Apert's Syndrome Mutation May Confer Advantage

August 28, 2007

LOS ANGELES -- The mutation that leads to Apert's syndrome may also confer a selective advantage on the germline cells that harbor it, researchers here said.

LOS ANGELES, Aug. 28 -- The mutation that leads to Apert's syndrome may also confer a selective advantage on the germline cells that harbor it, researchers here said.

The finding would explain why the syndrome -- characterized by prematurely fused cranial sutures and fused fingers and toes -- appears between 100 and 1,000 times more often than expected, according to Norman Arnheim, Ph.D., of the University of Southern California, and colleagues.

In a report online in PLoS Biology, the researchers also ruled out a competing theory -- that the mutation is in a "hot spot" that leads to increased genetic variation.

More than 98% of Apert's syndrome cases arise from two spontaneous single-nucleotide changes in the gene for fibroblast growth factor receptor two (FGFR2), the researchers said.

Of those, two thirds are accounted for by a cytosine to guanine switch at position 755 (C755G), which occurs between 100 and 1,000 time more often than expected, on the basis of what is known about such substitutions, Dr. Arnheim and colleagues said.

To test the competing theories, the researchers took normal testes from two men (frozen within 10 hours of death), divided them into small sections, and looked for the C775G mutation.

"You would expect that when a new mutation arose, it could arise virtually anywhere in the organ," Dr. Arnheim said.

"But when we divided the testes up, we didn't find that," he said. "What we found were some very big clusters of precursor cells that were mutant."

For instance, in one testis, divided into 192 pieces, 12 pieces with only 5.7% of the DNA in the organ contained 95% of the mutated cells. In the other testis from the same man, 95% of the mutants came from five pieces with only 2.6% of the total DNA in the organ. The pattern was similar for the testes from the other man, the researchers said.

The argument against the "hot spot" theory rests on a computer model of how such a mutation would affect the distribution of the mutant cells, Dr. Arnheim and colleagues said.

A C755G mutation could take place either during the growth phase of the germ cells -- between zygote formation and puberty -- or later, during the adult phase.

In the first case, all daughter cells of the mutated cell would have the C775G switch, producing an exponential growth of mutated cells.

In the latter stage, the adult self-renewing Ap spermatogonia cells (SrAp) divide to produce a daughter SrAp and a cell whose descendants will produce sperm. The result is that the number of SrAp cells remains roughly constant, and a mutation produces only one altered cell line, the researchers said.

But there are many more cells divisions in the adult phase -- by about 500 to one for a man in his 50s -- than in the earlier stage.

Because of that, in the computer model, mutations in the juvenile phase don't produce enough altered cell lines to account for the observed clumps of mutated cells.

And mutations in the adult phase would spread the mutations over the entire organ, the researchers said.

In the model, Dr. Arnheim and colleagues said, "95% of the mutants are found distributed among 95% of the testis pieces."

"This contrasts sharply with the experimental data where the mutation frequency varies greatly between testis pieces," they said.

On the other hand, if the C755G switch promoted occasional symmetric divisions of the SrAp cells -- resulting in two mutated lines rather than one -- the result would closely approximate the observed distribution, the researchers found.

If only one in 100 cell divisions were symmetric, Dr. Arnheim and colleagues said, "the distribution of (mutation) frequencies in the testis pieces now matches the data."

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