Angelina Jolie recently revealed she underwent a double mastectomy; a prophylactic measure to combat the risk of breast cancer associated with BRCA1 gene she carries. Like many other ‘disease’ genes BRCA1 and BRCA2 show evidence of positive selection, suggesting a fitness advantage. To understand how BRCA provides an evolutionary advantage we have to look at the other side of the BRCA coin and introduce the concepts of evolutionary tradeoffs and antagonistic pleiotropy.
An evolutionary tradeoff is just what it sounds like; the gain or enhancement of one trait which causes the loss or suppression of another trait. At the gross level the concept is easy to grasp; a specialized sprinter must forsake stamina for speed. Perhaps the classic example is sickle-cell which provides resistance and lowers infant mortality from malaria in its heterozygous state but in the homozygous state produces disease and increases mortality. These tradeoffs are observed in all species, even in viruses; a ‘generalist’ virus experiences reduced replication in favor of wide host range while a ‘specialist’ replicates better but with a narrow range of hosts (Nikolin 2012).[N.B. the word “trade” should not be read in any way that suggests purpose or intention]
Pleiotropy occurs when a locus affects more than one phenotype; antagonistic pleiotropy refers to a gene with both, positive and harmful effects. Pleiotropy is also one good reason – there are many – why Myriad’s patent on human genes should be rejected. (Rosenfeld 2013).
BRCA is typically referred to as a cancer gene, but it’s more than that, it is also a ‘fertility’ gene (Smith 2012). In this case, BRCA is associated with increased reproductive potential. The tradeoff is that it comes with the price of increased post-reproductive mortality. Using historical data from the Utah Population Database, Smith et al found that BRCA1/2 carriers had more children, shorter interbirth interval and end child-bearing at a later age.
It’s evolutionary economics; an improvement in fitness during reproductive years is valuable and more than compensates (evolutionarily speaking) for the cost of increased mortality during post-reproductive period. That’s why BRCA1/2 shows signs of positive selection. But of course BRCA is not unique; many other disease genes are maintained in the population due to the effects of antagonistic pleiotropy and this pattern of early-benefit/ post-reproductive mortality.
Just like us, dogs carry the genetic legacy of life history tradeoffs and are subject to many of the same diseases, in fact, Smith suggests antagonistic pleiotropy may be far more widespread than we realize. Dogs carry two other burdens not (typically) observed in human populations; inbreeding and strong artificial selection. Too often, these choices result in exaggerated disease risk. A few examples:
- Scottish Terriers 20X higher incidence of bladder cancer
- Fox Terrier 22X for tetralogy of Fallot
- Boxer 25X for atrial defect
- Bulldog 13 fold for pulmonic stenosis
In the case of purebred dogs, breed-type (or behavior) can be considered a fitness advantage because, just like under natural conditions, individuals with the desirable trait get to reproduce. We know that most genes have multiple functions, this means very few traits travel alone. In the process of selecting for a particular trait, breeders unwittingly select for genetic diseases. Pleiotropy is not something that is widely talked or written about among breeders. It should be.
“evolutionary insights can enhance our ability to understand,diagnose and heal.” – SC Stearns, Evolutionary medicine: its scope, interest and potential
- OMIA – Online Mendelian Inheritance in Animals (dogs)
- University of Cambridge – Inherited Diseases in Dogs
- Possible pleiotropic effect between skin cancer and Alzheimer’s disease
- Evolutionary medicine: its scope, interest and potential.
- Evolutionary Medicine Month – UCLA
- Myriad Didn’t Invent Your Genes and Shouldn’t Own Them
Nikolin VM, Osterrieder K, von Messling V, Hofer H, Anderson D, Dubovi E, Brunner E, & East ML (2012). Antagonistic pleiotropy and fitness trade-offs reveal specialist and generalist traits in strains of canine distemper virus. PloS one, 7 (12) PMID: 23239996
Rosenfeld J & Mason CE (2013). Pervasive sequence patents cover the entire human genome., Genome medicine, PMID: 23522065
Smith K., Hanson H., Mineau G., & Buys S. (2011). Effects of BRCA1 and BRCA2 mutations on female fertility Proceedings of the Royal Society B: Biological Sciences, 279 (1732), 1389-1395 DOI: 10.1098/rspb.2011.1697