DEAR OLD DAD

BITS AND PIECES OF THE PATERNAL AGE EFFECT
PRE SEBAT AND WIGGLER'S COLD SPRING HARBOR LABS STUDY OF SPORADIC AUTISM AND CNVs



Dear old dad.Glaser RL, Jabs EW.
Institute of Genetic Medicine at Johns Hopkins University, Baltimore, MD 21287, USA.

The origin and frequency of spontaneous mutations that occur with age in humans have been a topic of intense discussion. The mechanisms by which spontaneous mutations arise depend on the parental germ line in which a mutation occurs. In general, paternal mutations are more likely than maternal mutations to be base substitutions. This is likely due to the larger number of germ cell divisions in spermatogenesis than in oogenesis. Maternal mutations are more often chromosomal abnormalities. Advanced parental age seems to influence some mutations, although it is not a factor in the creation of others. In this review, we focus on patterns of paternal bias and age dependence of mutations in different genetic disorders, and the various mechanisms by which these mutations arise. We also discuss recent data on age and the frequency of these mutations in the human male germ line and the impact of these data on this field of research.
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Evidence for Selective Advantage of Pathogenic FGFR2 Mutations in the Male Germ Line
Anne Goriely,1 Gilean A. T. McVean,3 Maria Röjmyr,4 Björn Ingemarsson,4 Andrew O. M. Wilkie1,2*
Observed mutation rates in humans appear higher in male than female gametes and often increase with paternal age. This bias, usually attributed to the accumulation of replication errors or inefficient repair processes, has been difficult to study directly. Here, we describe a sensitive method to quantify substitutions at nucleotide 755 of the fibroblast growth factor receptor 2 (FGFR2) gene in sperm. Although substitution levels increase with age, we show that even high levels originate from infrequent mutational events. We propose that these FGFR2 mutations, although harmful to embryonic development, are paradoxically enriched because they confer a selective advantage to the spermatogonial cells in which they arise.

1 Weatherall Institute of Molecular Medicine, John Radcliffe Hospital, University of Oxford, Oxford OX3 9DS, UK.
2 Nuffield Department of Clinical Laboratory Sciences, John Radcliffe Hospital, University of Oxford, Oxford OX3 9DS, UK.
3 Department of Statistics, University of Oxford, South Parks Road, Oxford OX1 3TG, UK.
4 Pyrosequencing AB, Vallongatan 1, SE-752 28 Uppsala, Sweden.

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Evolutionary Oxymoron
Beckman
Sci. Aging Knowl. Environ 6 August 2003: 108
DOI: 10.1126/sageke.2003.31.nw108



Additional data confirmed that the glitches occurred in sperm stem cells. Together, the data suggest that older men produce more Apert children because sperm generation favors Apert sperm. Younger fathers likely generate Apert mutations, Wilkie says, and these accumulate throughout life because of the mutations' preferential treatment.

The result is puzzling because it suggests that the developing sperm's environment nurtures mutations that hurt the offspring, says geneticist James Crow of the University of Wisconsin, Madison: "When I first read the paper, I didn't want to believe it, but I couldn't find a flaw." He says it's "rather surprising" that harmful mutations would be preferred during sperm development. Now scientists must determine what troubles the developing sperm's domicile.

--Mary Beckman
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Dear Old Dad
Rivka L. Glaser, and Ethylin Wang Jabs


A strong paternal age effect is evident in some disorders, such as achondroplasia and Apert, Crouzon, and Pfeiffer syndromes, in which the birth frequency of affected individuals increases rapidly with paternal age (Fig. 2A). For these disorders, the data are compatible with an exponential model of increase in the relative frequency of affected children (O/E) with increasing paternal age; the linear model is not compatible with the data. In these disorders, the average age of fathers of affected children is 5 to 7 years older than the average age of fathers in the general population. However, for other disorders, such as neurofibromatosis, a much weaker paternal age effect is seen. The rate of increase in the frequency of sporadic cases of this disorder (O/E) is much less marked, and no distinction between a linear or exponential model of increase can be made, because the data fit both models equally (Fig. 2B). In these disorders, the average age of fathers of affected children is 2 to 5 years older than the average age of fathers in the general population.



Bilateral retinoblastoma, multiple exostoses, neurofibromatosis (NF1), Sotos syndrome, and Treacher Collins syndrome were shown by Risch et al. to have a weak paternal age effect (Fig. 1 and Fig. 2B). The mutations associated with these disorders are less homogeneous with regard to type and parental origin than are mutations associated with disorders that have a strong paternal age effect and an almost exclusively paternal origin of mutation.
Base substitutions, as well as deletions, insertions, rearrangements, and translocations, are found with approximately equal frequency in these disorders (34). Large deletions in bilateral retinoblastoma and Sotos syndrome are more often paternally derived than maternally derived (Fig. 4). In contrast, small deletions in Treacher Collins syndrome do not show a preference for parental origin (Fig. 5) (35). In NF1, 89% of base substitutions are paternal in origin, whereas only 20% of large deletions are paternal in origin (see citations in Fig. 3, Fig. 4, and Fig. 5). Conversely, in NF2, base substitutions do not show a bias of parental origin, whereas deletions do; 90% of deletions are paternal in origin (Fig. 3 and Fig. 5) (36). The facts that ratios of paternally derived mutations to maternally derived mutations differ depending on mutation type and that some mutations are not strongly associated with parental age argue for the existence of more than one mechanism underlying the origin of these mutations.



It is intriguing that two studies found that mutation frequency in sperm increased with a man's age, but mutation frequency in white blood cells did not, suggesting cell type-specific selection. Both cell types arise from populations of rapidly regenerating stem cells, so why would mutations accumulate in only one cell type? The age-related accumulation of mutations in several genes in lymphocytes is well documented (67-69). However, those studies analyzed the age-related increases in deletions as well as point mutations, whereas only point mutations were analyzed by Goriely et al. and us. Perhaps only some mutation types accumulate with age. An alternative explanation is that the mutations in Apert syndrome may be selected against in blood or selected for in sperm, depending on the function they confer on different cell types. Quality-control mechanisms, such as DNA repair or apoptosis, may vary in their efficiency in different cell types, resulting in accumulation of mutations in only one cell type. Blood cells with deleterious mutations can be removed by the spleen, whereas for sperm with mutations, no such mechanism exists. Recently, apoptosis has been shown in sperm to decrease with age, with a concomitant increase in DNA damage (50).

In contrast to gross deletions, small deletions (fewer than 20 base pairs) are thought to arise during replication by mispairing and misalignment of direct repeats or short runs of identical bases (49). This type of mutation tends to be paternal in origin ( = 3.33), similar to what is observed for point mutations (Fig. 5). This type of mutation may occur during replication, which may explain the higher mutation frequency seen in males as compared with females. However, small deletions are not associated with older paternal age, whereas point mutations, which also are thought to arise during replication, are.

1: Neurogenetics. 2000 Sep;3(1):17-24. Related Articles, Links


The parental origin of new mutations in neurofibromatosis 2.

Kluwe L, Mautner V, Parry DM, Jacoby LB, Baser M, Gusella J, Davis K, Stavrou D, MacCollin M.

Department of Neurosurgery, University Hospital Eppendorf, Hamburg, Germany. kluwe@uke.uni-hamburg.de

Neurofibromatosis 2 (NF2) is an autosomal dominant disorder characterized by schwannomas and meningiomas that develop after inactivation of both copies of the NF2 gene. Approximately half of all patients with NF2 have unaffected parents and the disease results from new mutations at the NF2 locus. Loss of heterozygosity (LOH) in tumor specimens due to deletions covering the normal NF2 allele can be used to infer the haplotypes surrounding underlying mutations and determine the allelic origin of new mutations. We studied 71 sporadic NF2 patients using both LOH and pedigree analysis and compared the parental origin of the new mutation with the underlying molecular change. In the 45 informative individuals, 31 mutations (69%) were of paternal and 14 (31%) were of maternal origin (P=0.016). Comparison with corresponding constitutional mutations revealed no correlation between parental origin and the type or location of the mutations. However, in 4 of 6 patients with somatic mosaicism the NF2 mutation was of maternal origin. A slight parent of origin effect on severity of disease was found. Further clinical and molecular studies are needed to determine the basis of these unexpected observations.
The parental origin of mutations in the remaining disorders in the group with a strong paternal age effect has yet to be established, because either the gene is not known, as in acrodysostosis and fibrodysplasia ossificans progressiva, or there are many different mutations, as in basal cell nevus, cleidocranial dysostosis, Marfan, oculodentodigital dysplasia (ODDD), and Waardenburg syndromes. Among the latter group of disorders, a range of mutation types--base substitutions, deletions, insertions, and duplications--are found with fairly equal frequency (34). Although a strong paternal age effect has been observed for all of these disorders, it remains to be seen whether these different types of mutations are of paternal orig