New research with rhesus macaques shows that dominance rank has a major impact on gene regulation of the immune system. Through experimental manipulations of the dominance rank of individuals and associated measures of gene expression, this work by Jenny Tung and colleagues helps to demonstrate that social status can be a major driver of health in socially living animals, including humans. These results provide an important empirical link for social determinants of health research by showing that dominance rank within a social system is linked directly to regulatory processes of the immune system.
The paper, Social Environment Is Associated with Gene Regulatory Variation in the Rhesus Macaque Immune System (pdf here), came out in April in Proceedings of the National Academy of Sciences. The research was carried out by Jenny Tung, now an assistant professor at Duke University, at the Yerkes National Primate Center. Tung performed the research while she was a post-doc at the University of Chicago, working with senior author Yoav Gilad in the Department of Human Genetics. At the Primate Center, Tung manipulated social rank by sequentially introducing female macaques into a new cage; the earlier arrivals generally end up with a high rank and later introductions come out low in the dominance hierarchy.
Here is the line in the abstract that really got me: “We show that dominance rank results in a widespread, yet plastic, imprint on gene regulation, such that peripheral blood mononuclear cell gene expression data alone predict social status with 80% accuracy.” That result is incredible. In other words, from the biology alone it was possible to accurately sort where female macaques fell into their experimentally-induced social structure.
High rank, medium rank, and low rank all looked significantly different in their gene expression patterns. Indeed, Tung found that for those few individuals whose rank changed while housed in a particular cage showed a corresponding change in their biological profile. As Tung stated in a Duke Press release, “Our study supports the idea that low social status can be bad for the body. But it hints at the idea that if you improve your social situation, your health improves, too.”
On Gene Regulation
Social rank in this research has a clear and demonstrable impact on the regulation of genes linked to health. Tung et al. write, “when conditioning on the direction of the rank effect on gene regulation, we observed enrichments for interleukin signaling (P = 0.01, q = 0.05), T-cell activation (P = 0.01, q =0.05), and chemokine and cytokine inflammation (P = 0.02, q =0.07) among genes more highly expressed in low-ranking individuals.”
The following figure taken from the paper illustrates a clear linear relationship between ranks 1 through 5 in a five female social group and three genes linked to systemic inflammation and health: (1) PTGS2, a signaling molecule linked to inflammation and negatively regulated by glucocorticoids (e.g., stress hormones); (2) IL8RB, a receptor for the inflammatory cytokine IL8 and associated with injured tissue (yes, there were aggressive flare-ups among the macaques); and (3) NFATC1, which is linked to T-cell stimulation. The basic point from the figure is that the lower you rank, the more your body is up-regulating the genes associated with chronic inflammation – and in evolutionary terms, with greater maintenance costs.
Overall, dominance position had a broad regulatory effect on gene expression. The authors write:
We investigated the mechanistic basis of these effects using cell type-specific gene expression profiling and glucocorticoid resistance assays, which together contributed to rank effects on gene expression levels for 694 (70%) of the 987 rank related genes. We also explored the possible contribution of DNA methylation levels to these effects, and identified global associations between dominance rank and methylation profiles that suggest epigenetic flexibility in response to status-related behavioral cues.
The authors do acknowledge that the associations they find are not of the “smoking gun” order. For example, by administering an artificial glucocorticoid, the researchers could test first for chronic stress (yes, the lower animals exhibited it) and then look at the link between stress response and the gene expression-rank dynamic. “The effects of GC regulation were modest.”
They do point to an interesting result, that both higher glucocorticoid signaling and lower number of immune blood cells can contribute to the empirical relationship between gene expression and social rank. In other words, there can be cumulative effects via different mechanisms. This research then is a good example of social causation, which can be iterative and diverse. There are few smoking guns in social science research, no matter how much scientists might wish for them; rather, cascades of effect – just at Tung et al. demonstrate – are important in understanding how things work.
The research shows that rank in adulthood matters. In a social primate like rhesus macaques, social position produces consistent effects on the gene regulation of the immune system. This work provides a concrete experimental demonstration of how social rank can impact health, and backs up foundational work in humans that has demonstrated the real health costs associated with social rank. The famous Whitehall Study of civil servants in the United Kingdom, for example, “found a strong association between grade levels of civil servant employment and mortality rates from a range of causes. Men in the lowest grade (messengers, doorkeepers, etc.) had a mortality rate three times higher than that of men in the highest grade (administrators).”
Jenny Tung is now helping out with the genetics and epigenetics of the long-standing babon research at Amboseli. Her work there will examine social position and gene regulation over the life course, and contribute to the foundational work by Jeanne Altmann and Robert Sapolsky on the links between stress, inequality, and health. Altmann recently co-published a PNAS article that shows dominant males heal much more quickly from wounds than lower ranking males (see Time Healthland for a good write-up of the research). Sapolsky wrote the foundational paper The Influence of Social Hierarchy on Primate Health, which I discussed way back in 2007. Together, this work with primates (and there’s a lot more! for example, Stephen Suomi’s recent paper, Primate evidence on the late health effects of early-life adversity) clearly shows how social systems can drive our biology, and that inequality plays a major role in our health both in the short and the long term.
Tung et al.’s research plays into arguments about the impact of social status and inequality on people’s behavior, brains, and health that have formed a long tradition on this blog. I list some of those posts below.
I will end with this paragraph that presents a coherent summary of why Jenny Tung’s research matters:
Measurements of the gene expression of 49 different female monkeys of varying rank revealed significant changes in the expression of 987 genes, including 112 genes associated with immune system function. The results were consistent with earlier data showing that monkeys of low rank who suffered chronic stress ended up with compromised immune function. It was also consistent with human studies linking low socioeconomic status and high social stress to elevated disease risk.
Tung, J., Barreiro, L.B., Johnson, Z.P., Hansen, K.D., Michopoulous, V., Toufexis, D., Michelini, K.M., Wilson, M.E., and Gilad, Y. 2012. Social environment is associated with gene regulatory variation in the rhesus macaque immune system. Proceedings of the National Academy of Sciences USA 109: 6490-6495
Female macaques: Yerkes National Primate Research Center
Jenny Tung: Goldsea Asian American Business