'Selfish' sperm: FGFR2 and embryo development 9/10/03. by John Pickrell Parents who plan to have children later in life may now have a fresh concern, along with the increased challenge of conceiving and other complications. Rare mutations may be giving sperm cells a selective advantage, even though they cause damage to offspring.

As men age, they are more likely to accumulate aberrant sperm that cause genetic deformities in the embryos they produce. But a new study adds a further twist: some mutations appear to create 'selfish' sperm that multiply in the testes, but later damage the embryo.

The researchers, led by Andrew Wilkie, Nuffield Professor of Pathology at the University of Oxford, describe the phenomenon as a "type of evolutionary conflict…a mutation that is harmful to the organism but may nevertheless be advantageous in the testis."

Accumulating damage

Mutation rates are known to increase in sperm as men age. This increase has been thought to be due to a gradual accumulation of errors made during the repetitive copying of DNA that occurs as sperm are produced throughout a man's life. A gradual breakdown of the body's built-in DNA repair kit, which should copy-edit out any errors, may also contribute. Eggs are not plagued by the same problems, as women already come equipped with their entire complement at birth.

A general problem with DNA replication might be expected to introduce errors at random throughout the genome. Oddly, however, three genes – RET, FGFR2 and FGFR3 – are known to pick up errors at many times the normal rate of mutation in sperm. Mistakes in one of these genes, fibroblast growth factor receptor 2 (FGFR2), which the new study focuses on, are responsible for several severe genetic disorders, including Apert syndrome, which causes premature fusion of the skull bones and webbing of the fingers and toes. It occurs in around one in every 70 000 live births.

It is clear that something is going awry in sperm, says Professor Wilkie: "In around 80 cases of Apert syndrome and two related disorders, without exception the faulty gene has come from the healthy father." Moreover, the incidence of the disorders is closely linked to the age of the father.

The chances of a mutation appearing at a randomly selected point in an average human gene are around one in ten million or lower, says Professor Wilkie.

In some men, by contrast, the chances of the FGFR2 gene having the mutation that causes Apert syndrome are up to one in 10 000. "If the entire genome mutated at this rate, we wouldn't be alive – the function of important genes would be disrupted all the time. The $64 000 question is, why are these particular FGFR2 mutations so common?"

Cell selection

Few studies have been able to examine directly mutations affecting the male germ line. Using techniques developed over the last seven years, Professor Wilkie, Dr Anne Goriely, also at Oxford, and others in the UK and Sweden set out to examine the genetic basis for the high levels of mutation underlying Apert syndrome. They concentrated on one particular site in FGFR2, looking for all possible mutations at this site in sperm samples from fathers with and without affected offspring, and of varying ages.

According to conventional theory, the number of new mistakes in the FGFR2 gene should increase as men age. But, says Professor Wilkie, that is not the whole story. The number of sperm carrying the harmful Apert mutation not only increased with age, but the levels were even higher than a less harmful mutation that is expected to arise more frequently at this particular position.

The researchers conclude that the genetic mutation leading to Apert syndrome occurs rarely, but offers cells carrying it some growth advantage. One possibility is that the Apert syndrome mutation affects the behaviour of the stem cells that give rise to sperm. Instead of producing equal numbers of sperm cells and more stem cells to produce future sperm, they occasionally produce excess stem cells. This would mean that these mutant cells, spewing out mutant sperm, slowly increase in number relative to non-mutated counterparts.

Since the mutation has no ill-effects in the testes, as men age the cells carrying the mutation become disproportionately common, increasing the likelihood that one will successfully fertilise an egg. This is when problems arise, as the mutation severely impairs the ability of FGFR2 to function during development of the embryo.

The exact role FGFR2 may play in sperm and their precursor cells is unknown, but the related gene RET is involved in how spermatagonial stem cells, the sperm precursors in testes, divide to produce sperm.

"This has been a very difficult idea to accept," said James F Crow, a geneticist at the University of Wisconsin in Madison, as the idea goes against established theory that genes harmful to the individual cannot survive. "If true and confirmed this suggests there really is some selection taking place in [sperm and egg cells]," says Professor Crow, "there has been very little [previous] evidence that this happens, but that's what this data seem to show."

Further reading

Goriely A et al. Evidence for selective advantage of pathogenic FGFR2 mutations in the male germ line. Science 2003 301: 643–46. Abstract

Crow JF. There's something curious about paternal-age effects. Science 2003 301: 606–7. Abstract

Links

Professor Andrew Wilkie, University of Oxford, research page