Cystic fibrosis is one of those ‘classical’ recessive diseases you learn about in medical genetics. It’s frequent enough that doctors will always be interested in it, and its inheritance pattern is relatively simple, following a rough Mendelian pattern of recessive expression. The reality is a little more complicated than that though, as there are different mutations in the CFTR gene, and some variants can complement so that two carriers don’t necessarily have a risk of producing a child which expresses the disease.
But CF is also interesting from an evolutionary perspective. Why is such a lethal disease present at such high frequencies in Northern Europeans? On the order of 1 out of 25 Northern Europeans carry a mutant allele on CFTR. Apparently, 1 in 19 Irish carries a mutation for CF, while Finland it’s prevalent at a frequency of around 1 in 90, which is actually in the range of non-European populations.
Though it is well known that inbred populations can manifest high frequencies of deleterious alleles, as a whole Northern Europe is not an inbred population. So what’s going on? One hypothesis is that heterozygotes for CF (carriers) have a higher fitness than wild-type individuals, so the low but persistent frequency of CF expressing individuals is an outcome of this overdominant effect. The analogy then presents to sickle-cell anemia. Heterozygotes are more resistant to malaria, an endemic and pervasive disease in much of the tropics and subtropics.
So what might be causing the high frequency of mutant CF alleles in Northern Europe? One candidate has been tuberculosis, a very common disease in the recent past in Europe. A new paper out of Brazil supports this contention with epidemiological methods, Cystic fibrosis carriership and tuberculosis: hints toward an evolutionary selective advantage based on data from the Brazilian territory:
Applying spatial epidemiology, we studied the link between CF carriership rate and tuberculosis (TB) incidence in Brazil. We corrected for 5 potential environmental and 2 immunological confounders in this relation: monthly income, sanitary provisions, literacy rates, racial composition and population density along with AIDS incidence rates and diabetes mellitus type 2. Smoking data were incomplete and not available for analysis.
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A significant, negative correlation between CF carriership rate and TB incidence, independent of any of the seven confounders was found.
The immediate objection is that one may not have controlled for all the confounds. Though do note there are molecular biological rationales for why CFTR heterozygotes may be more fit when infected with tuberculosis.
All that being said Brazil is a diverse place, and it is hard to imagine there might not be a confound out there geographically. Fortunately, we won’t be doing a randomized controlled field trial by infecting individuals with tuberculosis, so we’re just going to have to keep looking at these correlational studies.
Something has to be driving selection for this nasty disease as part of the genetic correlation.