My choice for Paper Of The Week this week is a report from a few weeks back (digging through the pile...) in which a polymorphism conferring increased risk of renal cell carcinoma is investigated for allele-specific functions. The paper is "Common genetic variants at the 11q13.3 renal cancer susceptibility locus influence binding of HIF to an enhancer of cyclin D1 expression" by Schödel, et al. (Nature Genetics 44:420-425).
Although the authors had several clues that the risk SNPs would (likely) affect expression of CCND1 (cyclin D1) in a manner regulated by hypoxia-induced factors - namely, that HIFs were known to regulate CCND1 but from an unknown binding site and that CCND1 is an established oncogene, among others - they accumulated much new data to nail down the role of EPAS1 (HIF-2) in regulating CCND1 expression.
One nice aspect of this work is the authors' taking advantage of signals seen in a renal carcinoma cell line and not in a breast cancer cell line (serving then as control). For example, they looked at the epigenetic enhancer marks at the 11q13.3 susceptibility locus with FAIRE (ormaldehyde-assisted isolation of regulatory elements to identify regions of nucleosome occupancy), and EPAS1 binding as assessed by ChIP-qPCR. The use of pVHL-defective RCC cell lines verified the role of VHL (von Hippel–Lindau tumor suppressor) in this cancer and consequence of allele-specific expression of CCND1.
Taken together, the data presented show that the haplotype associating with reduced renal cell cancer risk hinders EPAS1 binding, "resulting in an allelic imbalance in cyclin D1 expression, thus affecting a link between hypoxia pathways and cell cycle control." This is nice work and a fine example of the approaches needed to develop a clear understanding of polymorphism and disease risk from a functional perspective.
Friday, May 4, 2012
Friday, April 27, 2012
POTW: Bitter taste perception - a follow-up
Back in December, I posted an item on taste receptors expressed in the gut with mention of possible roles in sensing the microbiome. This week's Paper of the Week is entitled "Evolution of functionally diverse alleles associated with PTC bitter taste sensitivity in Africa" by the Tishkoff group and heightens those earlier, intriguing possibilities.
The publication dissects the long evolutionary history of the TAS2R38 gene encoding a bitter taste receptor. From RefSeq, we know that TAS2R38 encodes a seven-transmembrane G protein-coupled receptor that controls the ability to taste glucosinolates, a family of bitter-tasting compounds found in plants of the Brassica sp. Interestingly, TAS2R38 allows detection of bitter thiourea compounds, including 6-n-propylthiouracil (PROP) and phenylthiocarbamide (PTC). Humans who cannot taste these compounds tend to be poor at discriminating fat in foods, even though they prefer higher fat versions of these foods (Keller, KL 2012 J Food Science 77:S143). This would lead one to suppose, naturally, that the development of certain haplotypes of tasters and nontasters would arise as adaptation to the local diet. Tishkoff, et al show that is not likely to be the case.
First, the authors propose that the evolution of the three nonsynonymous mutations, which comprise the commonly observed haplotypes, likely represent an alternate path for building a diverse set of receptors in humans, which can then participate in various biological processes. They go on to suggest that a complex selection model, involving "ancient balancing and recent diversifying selection," has allowed both common and rare nonsynonymous variation, respectively, to persist in the coding exon of TAS2R38 in Africa. Importantly, different types of selection may have acted upon the noncoding regions compared to the TAS2R38 coding exon in all populations.
Second, diet is not the driver of haplotype frequencies. The authors propose that the three common haplotypes observed may appear at high frequencies due to selective pressures distinct from diet. Recent reports have demonstrated that bitter taste receptors are expressed in many cell types in the human gastrointestinal tract and lungs (second reference). Here this expression can affect glucose and insulin levels (Dotson et al. 2008), eliminate harmful inhaled substances, and promote relaxation of airways for better breathing. Thus, bitter taste loci, including TAS2R38, posses various functions and, as the authors write "raise[s] the possibility that common variants at TAS2R38 may be under selection due to their physiological roles in human health beyond oral gustatory function." The authors were not able to distinguish which selective forces - taste, gut microbiome organisms or biochemical production, or inhalants - are acting upon the TAS2R38 haplotypes.
Third, the genetic analysis and evolutionary history of TAS2R38 suggest that, in contrast to a common variant-common disease hypothesis, sensitivity to PTC bitter taste indicates that both rare and common variants together are able to significantly affect normal variation of phenotypes. This, of course, has implications, as genome-wide association studies tackle a wider range of phenotypes in a more diverse set of populations, and as genome sequencing (whole and exome) seek to identify and associate rare variants with disease risk and occurrence.
The publication dissects the long evolutionary history of the TAS2R38 gene encoding a bitter taste receptor. From RefSeq, we know that TAS2R38 encodes a seven-transmembrane G protein-coupled receptor that controls the ability to taste glucosinolates, a family of bitter-tasting compounds found in plants of the Brassica sp. Interestingly, TAS2R38 allows detection of bitter thiourea compounds, including 6-n-propylthiouracil (PROP) and phenylthiocarbamide (PTC). Humans who cannot taste these compounds tend to be poor at discriminating fat in foods, even though they prefer higher fat versions of these foods (Keller, KL 2012 J Food Science 77:S143). This would lead one to suppose, naturally, that the development of certain haplotypes of tasters and nontasters would arise as adaptation to the local diet. Tishkoff, et al show that is not likely to be the case.
First, the authors propose that the evolution of the three nonsynonymous mutations, which comprise the commonly observed haplotypes, likely represent an alternate path for building a diverse set of receptors in humans, which can then participate in various biological processes. They go on to suggest that a complex selection model, involving "ancient balancing and recent diversifying selection," has allowed both common and rare nonsynonymous variation, respectively, to persist in the coding exon of TAS2R38 in Africa. Importantly, different types of selection may have acted upon the noncoding regions compared to the TAS2R38 coding exon in all populations.
Second, diet is not the driver of haplotype frequencies. The authors propose that the three common haplotypes observed may appear at high frequencies due to selective pressures distinct from diet. Recent reports have demonstrated that bitter taste receptors are expressed in many cell types in the human gastrointestinal tract and lungs (second reference). Here this expression can affect glucose and insulin levels (Dotson et al. 2008), eliminate harmful inhaled substances, and promote relaxation of airways for better breathing. Thus, bitter taste loci, including TAS2R38, posses various functions and, as the authors write "raise[s] the possibility that common variants at TAS2R38 may be under selection due to their physiological roles in human health beyond oral gustatory function." The authors were not able to distinguish which selective forces - taste, gut microbiome organisms or biochemical production, or inhalants - are acting upon the TAS2R38 haplotypes.
Third, the genetic analysis and evolutionary history of TAS2R38 suggest that, in contrast to a common variant-common disease hypothesis, sensitivity to PTC bitter taste indicates that both rare and common variants together are able to significantly affect normal variation of phenotypes. This, of course, has implications, as genome-wide association studies tackle a wider range of phenotypes in a more diverse set of populations, and as genome sequencing (whole and exome) seek to identify and associate rare variants with disease risk and occurrence.
Friday, March 16, 2012
POTW: Evolutionary constraints and the discovery of disease markers
My selection for Paper of the Week for 16 March 2012 is by Joel Dudley, et al. and published as a letter in Molecular Biology & Evolution. Its title is "Evolutionary meta-analysis of association studies reveals ancient constraints affecting disease marker discovery."
The authors examined over 5800 disease-associating variants, comparing the genomic neighborhood across a panel of species. This covered 230 different disease and disease risk phenotypes. Importantly, the authors demonstrate that there is a propensity to discover such disease SNPs at "conserved genomic positions, because the effect size (odds ratio) and allelic P-value of genetic association of a SNP relates strongly to the evolutionary conservation of their genomic position." This then allowed them to develop a new means to rank such association SNPs in which a conservation score, based on the evolutionary analysis, is incorporated into the P-value of the genotype-phenotype association.
As many GWAS SNPs alter gene expression - either through altered transcription factor binding or microRNA-mRNA interaction, and as such evolutionary mechanisms most likely involve a sensing or monitoring of the environment with concomitant changes in gene expression, this makes sense. In fact, the role of such types of SNPs (those under selective pressure) and their role in heart disease, was a topic on which we published in 2010.
The article by Dudley, et al. is really nice work and one whose insight we will use to inform our GWAS analysis.
The authors examined over 5800 disease-associating variants, comparing the genomic neighborhood across a panel of species. This covered 230 different disease and disease risk phenotypes. Importantly, the authors demonstrate that there is a propensity to discover such disease SNPs at "conserved genomic positions, because the effect size (odds ratio) and allelic P-value of genetic association of a SNP relates strongly to the evolutionary conservation of their genomic position." This then allowed them to develop a new means to rank such association SNPs in which a conservation score, based on the evolutionary analysis, is incorporated into the P-value of the genotype-phenotype association.
As many GWAS SNPs alter gene expression - either through altered transcription factor binding or microRNA-mRNA interaction, and as such evolutionary mechanisms most likely involve a sensing or monitoring of the environment with concomitant changes in gene expression, this makes sense. In fact, the role of such types of SNPs (those under selective pressure) and their role in heart disease, was a topic on which we published in 2010.
The article by Dudley, et al. is really nice work and one whose insight we will use to inform our GWAS analysis.
POTW: Exercise and gene methylation
The Paper of the Week for 9 March 2012 was entitled "Acute Exercise Remodels Promoter Methylation in Human Skeletal Muscle" by Barres, et al. It appeared in Cell Metabolism as a Short Article.
The exercise test was performed on a stationary bicycle. One cohort of subjects were exercised until reaching either 40% or 80% of VO2 peak. A second cohort was exercised until 1,674 kJ were expended. These were acute interventions, making the findings all the more remarkable.
I found the following to be key points of this paper:
1. In both healthy, sedentary women and men, it was observed that whole genome methylation was decreased in skeletal muscle.
2. While exercise induced expression of PPARGC1A (PGC-1α), PDK4, and PPARD, the authors also noted reduced methylation at each of the promoters for these genes.
PPARGC1A is a key transcriptional regulator of OXPHOS (oxidative phosphorylation) genes. It is also an important type 2 diabetes gene.
The exercise test was performed on a stationary bicycle. One cohort of subjects were exercised until reaching either 40% or 80% of VO2 peak. A second cohort was exercised until 1,674 kJ were expended. These were acute interventions, making the findings all the more remarkable.
I found the following to be key points of this paper:
1. In both healthy, sedentary women and men, it was observed that whole genome methylation was decreased in skeletal muscle.
2. While exercise induced expression of PPARGC1A (PGC-1α), PDK4, and PPARD, the authors also noted reduced methylation at each of the promoters for these genes.
PPARGC1A is a key transcriptional regulator of OXPHOS (oxidative phosphorylation) genes. It is also an important type 2 diabetes gene.
Friday, March 2, 2012
POTW: Epigenetics and cognitive function
This weeks Paper of the Week adds some detail to connections between cognitive function and epigenetics as histone modifications. The paper is "An epigenetic blockade of cognitive functions in the neurodegenerating brain" by Gräff, et al. The paper was published in Nature on 29 Feb 2012.
What makes this a noteworthy paper, in my opinion, is the link between Alzheimer disease and lifestyle choices. The lifestyle choices of smoking, diet and physical activity (and likely others) have the ability to affect epigenetic patterns of either DNA methylation or histone acetylation. The authors demonstrate that cognitive abilities in a brain with developing neurodegeneration are held in check by an epigenetic-based restriction of gene transcription, and this is potentially reversible. This repression of mRNA synthesis is mediated by histone deacetylase 2 (or HDAC2). Furthermore, this repression is increased by Alzheimer’s-disease-related neurotoxic insults in vitro, in two mouse models of neurodegeneration and in patients with Alzheimer’s disease.
Imagine if something in the diet or something like exercise could reduce or repress the built-up activity of HDAC2 that occurs as a result of the neurotoxic insults described in the paper. That would be exciting. Thus, I see this work as important in showing, again, how environment and epigenetics can affect disease state. It is certainly likely that certain lifestyle choices would have greater or lesser impact on neurodegenerative processes and either augment or enhance the genetic risk of disease. Although not demonstrated in this article, it could be that an APOE epsilon 4 (E4) genotype, with its increased risk of Alzheimer disease could be partially ameliorated via those lifestyle choices that inhibit or curtail excessive HDAC2 activity. That woud indeed be quite exciting.
What makes this a noteworthy paper, in my opinion, is the link between Alzheimer disease and lifestyle choices. The lifestyle choices of smoking, diet and physical activity (and likely others) have the ability to affect epigenetic patterns of either DNA methylation or histone acetylation. The authors demonstrate that cognitive abilities in a brain with developing neurodegeneration are held in check by an epigenetic-based restriction of gene transcription, and this is potentially reversible. This repression of mRNA synthesis is mediated by histone deacetylase 2 (or HDAC2). Furthermore, this repression is increased by Alzheimer’s-disease-related neurotoxic insults in vitro, in two mouse models of neurodegeneration and in patients with Alzheimer’s disease.
Imagine if something in the diet or something like exercise could reduce or repress the built-up activity of HDAC2 that occurs as a result of the neurotoxic insults described in the paper. That would be exciting. Thus, I see this work as important in showing, again, how environment and epigenetics can affect disease state. It is certainly likely that certain lifestyle choices would have greater or lesser impact on neurodegenerative processes and either augment or enhance the genetic risk of disease. Although not demonstrated in this article, it could be that an APOE epsilon 4 (E4) genotype, with its increased risk of Alzheimer disease could be partially ameliorated via those lifestyle choices that inhibit or curtail excessive HDAC2 activity. That woud indeed be quite exciting.
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