Content area
Full text
Abstract
The incidence of base substitutions in humans increases with the age of the father, which shows up as an increased incidence of mutational disorders in the children of older fathers. There is a less obvious implication: an extended period of high average paternal age in a population will lead to increased genetic load. We mention some societies that have had high average paternal age for many generations. This may explain some surprising regional differences in recent measurements of deleterious mutations. High average paternal age also influences life history evolution, strengthening selection against mortality in late life while weakening selection against child mortality.
KEY words: PATERNAL AGE, MUTATION RATE, GENETIC LOAD, POLYGYNY.
It is now clear that most mutations occur in males, and that the number of mutations transmitted increases approximately linearly with the father's age. The recent DECODE study (Kong et al. 2012) determined the mutation rate by direct sequencing of family trios. They found that mothers contribute an average of 15 new mutations, regardless of age, while men contribute (25 + 2(g - 20)) new mutations, where g is the paternal age. If both parents are 30, each child inherits 60 new nucleotide changes on average, 15 from the mother and 45 from the father. If the father is 45, each child inherits 90 nucleotide changes-a 50% increase.
The age-related increase in mutations of paternal origin is believed to be caused by the large number of cell divisions in spermatogenesis, leading to copying errors (Penrose 1955). Before puberty, gonocytes divide some 30 times to produce spermatogonial stem cells. After puberty, those stem cells continue dividing indefinitely. The spermatocytes in a 30-year-old man have undergone 380 divisions, while those in a 50-year-old man have undergone 840. This is in strong contrast with egg formation, which involves only 24 cell divisions, all completed before a women's birth (Glaser and Jabs 2004).
Mutation Mechanisms
A number of different mechanisms cause mutations. Some are strongly dependent on paternal age, and some are not. Base substitutions, which account for the great majority of all mutations, increase dramatically with paternal age, but chromosomal abnormalities such as Down syndrome are associated with high maternal age. Most large deletions are generated by nonallelic homologous recombination (also known as illegitimate...