Scientists from Yale University reported in the November 16th issue of Nature that about 30% of human skin cells harbor copy number variations (CNVs), or DNA segments that are deleted or duplicated. CNVs had previously thought to be associated with diseases, including cancer, but this study suggests that widespread somatic mosaicism in the human body may be part of the normal human condition.

This mosaicism in somatic cell linages may result from DNA replication errors, DNA repair, mitosis, and mobilization of transposable genetic elements. Such a phenomenon, the investigators said, could have far-reaching physiological consequences, yet is still poorly understood and very difficult to study. But the derivation of induced pluripotent stem cells (iPS cells) offers the opportunity to analyze the genome of a single cell at high resolution and sensitivity.

iPS cells offer good model systems in which to study CNVs in human somatic cells because a number of studies have reported genomic instability in stem and precursor cells, indicating that copy number variation/structural variation arises in these cells, in addition to single base-pair changes. These changes, scientists say, could be caused by the de-differentiation procedures, result from extensive time in culture, or pre-exist in the somatic tissue of origin at low frequency.

In the two-year Yale study, the investigators performed a whole-genome and transcriptase analysis of 20 human iPS lines derived from skin samples of seven individuals from two families using next-generation sequencing.

The iPS lines were characterized according to their morphology, expression of pluripotency factors at the protein level, gene expression analyses, reverse transcription PCR (RT–PCR), microarrays, complete transcriptome by high-throughput RNA sequencing (RNA-seq), and demethylation of canonical pluripotency factor promoters

The results of their study showed that, on average, an iPSC line manifests two CNVs that were not apparent in the fibroblasts from which the iPSC was derived.

But the investigators showed that at least 50% of the iPSC CNVs were present at low-frequency somatic genomic variants in parental fibroblasts—that is, the fibroblasts from which each corresponding human iPSC line is derived and are present in iPSC lines owing to their clonal origin. This shows, they said, that the reprogramming process does not necessarily lead to de novo CNVs in iPSCs because most of the line-manifested CNVs reflect somatic mosaicism in the human skin.

Moreover, they concluded, these findings demonstrate that clonal expansion, and iPSC lines in particular, can be used as a discovery tool to reliably detect low-frequency CNVs in the tissue of origin. Flora Vaccarino, M.D., Harris professor of child psychiatry at the Yale Child Study Center and the study’s lead author, commented that iPS cell lines could act as a “magnifying glass” to see the mosaic of genomic differences in the body’s cells

Dr. Vaccarino also said, “The observation of somatic mosaicism has far-reaching consequences for genetic analyses, which currently use only blood samples. When we look at the blood DNA, it’s not exactly reflecting the DNA of other tissues such as the brain. There could be mutations that we’re missing.”

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