. On the identification of low allele frequency mosaic mutations in the brains of Alzheimer's disease patients. Alzheimers Dement. 2015 Apr 29; PubMed.


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  1. This is a very interesting area of research, as has been recently shown by Acuna-Hidalgo R. et al. when reporting that post-zygotic point mutations are an under-recognized source of de novo genomic variation (Acuna-Hidalgo et al., 2015). Mosaicism is a known event but difficult to study, especially when the proportion of cells with a different genotype is low.

    The Frigerio et al. paper uses a combined approach to start looking at this issue in Alzheimer’s disease. The authors went to great lengths to validate and optimize their pipeline, which seems to be very efficient but somehow not very specific (with a low rate of variants being validated).

    Technically my only concern is associated with the study of somatic CNVs given the reported systematic biases in loci copy number originating from DNA isolation methods (van Heesch et al., 2013). This study gives us the technical possibility to detect mosaic variants in the brain and shows that these variants do exist in AD-related genes. However, it remains challenging to understand the role of these changes in Alzheimer’s disease, particularly since the pathogenicity of the variants found is not clear.


    . Post-zygotic Point Mutations Are an Underrecognized Source of De Novo Genomic Variation. Am J Hum Genet. 2015 Jul 2;97(1):67-74. Epub 2015 Jun 6 PubMed.

    . Systematic biases in DNA copy number originate from isolation procedures. Genome Biol. 2013 Apr 24;14(4):R33. PubMed.

    View all comments by Rita Guerreiro
  2. I have tried several times without success to raise interest and funding for a study like that published by Bart De Strooper. Clinicians and geneticists at VUMC thought mosaicism was not present. I am convinced that mosaicism would explain at least some non-familial early cases. We have many presenile AD cases without any known mutations in the presenilins or APP as per blood test. I still would like to do this research and confirm this important study by De Strooper's group with our material from the Netherlands Brain Bank. We have more than 1,000 AD brains, both frozen and paraffin-embedded tissue, serum, sometimes skin, and in many cases DNA from blood.

    I think it is important to do these studies. We can select the most pure cases and get this study done; however, we need financing and interest by geneticists.

    View all comments by Annemieke J.M. Rozemuller
  3. In response to the comment by Rita Guerrero above, we have now demonstrated a similar bias in DNA isolation from human brain, which could lead to a false impression of CNV mosaicism, see Nacheva et al., 2017


    . DNA isolation protocol effects on nuclear DNA analysis by microarrays, droplet digital PCR, and whole genome sequencing, and on mitochondrial DNA copy number estimation. PLoS One. 2017;12(7):e0180467. Epub 2017 Jul 6 PubMed.

    View all comments by Christos Proukakis

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