Heterozygosity of the major histocompatibility complex predicts later self-reported pubertal maturation in men, suggesting a genetic trade-off between immunocompetence and sexual maturation in human males

Heterozygosity of the major histocompatibility complex predicts later self-reported pubertal maturation in men. Steven Arnocky, Carolyn Hodges-Simeon, Adam C. Davis, Riley Desmarais, Anna Greenshields, Robert Liwski, Ellen E. Quillen, Rodrigo Cardenas, S. Marc Breedlove & David Puts. Scientific Reports volume 11, Article number: 19862. Oct 6 2021. https://www.nature.com/articles/s41598-021-99334-5

Abstract: Individual variation in the age of pubertal onset is linked to physical and mental health, yet the factors underlying this variation are poorly understood. Life history theory predicts that individuals at higher risk of mortality due to extrinsic causes such as infectious disease should sexually mature and reproduce earlier, whereas those at lower risk can delay puberty and continue to invest resources in somatic growth. We examined relationships between a genetic predictor of infectious disease resistance, heterozygosity of the major histocompatibility complex (MHC), referred to as the human leukocyte antigen (HLA) gene in humans, and self-reported pubertal timing. In a combined sample of men from Canada (n = 137) and the United States (n = 43), MHC heterozygosity predicted later self-reported pubertal development. These findings suggest a genetic trade-off between immunocompetence and sexual maturation in human males.

Discussion

Our results support the prediction that greater MHC heterozygosity, a genetic contributor to pathogen resistance33,34, predicts later pubertal timing. In a combined data set derived from two independent samples, MHC heterozygosity predicted relative, but not absolute, recalled puberty. Because males lack a salient, singular pubertal event like menarche, when considering retrospective reports relative pubertal timing may be more accurate because men may be better able to recall whether they matured earlier or later than their peers rather than the precise ages of pubertal events48,49.

Correlations between immunocompetence and pubertal timing could reflect the linked heritability of both traits, common developmental underpinnings50, or pleiotropic effects of MHC genes, which could influence both immunocompetence and sexual maturation. Indeed, some research has shown that MHC class II expression occurs alongside maturation of the adrenal cortex51. Interestingly, dehydroepiandrosterone (DHEA), which is produced by the adrenal cortex and affects aspects of reproductive development, has been implicated in immune function in humans and other species52,53.

LHT offers a framework to explain why immunocompetence and pubertal timing may be related at a functional level: Individuals with reduced extrinsic mortality risk due to lower vulnerability to pathogens may be able to continue growth and delay sexual maturation and reproduction. If so, then selection should favor mechanisms, potentially including pleiotropy and genetic linkage, that couple immunocompetence and the timing of sexual maturation. This possibility aligns with some research on intra-species differences in LH. For example, Tasmanian devil populations affected by an infectious facial tumor disease had a 16-fold higher chance of reaching sexual maturity at an earlier age than usual26. In a study of 22 small-scale human societies, populations with higher extrinsic mortality risk displayed earlier puberty and reproduction—as well as shorter adult height and life expectancy5.

Future work must reconcile research showing opposing patterns, such as among perinatal HIV infection and slower pubertal maturation54. Perhaps the distinction lies in genetic versus acquired factors affecting immunocompetence, or environmental factors (e.g., food energy availability of safety/survival rates), which might also influence luteinizing hormone (LH) release in diverse human populations55. For example, malnutrition has been linked to delayed pubertal maturation in humans44. Accordingly, future research should consider the role of energy availability in the environment as a potentially important moderator of the potential link between MHC and pubertal development. For instance, perhaps the influence of infectious burden on energy availability may be lower in populations with energy abundance and substantial health infrastructure, such as in Western industrialized nations.

Our findings also help explain why MHC heterozygous men have been found to be taller in adulthood56. Height is driven by long bone growth via chondrogenesis at the growth plate57, and epiphyseal fusion at puberty terminates growth. Later pubertal maturation allows more long bone growth before epiphyseal fusion, resulting in taller adult height18; therefore, heterozygous individuals may be taller because they begin puberty later. Future research could test whether pubertal timing mediates the relationship between MHC heterozygosity and adult height. It may be useful to examine the potential moderating role of early stressors in the environment to the MHC-pubertal timing link. From this perspective, developmental plasticity gives rise to an array of phenotypes that emerge in response to specific local social and ecological conditions58. These genetic variants are putatively adaptive insofar as they contribute to greater fitness in the environments in which they manifest. Accordingly, an interaction between HLA homozygosity and early life stressors may be a stronger predictor of pubertal timing than either variable alone.

Within the context of LHT, some researchers have predicted that greater investment in immunocompetence should correspond with later sexual maturation. Although previous research linking early pubertal maturation to a diverse range of health problems supports this notion, this is the first research to demonstrate a correlation between MHC heterozygosity and later recalled pubertal development. Such a link has important implications for understanding the development of puberty-linked physical and mental health outcomes. These results suggest that variation in genetic influences on pubertal timing may reflect a trade-off between somatic growth and maintenance and reproduction, at least in energy-rich environments. However, within the broader context of well-established positive links between environmental condition and earlier (rather than later) pubertal timing, these findings imply that understanding variability in reproductive effort will likely rely upon examining more complex interactions between genetics and local ecological condition.