Lactase peristence & Cystic Fibrosis

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Yann points to a new paper, new paper, Cystic Fibrosis: Cystic fibrosis and lactase persistence: a possible correlation (Open Access):

The simplest and most economical explanation is that a dairy-milk diet became established in a single area and remained restricted to that area for a period of time sufficient to allow the T and the F508del alleles to attain high values. Then, in a second phase, the population of that area exported to the rest of Europe its dairy-milk diet culture together with the two adaptive genes, that is, the adaptogen and the two genetic adaptations to it. These two alleles would have then been amplified in the recipient populations because of their adaptive value owing to the co-imported dairy milk diet.

The two models to explain the high frequency of the deleterious CF allele in Europeans are that it has a high mutational bias and heterozygote advantage for those with one copy. Most people would say that the latter is much more likely. The authors here propose that the derived CF allele was a really kludgey adaptive response to a new cultural regime predicated on raw milk consumption. Paul has some Ireland related thoughts (as usual!). I’ve never seen the term “adaptopgen” before. In any case, I need to think on this case more…but I do think that if human evolution has been on hyperdrive the last 10,000 years we should be many kludgey genetic responses laying around the adaptive landscape…..

Related: Lactase persistence posts. Another from Yann, Is there a fitness advantage to being a CFTR carrier?

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  1. Makes you wonder just how high the frequency of the deleterious CF allele might have been in the past. Could heterozygote advantage have been enough to drive it above 10%? Could have been pretty high, I think, given that lactase persistence has been at very high frequency in N Europe for a thousand years or more – so what we see must be a fading echo.

  2. I’ve never been tested for CF, but have some of the symptoms, including very caustic sweat – enough to discolor pillows and shirt collars – along with many chronic lung infections.  
    I’m also lactose intolerant… 
    Sometimes when I read these articles I have to think that that’s the price the Irish pay for having so little Neolithic ancestry…

  3. From the paper: “Therefore, these data conclusively disprove the ‘European-restricted’ high mutation rate hypothesis, thus proving, by exclusion, that the high CF gene frequency is due to a CF/+ heterozygous advantage.” 
    This is quite a leap! Heterozygote advantage is the only possible hypothesis left?! ….were the reviewers and editor asleep at the switch?

  4. “A reasonable answer is that CF alleles, being ‘loss of function’ alleles, were certainly present when the selective pressure due to the combined effect of lactose intolerance and dairy milk started, whereas lactose-tolerance, a sophisticated phenotypic modification (a single gene onthogenetically regulated in all mammals to express itself only during weaning had to be ‘convinced’ to continue to work through post-weaning life), was not so easily available or even absent in the exposed populations.” 
    Lactase persistence is so sophisticated that it has evolved repeatedly in pastoralist populations around the world. Four times in Africa! Are the authors unaware of Tishkoff et al. 2007?  
    My bet is that there is no advantage to the CF allele and that the gene was brought to relatively high frequency by the demographic effects of population and geographic expansion into Europe in the wavefront/surfing process described by Excoffier et al (MBE 2005). Selection can be painfully slow removing deleterious recessives.

  5. You might want to calculate exactly how painfully slow it is. In the absence of heterozygote advantage, what should the frequency of this lethal recessive have been 1000 years ago, assuming that it is 2% today? 2000 years ago? Try this with and without reproductive compensation. I think you will be surprised.

  6. Lactase persistence is so sophisticated that it has evolved repeatedly in pastoralist populations around the world. Four times in Africa! Are the authors unaware of Tishkoff et al. 2007?  
    And the CF mutation was the one that happened to pop up in Ireland in response to the new diet. What’s hard to understand about that? Luck of the Irish.

  7. Here’s an interesting article on Lactase Persistance in Neolithic Sweden
    It states – on pages 43 and 44 of the PDF: 
    The allele associated with lactase persistence was found in 50% of the farmer samples and in 10% of the hunter-gatherer samples. The farming 
    samples did not differ from modern Swedes whereas the hunter-gatherers did. Further, the Neolithic samples were significantly different from modern 
    Norwegian and Saami samples when mitochondrial HVSI was compared. These results may, however, be influenced by five of the hunter-gatherer samples sharing a haplotype not found among any published modern populations. 
    Our data suggests that the frequency of the allele linked to lactase persistence in the investigated farmer population was, already 5,500 years ago, 
    closer to modern Swedish frequencies than to those seen in the contemporary hunter-gatherers. This may be caused by cultural induced selection in the 
    farmers. An alternative explanation that would not rely on an extreme cultural induced selection pressure, but with limited archaeological support 
    (Lidén in press), would be that only those with the genetic base for consuming unrefined milk became farmers while remaining people stayed huntergatherers.
    It stated at the beginning of the PDF that farming came to Sweden approx 6,200 year ago.