Evaluation of two mouse models of high genetic variation for suitability to test a heterozygote instability hypothesis
Abstract
Characterization of genetic variation underlying complex phenotypes is incomplete yet critical to understanding mutational mechanisms and phenotypes. Heterozygote Instability (HI) is a new, poorly understood source of mutations needing models for mechanistic study. Two models ideal for characterizing HI-associated mutational mechanisms are outbred mice and mouse basal cell carcinoma (BCC). Both have discontinuous landscapes of heterozygosity essential to assess HI-induced mutations. Here, heterozygosity and copy number variants (CNVs) in two outbred mouse stocks are characterized with 1690, and 3935 autosomal CNVs detected. A positive correlation exists between chromosomal heterozygosity and CNV occurrence (R2 = 0.14 and 0.09), and 41 and 22% of CNVs co-localized with heterozygosity. Genetic variation in human BCC is documented to target characterization in mouse BCC toward filling an identified knowledge gap. An outbred BCC mouse model permits HI hypothesis testing in contexts of meiosis, mitosis, replication, and recombination in gametes, stem cells, and cancer cells.