Monday, 17 September 2012

The Old Man and the G (G to A transistion, that is)

When I was a kid, my dad used to make the same joke every time my mom's birthday came around. "Twenty-nine again, eh?" he'd say. We'd laugh a bit at my mom's expense, but at that age I didn't really understand why adults, particularly women, cared so much about their age. Women dye their hair and buy "rejuvenating" creams. Female models over 30 are relegated to Dove ads. Men, on the other hand, compare themselves to fine wines. The Bernie Ecclestones of the world outnumber the Duchesses of Alba.

Much of this underscores the importance of maternal age on fetal health. Pregnant women over the age of 35 are routinely screened for chromosomal abnormalities in their fetuses. Meiosis, the process through which oocytes (eggs) and sperm are generated, is very different in men and women. Men produce sperm on-the-go from germ cells with a virtually unlimited production capacity. Those germ cells spring into action whenever they're needed, and men can produce viable sperm from puberty 'til death. Women's germ cells are already half-way to being oocytes (eggs) by the time they're born. Women don't have an unlimited capacity to produce oocytes because their germ cells don't self-renew. Biology can be a bit quirky, and oogenesis is a particularly odd example. The partially mature oocytes in a newborn baby girl are stuck half-way through a cell division, with their chromosomes aligned in the centre of the cell. One of the problems with this is that large chromosomal abnormalities, such as those seen in Down syndrome, can occur more easily when the DNA is coiled and lined up side-by-side for a long time. The only place I can think of where this happens is in oocytes. The longer the cells remain with their DNA lined up ready for division, the greater the chance that things will go wrong when meiosis resumes. Hence the routine screening for women over 35. When things go wrong they go really wrong, with big chunks of one chromosome getting stuck on another chromosome. You don't need to look very closely at the DNA to see the abnormalities. You need a microscope, but not a DNA sequencer.

So women have all their oocytes with them when they're born and they don't produce any more. But sperm production is ongoing, and it relies on continued cell division in the adult. Each cell division carries its own risks. DNA must be reliably copied, checked for mutations, packaged and sent off to make a new cell. Since most mutations occur during DNA replication, every cell division presents an opportunity for mutations to arise. Sperm are no exception. Recent work on Icelandic parent-offspring trios (mom, dad, baby) shows that the number of new mutations in a baby is strongly correlated with the age of the father at the time of conception. The age of the mother has no detectable impact. The child of a 20-year-old father has an average of 25 mutations, while the child of a 40-year-old father has about 65. That translates to about 2 additional mutations for each year of paternal age. The number of mutations doubles every 16.5 years, and is surprisingly linear. Many mutations have no obvious consequences, but others can give rise to diseases ranging from autism to cancer predisposition syndromes. Many diseases, particularly those associated with impaired brain function such as autism, schizophrenia, dyslexia and reduced intelligence are caused by multiple mutations working together and are associated with paternal age. Increased paternal age increases the probability of having enough mutations to make a difference in a child's overall health.

A French teacher of mine had an amusing way to remember the gender of disaster words. Un probleme, c'est masculine. To really make a mess you need the feminine: une catastrophe. The same idea seems to apply to DNA. Massive damage to the DNA comes from ageing mothers, while ageing fathers provide multiple smaller problems. Catastrophic DNA damage rarely makes it into viable babies; they don't usually make it past the first few weeks of a pregnancy. A fetus with a collection of DNA "problems" is much more likely to make it through gestation. So next time your charming partner makes a crack about your age, you can do what my mom used to do and tell him to put a cork in it. Even fine wine ages poorly without one. And you might need to double your order of hair dye.

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