New Mutations Genetic Hot Spots OLDER FATHERS or MATERNAL GRANDFATHERS????

De Novo Mutations


"Inherited mutations had to start somewhere, and that somewhere is a de novo mutation. A de novo mutation is a new mutation that occurs in a germ cell and is then passed on to an offspring. All germline mutations started as a de novo mutation in some ancestor."





De Novo Mutation----- Does Any One Ask How Old the Fathers were? Why de novo mutations? Are there any factors that the parents of these kids had in common?








rodup. at 16p11.2) [View Printable]

Jamie_CruikshankTadpoleGroup: AdministratorsPosts: 43Joined: May 31, 2006

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This is one of the articles (found in the New Enland Journal of Medicine, January 2008) that I recently read that indicate we are getting closer to finding a correlation between genetic variants and patients who display autistic characteristics. Association between Microdeletion and Microduplication at 16p11.2 and Autism. N Engl J Med. 2008 Jan 9; Weiss LA, Shen Y, Korn JM, Arking DE, Miller DT, Fossdal R, Saemundsen E, Stefansson H, Ferreira MA, Green T, Platt OS, Ruderfer DM, Walsh CA, Altshuler D, Chakravarti A, Tanzi RE, Stefansson K, Santangelo SL, Gusella JF, Sklar P, Wu BL, Daly MJ, BACKGROUND: Autism spectrum disorder is a heritable developmental disorder in which chromosomal abnormalities are thought to play a role. METHODS: As a first component of a genomewide association study of families from the Autism Genetic Resource Exchange (AGRE), we used two novel algorithms to search for recurrent copy-number variations in genotype data from 751 multiplex families with autism. Specific recurrent de novo events were further evaluated in clinical-testing data from Children's Hospital Boston and in a large population study in Iceland. RESULTS: Among the AGRE families, we observed five instances of a de novo deletion of 593 kb on chromosome 16p11.2. Using comparative genomic hybridization, we observed the identical deletion in 5 of 512 children referred to Children's Hospital Boston for developmental delay, mental retardation, or suspected autism spectrum disorder, as well as in 3 of 299 persons with autism in an Icelandic population; the deletion was also carried by 2 of 18,834 unscreened Icelandic control subjects. The reciprocal duplication of this region occurred in 7 affected persons in AGRE families and 4 of the 512 children from Children's Hospital Boston. The duplication also appeared to be a high-penetrance risk factor. CONCLUSIONS: We have identified a novel, recurrent microdeletion and a reciprocal microduplication that carry substantial susceptibility to autism and appear to account for approximately 1% of cases. We did not identify other regions with similar aggregations of large de novo mutations. Copyright 2008 Massachusetts Medical Society. For more info see: http://www.ncbi.nlm.nih.gov
Posted Feb 4, 2008, 11:09 pm
Maybe the genes in the sperm at 16p11.2 mutated before fertilization???? Why not???


James F. Crow The High Spontaneous Mutations Rate is it a Health Risk? http://www.pnas.org/cgi/content/full/94/16/8380


ABSTRACT
The human mutation rate for base substitutions is much higher in males than in females and increases with paternal age. This effect is mainly, if not entirely, due to the large number of cell divisions in the male germ line. The mutation-rate increase is considerably greater than expected if the mutation rate were simply proportional to the number of cell divisions. In contrast, those mutations that are small deletions or rearrangements do not show the paternal age effect. The observed increase with the age of the father in the incidence of children with different dominant mutations is variable, presumably the result of different mixtures of base substitutions and deletions. In Drosophila, the rate of mutations causing minor deleterious effects is estimated to be about one new mutation per zygote. Because of a larger number of genes and a much larger amount of DNA, the human rate is presumably higher. Recently, the Drosophila data have been reanalyzed and the mutation-rate estimate questioned, but I believe that the totality of evidence supports the original conclusion. The most reasonable way in which a species can cope with a high mutation rate is by quasi-truncation selection, whereby a number of mutant genes are eliminated by one "genetic death."



The genetic defect was found in children with autism but not in their parents, indicating that it was a spontaneous mutation that occurred sometime after fertilization. The location, called 16p11.2, is what is known as a genetic "hot spot," meaning it is unusually susceptible to such mutations.