Exploring the variation within

Department of Genetics at Harvard Medical School, Boston, Massachusetts, USA, and in the Program in Medical and Population Genetics at the Broad Institute of MIT and Harvard, Cambridge, Massachusetts, USA.
Nature Genetics (Impact Factor: 29.35). 05/2012; 44(6):614-6. DOI: 10.1038/ng.2311
Source: PubMed


We usually think of an individual's cells as sharing the same genome. Challenging this notion, two new studies show that somatic mosaicism is common and can be an early herald of cancer.

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    • "Even mtDNA mutations, generally considered to be acquired later in life, could arise in early development.69 Early somatic mutations may not, however, simply be accidents predisposing to later disease but could provide the basis for selection within an organism.11,70 This could be particularly relevant to selection of neuronal precursors and neurons that survive the massive apoptotic programmed cell death in early central nervous system development,71 which affects most neuronal populations, including dopaminergic neurons in the SN at the time of maximal competition for synaptic contact.72 "
    [Show abstract] [Hide abstract] ABSTRACT: Alpha-synuclein (SNCA) is crucial in the pathogenesis of Parkinson's disease (PD), yet mutations in the SNCA gene are rare. Evidence for somatic genetic variation in normal humans, also involving the brain, is increasing, but its role in disease is unknown. Somatic SNCA mutations, arising in early development and leading to mosaicism, could contribute to PD pathogenesis and yet be absent or undetectable in DNA derived from peripheral lymphocytes. Such mutations could underlie the widespread pathology in PD, with the precise clinical outcome dependent on their type and the timing and location of their occurrence. We recently reported a novel SNCA mutation (c.150T>G, p.H50Q) in PD brain-derived DNA. To determine if there was mosaicism for this, a PCR and cloning strategy was used to take advantage of a nearby heterozygous intronic polymorphism. No evidence of mosaicism was found. High-resolution melting curve analysis of SNCA coding exons, which was shown to be sensitive enough to detect low proportions of 2 known mutations, did not reveal any further mutations in DNA from 28 PD brain-derived samples. We outline the grounds that make the somatic SNCA mutation hypothesis consistent with genetic, embryological, and pathological data. Further studies of brain-derived DNA are warranted and should include DNA from multiple regions and methods for detecting other types of genomic variation. © 2013 Movement Disorder Society.
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  • [Show abstract] [Hide abstract] ABSTRACT: The cells in our body do not all contain identical genomes, which has implications for health and disease.
    No preview · Article · Jul 2013 · Science
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    [Show abstract] [Hide abstract] ABSTRACT: Persistent hyperplastic primary vitreous (PHPV) represents a developmental eye disease known to have diverse manifestations ranging from a trivial remnant of hyaloid vessels to a dense fibrovascular mass causing lens opacity and retinal detachment. PHPV can be modeled in mice lacking individual genes, but certain features of such models differ from the clinical realm. For example, mice lacking the Arf gene have uniformly severe disease with consistent autosomal recessive disease penetrance. We tested whether the graded somatic loss of Arf in a subset of cells in chimeric mice mimics the range of disease in a non-heritable manner. Wild type ↔ Arf (-/-) mouse chimeras were generated by morulae fusion, and when the mice were 10 weeks old, fundoscopic, slit-lamp, and histological evaluations were performed. The relative fraction of cells of the Arf (-/-) lineage was assessed with visual, molecular genetic, and histological analysis. Objective quantification of various aspects of the phenotype was correlated with the genotype. Sixteen chimeras were generated and shown to have low, medium, and high contributions of Arf (-/-) cells to tail DNA, the cornea, and the retinal pigment epithelium (RPE), with excellent correlation between chimerism in the tail DNA and the RPE. Phenotypic differences (coat color and severity of eye disease) were evident, objectively quantified, and found to correlate with the contribution of Arf (-/-) cells to the RPE and tail-derived DNA, but not the cornea. Generating animals composed of different numbers of Arf (-/-) cells mimicked the range of disease severity observed in patients with PHPV. This establishes the potential for full manifestations of PHPV to be caused by somatic mutations of a single gene during development.
    Full-text · Article · Mar 2014 · Molecular vision
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