Sci. Aging Knowl. Environ., 6 August 2003
Sperm development encourages mutations that harm offspring
Key Words: FGFR2 fibroblast growth factor receptor 2 selective advantage pyrosequencing achondroplasia
Sometimes even a normal home can foster a troubled individual, and this truism applies to a particular type of mutant sperm as well as to people, according to new research. Sperm production nurses mutations that afflict children with a rare deforming condition called Apert syndrome. The results explain why this particular genetic disorder occurs more frequently than expected.
The mutations that cause dwarfism and Apert syndrome, in which babies are born with fused, mittenlike fingers, come exclusively from fathers. The older pop is, the likelier he is to beget an affected child due to faulty DNA in his sperm. Sperm production starts with a stem cell--containing two of each chromosome--that duplicates its DNA and splits in two. One of the pair remains a stem cell; the other becomes a sperm progenitor cell that multiplies to yield a clutch of egg-ready sperm. The stem cells stick around for life, so sperm generated by older men carry DNA that's been subjected to many rounds of copying, each of which introduces errors. Because they know how many times sperm stem and progenitor cells copy their DNA, as well as the error rate of the DNA-copying machinery, scientists can predict how often to expect a child with dwarfism or Apert syndrome; affected children are born more often than anticipated. To understand why, Andrew Wilkie, a geneticist at Oxford University, and colleagues set out to spot blunders at a particular location in sperm DNA: In the most common Apert mutation, a DNA letter changes from a cytosine (C) to a guanine (G). As a start, the team counted how often the C converted to either G, thymine (T), or adenine (A).
Older men harbored more mutant sperm than younger men did, but all men--whether or not they had sired Apert children--produced sperm in which the crucial DNA letter had changed to G or T, but not A. "The process giving rise to the mutations is universal," says Wilkie. Although all men of the same age create the mutations at roughly the same rate, "Apert fathers have been unlucky," because a mutant sperm happened to fertilize an egg.
G occurred 1.7 times more often then T did, the researchers found. This observation perplexed them because DNA duplication errors reprogram C to T more often than to G. They posited that sperm with the G mutation outgrow their compatriots. To test this idea, they determined which of the dads' two chromosomes the errors sat on. If the Apert mutations arise only a few times in an individual and then are propagated during sperm production, they would appear preferentially on one or the other chromosome in the final pool of sperm, the researchers reasoned. If the defects occur often, however, the changes would surface on each chromosome about half the time. The G mutations distributed themselves unequally in each individual, the researchers found, suggesting that sperm creation cultivates the G defect. Additional data confirmed that the glitches occurred in sperm stem cells. Together, the data suggest that older men produce more Apert children because sperm generation favors Apert sperm. Younger fathers likely generate Apert mutations, Wilkie says, and these accumulate throughout life because of the mutations' preferential treatment.
The result is puzzling because it suggests that the developing sperm's environment nurtures mutations that hurt the offspring, says geneticist James Crow of the University of Wisconsin, Madison: "When I first read the paper, I didn't want to believe it, but I couldn't find a flaw." He says it's "rather surprising" that harmful mutations would be preferred during sperm development. Now scientists must determine what troubles the developing sperm's domicile.
August 6, 2003
Science of Aging Knowledge Environment. ISSN 1539-6150