Immune Gene Expression May Drive Social Status

North of Mt. Kilimanjaro, scientists have been observing more than 1,500 wild savannah baboons (Papio cynocephalus) over four decades as a part of The Amboseli Baboon Project.

Source: Paul Mannix (Baboon, Amboseli National Park, Kenya) [CC BY-SA 2.0]

Social hierarchy causes psychological stress. Compounded by poor resources, stress wreaks havoc on the immune system. It destroys the organism’s ability to fend off pathogens, to suppress the growth of cancer-causing mutations, and to adapt to environmental shocks. So, when inequality increases, the worst-off can expect to live shorter, sicker, and more generally miserable lives than those at the top. At least that was the story up until now. New research, however, suggests that we got at least a part of this story backwards.

High social status may be a result of, and not only a cause of, changes in inflammation, according to a new study of primates in Kenya by a Duke team of biologists. However, the team discovered the role of immune gene expression only in males, while the same could not explain the social status of females. Genetics alone did not pre-determine dominance rank.

“We found signatures of dominance status in proinflammatory pathways. But there was a lot of context dependence. Not all hierarchies are the same," said Jenny Tung, Associate Professor of Biology and Evolutionary Anthropology at Duke University and Associate Director of the Amboseli Baboon Research Project in Kenya.

Scientists often turn to our species’ closest relatives in the animal kingdom, non-human primates in the wild, to understand the relationship between social hierarchies and health. One of the oldest and most successful such programs today is the Amboseli Baboon Research Project in Kenya, where during the four decades since its inception, some 1,500 baboons have been studied over several generations. The effort started when in 1963 a young couple of field biologists, Jeanne and Stuart Altmann, traveled through Kenya and Tanzania in search of a site to study the natural history of savannah baboons. Now at Princeton, Jeanne Altmann co-directs the project with Susan C. Alberts of Duke, the couples’ graduate student back in the 1980s. Other members of the group are Jenny Tung of Duke and Elizabeth Archie of Notre Dame, both of whom trained as graduate students with Alberts.

Decades of observing baboons in their natural habitat allowed researchers to precisely define group social hierarchies. According to Tung, researchers at the Amboseli Baboon Research Project have recorded daily observations on wild savannah baboons since 1971. In addition, continued access to the population in the Amboseli Park today allowed Tung’s team to collect blood specimens from baboons they knew from long-term observations. To gather data for this study, Tung traveled to Kenya over a period of four years with her graduate student Amanda J. Lea, the first author on the study and now a postdoc at Princeton University.

Thanks to recent advances in technology, Tung’s lab at Duke is today able to obtain unprecedented insight into an organism’s biology just from a drop of blood. To understand the direction of the relationship between immune system regulation and social status in wild baboons, the team combined genotypes, gene expression data, and other molecular markers of 61 baboons with detailed observational data of the same subjects’ social rank in their natural habitat in Amboseli, Kenya. They set out to answer the question of whether changes in immune system regulation could precede social status position, rather than the other way around. In other words, could immune gene expression drive dominance rank instead of only being influenced by it?

“Fundamentally, we try to establish whether something is causal, rather than just correlated. A classical way to do this is to use a randomized controlled design, but we can’t force wild savannah baboons to change their immune gene expression,” said Professor Tung.

So, instead of a randomized controlled design, Tung and her colleagues used what is called the Mendelian randomization approach. “Maybe nature did that randomization for us,” Tung explains. “Maybe nature randomly gave subjects different immune system regulation genes, and these genes do not have a relationship with dominance.”

Lea explains the Mendelian randomization approach as having its roots in human epidemiology. For example, in assessing the relationship between triglycerides and heart disease, epidemiologists cannot assign high and low levels of triglycerides randomly to different patients. Instead, they exploit the fact that genotypes are randomized at birth. After sorting subjects based on genes we know carry the risk for high triglycerides, the researchers can more accurately test whether blood triglyceride levels still predict heart disease. The two key assumptions that make this approach valid are (1) that specific genes used in fact do predict triglyceride levels in the blood, and (2) that the same genes do not, in fact, relate to other factors, such as access to health care, that may cause heart disease independent of blood triglyceride levels. Translating the analogy to their work, the researchers assume reasonably that genes direct immune system pathways. They also assume that genotypes are assigned randomly at birth, and that immune genes are neither determined by dominance rank nor do they cause dominance rank through mechanisms other than immune system function.

Armed with a wealth of behavioral data on baboon hierarchies in the wild, the team set out to apply this Mendelian randomization approach to test whether changes in immune system regulation could drive social status. Using blood samples from 61 baboons with different places in the hierarchies observed, the team profiled the subjects’ DNA to ascertain genotype, sequenced RNA to measure gene expression. They isolated white blood cells based on their cell-surface receptors and grew them in the lab to study their response when exposed to lipopolysaccharides, a component of Gram-negative bacteria. Instead of observing the whole organism’s response to an infection, they observed precise levels of biomarkers resulting from an exposure to a known antigen. The controlled setting of the laboratory enabled the team to exclude other potential factors modifying immune system regulation and to standardize the stimulus across subjects with different dominance rank in the wild.

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Overall, the experiments found that high-status males had 2,277 genes that were regulated differently, and in specific ways, that in low-status males. The team also discovered that these were enriched for the gene encoding the toll-like receptor 4 (TLR4) that is responsible for the detection of Gram-negative bacteria, as well as a set of downstream genes activated by TLR4 that play a role in an NFkB-mediated proinflammatory pathway. In contrast, only 25 genes’ expression differed between low and high-status females. More than just differing across the hierarchy, the immune systems of low and high ranking males responded differently when stimulated in the lab with lipopolysaccharides, a component of Gram-negative bacteria.

The team believes that it is context-dependence and diversity of natural hierarchies that explain sex-specific differences they discovered. Both male and female baboons live in hierarchies. However, Tung and her team observed that males live in highly competitive, dynamic hierarchies based on fighting ability. Dominant baboons can be challenged at any time by subordinate members of the community, and the winner of the fight gains new dominance over the defeated. In contrast, the team found that females live in relatively stable nepotism-based hierarchies.

Tung calls for precautions when trying to apply the team’s research to human hierarchies. She explains that the primary aim of her research is to understand the costs and benefits of being social. She is interested in how social adversity, social status, and social integration are related to evolutionary fitness traits of animals, the main of which is their ability to reproduce and pass on their genetic code to the offspring.

But Tung also concedes: “We, ourselves, are social animals, and there are a lot of cases where social structures affect health.” This phenomenon is known by scientists as the social gradient in health. “It is important to understand conditions under which social gradients arise, and what the physiological mechanisms are that connect social hierarchies to health and disease outcomes.”

Tung and her colleagues’ research suggests that the reason we observe the link between social status and health may be because of so-called “health selection,” where certain physiological and molecular mechanisms give rise to differences in ability to advance in a social hierarchy and to obtain dominance.

But even more interestingly, the same research warns that any link between health and social rank is context dependent. According to Tung and Lea, future research should also consider how hierarchies arise, how dynamic they are, how they overlap with competing social hierarchies, and how they may be similar or different across species.

The team’s paper is posted on bioRxiv, the open-source online archive of biology research papers. The lead author is Amanda J. Lea and the senior author is Jenny Tung. Other co-authors include Elizabeth A. Archie, Susan C. Alberts, and a team of researchers affiliated with the Institute of Primate Research of the National Museums of Kenya: Mercy Y. Akinyi (also at Duke), Ruth Nyakundi, Peter Mareri, Fred Nyundo, and Thomas Kariuki.