Biology subjects

Coveney, C. R.

Publications and source records attributed to Coveney, C. R..

5 recordsLinked to original sources

bioRxiv2026

Evolutionary trade-offs between growth and reproduction under obesogenic conditions: sex-biased skeletal and gonadal maturation in mice

Adolescence is a brief period during which finite energy resources are reallocated from linear growth toward reproductive maturation. Rising childhood obesity and earlier onset of puberty suggest that modern, energy rich diets may distort these evolved energy allocation rules, but causal mechanisms remain unclear. Here, we expose male and female wild-type and leptin receptor deficient (Db/Db) to either high fat or normal chow diets. We longitudinally analyze metabolic, skeletal, gonadal, endocrine and insulin-receptor phenotypes from 4-10 weeks of age (sexual maturation window in mice). In WT males, HFDs increased adiposity and impaired glucose tolerance, and selectively remodeled joint morphology, advanced gonadal maturation, and shifted insulin receptor expression from growth plates to testes. Together, these changes indicate a rebalancing of energy use toward reproduction at the expense of skeletal and metabolic health. WT females showed subtler systemic metabolic disruption but clear diet-responsive changes in growth plate and ovarian maturation. Our findings indicate that energy-rich diets during adolescence shift evolved allocation rules to prioritize reproductive readiness over skeletal robustness in a sex-dependent manner, with potential consequences for precocious puberty and bone health in humans.

evolutionary biology↗

bioRxiv2025

Massively parallel functional screen identifies thousands of regulatory differences in human versus chimpanzee postcranial skeletal development

Every element of the human skeleton exhibits some differences in comparison to our closest living relatives, chimpanzees. Many of these skeletal modifications underpin key events in human evolution, enabling our species to walk upright, manipulate tools with precision, and support enlarged brains. Identifying the genomic changes that underlie these features remains an outstanding challenge due to the substantial number of differences between the human and chimpanzee genomes. To identify human-chimp sequence differences that modulate gene expression in the developing postcranial skeleton, we used a massively parallel reporter assay (MPRA) to screen the human and chimp versions of 70,000 regulatory elements present in the prenatal skeletal template for differential activity. After testing our library in two cartilage and one bone marrow-derived lymphoblast line, we identify 30,736 regions (45.2%) with activity in our assay. Of the active regions, we find that 11,542 (37.6%; or 17% of the entire pool) regions exhibited differential activity between the human and chimpanzee. We find that human ancestor quickly evolved regions (HAQERs) were predictive of differential activity while Human Accelerated Regions were not and both sets failed to predict the magnitude of effect, unlike the total number of base pair differences between species, which was weakly correlated with effect size. These findings reveal that human skeletal evolution involves widespread regulatory changes distributed across thousands of elements rather than concentrated effects at a few key loci, supporting a polygenic model for the evolution of complex morphological traits.

evolutionary biology↗

bioRxiv2024

Complex regulatory interactions at GDF5 shape joint morphology and osteoarthritis disease risk

Our ability to pinpoint causal variants using GWAS is dependent on understanding the dynamic epigenomic and epistatic context of each associated locus. Being the best studied skeletal locus, GDF5 associates with many diseases and has a complex cis-regulatory architecture. We interrogate GDF5 regulatory interactions and model disease variants in vitro and in vivo. For all regulatory regions we see that local epigenetic activation/repression impacts patterns of joint-specific expression and disease risk. By modeling the most cited risk variant in mice we found that it had no impact on expression, joint morphology, or disease. Yet, we identified significant epistatic expression interactions between this risk variant and others lying within regulatory regions subject to repression or activation. These findings are important lessons on how regulatory interactions and local epistasis work in the etiology of disease risk, and that assessment of individual variants of high GWAS significance need not alone be considered causal. TeaserGenetic interactions at the most studied skeletal disease locus reveal hidden complexities in pinpointing causal mutations.

genetics↗

bioRxiv2021

Ciliary IFT88 safeguards coordinated epiphyseal vascularisation, resorption and ossification from disruptive physiological mechanical forces

In the musculoskeletal system, appropriate cell and tissue responses to mechanical force delineate morphogenesis and ensure lifelong health. Despite this, how mechanical cues are integrated into biological programmes remains unclear. Primary cilia are microtubule-based organelles that tune a range of cell activities, including signalling cascades activated or modulated, by extracellular biophysical cues. Here, we demonstrate that the inducible, cartilage-specific deletion of Intraflagellar transport protein 88 (IFT88), which reduces ciliation in the adolescent mouse growth plate (GP), uncouples chondrocyte differentiation from cartilage resorption and mineralisation in a mechano-dependent manner. Targeting IFT88, inhibits hypertrophic chondrocyte VEGF expression, vascular recruitment, osteoclastic activity and the replacement of cartilage with bone. These effects are largely restricted to peripheral tibial regions beneath the load-bearing compartments of the knee. Increases in physiological loading, in control mice, also impairs ossification in the peripheral GP, mimicking the effects of IFT88 deletion. Strikingly, limb immobilisation rescues disrupted VEGF and restores epiphyseal dynamics in Ift88cKO mice. These data indicate, that during this pivotal phase in adolescent skeletal maturation that defines the cessation of growth, ciliary IFT88 protects the coordinated ossification of the growth plate from an otherwise disruptive heterogeneity of physiological mechanical forces.

physiology↗

bioRxiv2020

The ciliary protein IFT88 controls post-natal cartilage thickness and influences development of osteoarthritis.

Mechanical and biological cues drive cellular signalling in cartilage development, health, and disease. Proteins of the primary cilium, implicated in transduction of biophysiochemical signals, control cartilage formation during skeletal development, but their influence in post-natal cartilage remains unknown. Ift88fl/fl and AggrecanCreERT2 mice were crossed to create a cartilage-specific, inducible knockout mouse AggrecanCreERT2;Ift88fl/fl. Tibial articular cartilage (AC) thickness was assessed, through adolescence and adulthood, by histomorphometry and integrity by OARSI score. In situ mechanisms were investigated by immunohistochemistry (IHC), RNA scope and qPCR of micro-dissected cartilage. OA was induced by surgical destabilisation (DMM). Mice voluntarily exercised using wheels. Deletion of IFT88 resulted in progressive reductions in medial AC thickness during adolescence, and marked atrophy in adulthood. At 34 weeks of age, medial thickness was reduced from 104.00m, [100.30-110.50, 95% CI] in Ift88fl/fl to 89.42m [84.00-93.49, 95% CI] in AggrecanCreERT2;Ift88fl/fl (p<0.0001), associated with reductions in calcified cartilage. Occasionally, atrophy was associated with complete, spontaneous, medial cartilage degradation. Following DMM, AggrecanCreERT2;Ift88fl/fl mice had increased OA scores. Atrophy in mature AC was not associated with obvious increases in aggrecanase-mediated destruction or chondrocyte hypertrophy. Ift88 expression positively correlated with Tcf7l2, connective tissue growth factor (Ctgf) and Enpp1. RNA scope revealed increased hedgehog (Hh) signalling (Gli1), associated with reductions in Ift88, in AggrecanCreERT2;Ift88fl/fl cartilage. Wheel exercise restored both AC thickness and levels of Hh signalling in AggrecanCreERT2;Ift88fl/fl. Our results demonstrate that IFT88 is chondroprotective, regulating AC thickness, potentially by thresholding a Hh response to physiological loading that controls cartilage calcification.

molecular biology↗