Biology subjects

Mellersh, C.

Publications and source records attributed to Mellersh, C..

3 recordsLinked to original sources

bioRxiv2026

Pedigree-tracking improved population monitoring of recessive disease-causing alleles in pedigreed canine populations

Background Most monogenic inherited diseases in dogs are recessive, so their successful control depends on genetic testing to identify carriers of the disease-causing allele. However, currently used methods for disease allele monitoring in canine populations typically only consider part of the entire pedigree, since not all dogs have a known genotype through genetic test or "hereditary status" (a determinable genotype assigned to offspring based on known parental genotypes). Methods This study uses probabilistic inference with unknown parent groups (UPGs) in five Royal Kennel Club (RKC)-registered pedigrees to estimate genotype probabilities for all individuals using available genetic test results for two monogenic recessive diseases: primary lens luxation (PLL) and progressive retinal atrophy rod-cone degeneration 4 (PRA-rcd4). From these estimates, the population trends in disease-causing allele frequencies were estimated, and the inference quality was assessed through leave-one-out cross-validation and simulation. Results For dogs born after the introduction of the genetic test, the estimated disease-causing allele frequencies differed between methods. For instance, dogs born in 2020 reported up to 0.092 higher disease-causing allele frequencies with estimated genotype probabilities than those based on genetic tests and hereditary status alone. Inference performance varied across breeds, dependent on population allele frequency, with Pearson correlations between true (per genetic test result) and estimated allele dosages ranging from 0.47 to 0.67. The gene drop simulations indicated a tendency to underestimate disease-causing allele frequencies in retrospective estimates, particularly for dogs born before 1990. Impact Overall, by leveraging all available pedigree and genetic test data through probabilistic pedigree-based inference, disease-causing allele frequencies were monitored more comprehensively within the pedigreed population rather than relying on genetic test results or hereditary status alone. Such monitoring can inform responsible breeding decisions, helping to conserve genetic diversity whilst supporting improvements in future canine health and welfare.

genetics↗

bioRxiv2025

Reproducibility of the evaluation of genetic variant pathogenicity based on the animal variant classification guidelines

Until recently, due to the absence of standardized guidelines tailored for veterinary use, the evaluation of genetic variant pathogenicity for single-gene diseases was based on a personal interpretation of the presented evidence, which has led to ambiguous interpretation. With the publication of the animal variant classification guidelines (AVCG), a more objective approach became available. Variants are evaluated based on twenty-three criteria and labeled as pathogenic, likely pathogenic, variant of uncertain significance, likely benign or benign. While the accuracy was thoroughly tested in the original publication, the reproducibility of the various steps involved was only briefly checked, which is why the current study was performed. Each variant from a set of 150 published likely causal variants for single-gene diseases from three species (dog, cat, horse) was independently and blindly assessed by three different reviewers, each applying the same AVCG. An overall agreement of 93% for decisions on the scope, i.e. whether they fit the inclusion criteria to allow evaluation with AVCG, was found. More importantly, the reproducibility was 65% for the pathogenicity classification and this increased to 83% clinically relevant agreement. While a direct comparison of the reproducibility with human literature is not possible for the scope, the reproducibility on pathogenicity classification is in line with reports using the human American College for Medical Genetics and Genomics and Association for Molecular Pathology guidelines for human variants. Overall, based on the current study, the reproducibility of the guidelines in veterinary species is within current expectations.

genetics↗

bioRxiv2018

An ABCA4 loss-of-function mutation causes a canine form of Stargardt disease

Autosomal recessive retinal degenerative diseases cause visual impairment and blindness in humans and dogs. Currently, no standard treatment is available but pioneering gene therapy-based canine models have been instrumental for clinical trials in humans. To study a novel form of retinal degeneration in Labrador retriever dogs with clinical signs indicating cone and rod degeneration, we used whole-genome sequencing of an affected sib-pair and their unaffected parents. A frameshift insertion in the ATP binding cassette subfamily A member 4 (ABCA4) gene (c.4176insC), leading to a premature stop codon in exon 28 (p.F1393Lfs1395) was identified. In contrast to unaffected dogs, no full-length ABCA4 protein was detected in the retina of an affected dog. The ABCA4 gene encodes a membrane transporter protein localized in the outer segments of rod and cone photoreceptors. In humans, the ABCA4 gene is associated with Stargardt disease (STGD), an autosomal recessive retinal degeneration leading to central visual impairment. A hallmark of STGD is the accumulation of lipofuscin deposits in the retinal pigment epithelium. The discovery of a canine homozygous ABCA4 loss-of-function mutation may advance the development of dog as a large animal model for human STGD.\n\nAuthor summaryStargardt disease (STGD) is the most common inherited retinal disease causing visual impairment and blindness in children and young adults, affecting 1 in 8-10 thousand people. For other inherited retinal diseases, the dog has become an established comparative animal model, both for identifying the underlying genetic causes and for developing new treatment methods.\n\nTo date, there is no standard treatment for STGD and the mouse model is the only available animal model to study the disease. As a nocturnal animal, the morphology of the mouse eye differs from humans and therefore the mouse model is not ideal for developing methods for treatment. We have studied a novel form of retinal degeneration in Labrador retrievers showing clinical signs similar to human STGD. To investigate the genetic cause of the disease, we used whole-genome sequencing of a family quartet including two affected offspring and their unaffected parents. This led to the identification of a loss-of-function mutation in the ABCA4 gene. The findings of this study may enable the development of a canine model for human STGD.

genetics↗