AUTISM PREVENTION FATHER BABIES 24-34 PATERNAL AGE IS KEY IN NON-FAMILIAL AUTISMVaccines

"It is very possible that PATERNAL AGE is the major predictor of(non-familial) autism." Harry Fisch, M.D., author "The Male Biological Clock". Sperm DNA mutates and autism, schizophrenia bipolar etc. results. What is the connection with autoimmune disorders? Having Type 1 diabetes, SLE,etc. in the family, also if mother had older father. NW Cryobank will not accept a sperm donor past 35th BD to minimize genetic abnormalities.VACCINATIONS also cause autism.

Tuesday, May 22, 2007

Gain-of-function amino acid substitutions drive positive selection of FGFR2 mutations in human spermatogonia



Published online before print April 19, 2005, 10.1073/pnas.0500267102
PNAS | April 26, 2005 | vol. 102 | no. 17 | 6051-6056






GENETICS
Gain-of-function amino acid substitutions drive positive selection of FGFR2 mutations in human spermatogonia

Anne Goriely *, Gilean A. T. McVean , Ans M. M. van Pelt , Anthony W. O'Rourke , Steven A. Wall ¶, Dirk G. de Rooij , and Andrew O. M. Wilkie *, ¶, ||, **

*Weatherall Institute of Molecular Medicine, University of Oxford, John Radcliffe Hospital, Oxford OX3 9DS, United Kingdom; Department of Statistics, University of Oxford, South Parks Road, Oxford OX1 3TG, United Kingdom; Department of Endocrinology, Utrecht University, 3584 CH, Utrecht, The Netherlands; Oxford Regional Genetics Laboratories, Churchill Hospital, Oxford OX3 7LJ, United Kingdom; ¶Department of Plastic Surgery, Craniofacial Unit, Radcliffe Infirmary, Oxford OX2 6HE, United Kingdom; and ||Nuffield Department of Clinical Laboratory Sciences, University of Oxford, John Radcliffe Hospital, Oxford OX3 9DU, United Kingdom

Edited by James F. Crow, University of Wisconsin, Madison, WI, and approved March 14, 2005 (received for review January 12, 2005)


Despite the importance of mutation in genetics, there are virtually no experimental data on the occurrence of specific nucleotide substitutions in human gametes. C>G transversions at position 755 of FGF receptor 2 (FGFR2) cause Apert syndrome; this mutation, encoding the gain-of-function substitution Ser252Trp, occurs with a birth rate elevated 200- to 800-fold above background and originates exclusively from the unaffected father. We previously demonstrated high levels of both 755C>G and 755C>T FGFR2 mutations in human sperm and proposed that these particular mutations are enriched because the encoded proteins confer a selective advantage to spermatogonial cells. Here, we examine three corollaries of this hypothesis. First, we show that mutation levels at the adjacent FGFR2 nucleotides 752-754 are low, excluding any general increase in local mutation rate. Second, we present three instances of double-nucleotide changes involving 755C, expected to be extremely rare as chance events. Two of these double-nucleotide substitutions are shown, either by assessment of the pedigree or by direct analysis of sperm, to have arisen in sequential steps; the third (encoding Ser252Tyr) was predicted from structural considerations. Finally, we demonstrate that both major alternative spliceforms of FGFR2 (Fgfr2b and Fgfr2c) are expressed in rat spermatogonial stem cell lines. Taken together, these observations show that specific FGFR2 mutations attain high levels in sperm because they encode proteins with gain-of-function properties, favoring clonal expansion of mutant spermatogonial cells. Among FGFR2 mutations, those causing Apert syndrome may be especially prevalent because they enhance signaling by FGF ligands specific for each of the major expressed isoforms.


Apert syndrome | FGF receptor 2 | paternal age | selfish mutation

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