MRG selection and the evolution of pain

I ran across a 2003 paper on the evidence of recent positive selection on the MRG gene family in humans. This gene family is specific to neurons in its activity, and specifically limited to "nociceptive sensory neurons of the dorsal root and trigeminal ganglia," in other words, neurons involved in the perception of pain.

They find evidence of positive selection in both humans and mice, and further infer that at least some of the selection in the human lineage occurred recently in evolutionary history (although they do not compare with apes to test this hypothesis).

Pairwise comparisons of evolutionary distances were carried out on these genes. They showed that human MRGX genes are closely related to one another (average pairwise Ks is 0.15; Fig. 1A). The Ks between even the most distantly related MRGX genes is much lower than the average Ks between human and mouse orthologs estimated at 0.47 (Makolowski and Boguski 1998). Hence, the human MRGX subfamily likely arose from recent amplifications that postdated human-mouse divergence. In particular, MRGX4 and 5 show very little synonymous divergence (Ks = 0.006), indicating that they are likely the result of a duplication postdating human-chimp divergence (average Ks between human and chimp orthologs is around 0.015) (Choi and Lahn 2003:2252, references therein).

On the function of the genes and the possible source of selection, they have this to say:

The perception of hazardous stimuli as being painfuland the subsequent avoidance of such stimuli -- are critical to the survival of animals. When a species encounters evolutionary shifts in ecological conditions (such as habitat, climate, diet, predator-prey relationship, and social interactions), or its own internal physiology, previously innocuous stimuli may now impair fitness, and conversely, formerly aversive stimuli may become harmless or even beneficial. In the face of such evolutionary changes, a species would be under selective pressure to tune its nociceptive sensitivity and selectivity, so as to continue to correctly interpret those stimuli that endanger survival as being painful, while remaining undisturbed by innocuous stimuli (Kavaliers 1988). We hypothesize that such selective pressure has operated on MRG to drive its rampant amplification and fast protein evolution. Indeed, nociceptive properties do vary remarkably between species, among individuals of the same species, and between genders (Kavaliers 1988). Humans, for example, exhibit highly variable sensitivity to pain, including drastically different responses to identical injuries or pathologies (Libman 1934; Chen et al. 1989). Exceptionally heightened or reduced nociceptive sensitivity can have severe or even fatal consequences (Indo et al. 1996; Ophoff et al. 1996; Friedberg and Jason 2001). Similarly, closely related laboratory mice can differ by orders of magnitude in their pain threshold to noxious stimuli (Mogil et al. 1999). Such diversity in nociceptive response attests to the dynamic quality in the evolution of nociception (Kavaliers 1988). It will be of interest to see what role MRG plays in between- or within-species differences of nociception (Choi and Lahn 2003:2256, references therein).

This gene accompanies several other genes related to brain function whose history of positive selection has been uncovered by the Lahn lab, including those covered by Dorus (2004), discussed in another post.


Choi SS and Lahn BT. 2003. Adaptive evolution of MRG, a neuron-specific gene family implicated in nociception. Genome Res 13:2252-2259. Genome Research Online