McCallum, R. | Search bioRxiv

bioRxiv2026

Synonymous HTT CAA/CCA-loss variants associated with early Huntington disease onset enhance toxicity beyond somatic instability

Huntington disease is a fatal neurodegenerative disorder caused by CAG repeat expansion encoding polyglutamine in the HTT gene. Recent studies have shown that loss of CAA/CCA interruptions within polyglutamine-coding CAG tracts and adjacent polyproline-coding region are linked to earlier disease onset. It has been hypothesized that somatic repeat instability, influenced by these interrupted CAG tracts, may mediate this effect. Here we demonstrate that HTT CAA/CCA-loss variant linked to early disease onset exacerbates mutant HTT toxicity in cellular models through mechanisms independent of somatic repeat instability. The CAA/CCA-loss variant exhibits significantly higher toxicity than canonical HTT sequences in both transient expression and stable cell line models. Notably, this enhanced toxicity persists in knockout cells of the mismatch repair gene MSH3 where somatic instability is blunted, with a consistent toxicity hierarchy (CAA/CCA-loss > CCA-loss > CAA-loss > canonical HTT) in both wildtype and MSH3 knockout cells. Furthermore, the CAA/CCA-loss variant generates elevated levels of repeat-associated non-AUG (RAN) translation products. In HEK293-based cellular models, these results suggest that the disease-accelerating effects of HTT CAA/CCA-loss variants involve intrinsic properties of the altered sequence context, highlighting the importance of understanding sequence-specific mechanisms in HD pathogenesis beyond polyglutamine length and somatic instability.

genetics↗

bioRxiv2020

Honey bee queen production: Canadian costing case study and profitability analysis

The recent decline in honey bee (Hymenoptera: Apidae) colony health worldwide has had a significant impact on the beekeeping industry as well as on pollination-dependent crop sectors in North America and Europe. The pollinator crisis has been attributed to many environmental and anthropological factors including less nutrient rich agricultural monocultures, pesticide exposure, new parasite and pathogen infestations as well as beekeeper management and weather. Canadian beekeepers have indicated that issues with honey bee queens are the most significant factor affecting their colony health. In Canada, beekeepers manage colony losses by relying on the importation of foreign bees, particularly queens from warmer climates, to lead new replacement colonies. Unfortunately, the risks associated with imported queens include the introduction of new and potentially resistant pests and diseases, undesirable genetics including bees with limited adaptations to Canadas unique climate and bees negatively affected by transportation. Importing a large proportion of our queens each year also creates an unsustainable dependency on foreign bee sources, putting our beekeeping and pollination sectors at an even greater risk in the case of border closures and restrictions. Increasing the domestic supply of queens is one mitigation strategy that could provide Canadian beekeepers, farmers and consumers with a greater level of agricultural stability through locally bred, healthier queens. Our study is the first rigorous analysis of the economic feasibility of Canadian queen production. We present the costs of queen production for three case study operations across Canada over two years as well as the profitability implications. Our results show that for a small to medium sized queen production operation in Canada, producing queen cells and mated queens can be profitable. Using a mated queen market price ranging from $30 to $50, a producer selling mated queens could earn a profit of between $2 and $40 per queen depending on price and the cost structure of his operation. If the producer chose to rear queens for his own operation, the cost savings would also be significant as imported queen prices continue to rise. Our case studies reveal that there is potential for both skilled labour acquisition over time in queen production as well as cost savings from economies of scale. Our queen producers also reduced their production costs by re-using materials year to year. Domestic queen production could be one viable strategy to help address the current pollinator crisis in Canada.

ecology↗