Life aboard the International Space Station

As some of you who follow me on Twitter may already know, NASA astronaut Suni Williams and I were childhood friends. We were on the same swim team together. She is aboard the International Space Station (ISS) at this moment on Expedition 32, beginning a 4-month stay about a week and a half ago. Since her first trip to the ISS in 2006, I've been in touch with her and that got me on the invite list to attend a special launch party for her current mission. At that event, there was a special presentation by Captain Dan Burbank. He was Commander of Expedition 30 to the ISS and returned to Earth on 27 April 2012 after a five-month stay aboard the ISS.

I was curious to learn about the behavior of the astronauts on the ISS in terms of diet, physical activity (especially with regard to bone loss and muscle function) and sleep. Many of you know how our research group examines the role of environmental factors in modifying disease risk. These are GxE, or gene-by-environment, interactions. Diet, dietary components (eg, certain fatty acids, protein content, carbohydrates), exercise (or sedentary behavior) and sleep are key environmental factors for our work.

Dan told me that he would normally consume about 3500 calories per day on Earth but that increased by about 500 calories aboard the ISS. He could not say if it was more carbs or fat or protein or just a bit more of everything. He did not speak much about exercise other than to tell us all during his slide presentation that there is a new resistance machine on board that provides 400 pounds of resistance. The previous machine provided only 100 pounds of resistance and the 400 level is what is needed to stem bone loss. He told us that when one types on a keyboard, only a few strokes are needed to send the person across the room in microgravity. So, they "stand" with feet hooked under railings, like as bar rail. This gives them calluses on the tops of their feet, while those on the soles begin to fade.

What was perhaps the most interesting to me was Captain Dan's sleep habits. He said that on the ISS he needed only 4 to 7 hours of sleep per night. What's more, he did not strap himself in to provide a feeling of lying down, but could sleep anywhere, floating in his room.

All in all, it was a really cool experience to meet an astronaut, to learn about life aboard the ISS, and to see someone I know launch with a Soyuz rocket to begin her latest adventure.

Good luck and continued success with your mission, Suni!

The WHO's report on noncommunicable diseases

The World Health Organization of the United Nations has released a report titled "Global status report on noncommunicable diseases." Access to the report and its individual chapters is at this link. I was particularly interested in Chapter 1 and the major contributing factors to noncommunicable diseases (NCD).

According to the above report and others from the WHO, the four primary contributors to global increases in NCDs, such as type 2 diabetes, cancer, and cardiovascular diseases, are:

tobacco

harmful use of alcohol

unhealthy diet

physical inactivity

While such a list is really not surprising, what I do take from this, with respect to my own research on the genetic basis for the differential response to the diet as it pertains to metabolic diseases, is these are our key environmental factors used to assess gene by environment, or GxE, interactions. In other words, while these factors are strong contributors to NCD onset and progression, genetic differences exert different influences on the disease risk, onset and progression in different individuals. That influence could be negative - increasing risk - or positive - being more protective.

Thus, the importance of GxE identification cannot be overlooked, and ought really to be emphasized in genetic association studies.

POTW: Uncovering the function of an intergenic SNP

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.

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.

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.