Germline origins in the human F9 gene: frequent G : C--> A : T mosaicism and increased mutations with advanced maternal age

The factor IX gene (F9) is an advantageous system for analyzing recent spon taneous germline mutation in humans. Herein, the male:female ratio of mutat ion ("r") in F9 have been estimated by Bayesian analysis from 59 germline o rigin families. The overall "r" in F9 was estimated at 3.75. The "r"s varie d with the type of mutation. The "r"s ranged from 6.65 and 6.10 for transit ions at CpG and A:T to G:C transitions at non-CpG dinucleotides, respective ly, to 0.57 and 0.42 for microdeletions/microinsertions and large deletions (>1 kb), respectively. The "r" for the two subtypes of non-CpG transitions differed (6.10 for A:T to G:C vs 0.80 for G:C to A:T). Somatic mosaicism w as detected in 11% of the 45 origin individuals for whom the causative muta tion was visualized directly by genomic sequencing of leukocyte DNA (estima ted sensitivity of approximately one part in 20). Four of the five defined somatic mosaics had G:C to A:T transitions at non-CpG dinucleotides, hintin g that this mutation subtype may occur commonly early in embryogenesis. The age at conception was analyzed for 41 US Caucasian families in which the a ge of the origin parent and the year of conception for the first carrier/he mophiliac were available. No evidence for a paternal age effect was seen. H owever, an advanced maternal age effect was observed (P=0.03) and was parti cularly prominent for transversions (average of the 79th percentile when ma ternal age was normalized for the year of conception). This suggests that a n increased maternal age results in a higher rate of transmitted mutation, whereas the increased number of mitotic replications associated with advanc ed paternal age has little, if any, effect on the rate of transmitted mutat ion.