The Long Epigenetic Shadow of A Genetic Mutation

The evidence that parents pass epigenetic information on to their offspring and that information influences offspring physiology and behavior is continuing to grow. In the field of obesity research, it is now beyond doubt that maternal obesity, and paradoxically calorie restriction, programs the physiology of offspring such they are extremely susceptible to developing metabolic syndrome. Some evidence has indicated that paternal obesity can also have similar effects, which separates out the in utero effects of maternal obesity and indicates that epigenetic programs are being passed on to the next generation through the germ cells.

 

Paternal germ line transmission of epigenetic programs has been understudied compared to maternal transmission. However, a particularly remarkable study on paternal transmission of metabolic state has recently been published in Human Molecular Genetics by Jo Nadeau and David Buchner (http://www.ncbi.nlm.nih.gov/pubmed/20696673) entitled:

 

Hum Mol Genet. 2010 Aug 18. [Epub ahead of print]

Ancestral paternal genotype controls body weight and food intake for multiple generations.

Yazbek SNSpiezio SHNadeau JHBuchner DA

 

There are several remarkable points that make this paper extremely interesting. The first is the high quality of the work. The samples sizes are large, many different crosses are tested and the read out was body weight, which is a very reliable and simple measure of effect. The authors build on a previous discovery of a mutation that causes resistance to obesity. They find that the obesity resistance phenotype is passed on to offspring even when the mutation itself is not inherited, thus indicating the existence of some heritable epigenetic effect. Astoundingly, the phenotype is only transmitted from fathers and cannot be inherited from mothers. Further, it can be transmitted for at least two generations through the paternal germline, which means that a mouse is obesity-resistant if it’s paternal grandfather had the mutation. This work clearly emphasizes the challenges ahead for understanding non-mendelian diseases. We are the sum of many effects: genetic programs, environmental epigenetic programs, transgenerational epigenetic programs, stochastic effects, microbiome effects and lifestyle decisions.

 

Food for thought.

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