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: 29.65). 05/2012; 44(6):614-6. DOI: 10.1038/ng.2311
Source: PubMed

ABSTRACT 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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    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.
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    ABSTRACT: The large number of cell divisions required to make a human body inevitably leads to the accumulation of somatic mutations. Such mutations cause individuals to be somatic mosaics. Recent advances in genomic technology now allow measurement of somatic diversity. Initial studies confirmed the expected high levels of somatic mutations within individuals. Going forward, the big questions concern the degree to which those somatic mutations influence disease. Theory predicts that the frequency of mutant cells should vary greatly between individuals. Such somatic mutational variability between individuals could explain much of the diversity in the risk of disease. But how variable is mosaicism between individuals in reality? What is the relation between the fraction of cells carrying a predisposing mutation and the risk of disease? What kinds of heritable somatic change lead to disease besides classical DNA mutations? What molecular processes connect a predisposing somatic change to disease? We know that predisposing somatic mutations strongly influence the onset of cancer. Likewise, neurodegenerative diseases may often begin from somatically mutated cells. If so, both neurodegeneration and cancer may be diseases of later life for which much of the risk may be set by early life somatic mutations.
    Current Biology 06/2014; 24(12):R577-R581. DOI:10.1016/j.cub.2014.05.021 · 9.92 Impact Factor
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    ABSTRACT: That each of us is truly biologically unique, extending to even monozygotic, "identical" twins, is not fully appreciated. Now that it is possible to perform a comprehensive "omic" assessment of an individual, including one's DNA and RNA sequence and at least some characterization of one's proteome, metabolome, microbiome, autoantibodies, and epigenome, it has become abundantly clear that each of us has truly one-of-a-kind biological content. Well beyond the allure of the matchless fingerprint or snowflake concept, these singular, individual data and information set up a remarkable and unprecedented opportunity to improve medical treatment and develop preventive strategies to preserve health.
    Cell 03/2014; 157(1):241-253. DOI:10.1016/j.cell.2014.02.012 · 33.12 Impact Factor