Apert

Sporadic genetic defects may spring from germ cell selection
By John Timmer | Published: July 16, 2008 - 09:01AM CT

Apert syndrome, which causes craniofacial defects and fusion of the digits, is somewhat oddly behaved as a genetic disease. It can be inherited as an autosomal dominant disorder, but many of the cases are sporadic. Almost all of these sporadic cases can be traced back to mutations at two specific bases in the gene. Estimates based on the general rate of mutation that occurs throughout the human genome suggest that these two mutations are occurring somewhere between 100 and 1,000 times more often than would be expected. A paper that will be released by PNAS this week attempts to provide an explanation for this unexpected behavior, as its authors suggest that the same mutations that cause so many problems for developing infants actually help the germ cells in which they originated.
As predicted, the frequency of the Apert-specific mutations increased with age; men in their 60s had two orders of magnitude more of these mutations than men in their 20s.

The theory behind this behavior is several decades old, and is based on applying evolutionary principles to the behavior of the male germline. Unlike in females, the precursors of the male germ cells proliferate throughout their carrier's life. As a result, any mutation that causes them to divide faster than their peers should result in an excess of these mutations, and one that grows as the person ages. The authors speculate that the two mutations that cause Apert syndrome may represent this theory in action.

To test this, they obtained the testes of several healthy adults who died at a research hospital, and checked for the presence of the two Apert mutations, as well as changes in a nearby DNA base that acted as a control. As predicted, the frequency of the Apert-specific mutations increased with age; men in their 60s had two orders of magnitude more of these mutations than men in their 20s.

This sort of behavior could occur through a mutational hotspot mechanism, but the authors also showed that the occurrence of the mutations was clustered, as would be predicted by a population expansion from a single, ancestral mutation. The control base, in contrast, displayed a pattern of rare mutations that were distributed randomly about the testes.

The gene affected in Apert syndrome is a receptor for fibroblast growth factors, or FGFs, and these genes frequently control the proliferation of cells, suggesting an obvious mechanism for its promotion of germ cell expansion. But the authors note several other sporadic genetic diseases that show similar patterns of inheritance, and suggest this behavior may be involved in other syndromes.

PNAS, 2008. DOI: 10.1073/pnas.0801267105