Genes 2 Brains 2 Mind 2 Me

For humans, there are few sights more heart-wrenching than an orphaned child (or any orphaned vertebrate for that matter).  Isolated, cold, unprotected, vulnerable – what could the cold, hard calculus of natural selection – “red in tooth and claw” – possibly have to offer these poor, vulnerable unfortunates?

So I wondered while reading, “Functional CRH variation increases stress-induced alcohol consumption in primates” [doi:10.1073/pnas.0902863106].  In this paper, the authors considered the role of a C-to-T change at position -248 in the promoter of the corticotropin releasing hormone (CRH or CRF) gene.  Its biochemical role was examined using nuclear extracts from hypothalamic cells, to demonstrate that this C-to-T nucleotide change disrupts protein-DNA binding, and, using transcriptional reporter assays, that the T-allele showed higher levels of transcription after forskolin stimulation.  Presumably, biochemical differences conferred by the T-allele can have a physiological role and alter the wider functionality of the hypothalamic-pituitary-axis (HPA axis), in which the CRH gene plays a critical role.

The authors ask whether primates (rhesus macaques) who differ in genotype (CC vs. CT) show any differences in physiological stress reactivity – as predicted by differences in the activity of the CRH promoter.  As a stressor, the team used a form of brief separation stress and found that there were no differences in HPA function (assessed by ACTH and Cortisol levels) in animals who were reared by their mothers.  However, when the stress paradigm was performed on animals who were reared without a mother (access to play with other age-matched macaques) there were significant differences in HPA function between the 2 genetic groups (T-alleles showing greater release of stress hormones).  Further behavioral assessments found that the peer reared animals who carried the T-allele explored their environment less when socially separated as adults (again no C vs. T differences in maternally reared animals).  In a separate assessment the T-carriers showed a preference for sweetened alcohol vs. sweetened water in ad lib consumption.

One way of summarizing these findings, could be to say that having no mother is a bad thing (more stress reactivity) and having the T-allele just makes it worse!  Another way could be to say that the T-allele enhances the self-protection behaviors (less exploration could be advantageous in the wild?) that arise from being orphaned.  Did mother nature (aka. natural selection) provide the macaque with a boost of self-preservation (in the form of a T-allele that enhances emotional/behavioral inhibition)?  I’m not sure, but it will be fun to report on further explorations of this query.  Click here for an interview with the corresponding author, Dr. Christina Barr.

—p.s.—

The authors touch on previous studies (here and here) that explored natural selection on this gene in primates and point out that humans and macaques both have 2 major haplotype clades (perhaps have been maintained in a yin-yang sort of fashion over the course of primate evolution) and that humans have a C-to-T change (rs28364015) which would correspond to position -201 in the macaque (position 68804715 on macaque chr. 8), which could be readily tested for similar functionality in humans.  In any case, the T-allele is rare in macaques, so it may be the case that few orphaned macaques ever endure the full T-allele experience.  In humans, the T-allele at rs28364015 seems more common.

Nevertheless, this is yet another – complicated – story of how genome variation is not destiny, but rather a potentiator or life experience – for better or worse.  Related posts on genes and early development (MAOA-here), (DAT-here), (RGS2-here), or just click the “development tag“.