Abstract
Determining the genetic bases of age-related disease remains a major challenge requiring a spectrum of approaches from human and clinical genetics to the utilization of model organism studies. Here we report a large-scale genetic screen in mice employing a phenotype-driven discovery platform to identify mutations resulting in age-related disease, both late-onset and progressive. We have utilized N-ethyl-N-nitrosourea mutagenesis to generate pedigrees of mutagenized mice that were subject to recurrent screens for mutant phenotypes as the mice aged. In total, we identify 105 distinct mutant lines from 157 pedigrees analysed, out of which 27 are late-onset phenotypes across a range of physiological systems. Using whole-genome sequencing we uncover the underlying genes for 44 of these mutant phenotypes, including 12 late-onset phenotypes. These genes reveal a number of novel pathways involved with age-related disease. We illustrate our findings by the recovery and characterization of a novel mouse model of age-related hearing loss.
Highlights
Determining the genetic bases of age-related disease remains a major challenge requiring a spectrum of approaches from human and clinical genetics to the utilization of model organism studies
We demonstrate that this is a successful approach for identifying mouse mutants with late-onset phenotypes, and importantly find that these mutant models reveal a significant number of novel genes and pathways involved with such diseases
Our studies revealed a mutation in the aggrecan (Acan) gene in pedigree MPC-227, causing an A1946V substitution in the C-type-lectin domain, which results in late-onset joint deterioration and obesity, both novel phenotypic associations with this locus (Supplementary Fig. 2)
Summary
We detected between 0.58 and 1.22% phenodeviance, suggesting a low average FPR of 0.71% across the procedures examined (Supplementary Table 1) Categorical data, such as X-ray abnormalities, were scored as potential mutants when observed in multiple affected G3 mice (Z3) in a pedigree. We have either uncovered a gene for which there was no prior functional information, or alternatively, we have assigned novel functionality to a gene with known functions For these mutants there is only a single medium or high-confidence coding mutation in the minimal mapping region and for laminin alpha 5 (Lama5) and tryptophanyl tRNA synthetase 2, mitochondrial (Wars2) (pedigrees MPC-205 and MPC-151, respectively) we have carried out complementation studies using a knockout (KO) allele to confirm these mutations as the causative allele (Table 3). MPC-201 Vision (a) Progressive (a) Z12 reduction in (b) Z12 visual acuity (b) Retinal degeneration
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have