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

Hum Mol Genet. 2013 Jun 4. [Epub ahead of print]

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

Shinde DN, Elmer DP, Calabrese P, Boulanger J, Arnheim N, Tiemann-Boege I.

Source

Molecular and Computational Biology Program, University of Southern California, Los Angeles 90089, California, United States of America.

Abstract

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. The classic example of a genetic disorder exhibiting a PAE is achondroplasia, caused predominantly by a single nucleotide substitution (c.1138G>A) in FGFR3. 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.1138G>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 2.7x10-6. 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.

PMID: 23740942 [PubMed - as supplied by publisher]

Common Genetic Disease Linked to Father’s Age

Common Genetic Disease Linked to Father’s Age

1 hour ago

Genetic mutation of a testis stem cell actually gives the disease an edge, making older fathers more likely to pass it along to their children

Scientists at USC have unlocked the mystery of why new cases of the genetic disease Noonan Syndrome are so common: a mutation that causes the disease disproportionately increases a normal father’s production of sperm carrying the disease trait. 

When this Noonan syndrome mutation arises in a normal sperm stem cell it makes that cell more likely to reproduce itself than stem cells lacking the mutation. The father then is more likely to have an affected child because more mutant stem cells result in more mutant sperm. The longer the man waits to have children the greater the chance of having a child with Noonan syndrome.

Noonan Syndrome is among the most common genetic diseases with a simple inheritance pattern. About one of every 4,000 live births is a child with a new disease mutation. The disease can cause craniofacial abnormalities, short stature, heart defects, intellectual disability and sometimes blood cancers.

By examining the testes from 15 unaffected men, a team led by USC molecular and computational biologists Norman Arnheim and Peter Calabrese found that the new mutations were highly clustered in the testis, and that the overall proportion of mutated stem cells increased with age. Their computational analysis indicated that the mutation gave a selective edge over non-mutated cells.

“There is competition between stem cells with and without the mutation in each individual testis,” said Arnheim, who has joint appointments at the USC Dornsife College of Letters, Arts and Sciences and the Keck School of Medicine of USC. “But what is also unusual in this case is that the mutation which confers the advantage to testis stem cells is disadvantageous to any offspring that inherits it.”

The new findings also suggest an important new molecular mechanism to explain how certain genetic disease mutations can alter sperm stem cell function leading to exceptionally high frequencies of new cases every generation.

The Arnheim and Calabrese team included USC postdoctoral research associates Song-Ro Yoon, and Soo-Kung Choi, graduate student Jordan Eboreime and Dr. Bruce D. Gelb of the Icahn School of Medicine at Mount Sinai in New York City. A paper detailing their research will be published on June 6 in The American Journal of Human Genetics.

This research was supported by the National Institute of General Medical Sciences grant number R01GM36745 and the National Heart, Lung and Blood Institute (National Institutes of Health) grant number HL071207.

###

Contact: Robert Perkins at (213) 740-9226 or perkinsr@usc.edu