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. 2008 Nov 11;105(45):17453-6.
doi: 10.1073/pnas.0805638105. Epub 2008 Nov 6.

Extensive genomic copy number variation in embryonic stem cells

Qi Liang  1 , Nathalie Conte, William C Skarnes, Allan Bradley
Affiliations

Extensive genomic copy number variation in embryonic stem cells

Qi Liang et al. Proc Natl Acad Sci U S A. .

Abstract

Recent analysis of the human and mouse genomes has revealed that highly identical duplicated elements account for >5% of the sequence content. These elements vary in copy number between individuals. Copy number variations (CNVs) contribute significantly to genetic differences among individuals and are increasingly recognized as a causal factor in human diseases with different etiologies. In inbred mouse strains, CNVs have been fixed by inbreeding, but they are highly variable among strains. Within strains, de novo germ-line CNVs can occur, leading to interindividual variation. By analyzing the genome of clonal isolates of mouse ES cells derived from common parental lines, we have uncovered extensive and recurrent CNVs. This variation arises during mitosis and can be cotransmitted into the mouse germ line along with engineered alleles, contributing to genetic variability. The frequency and extent of these genomic changes in ES cells suggests that all somatic tissues in individuals will be mosaics composed of variants of the zygotic genome. Human ES (hES) cells and derived somatic lineages may be similarly affected, challenging the concept of a stable somatic genome.

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Conflict of interest statement

The authors declare no conflict of interest.

Figures

Fig. 1.
Fig. 1.
A 1.5-Mb amplification in Chr.1 (CNV-1) detected in a germ-line-competent AB2.2 ES cell clone that was transmitted to its descendents. (A) CGH array analysis of the ES cell clone vs. the AB2.2 parental cells as control. (B) CGH array analysis of F1 generation mice vs. the same control.
Fig. 2.
Fig. 2.
Accumulation of CNVs in ES cells during rounds of single-cell cloning. (A) CNVs detected in AB2.2 ES cell clones. (B) CNVs in E14 ES cell clones. The clone ID corresponds to the ID in Tables S1 and S2. The CNV numbers detected in each clone are indicated. The filled colored squares indicate recurrent CNVs detected in different clones. CNV-2 and -30 are examples of CNVs shared between these clones.
Fig. 3.
Fig. 3.
Examples of recurrent CNVs in ES cells and mice. (A) CNV-28 that arose independently in subclones of 2 different parental ES cell lines. (B) CNVs detected in ES cell clones or fixed in different mouse strains. CNV-18 and -19 are adjacent and have the same breakpoints.
Fig. 4.
Fig. 4.
Genomic variation arising during ES cell culture. The parental cells (green) segregate variants (yellow, orange, and red). Clones with major chromosomal changes (red) cannot be transmitted into the mouse germ line and typically exhibit trisomies or multiple deletions or duplications. Some clones have a few small (1- to 2-Mb) CNVs that do not affect germ-line transmission. These CNVs may be transmitted into the mouse germ line along with an engineered allele.
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