Germline selection

Mutations go up with paternal age.  Generally,  the increase is nearly linear with age, but a few increase far more rapidly.  In those cases, a special mechanism is involved.

One of those cases is Apert syndrome,  a nasty congenital disorder characterized by skeletal malformations (skull, face, hands , and feet).   It’s rare, hitting about 1 in 100,000 kids.

It’s an autosomal dominant, caused by mutations in the FGFR2 gene (fibroblast growth factor receptor 2) .  Oddly enough, almost all cases are caused by two particular mutations  of the FGFR2 gene, either the S252W mutation or the P253R mutation. Which means that it ought to be far rarer than it actually is. The per-generation mutation rate per nucleotide is about 1 x 10-8,  so with two possible sites, you’d expect to see a frequency of about 1 in fifty million.  It’s 500 times more common than it should be.

You’re more likely to have heard of achondroplasia, standard dwarfism.  It’s caused by mutations of the FGFR3 gene.  Almost all cases are caused by a single mutation, a G-to-A transition at nucleotide 1138 that results ion a substitution of arginine for a glycine.. It’s not common – roughly 1 in 20,000 births – but it ought to be more like one in 100 million.  Five thousand times more common that it ought to be.

The fact that these two genetic diseases are caused by two closely related genes, FGFR2 and FGFR3 is no coincidence.

Here’s what seems to be happening: you have cells in the testes that reproduce, producing one daughter cell like the parent and one that develops into a sperm cell. That’s the way it’s supposed to be.  But carrying certain very specific mutations of FGFR2 or FGFR3 seem to  cause occasional divisions that result in two daughter cells – so the pre-sperm cells that carry such mutations gradually become more and more common in the testes and produce a growing fraction of sperm with those mutations.  It’s rather like cancer. You get clumps of cells producing the bad sperm.

Same things is happening with MEN2B (RET gene), which is also more common than it should be, although not as much so as achondroplasia.

Without this unusual mutational mechanism, there would be a shortage of dwarfs.

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9 Responses to Germline selection

  1. marcel says:

    Aren’t you supposed to link to this page so everyone is clear that this is a pun. (I only learned the collective noun for dwarves a few days ago, so that I could make the same pun in a comment on another web site). As it is, this humor is so dry, many (perhaps not those who know you well) will not recognize this is a joke. Are the genetics corrects, or was that merely a buildup to the punchline?

  2. infowarrior1 says:

    Well. Looks like the testicles is going to be an area of treatment in times to come. The thought of which makes your testicles shrivel

  3. Magus Janus says:

    forgive my total ignorance on the subject, but is it perhaps possible something similar is going on with respects to the ghey, or is it simply way too prevalent for even something genetic like this to make happen?

    • gcochran9 says:

      It would result in simple Mendelian inheritance patterns that do not actually exist. I don’t think there’s an older-father effect. And homosexuality is way more common than dwarfism or Apert syndrome.

      So no.

  4. dave chamberlin says:

    One geneticist titled mutants “hopeful monsters,” I don’t know why I think that is funny but I do. From what little I can learn from wikipedia there are three species known to engage in sex when the female is not in estrus, they are humans, chimps and dolphins. That is a pretty short list and one quite pointed to the most intelligent species on land and water. What I find interesting is that sex for the fun of it combined with a short estrus cycle allows for a far higher rate of spontaneous abortions. Now we have a very elite group of big brained animals that have devised their very own form of faster evolution because procreating hopeful monsters two times out of three (I believe that is the spontaneous abortion rate in humans) is no big deal. Causation gets sticky here as it often does in complex situations. We can’t just credit sexual friskiness to higher intelligence, those big brains evolved faster when the hopeful monsters became more frequent without hurting fitness.

    • dave chamberlin says:

      Yo, Cochran….After a couple more days of thought there is one kernel worth emphasizing in this otherwise babblicious post. A while back you wondered why humans had such a high spontaneous abortion rate, higher than any other species. Me thinks the answer is what it has has to be, it has an evolutionary advantage. It allowed our ancestors to move faster down the evolutionary road to bigger better brains since as stated above we were able to create more hopeful monsters without denting fitness.

      Gould’s punctuated equilibrium is missing a piece to make it logical. That piece is how it works. Now lets open a gate of opportunity for a species to evolve a thousand tiny steps that yield a net result of evolving to a highly successful niche. The advantage given by each one thousandth mutation increase in chimp/man ancestor intelligence will never give enough push to move us down the evolutionary road. Humans were the lucky winner because of hands, geography (dividing the world into three continents with one meeting point sure as hell helped the hybridization thing to happen), higher spontaneous abortion rate, and a world filled with new food sources just waiting to be exploited by a slightly smarter ape.

  5. Brian says:

    I’m sure he meant to say dwarrows.

  6. Genetic Garbage says:

    I know that my girlfriend will want children once we’re married, but I suspect that my age (almost 40) combined with my unspectacular pedigree will place my children at a huge competitive disadvantage.

    I can’t imagine raising children, boys in particular, who will have just enough sense to realize their lowly caste but not enough to escape it. I’d forgive them for hating me for having brought them into such an existence.

    I probably should use a sperm donor, but I could never do so openly. My girlfriend would lose any respect she ever had for me.

    I agree with nearly everything on this site, but it has the unfortunate effect of convincing me that I really ought to be sterilized _at best_.

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