Gene function & annotation

Functional and Mechanistic Validation of L-LCORL Truncation Variants Driving Increased Growth Across Species

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Abstract

The genomic region encompassing LCORL has long been identified as a major QTL influencing growth and body size across many species. Recently, truncating variants in the long isoform of LCORL (L-LCORL) have been reported as potentially causative. Given the cross-species conservation of the effects of LCORL, and to further validate the causative role of these truncating variants, we created a gene-edited mouse line carrying a mutation orthologous to the naturally occurring frameshift mutation in cattle. A cohort of 120 mice, balanced by sex and genotype (wild-type, heterozygous, and homozygous) were weighed weekly starting at 21 days of age. At 77 days, mice were sacrificed to collect carcass phenotypes and tissues were harvested for RNA sequencing.L-LCORL truncated mice recapitulate the growth phenotype observed across species, exhibiting a 16% increase in growth rate (p = 1.625e-7) during their peak growth period, and an 11% increase in final body size (p = 1.511e-13) compared to their wild-type contemporaries. Carcass phenotypes demonstrated a larger frame size; body and leg lengths had effect sizes that rivaled the difference between males and females (2-4%, p p Initial molecular analyses focused on hypothalamic tissue because LCORL is highly expressed in the ventromedial hypothalamus, a region critical for regulating energy balance and somatic growth. RNA-seq analysis revealed several differentially expressed genes relevant to growth and feed intake behaviors. Notably, Bche, a protein that degrades ghrelin, was upregulated (q = 0.002, logFC = 1.13), suggesting reduced ghrelin activity. Other feeding-related genes including Nts (q = 0.002) and Ppp1r9b (q = 0.032) were also differentially expressed. Gene set enrichment analysis supported these results, showing significant positive enrichment of biological processes such as 'response to nutrient' and 'regulation of response to nutrient', and significant negative enrichment of 'feeding behavior' (adjusted p Our findings confirm that truncating variants in L-LCORL are causative for increased growth and indicate that LCORL acts within the hypothalamus to influence growth, potentially through altered ghrelin signaling and enhanced IGF pathway activity. These naturally segregating variants in livestock populations offer a valuable opportunity to improve growth performance and feed efficiency. Incorporating genotyping for these variants could enable more precise selection decisions and inform nutritional management strategies aligned with an animal's genetic potential for growth.

Keywords: 2026

How to Cite:

Majeres, L., Freeman, T. & Beever, J., (2026) “Functional and Mechanistic Validation of L-LCORL Truncation Variants Driving Increased Growth Across Species”, World Congress on Genetics Applied to Livestock Production Digital Archive 2026(1): 2287250. doi: https://doi.org/10.31274/wcgalp.24248

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