The Thrifty Gene Hypothesis

James Neel-1962

Genes that predispose us to obesity were advantageous in early human history when starvation was an issue.

Early Humans went through cycles of feast and famine and thus more efficient at food storage and utilization were more likely to survive and reproduce during famine.

Feast-Famine Cycle

Physical Activity Chakravarthy and Booth (2004)

Physical activity was as important as food related adaptations

Early humans went through Physical-Activity cycle that mimics feast-famine cycle physiologically.

People who were more capable physically of surviving the hunt or gathering food, would survive and pass down their genetics

Physiological response to Feasting and Recovery from Exercise, as well as to Famine and Exercise are remarkably similar

Combined these similar processes provide a much larger genetic drive for “thrifty genes”

Chakravarthy, M. V. & Booth, F. W. (2004). Eating, exercise, and “thrifty” genotypes: connecting the dots toward and evolutionary understanding of modern chronic diseases. J Appl Physiol, 96(1), 3–10.

Feast-Famine and Physical Activity Cycle Model

Chakravarthy, M. V. & Booth, F. W. (2004). Eating, exercise, and “thrifty” genotypes: connecting the dots toward and evolutionary understanding of modern chronic diseases. J Appl Physiol, 96(1), 3–10.

Modern Problem

Chakravarthy, M. V. & Booth, F. W. (2004). Eating, exercise, and “thrifty” genotypes: connecting the dots toward and evolutionary understanding of modern chronic diseases. J Appl Physiol, 96(1), 3–10.

Critiques and Problems

Complex-Not just one gene

The Natural Selection Driver Death

Minor famine’s occurred frequently throughout history, but severe Famines much less frequent (~150years)

Birth During even minor

famine’s, reproduction is reduced because lower body fat intake negatively impacts reproduction

Prentice, A. M., Hennig, B. J. & Fulford, A. J. (2008). Evolutionary origins of the obesity epidemic: natural selection of thrifty genes or genetic drift following predation release? International Journal of Obesity, 32, 1607–1610.

When did genetic changes start? Hunter-Gather era

Rate of selection calculations show that 99% of us would have the thrifty genes if started back then.(Speakman, 2008).

Why aren’t we all fat? Thrifty genes not meant to make fat, but rather

enhance fuel storage, utilization, and efficiency. Agricultural era

Genes related to glucose and fat metabolism have been positively selected within the last 10,000 years (Voight, 2006)

We all have thrifty genes?

Stoger Thrifty phenotype hypothesis because energy efficiency and fitness

was essential to early man, “unthrifty” genes never were allowed to become established

Endurance hypothesis (Brambley and Lieberman, 2004)

If we all have thrifty genes, then why is obesity seemingly more heritable in certain groups like the Pima Indians?

Thrifty Epigenome: The missing link? Old theory: Have the gene or don’t New theory: The function (the degree of

expression) of the gene matters Epigenetics- manipulates how the gene

functions (whether it’s turned on/off, and the degree of transcription)

Genome=Hardware Epigenome=Software

Most susceptible to change while fetus is in development

Genetic imprinting- can be passed on for a couple generations

Short term adaptation to the environment

Epigenome adapts to the predicted environment when in utero. Mother experiences famine,

epigenome overeacts and up regulates genes for food storage and utilization

Mismatch When

predicted environment does NOT equal actual environment disease (obesity) occurs

Godfrey, K. M., Lillycrop, K. A., Burdge, G. C., Gluckman, P. D. & Hanson, M. A. (2007). Epigenetic mechanism and the mismatch concept of the developmental origins of health and disease. Pediatric Research, 61(5), 5–10.

Evidence

Ravelli et al. (1976) Obesity much higher in individuals

whose mother went through famine during pregnancy

Dong et al. 2005) Found Genetic imprinting in obesity

related genes

Conclusion Obesity is a polygenic problem

Very complex- not a single gene issue It not only matters whether one has a

combination of genes, but how they function. Eaton et al. (1988) put it best when they said

that we have “ ‘Stone Age’ genes and ‘Space Age’ circumstances.”

Physical Activity and food were likely intricately linked from the start of mankind and it’s a mistake to consider one and not the other.

References Bramble, D. M. & Lieberman, D. E. (2004). Endurance running and the evolution of Homo. Nature, 432, 345–352. Bribeescas, R. G. (2001). Serum leptin levels and anthropmetric correlates in ache Amerindians of eastern

Paraguay. Am J Phys Anthropol, 115, 297–303. Chakravarthy, M. V. & Booth, F. W. (2004). Eating, exercise, and “thrifty” genotypes: connecting the dots toward

and evolutionary understanding of modern chronic diseases. J Appl Physiol, 96(1), 3–10. Dong, C., Lie, W. D., Geller, F., Lei, L., Li, D., Gorlova, O. Y., Hebebrand, J., Amos, C. I., Nichols, R. D. & Price, R. A.

(2005). Possible Genomic Imprinting of Three Human Obesity–Related Genetic Loci. The American Journal of Human Genetics, 76(3), 427–437.

Eaton, S. B., Konner, M. & Shostak, M. (1988). Stone agers in the fast lane: chronic degenerative diseases in evolutionary perspective. Am J Med, 84, 739–749.

Godfrey, K. M., Lillycrop, K. A., Burdge, G. C., Gluckman, P. D. & Hanson, M. A. (2007). Epigenetic mechanism and the mismatch concept of the developmental origins of health and disease. Pediatric Research, 61(5), 5–10.

Midgeley, A. W., McNaughton, L. R., & Jones, A. M. (2007). Training to enhance the physiological determinants of long-distance running performance: can valid recommendations be given to runners and coaches based on current scientific knowledge. Sports Med, 37(10), 857–880.

Neel, J. V. (1962). Diabetes mellitus a ‘thrifty’ genotype rendered detrimental by ‘progress’? Am J Hum Genet, 14, 352–353.

Prentice, A. M., Hennig, B. J. & Fulford, A. J. (2008). Evolutionary origins of the obesity epidemic: natural selection of thrifty genes or genetic drift following predation release? Internationa Journal of Obesity, 32, 1607–1610.

Prentice, A. M. (2005). Starvation in humans: evolutionary background and contemporary implications. Mech Ageing Dec, 126, 976–981.

Ravelli, G. P., Stein, Z. A. & Susser, M. W. (1976). Obesity in young men after famine exposure in utero and early infancy. N Eng J Med, 295, 349–353.

Speakman, J. R. (2008). Thrifty genes for obesity, an attractive but flawed idea, and an alternative perspective: the ‘drifty gene’ hypothesis. International Journal of Obesity, 32, 1611–1617.

Stoger, R. (2008). The thrifty epigenotype: an acquired and heritable predisposition for obesity and diabetes? BioEssays, 30(2), 156–166.

Voight, B. F., Kudaravalli, S., Wen, X. & Pritchard, J. K. (2006). A map of recent positive selection in the human genome. PLoS Biol, 72.