AUTHOR=Chen Jing , Li Renhua , Knapp Sarah , Zhu Guizhi , Whitener Robert L. , Leiter Edward H. , Mathews Clayton E. 

TITLE=Intergenomic and epistatic interactions control free radical mediated pancreatic β-cell damage

JOURNAL=Frontiers in Genetics

VOLUME=13

YEAR=2022

URL=https://www.frontiersin.org/journals/genetics/articles/10.3389/fgene.2022.994501

DOI=10.3389/fgene.2022.994501

ISSN=1664-8021

ABSTRACT=<p>Alloxan (AL)-generated Reactive Oxygen Species (ROS) selectively destroy insulin-producing pancreatic β-cells. A previous genome-wide scan (GWS) using a cohort of 296 F2 hybrids between NOD (AL-sensitive) and ALR (AL-resistant) mice identified linkages contributing to β-cell susceptibility or resistance to AL-induced diabetes on Chromosomes (Chr) 2, 3, 8, and a single nucleotide polymorphism in <italic>mt-Nd2</italic> of the mitochondrial genome (mtDNA). AL treatment of congenic and consomic NOD mouse stocks confirmed resistance linked to both the mtDNA and the Chr 8 locus from ALR [NOD.mt<sup>ALR</sup>.ALR-(<italic>D8Mit293-D8Mit137</italic>)]. To identify possible epistatic interactions, the GWS analysis was expanded to 678 F2 mice. ALR-derived diabetes-resistance linkages on Chr 8 as well as the <italic>mt-Nd2</italic><sup><italic>a</italic></sup> allele were confirmed and novel additional linkages on Chr 4, 5, 6, 7, and 13 were identified. Epistasis was observed between the linkages on Chr 8 and 2 and Chr 8 and 6. Furthermore, the <italic>mt-Nd2</italic> genotype affected the epistatic interactions between Chr 8 and 2. These results demonstrate that a combination of nuclear-cytoplasmic genome interactions regulates β-cell sensitivity to ROS-mediated ALD.</p>