into its active form 1α, 25- dihydroxy vitamin D3. This is transported in blood by vitamin D binding protein (DBP) and binds vitamin D receptor (VDR). The lower part shows gene sets analyzed in this study. The circles are proportional to number of genes in each set. The numbers in blue or pink circles indicate number of genes in each set that were present in AmiGO using the search terms “Vitamin D” (blue) or “Folate” (pink). Additional vitamin D (Vit D or VD) and folate (FA) gene sets are shown in shades of yellow and grey, respectively. The vitamin D gene sets that were generated included vitamin D targets identified by ChIP-Seq (VDR targets), genes involved in vitamin D action in bones, kidneys and intestines and all proteins involved in the VDR activation complex, including those directly interacting with VDR (VDRIP) and RXR (RXRIP) receptors. Folate gene sets include enzymes and receptors involved in dietary folate uptake and transport (FAU), proteins involved in nucleic acid synthesis (NAS) and methylation. The latter were sub-divided into genes involved in metabolism of methionine (Met), homocysteine (HCV) and S-adenosyl methionine methylation (SAM). The small blue and pink circles indicate the number of genes in the manually curated vitamin D and folate gene sets, respectively, that were also identified by AmiGO.
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pone.0146072.g001: Vitamin D and folate acquisition, metabolism and gene sets analyzed in this study.The upper part shows metabolism of vitamin D (yellow arrows) and folate (black arrows). Vitamin D3 can be obtained from the diet, but it is mainly synthesised in the skin from 7-dehydrocholesterol (7-DHC) in response to light. It is then transported into the liver where it is hydroxylated to produce 25-hydroxyvitamin D3 which is subsequently converted into its active form 1α, 25- dihydroxy vitamin D3. This is transported in blood by vitamin D binding protein (DBP) and binds vitamin D receptor (VDR). The lower part shows gene sets analyzed in this study. The circles are proportional to number of genes in each set. The numbers in blue or pink circles indicate number of genes in each set that were present in AmiGO using the search terms “Vitamin D” (blue) or “Folate” (pink). Additional vitamin D (Vit D or VD) and folate (FA) gene sets are shown in shades of yellow and grey, respectively. The vitamin D gene sets that were generated included vitamin D targets identified by ChIP-Seq (VDR targets), genes involved in vitamin D action in bones, kidneys and intestines and all proteins involved in the VDR activation complex, including those directly interacting with VDR (VDRIP) and RXR (RXRIP) receptors. Folate gene sets include enzymes and receptors involved in dietary folate uptake and transport (FAU), proteins involved in nucleic acid synthesis (NAS) and methylation. The latter were sub-divided into genes involved in metabolism of methionine (Met), homocysteine (HCV) and S-adenosyl methionine methylation (SAM). The small blue and pink circles indicate the number of genes in the manually curated vitamin D and folate gene sets, respectively, that were also identified by AmiGO.

Mentions: Fat-soluble vitamin D and water-soluble folate (folic acid, vitamin B9) are activated and degraded by ultraviolet (UV) radiation, respectively, and are necessary for human development and physiology [1–3]. These processes are controlled by many genes (Fig 1) that are thus likely to have been affected by the expansion of humans from tropical Africa into northern climes in the last 50–60,000 years, and may, therefore, have been targets of selection as humans adapted to new diets and environments. Seasonal variation in UV radiation at higher latitudes has been linked to natural selection in skin pigmentation of modern humans [3], and it has been suggested that lighter skin pigmentation was necessary to maintain homeostasis of vitamin D and protect against infections and skeletal deformities that are associated with reduced levels of this vitamin [3, 4]. Dietary intake of vitamin D is usually inadequate for normal physiological development and it is mainly produced in the skin by UV irradiation of 7- dehydrocholesterol. Its biologically active form (1α, 25-dihydroxyvitamin D3) acts as a hormone to regulate gene expression in several organs. It does so by binding the vitamin D receptor (VDR), which forms a heterodimer with retinoid X receptor (RXR), and recruits several other proteins to form the Vitamin D activation complex (Fig 1). Vitamin D3 regulates target gene expression in many tissues and has major roles in diverse physiological functions, being primarily responsible for calcium and phosphate homeostasis and bone remodeling [1]. In contrast, folate is exclusively obtained from the diet and is required for nucleic acid synthesis and repair, and methylation of DNA, proteins and fats [2, 5, 6].


Genes Regulated by Vitamin D in Bone Cells Are Positively Selected in East Asians.

Arciero E, Biagini SA, Chen Y, Xue Y, Luiselli D, Tyler-Smith C, Pagani L, Ayub Q - PLoS ONE (2015)

Vitamin D and folate acquisition, metabolism and gene sets analyzed in this study.The upper part shows metabolism of vitamin D (yellow arrows) and folate (black arrows). Vitamin D3 can be obtained from the diet, but it is mainly synthesised in the skin from 7-dehydrocholesterol (7-DHC) in response to light. It is then transported into the liver where it is hydroxylated to produce 25-hydroxyvitamin D3 which is subsequently converted into its active form 1α, 25- dihydroxy vitamin D3. This is transported in blood by vitamin D binding protein (DBP) and binds vitamin D receptor (VDR). The lower part shows gene sets analyzed in this study. The circles are proportional to number of genes in each set. The numbers in blue or pink circles indicate number of genes in each set that were present in AmiGO using the search terms “Vitamin D” (blue) or “Folate” (pink). Additional vitamin D (Vit D or VD) and folate (FA) gene sets are shown in shades of yellow and grey, respectively. The vitamin D gene sets that were generated included vitamin D targets identified by ChIP-Seq (VDR targets), genes involved in vitamin D action in bones, kidneys and intestines and all proteins involved in the VDR activation complex, including those directly interacting with VDR (VDRIP) and RXR (RXRIP) receptors. Folate gene sets include enzymes and receptors involved in dietary folate uptake and transport (FAU), proteins involved in nucleic acid synthesis (NAS) and methylation. The latter were sub-divided into genes involved in metabolism of methionine (Met), homocysteine (HCV) and S-adenosyl methionine methylation (SAM). The small blue and pink circles indicate the number of genes in the manually curated vitamin D and folate gene sets, respectively, that were also identified by AmiGO.
© Copyright Policy
Related In: Results  -  Collection

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Show All Figures
getmorefigures.php?uid=PMC4697808&req=5

pone.0146072.g001: Vitamin D and folate acquisition, metabolism and gene sets analyzed in this study.The upper part shows metabolism of vitamin D (yellow arrows) and folate (black arrows). Vitamin D3 can be obtained from the diet, but it is mainly synthesised in the skin from 7-dehydrocholesterol (7-DHC) in response to light. It is then transported into the liver where it is hydroxylated to produce 25-hydroxyvitamin D3 which is subsequently converted into its active form 1α, 25- dihydroxy vitamin D3. This is transported in blood by vitamin D binding protein (DBP) and binds vitamin D receptor (VDR). The lower part shows gene sets analyzed in this study. The circles are proportional to number of genes in each set. The numbers in blue or pink circles indicate number of genes in each set that were present in AmiGO using the search terms “Vitamin D” (blue) or “Folate” (pink). Additional vitamin D (Vit D or VD) and folate (FA) gene sets are shown in shades of yellow and grey, respectively. The vitamin D gene sets that were generated included vitamin D targets identified by ChIP-Seq (VDR targets), genes involved in vitamin D action in bones, kidneys and intestines and all proteins involved in the VDR activation complex, including those directly interacting with VDR (VDRIP) and RXR (RXRIP) receptors. Folate gene sets include enzymes and receptors involved in dietary folate uptake and transport (FAU), proteins involved in nucleic acid synthesis (NAS) and methylation. The latter were sub-divided into genes involved in metabolism of methionine (Met), homocysteine (HCV) and S-adenosyl methionine methylation (SAM). The small blue and pink circles indicate the number of genes in the manually curated vitamin D and folate gene sets, respectively, that were also identified by AmiGO.
Mentions: Fat-soluble vitamin D and water-soluble folate (folic acid, vitamin B9) are activated and degraded by ultraviolet (UV) radiation, respectively, and are necessary for human development and physiology [1–3]. These processes are controlled by many genes (Fig 1) that are thus likely to have been affected by the expansion of humans from tropical Africa into northern climes in the last 50–60,000 years, and may, therefore, have been targets of selection as humans adapted to new diets and environments. Seasonal variation in UV radiation at higher latitudes has been linked to natural selection in skin pigmentation of modern humans [3], and it has been suggested that lighter skin pigmentation was necessary to maintain homeostasis of vitamin D and protect against infections and skeletal deformities that are associated with reduced levels of this vitamin [3, 4]. Dietary intake of vitamin D is usually inadequate for normal physiological development and it is mainly produced in the skin by UV irradiation of 7- dehydrocholesterol. Its biologically active form (1α, 25-dihydroxyvitamin D3) acts as a hormone to regulate gene expression in several organs. It does so by binding the vitamin D receptor (VDR), which forms a heterodimer with retinoid X receptor (RXR), and recruits several other proteins to form the Vitamin D activation complex (Fig 1). Vitamin D3 regulates target gene expression in many tissues and has major roles in diverse physiological functions, being primarily responsible for calcium and phosphate homeostasis and bone remodeling [1]. In contrast, folate is exclusively obtained from the diet and is required for nucleic acid synthesis and repair, and methylation of DNA, proteins and fats [2, 5, 6].

Bottom Line: Comparing allele frequency-spectrum-based summary statistics between these gene sets and matched control genes, we observed a selection signal specific to East Asians for a gene set associated with vitamin D action in bones.Examination of population differentiation and haplotypes allowed us to identify several candidate causal regulatory variants in each gene.We also observed haplotype sharing between East Asians, Finns and an extinct archaic human (Denisovan) sample at the CXXC1 locus, which is best explained by incomplete lineage sorting.

View Article: PubMed Central - PubMed

Affiliation: The Wellcome Trust Sanger Institute, Wellcome Genome Campus, Hinxton, CB10 1SA, United Kingdom.

ABSTRACT
Vitamin D and folate are activated and degraded by sunlight, respectively, and the physiological processes they control are likely to have been targets of selection as humans expanded from Africa into Eurasia. We investigated signals of positive selection in gene sets involved in the metabolism, regulation and action of these two vitamins in worldwide populations sequenced by Phase I of the 1000 Genomes Project. Comparing allele frequency-spectrum-based summary statistics between these gene sets and matched control genes, we observed a selection signal specific to East Asians for a gene set associated with vitamin D action in bones. The selection signal was mainly driven by three genes CXXC finger protein 1 (CXXC1), low density lipoprotein receptor-related protein 5 (LRP5) and runt-related transcription factor 2 (RUNX2). Examination of population differentiation and haplotypes allowed us to identify several candidate causal regulatory variants in each gene. Four of these candidate variants (one each in CXXC1 and RUNX2 and two in LRP5) had a >70% derived allele frequency in East Asians, but were present at lower (20-60%) frequency in Europeans as well, suggesting that the adaptation might have been part of a common response to climatic and dietary changes as humans expanded out of Africa, with implications for their role in vitamin D-dependent bone mineralization and osteoporosis insurgence. We also observed haplotype sharing between East Asians, Finns and an extinct archaic human (Denisovan) sample at the CXXC1 locus, which is best explained by incomplete lineage sorting.

Show MeSH
Related in: MedlinePlus