Thursday, April 29, 2010

The Complexity of a Complex Disorder

A group of researchers led by Timothy Aitman of the MRC Clinical Sciences Centre and Imperial College London used the SHR (spontaneously hypertensive rat) to identify the few genes they thought predisposed this strain to hypertension (several genes had already been identified but the group knew or felt a few others remained to be discovered). Sequencing this SHR rat with the NextGen approach and comparing those data to the rat reference genome, led to quite a surprise. 788 genes are mutated in SHR compared to the reference genome, including 60 that are deleted altogether.

My take on this is many genes are likely involved in a complex disorder and many genes - with specific variants - may work in concert to produce the disease phenotype – either via gene-gene interactions or affecting interconnecting pathways.

This type of result is very likely to be repeated with other metabolically sensitive disorders and afflictions such as dyslipidemia, obesity and type 2 diabetes. A series of variations in genes combined with deviations from a standard environment - both in terms of diet and microbiome - are likely to combine to tip the balance and enhance onset and/or progression of said affliction.



EurekAlert: Hypertensive rat genome sequence expected to uncover genetic basis of human hypertension

Atanur SS, Birol I, Guryev V, Hirst M, Hummel O, Morrissey C, Behmoaras J, Fernandez-Suarez XM, Johnson MD, McLaren WM, Patone G, Petretto E, Plessy C, Rockland KS, Rockland C, Saar K, Zhao Y, Carninci P, Flicek P, Kurtz T, Cuppen E, Pravenec M, Hubner N, Jones SJM, Birney E, Timothy J. Aitman TJ. (2010) The genome sequence of the spontaneously hypertensive rat: Analysis and functional significance. Genome Res. (in press).

Thursday, April 22, 2010

Optimal values

If a little of this or that is good, then more must be better for me, right? No, but unfortunately, many of us think this way. Still others with some knowledge of how things are in a biological or physiological or medical context understand that a plateau of effect is often reached whereby a given compound or nutrient is no longer effective. But often ignored is the adverse effect of taking in too much of that substance. Hence, there is an inverse bell curve, as shown below, that most probably explains the effects of most substances we each encounter whether at the dining table or elsewhere in the environment.

Allow me to provide a short example. Athletes who take oxygen from the sidelines ostensibly to "recover." A higher intake of oxygen will actually saturate the hemoglobin in the red blood cells and hinder exchange of carbon dioxide transfer from peripheral tissues. Sure, breathing pure oxygen reduces respiration rate - less huffing and puffing after scoring that touchdown - but has little value in allowing the muscles to recover.

Thus, as has been so often said - everything in moderation.

Tuesday, April 6, 2010

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.


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.