Somatic Mosaicism in the Human Genome

Freed, Donald; Stevens, Eric L.; Pevsner, Jonathan

doi:10.3390/genes5041064

Cited by 125 publications

(99 citation statements)

References 209 publications

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“…Recent advances in genomics, especially in single-cell genomics, have revealed that genome mosaicism in human somatic tissues is a far more frequent phenomenon than once believed (22)(23)(24)(25)(26). In this study, we demonstrated a great degree of variation in genome mosaicism among different somatic tissue types.…”

Section: Discussionsupporting

confidence: 48%

iPSCs and fibroblast subclones from the same fibroblast population contain comparable levels of sequence variations

Kwon

Connelly

Hansen

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

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Genome integrity of induced pluripotent stem cells (iPSCs) has been extensively studied in recent years, but it is still unclear whether iPSCs contain more genomic variations than cultured somatic cells. One important question is the origin of genomic variations detected in iPSCs-whether iPSC reprogramming induces such variations. Here, we undertook a unique approach by deriving fibroblast subclones and clonal iPSC lines from the same fibroblast population and applied next-generation sequencing to compare genomic variations in these lines. Targeted deep sequencing of parental fibroblasts revealed that most variants detected in clonal iPSCs and fibroblast subclones were rare variants inherited from the parental fibroblasts. Only a small number of variants remained undetectable in the parental fibroblasts, which were thus likely to be de novo. Importantly, the clonal iPSCs and fibroblast subclones contained comparable numbers of de novo variants. Collectively, our data suggest that iPSC reprogramming is not mutagenic.iPSCs | fibroblasts | reprogramming | genomic variation | exome sequencing G enomic integrity of human induced pluripotent stem cells (iPSCs) is an unresolved question and a crucial issue for iPSCs-based therapeutics. To understand the scope of acquired genetic changes that occur during iPSC generation, previous studies have compared single nucleotide variants (SNVs), copy number variations (CNVs), and chromosomal rearrangements in iPSCs to donor somatic cells or embryonic stem cells (ESCs) using various assays, including SNP array and next-generation sequencing methods (1-6). Whole genome or exome sequencing (WGS/ WES) of parental and iPSC pairs have demonstrated that there are, on average, 6-12 coding SNVs per iPSC line (1, 7-9) with varying theories regarding when these SNVs arose in the iPSCs. Most reports attributed de novo SNVs or CNVs in iPSCs to reprogramming-induced stress or long-term in vitro culture (2,3,7,8,(10)(11)(12)(13)(14). However, several studies also suggested that many of the "de novo" variants were either inherited rare preexisting variations in the founder source cells or benign variants regardless of reprogramming method used (1,9,15,16).To determine whether iPSCs are inherently more likely to accumulate mutations and further elucidate the origin of genomic variants present in iPSCs, we have undertaken a unique approach by establishing clonal fibroblast subclones and iPSCs from the same fibroblast population to directly assess whether the reprogramming process leads to more mutations by next-generation sequencing. De novo mutations, which were not detected in the starting pooled parental fibroblasts, were identified in each daughter cell line, both fibroblast subclones and iPSCs. These putative de novo mutation sites were then deep sequenced in the parental fibroblast population to determine whether they were present at low frequency as mosaic variants. In addition, highresolution single nucleotide polymorphism (SNP) arrays were used to search for de novo CNVs in both fibrobla...

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Section: Discussionsupporting

confidence: 48%

iPSCs and fibroblast subclones from the same fibroblast population contain comparable levels of sequence variations

Kwon

Connelly

Hansen

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

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“…In fact, the relationship between somatic mutation and carcinoma has been largely be mutated in cancers has been described [11].…”

Section: Discussionmentioning

confidence: 99%

Proteus Syndrome: About Two Paediatrics Cases

Kissou¹,

Tankoano²,

Somé³

et al. 2018

OJPed

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Proteus syndrome (PS) is a rare pathology characterized by mosaic and progressive hypertrophies, that can affect any organ or tissue of the body. A genetic mutation in the embryo is at the origin of the disease. Bones, fat, skin and connective tissue are the tissues most typically involved. The extent and severity of the abnormalities vary, giving different clinical presentations. The authors report two cases in two boys aged three and eight years respectively. In both, segmental and organ growth abnormalities, skin abnormalities and lipomas were present. The youngest patient was admitted for the management of severe malnutrition. He presented a major excrescence in the gluteal region, which required surgical management mainly because of its functional impact. In the second patient who was hospitalized following a viral meningoencephalitis, important vascular abnormalities were demonstrated, particularly at the cerebral and abdominal level. The clinical presentation was more severe in the latter, with the installation of an extended coma and a comitial state. PS is a pathology which could be incapacitating. It exposes to a high risk of benign tumours and deep venous thrombosis. The variability of abnormalities and the risks incurred required multidisciplinary management.

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“…The first inkling of this phenomenon as a cause of sporadic SAID arose from the observation that somatic mosaicism of NLRP3 was the cause of disease in previously genetically ‘negative’ cases of NOMID/CINCA. Somatic mosaicism, which is defined as the ‘occurrence of two genetically distinct populations of cells’ within an individual, is a mutation that occurs postzygotically and can either affect a proportion or subtype of cells 52. Somatic mosaicism in exon 3 of the NLRP3 gene was originally reported back in 2005, in a 15-year-old patient with CINCA, along with a negative family history for CAPS 53.…”

Section: Saids Of Unknown Aetiology and Somatic Mosaicism/mutationsmentioning

confidence: 99%

Autoinflammatory diseases: update on classification diagnosis and management

2016

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The spectrum of systemic autoinflammatory disorders broadens continually. In part, this is due to the more widespread application of massive parallel sequencing, helping with novel gene discovery in this and other areas of rare diseases. Some of the conditions that have been described fit neatly into a conventional idea of autoinflammation. Others, such as Interferon-mediated autoinflammatory diseases, are broadening the concept which we consider to be autoinflammatory disorders. There is also a widening of the clinical phenotypes associated with certain genetic mutations, as genetic testing is used more regularly and increasing numbers of patients are screened. It is also increasingly evident that both autoinflammatory and autoimmune problems are frequently seen as complications of primary immunodeficiency disorders.The aim of this review is to provide an update on some recently discovered conditions, and to discuss how these disorders help to define the concept of autoinflammation. The review will also cover recent discoveries in the biology of innate-immune mediated inflammation, and describe how this has provided the biological rationale for using anti-IL-1 therapies in the treatment of many such conditions. Finally, we discuss the importance of recognising somatic mutations as causes of autoinflammatory clinical phenotypes, and provide practical advice on how this could be tackled in everyday clinical practice.

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Somatic Mosaicism in the Human Genome

Cited by 125 publications

References 209 publications

iPSCs and fibroblast subclones from the same fibroblast population contain comparable levels of sequence variations

iPSCs and fibroblast subclones from the same fibroblast population contain comparable levels of sequence variations

Proteus Syndrome: About Two Paediatrics Cases

Autoinflammatory diseases: update on classification diagnosis and management

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