Natural disease history of a canine model of oligogenic RPGRIP1-cone-rod dystrophy establishes variable effects of previously and newly mapped modifier loci

Canine model of RPGRIP1-cone-rod dystrophy (CRD) was originally identified as a monogenic autosomal recessive disease characterized by early-onset blindness in a research colony. However, subsequent studies in the broader canine population revealed extensive variability in disease onset among RPGRIP1 mutants. Further studies led to the identification of a genetic modifier, a MAP9 variant that gave rise to earlier disease onset among RPGRIP1 mutants. We now describe the mapping of L3, an additional modifier locus, based on phenotypic variation specific to cone photoreceptor function. A genome-wide association study and haplotype analysis mapped L3 to a 4.1-Mb locus on canine chromosome 30, and containing 49 genes, at least 38 of which were indicated in retinal expression. RNA-seq and whole genome sequencing did not find critical disease-causing genetic variant. However, filtering of moderate variants resulted in 11 missense variants as candidates for L3. We then established the natural d..., Libraries of 300 bp insert size was prepared, llumina HiSeq2500 paired-end reads, (2 × 100 bp, one lane per sample); Casava was used for the fastq preparation (https://bioweb.pasteur.fr/packages/pack@casava@1.8.2, v 1.8.2).,