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.

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.

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.