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

Abstract

The factor IX gene (F9) is an advantageous system for analyzing recent spontaneous germline mutation in humans. Herein, the male:female ratio of mutation ("r") in F9 have been estimated by Bayesian analysis from 59 germline origin families. The overall "r" in F9 was estimated at 3.75. The "r"s varied with the type of mutation. The "r"s ranged from 6.65 and 6.10 for transitions at CpG and A:T to G:C transitions at non-CpG dinucleotides, respectively, 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 was detected in 11% of the 45 origin individuals for whom the causative mutation was visualized directly by genomic sequencing of leukocyte DNA (estimated 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, hinting that this mutation subtype may occur commonly early in embryogenesis. The age at conception was analyzed for 41 US Caucasian families in which the age of the origin parent and the year of conception for the first carrier/hemophiliac were available. No evidence for a paternal age effect was seen. However, an advanced maternal age effect was observed (P=0.03) and was particularly prominent for transversions (average of the 79th percentile when maternal age was normalized for the year of conception). This suggests that an increased maternal age results in a higher rate of transmitted mutation, whereas the increased number of mitotic replications associated with advanced paternal age has little, if any, effect on the rate of transmitted mutation.

Mosaicism and haemophilia

“…A paternal age effect has been demonstrated for certain conditions, most obviously for de novo achondroplasia, due to mutations at a CpG nucleotide pair [37]. Increasing paternal age, however, is not associated with an increase in de novo mutations for haemophilia A [33] or haemophilia B [38] in the limited series studied to date. In contrast, older females have a slightly higher likelihood of bearing a de novo germline mutation for haemophilia compared to younger females [38,39].…”

Tissue-specific time courses of spontaneous mutation frequency and deviations in mutation pattern are observed in middle to late adulthood in Big Blue mice

“…Lifelong spermatogonial stem cell divisions unique to the male germline are hypothesized to contribute to significant elevations in mutation frequency in males with age. Contrary to this hypothesis, germline mutations in the factor IX gene in hemophilia patients do not show a paternal age effect [Ketterling et al, 1993[Ketterling et al, , 1999. About three-fourths of the factor IX mutations causing hemophilia B are single-base substitutions, so the lack of evidence for a paternal age effect in factor IX is counter to the prevailing view that the risk of transmitting point mutations increases with the age of the father [Vogel and Motulsky, 1997;Crow, 2000].…”

Detection of mosaicRB1mutations in families with retinoblastoma

“…A mosaic PSEN1 mutation, present in approximately 8% of a proband's lymphocytes, as estimated by allele specific oligo hybridization (ASOH), was not detected by ABI sequencing; the same mutation present in about 14% of the cells of the cerebral cortex by ASOH was just barely discernible by ABI sequence analysis. It has been reported that overexposed autoradiographs of manual sequencing can detect mosaicism at levels of about 5% [Ketterling et al, 1999].…”