Differences in Frequency of Occurrence and Type of Mutation in Embryonic Stem Cells and Somatic Cells

Rachel B. Cervantes and Peter J. Stambrook, Ph.D.
University of Cincinnati
P01ES05652, P30ES06096, and T32ES07250

Background: The impact of environmental chemicals upon human health and well being is well documented, especially in the areas of carcinogenesis and mutagenesis. However, the effects of these chemicals and agents and their potential to cause mutagenicity in embryonic stem cells are not well known. Stem cells have been used to create a number of genetically modified species as experimental models of human genetic diseases. They are increasingly being considered for their potential in the treatment of human injury and disease. The types of mutations and their frequency of occurrence may have impacts on the future clinical uses of stem cells. These researchers have examined the spontaneous and induced mutagenic events in stem cells using a mouse model that is heterozygous for a marker encoding the enzyme adenine phosphoribosyltransferase (APRT).

Advance: These studies show that stem cells have significantly fewer mutations than mouse embryonic fibroblasts which is similar to adults cells in vivo. The distribution of spontaneous mutagenic events is very different between the two cell types. Loss of the functional allele is the major mutation type in both cell types; however, mitotic recombination accounted for all loss of heterozygosity detected in somatic cells. Mitotic recombination in stem cells was suppressed and chromosome loss/reduplication represented more that half of the loss of heterozygosity events. Long-term culture of the stem cells led to accumulation of cells with adenine phosphoribosyltransferase deficiency and uniparental disomy (UPD).

Implication: Because UPD allows all recessive genes on a given chromosome to be expressed, possibly leading to increased incidences of harmful recessive traits, the accumulation of UPD in cultured stem cells raises concerns regarding the clinical use of stem cells maintained in continuous culture. This concern does not necessarily argue against the therapeutic use of embryonic stem cells but indicates the need for screening such cultures to ensure the absence of UPD.

Citation: Cervantes RB, Stringer JR, Shao C, Tischfield JA, Stambrook PJ. Embryonic stem cells and somaticcells differ in mutation frequency and type. Proc Natl Acad Sci U S A. 2002 Mar 19;99(6):3586-90.