New evidence for positive selection helps explain the paternal age effect observed in achondroplasia.

[achondroplasia]

There are certain de novo germline mutations associated with genetic disorders whose mutation rates per generation are orders of magnitude higher than the genome average . Moreover , these mutations occur exclusively in the male germ line and older men have a higher probability of having an affected child than younger ones , known as the paternal age effect (PAE ). The classic example of a genetic disorder exhibiting a PAE is achondroplasia , caused predominantly by a single -nucleotide substitution (c .1138 G >A ) in FGFR 3 . To elucidate what mechanisms might be driving the high frequency of this mutation in the male germline , we examined the spatial distribution of the c .1138 G >A substitution in a testis from an 80 -year -old unaffected man . Using a technology based on bead-emulsion amplification , we were able to measure mutation frequencies in 192 individual pieces of the dissected testis with a false-positive rate lower than 2 .7 Ã— 10 (-6 ). We observed that most mutations are clustered in a few pieces with 95 % of all mutations occurring in 27 % of the total testis . Using computational simulations , we rejected the model proposing an elevated mutation rate per cell division at this nucleotide site . Instead , we determined that the observed mutation distribution fits a germline selection model , where mutant spermatogonial stem cells have a proliferative advantage over unmutated cells . Combined with data on several other PAE mutations , our results support the idea that the PAE , associated with a number of Mendelian disorders , may be explained primarily by a selective mechanism .

Diseases
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Diseases presenting "high frequency of this mutation in the male germline" symptom

achondroplasia

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