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COSEGREGATION OF CD14 LOCUS AND POLYMORPHIC ALLELES OF GLUCOCORTICOID RECEPTOR AND PROTOCADHERINS INTO CD14 KNOCKOUT MOUSE GENOME

Targeted mutagenesis technology has been used to investigate the biological characteristics of genes. We incidentally observed a discrepancy in the size of the glucocorticoid receptor (GCR) between CD14 knockout (KO) mice and backcross controls. The CD14 KO mice were generated using 129S4/SvJae-derived J1 embryonic stem cells, C57BL/6J donor blastocysts, and C57BL/6J backcross strain. In this study, the extent of genomic heterogeneity of the CD14 KO mice, potentially affecting their phenotype, was characterized in comparison to C57BL/6J controls. There were polymorphic alleles of the GCR gene in CD14 KO and C57BL/6J mice: a tandem repeat of 8 CAGs and 17 CAGs in the transactivation domain, respectively. The subsequent finding of eight CAGs in all 129 substrains examined and colocalization of CD14 and GCR genes on the same contig on chromosome 18 suggested that the GCR allele in the J1 embryonic stem cell genome cosegregated with the targeted CD14 locus. Interestingly, all three clusters of the protocadherin family, central genes in determining neuronal networks, were mapped between the CD14 and GCR loci. Further analyses revealed numerous nonsynonymous coding single-nucleotide polymorphisms within the protocadherin family between CD14 KO and C57BL/6J mice. In addition, heterogeneous profiles of endogenous retroviruses, which constitute approximately 10% of the genome, were observed between them. These findings suggest that cosegregation of genes flanking the targeted locus leads to a substantial level of genetic heterogeneity in CD14 KO mice compared with their backcross controls. Phenotypic changes observed in some KO mice may not be as definitive as expected.