Genetic Analysis of Substrain Divergence in NOD Mice

ABSTRACTThe NOD mouse is a polygenic model for type 1 diabetes that is characterized by insulitis, a leukocytic infiltration of the pancreatic islets. During ~35 years since the original inbred strain was developed in Japan, NOD substrains have been established at different laboratories around the world. Although environmental differences among NOD colonies capable of impacting diabetes incidence have been recognized, differences arising from genetic divergence have not previously been analyzed. We use both Mouse Diversity Array and Whole Exome Capture Sequencing platforms to identify genetic differences distinguishing 5 NOD substrains. We describe 64 SNPs, and 2 short indels that differ in coding regions of the 5 NOD substrains. A 100 kb deletion on Chromosome 3 distinguishes NOD/ShiLtJ and NOD/ShiLtDvs from 3 other substrains, while a 111 kb deletion in the Icam2 gene on Chromosome 11 is unique to the NOD/ShiLtDvs genome. The extent of genetic divergence for NOD substrains is compared to similar studies for C57BL6 and BALB/c substrains. As mutations are fixed to homozygosity by continued inbreeding, significant differences in substrain phenotypes are to be expected. These results emphasize the importance of using embryo freezing methods to minimize genetic drift within substrains and of applying appropriate genetic nomenclature to permit substrain recognition when one is used.