genes, genes, genes…more awesomeness in genomic medicine!

In Autism Spectrum Disorders, Genes, Genomic Medicine, Neuroscience on Thursday, 25 October 2012 at 14:26


Multiple papers recently published have documented links between de novo mutations and autism, schizophrenia, and intellectual disability. Here, I review the topic and raise some of the key questions on this issue going forward.

– Kong A, et al. Rate of de novo mutations and the importance of father’s age to disease risk. Nature. 2012;488:471-475.
– Wang J, et al. Genome-wide single-cell analysis of recombination activity and de novo mutation rates in human sperm. Cell. 2012;150:402-412.
– Rauch A, et al. Range of genetic mutations associated with severe non-syndromic intellectual disability: an exome sequencing study. Lancet. 2012 Sept 26. [Epub ahead of print]
– de Ligt J, et al. Diagnostic exome sequencing in persons with severe intellectual disability. N Engl J Med. 2012 Oct 3. [Epub ahead of print]


Below is a transcript of Dr. Topol’s post “De Novo Mutations and the Implications for the Father’s Biological Clock.” We look forward to your feedback.
Our topic is de novo mutations and the implication of these new mutations for expectant fathers. This is a really important topic that was highlighted by the cover article in August 2012 in Nature. It was also in recent multiple papers in Cell, where sperm was sequenced for the first time, as well as in multiple papers on de novo mutations in Nature and Nature Genetics.

While we have known about the possibility for new mutations to occur that are not heritable, the quantification of this has become possible now that we can do sequencing of sperm and compare that to the germline DNA of the father. What is fascinating is that there have been now multiple papers that have come out in recent weeks to demonstrate the link between de novo mutations and intellectual disability, schizophrenia, and autism — and especially the paper coming from the Icelandic group DECODE, which linked the father’s age with the incidence of de novo mutations.

These new mutations are not frequent, of course, but if there’s just one per exome, that is, throughout the coding elements of the genome, that can be quite damaging. In fact, it is characteristic of de novo mutations that they tend to be bad and have adverse consequences.

While there are many more in a typical genome, somewhere around 70 or more of various types of mutations, whether they’re single nucleotide polymorphisms or insertions/deletions, most of them do not fall in protein coding elements. But when they do, the data we have so far from this collective work suggest that they can be damaging.

The big issue going forward is — what can we do about this? Is this de novo mutation related to our environment? Can we try to reduce the age of fathers and set up the “male biological clock,” which, for all of the years, has been largely restricted to the mother’s story? Can we someday screen sperm for de novo mutations, screen them out or at least get a sense of the frequency? It seems unlikely that we would sequence and then use the sperm for in vitro fertilization, but perhaps we can leverage this knowledge. Of course, the age relationship is tricky because, so far, we don’t have much data to suggest an age range, but clearly there is a relationship with age of the father as it extends to 40 and beyond with a higher rate of de novo mutations.

We also know that, concurrently, the rate of diagnosis of autism is increasing. Could this have something to do with this de novo mutation increase and the overall trend of a higher paternal age?

There is a lot here to consider on a theme that is showing up in multiple papers: the way to quantify de novo mutations, understand their increased frequency as fathers age, and this very interesting link to multiple neurologic, neurocognitive, and neuropsychiatric conditions.

Over time, it’s likely that these de novo mutations will exert a phenotype that is beyond the neurology world. It will also be interesting to see how de novo mutations could potentially have a beneficial role. But one thing for sure is that this is part of the story about missing heritability: we couldn’t account for things that were happening in a new generation that were not present from the parents, and de novo mutations are certainly a part of that story.

Thanks for your attention. I look forward to your comments about de novo mutations and especially the father’s biological clock phenomenon.

Retrieved from: http://boards.medscape.com/forums?128@410.Oln9aayNn1L@.2a35a68e!comment=1

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