Thursday, April 28, 2005

Apert's Syndrome and Selfish Sperm

(The sperm scene in Woody Allen's Everything you always wanted to know about sex )

If economics is the dismal science, then the study of the natural world can't be far behind. The continual message is that selfishness is everywhere. In he April 19 issue of PNAS Goriely et al. report that a mutation causing Apert's syndrome, a craniofacial condition with severe health consequences, occurs at far above background levels compared to other sorts of mutations. Even though its effects are very detrimental to the humans who have it, the mutation is "favored" because it confers an advantage to the sperm precursors which carry it.

The mutation in question affects the DNA sequence for FGF receptor 2, resulting in a mutant receptor protein, called Ser255Trp, which is known to have innapropriate activity. (This mutation is genetically dominant, meaning that one mutant copy is enough to cause disease.) Goriely et al. had earlier observed that de novo mutations resulting in Ser255Trp are exclusively inherited from the unaffected father. Moreover, these mutations occur at more than 200x background level, and in particular are seen more often than other possible mutations at the same site. These two observations together suggested that the frequency of the occurence of this particular mutation was being enhanced in the father's sperm.

The current work follows up on these observations with three additional experiments to strengthen the case that this mutation is under selection during spermatogenesis. First, they analysed semen DNA for mutations in the sequence FGF receptor 2, and found mutations creating Ser255Trp were detected at nearly 19 times the rate of mutations at nearby spots (just outside codon 255; overall rates are approximately 1 in a million sperm). Thus this DNA region is not just error-prone; sperm bearing mutations which lead to Ser255Trp are specifically enriched. Secondly, during this work the scientists identified a fourth instance of a person with TWO sequence substitutions on this same (codon) spot, a conjunction expected to occur less than once in the entire human population. Finally, and most importantly, they show that the FGF receptor 2 is present in normal testes during sperm production. Thus there is "motive" and "opportunity" for the excessive activity of the Ser255Trp protein to directly affect sperm production.

So sperm bearing mutant DNA encoding Ser255Trp are present in a highly skewed proportion. Earlier work has shown that diffferent FGFs (the proteins which which stimulate FGF receptor) are present in distinct spots in the adult testis, and affect proliferation of cells giving rise to sperm. What would really nail the story would be to show that FGF10 or FGF2, the FGFs which overstimulate the Ser255Trp receptor in the human Apert's syndrome, are present in these spots. (Remember that the Dad's bodies are negative for the mutation.) But for now, the story is quite convincing that more mutant precursor cells give rise to disproportionately many mutant sperm, which in turn gives those sperm a numerical advantage in the contest to fertilize the egg.

In the end, the constant proliferation giving rise to sperm sets conditions for genetic selfishness analagous to what is seen in tumors. In cancer biology, cells with excessive proliferative capacity are not penalized, but rather come to dominate the tumor, even to the detriment of the host's health.

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