A New Twist on the Genetics of Sleep

Imprinted genes, genes expressed depending on parent of origin, may play a role.

Posted May 16, 2012

In the current issue of PLOS Genetics there is an fascinating paper on the role of the Gnas gene in regulation of REM and NREM sleep. The article is by an international team including groups based at the Department of Neuroscience and Brain Technologies, Istituto Italiano di Tecnologia, Genova, Italy; the Medical Research Council Mammalian Genetics Unit, Harwell, United Kingdom, and the Department of Integrative Biology and Physiology, University of Minnesota, Minneapolis, Minnesota, United States of America.

The authors (Lassi G, Ball ST, Maggi S, Colonna G, Nieus T, et al. (2012) Loss of Gnas Imprinting Differentially Affects REM/NREM Sleep and Cognition in Mice. PLoS Genet 8(5): e1002706. doi:10.1371/journal.pgen.1002706) report that REM and NREM sleep states are differentially modulated by the maternally expressed imprinted gene Gnas.

Normally mice, like many other mammals including us, exhibit imprinting of the Gnas locus.

What is imprinting? Currently, approximately 100 transcripts in the mammalian genome, and a number of non-coding RNAs, are known to be imprinting genes. An epigenetic mark, occurring during gametogenesis, and involving DNA methylation of CpG-rich domains, and chromatin alteration, leads to a bias in gene expression between maternally and paternally inherited imprinted genes. Thus an imprinted gene is expressed depending on parent of origin; that is whether it is transmitted by the maternal or paternal line.

This fact is extremely important for a theory of the evolution of sleep states in mammals as there are some explicitly defined evolutionary models of genomic imprinting. The most famous of these is David Haig’s genetic conflict model.

To vastly oversimplify a very complex model, the conflict theory of imprinting suggests that imprinting evolved due to conflict in reproductive interests between the sexes. Maternally expressed genes tend to down-regulate and conserve energetic resources of an organism while paternally expressed genes tend to oppose effects of the maternally expressed genes.

Now Gnas, (the locus at issue in this paper) encodes the stimulatory G-protein subunit which facilitates production of cyclic AMP and other energy related metabolic processes. But the authors engineered a mouse model that exhibits loss of imprinting of Gnas. They then measured sleep and behavioral learning processes in these mice. Sleep was measured with implanted electrodes and behavioral responding was measured with state of the art automated learning and fear conditioning paradigms for mice.

The basic finding reported in the paper was that the mice who had loss of imprinting of Gnas exhibited abnormally enhanced indices of NREM sleep and abnormal dimunition of REM activity.

The authors offer the reasonable idea that sleep functions in part to help regulate energy homeostasis and that is why sleep states can be so profoundly influenced by expression of a gene like Gnas.

It appears then that sleep state physiologies have been brought, at least in part, under control of imprinted genes.

But now that idea and fact carries with it potentially important implications for sleep science and sleep disorders.

If sleep functions can be influenced by forces of genetic conflict then we are likely to see some bizarre phenomena associated with sleep—just as we do in other arenas where genetic conflict holds sway (e.g. sexual behaviors). In addition, many sleep disorders might be profoundly influenced by genetic mechanisms that do not obey classical Mendelian rules of inheritance.

Interestingly, as has often been pointed out Prader-Willi syndrome (PWS) and Angelman syndrome (AS)exhibit opposing imprinting profiles and opposing sleep phenotypes. PWS is associated with excessive sleepiness and REM sleep abnormalities such as sleep-onset REM periods, REM fragmentation, intrusion of REM into stage 2 sleep, and short latencies to REM. Conversely, AS is associated with reductions in sleep.

The Lassi et al paper represents a potentially major step forward in understanding these complex disorders of sleep and behavior.