Crespi on Molecular Antagonistic Pleiotropy

By Bernard Crespi

Molecular Antagonistic Pleiotropy: Fertility-Mortality Tradeoffs Mediated by BRCA1 and 2

Trade-offs between growth, maintenance, and reproduction represent a central tenet of both life history theory and evolutionary medicine.  At the levels of genes, such tradeoffs have been predicted by George C. Williams to manifest as antagonistic pleiotropy, whereby deleterious late-life effects of alleles are counterbalanced by stronger selection for early-life benefits. A new paper by Smith et al. (2011) in Proceedings B provides remarkable new evidence of antagonistic pleiotropy in humans, mediated by reduced-function alleles of the famous breast cancer genes BRCA1 and BRCA2 that are associated with both enhanced female reproduction and higher risk of post-reproductive mortality. This paper is significant because it demonstrates one of the first molecularly-based tradeoffs with strong effects on human disease risk and rates of reproduction. What’s more, the work points towards broad generality in the impact of antagonistic pleiotropy on human health, and suggests mechanisms that may be causing the tradeoff – mechanisms that can serve as therapeutic targets to foil Nature’s harsh genetic gambit of more children versus early death.

The authors of this study identified two cohorts of females heterozygous for BRCA1 or BRCA2 mutations, who from previous work are expected to exhibit substantial increases in risk of breast and ovarian cancer. From historial-record data, they demonstrated, for the females born before 1930 and thus reproducing under relatively natural-fertility conditions, 1-2 more children born on average over the lifespan, a massive increase in relative-fitness terms.  Data from contemporary populations shows high levels of excess mortality, from breast and ovarian cancer, after age 45 for BRCA1 or 2 carriers, and females in their cohort born before 1930 showed comparable rates and causes of mortality. The proximate demographic mechanism of enhanced fertility for carriers was shorter interbirth intervals and later age at last birth – the former a notable demographic phenotype given that evolution along the human lineage has led to a halving of interbirth intervals since the chimp-human ancestor.

The proximate molecular mechanism mediating the cancer risk-reproduction tradeoff remains more obscure. Smith et al. (2011) suggest a role for telomere length, based on previous work showing associations of BRCA mutations with telomere length, and telomere length with reproduction.  Whether such associations are causal or secondary to other effects, for example tradeoffs between cell proliferation and DNA repair, or tradeoffs due to hormone level variation, remains to be ascertained. A key point, as regards the penetration of evolutionary thinking into medical research in this context, is that such tradeoffs at levels from alleles to organ systems are seldom considered, yet should be central to human physiological function and risks of disease in its myriad forms (Crespi 2011). Only by seeking will evolutionary, health-related tradeoffs be found.

The implications of this study are many. First, taken together with previous research on fertility-mortality tradeoffs involving the TP53 ‘master’ tumor-suppressor gene (Kang et al. 2009), these results suggest that tumor-suppressor genes in particular represent foci for antagonistic pleiotropy effects. SNP-based studies of such genes, using available databases (Stearns et al. 2010), should reveal additional relationships between such alleles and human survival, disease risk, and reproduction. Second, both the BRCA and TP53 pathways have been demonstrated to exhibit enrichments of recent positive selection in humans (Kang et al. 2009; O’Connell 2010) – what are the phenotypic targets of such ongoing selection, and how do they modulate risks of disease?  Third, molecular tradeoffs and positive selection are expected to mediate not just germline evolution but also the somatic evolution of cancer cell lineages within our bodies and lifetimes – can such tradeoffs be manipulated therapeutically in our favor?

Finally, to the extent that growth-survival-reproduction tradeoffs are central to development and physiological functions, they should orchestrate diverse aspects of health and well-being and, eventually, predict landscapes of individual disease-related risks. Indeed, my mother had eight children in 13 years, and died of breast cancer; would that my daughter were more free from antagonistic pleiotropy, through medical knowledge recognizing that few if any benefits come without cost.

References

Crespi, B. The origins and evolution of genetic disease risk in modern humans.  Year in Evolutionary Biology (Annals of the New York Academy of Sciences) 2010 1206:80-109.

Kang HJ, Feng Z, Sun Y, Atwal G, Murphy ME, Rebbeck TR, Rosenwaks Z, Levine AJ, Hu W. Single-nucleotide polymorphisms in the p53 pathway regulate fertility in humans. Proc Natl Acad Sci U S A. 2009 Jun 16;106(24):9761-6. Epub 2009 May 22.

O’Connell MJ. Selection and the cell cycle: positive Darwinian selection in a well-known DNA damage response pathway. J Mol Evol. 2010 Dec;71(5-6):444-57. Epub 2010 Nov 4.

Smith KR, Hanson HA, Mineau GP, Buys SS. Effects of BRCA1 and BRCA2 mutations on female fertility. Proc Biol Sci. 2011 Oct 26. [Epub ahead of print].

Stearns SC, Byars SG, Govindaraju DR, Ewbank D. Measuring selection in contemporary human populations. Nat Rev Genet. 2010 Sep;11(9):611-22. Epub 2010 Aug 3.