Early Embryonic Chromosome Instability Results in Stable Mosaic Pattern in Human Tissues

Abstract

The discovery of copy number variations (CNV) in the human genome opened new perspectives on the study of the genetic causes of inherited disorders and the aetiology of common diseases. Here, a single-cell-level investigation of CNV in different human tissues led us to uncover the phenomenon of mitotically derived genomic mosaicism, which is stable in different cell types of one individual. The CNV mosaic ratios were different between the 10 individuals studied. However, they were stable in the T lymphocytes, immortalized B lymphoblastoid cells, and skin fibroblasts analyzed in each individual. Because these cell types have a common origin in the connective tissues, we suggest that mitotic changes in CNV regions may happen early during embryonic development and occur only once, after which the stable mosaic ratio is maintained throughout the differentiated tissues. This concept is further supported by a unique study of immortalized B lymphoblastoid cell lines obtained with 20 year difference from two subjects. We provide the first evidence of somatic mosaicism for CNV, with stable variation ratios in different cell types of one individual leading to the hypothesis of early embryonic chromosome instability resulting in stable mosaic pattern in human tissues. This concept has the potential to open new perspectives in personalized genetic diagnostics and can explain genetic phenomena like diminished penetrance in autosomal dominant diseases. We propose that further genomic studies should focus on the single-cell level, to better understand the aetiology of aging and diseases mediated by somatic mutations.

Hydroxyurea induces de novo copy number variants in human cells

“…This hypothesis also predicts that CNVs will arise frequently in postzygotic cells, leading to somatic mosaicism within or between tissues. Indeed, substantial evidence exists for somatic mosaicism of pathogenic CNVs, such as in the NF1 and DMD genes (39,46,47), and for apparently benign CNVs in identical twins (48) and in different tissues within individuals (49,50). The overlap of some CNV hotspots with common fragile sites suggests a mechanistic link between the events leading to fragile site chromosome breaks and induction of some CNVs.…”

Microdeletion and Microduplication Syndromes

“…The advantage of the FISH approach is that single-cell information in the context of metaphase chromosomes becomes available. Besides the visualization of a balanced chromosomal aberration in a parent (leading to unbalanced situations in the index patient), mosaicism and complex rearrangements in a patient can also be detected (Mkrtchyan et al 2010; Fig. 3).…”

Extensive genetic variation in somatic human tissues

“…Evidence of genomic alterations has been found in human embryonic stem cells (3) and human iPS cells (4)(5)(6)(7). Recent findings suggest that immortalized cell lines (8) contain significant copy number differences, although it is unclear whether these variations arise in vitro during cell culturing or originate in vivo in somatic cell populations.…”

“…Somatic mosaicism has been studied in cultured cells (8), but only one study has documented copy number variation between unfixed human tissues within individuals using BAC arrays for array-comparative genomic hybridization (aCGH) (19). These arrays produce low-resolution data, and they have high error rates, leaving uncertainty.…”