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.

Cultural evolution and the road to obesity

It seems that little is known about a critical time in human civilization some 7500 to 6000 years ago, a time when groups began coalescing into societies with distinct hierarchies and structure. During this time in Mesopotamia the Ubaid culture took root and appears from recent surveys of a critically important site called Tell Zeidan in Syria to represent an especially transcendent time in human cultural evolution. The initial report, from 2008, of the Oriental Institute of the University of Chicago, which is conducting archeological excavations at Tell Zeidan, can be found here. The formation of ever larger towns and cities and trading centers certainly required advancements in agriculture. This in turn exerted an impact on the nutritional status of those inhabitants.

As I read an article this morning in the New York Times on this topic, the phrase "cultural evolution" drew to mind a very well written recent review by Kevin Laland and colleagues in Nature Reviews Genetics in which they present the argument that human evolution can be rapidly shaped by culture. This is not culture of the high-art type, but is described by the authors in terms of human activities that affect an entire group. These are activities such as farming, animal husbandry, and, in short, behavior - knowledge, skills, beliefs or values - acquired from other individuals. I believe the authors to be correct when stating that there can exist rapid changes in allele frequencies arising via positive selection on variants involved in gene-culture interactions. Table 2 of the review lists genes under recent rapid selection with an inferred cultural selection pressure. Of interest to our research are those genes involved in metabolic disorders, such as:

LEPR, PON1, RAPTOR, MAPK14, CD36, DSCR1, FABP2, SOD1, CETP, EGFR, NPPA, EPHX2, MAPK1, UCP3, LPA, MMRN1 all pertaining to energy metabolism, hot or cold tolerance; heat-shock genes and arising from dispersal and subsequent exposure to novel climates.

Thus, some number of human genes are undergoing rather rapid changes due to cultural shifts in society. The same appears to have taken place in chickens. Around 1900 separate chicken breeds began to be established for broiler (meat) production and egg-laying. An analysis of these breeds in comparison to Red Jungle fowl (the main wild ancestor) and Rhode Island Red standards revealed that just a small number of changes in the genome occurred in the production breeds to presumably yield the characteristics sought by those in the business. Of particular note are those sweeps affecting thyroid hormone function, photoperiod sensitivity, appetite and metabolism. Details of this exciting and very pertinent study are in the paper.

OK, it seems that the genome can adapt rather quickly given extreme pressures of selective breeding in the case of chickens or cultural adaptation in the case of humans. Now, consider changes in the diet of Americans over the last 100 years. A report from the Economic Research Service of the US Dept. of Agriculture shows how meat consumption in the USA has changed since 1909. Sometime in the 1950's per capita chicken consumption went from about 15 pounds/year to over 60. Over this same period, cheese consumption saw a similar 4-fold increase. Other interesting changes in beef, sweet potato and flour/grain intake can be viewed in the report.

With such rapid changes to the human diet, and this is without discussion of sugars and salt and the impacts of peer pressure and advertising, it really is no wonder that type 2 diabetes, obesity and cardiovascular diseases are on the rise.


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References

Laland KN, Odling-Smee J, Myles S. (2010) How culture shaped the human genome: bringing genetics and the human sciences together. Nat Rev Genet. 11:137-48.

Mentzer Morrison R, Buzby JC, Hodan Farah Wells HF (2010) Amber Waves 8:12-19.