Today's New York Times has an article, 'It Seems the Fertility Clock Ticks for Men, Too,' by Roni Rabin, that covers both declining male fertility and genetic risks tied to a father's age. The latter is something that I have written about here before, in response to a study linking autism to paternal age. That posting generated some interesting discussion and an email that pointed me to a very interesting article by Dolores Malaspina in the schizophrenia research forum: 'schizophrenia research and the male germ line.' The observations of increased risk are dramatic. I can't add much to that excellent commentary by an expert in the field, except for the small point that double-strand breaks are missing from Malaspina's list of possible genetic mechanisms. There is evidence, from Drosophila and people that double strand breaks increase with paternal age.
As discussed in comments to my earlier post, I am especially interested in knowing what genes these surprisingly specific effects act through. A 1997 PNAS article describes a few genes that are somehow quite special. In a 2003 comment in Science, Crow describes them as "hot-spots occurring almost exclusively in males and rising steeply with age. Three genes--fibroblast growth factor receptor 3 (FGFR3, mutated in achondroplasia), FGFR2 (mutated in Apert's syndrome), and RET (mutated in multiple endocrine neoplasia)--are examples of the hot-spot class. In this class, genes carry mutations that are clustered at just one or two nucleotide sites." He then discusses at length the hypothesis that these specific mutations are selected in the male germ line, a hypothesis that Goriely et al. put right in the title of their article: "Evidence for Selective Advantage of Pathogenic FGFR2 Mutations in the Male Germ Line." The title of Crow's commentary was "There's Something Curious About Paternal-Age Effects." The effects on complex behavioral diseases like autism and schizophrenia make this story even more curious.
Tuesday, February 27, 2007
Thursday, February 08, 2007
Reconstruction of the deadly 1918 influenza virus has been controversial because of the risk that the reconstructed virus might escape from the laboratory or fall into the wrong hands. On the other hand, research with this virus has indeed led to some important insights (reviewed by Garcia-Sastre and Whitley). One of the first of these was that the 1918 virus was probably avian in origin. Since that review the severity of symptoms has been attributed to an overactive innate immune response (Kobasa et al. 2007, summarized by Loo and Gale, 2007), and the infectivity to mammals has been attributed to two amino acid changes in the hemagglutinin gene (Tumpey et al., 2007, summarized by Enserink, 2007). Does this mean that the H5N1 virus now infecting birds in much of the world is only two point mutations away from causing a human pandemic? This is not clear. Certainly, there are those who think that we need to be more concerned about the birds (e.g. Juan Lobroth), and Yamada et al., 2006 present evidence that changes in hemagglutinin can be observed (already) in some H5N1 viruses isolated from humans even though human-to-human transmission remains extremely rare. Even so, we have learned what to look for.