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Abstract #85194 Published in IGR 21-1
Systems Genetics of Optic Nerve Axon Necrosis During Glaucoma
Stiemke AB; Sah E; Simpson RN; Lu L; Williams RW; Jablonski MMFrontiers in genetics 2020; 11: 31
In this study, we identify genomic regions that modulate the number of necrotic axons in optic nerves of a family of mice, some of which have severe glaucoma, and define a set of high priority positional candidate genes that modulate retinal ganglion cell (RGC) axonal degeneration. A large cohort of the BXD family were aged to greater than 13 months of age. Optic nerves from 74 strains and the DBA/2J (D2) parent were harvested, sectioned, and stained with p-phenylenediamine. Numbers of necrotic axons per optic nerve cross-section were counted from 1 to 10 replicates per genotype. Strain means and standard errors were uploaded into GeneNetwork 2 for mapping and systems genetics analyses (Trait 18614). The number of necrotic axons per nerve ranged from only a few hundred to more than 4,000. Using conventional interval mapping as well as linear mixed model mapping, we identified a single locus on chromosome 12 between 109 and 112.5 Mb with a likelihood ratio statistic (LRS) of ~18.5 ( genome-wide ~0.1). Axon necrosis is not linked to locations of major known glaucoma genes in this family, including , and . This indicates that although these genes contribute to pigmentary dispersion or elevated IOP, none directly modulates axon necrosis. Of 156 positional candidates, eight genes- (); (); (); (); (); (); (); and 9 ()-passed stringent criteria and are high priority candidates. Several candidates are linked to mitochondria and/or axons, strengthening their plausible role as modulators of ON necrosis. Additional studies are required to validate and/or eliminate plausible candidates. Surprisingly, IOP and ON necrosis are inversely correlated across the BXD family in mice >13 months of age and these two traits share few genes among their top ocular and retinal correlates. These data suggest that the two traits are independently modulated or that a more complex and multifaceted approach is required to reveal their association.
Department of Genetics, Genomics and Informatics, The University of Tennessee Health Science Center, Memphis, TN, United States.
Full articleClassification:
5.1 Rodent (Part of: 5 Experimental glaucoma; animal models)
3.4.2 Gene studies (Part of: 3 Laboratory methods > 3.4 Molecular genetics)
