Kristan, A. | bioRxiv Science

bioRxiv2026

Novel EGLN1 variants identified in patients with erythrocytosis: a functional study

Erythrocytosis, a disorder with increased erythrocyte production, has a heterogeneous aetiology, including rare congenital types linked to dysregulation of the oxygen-sensing pathway. Variants in the EGLN1 gene, encoding the prolyl hydroxylase that regulates hypoxia-inducible factor (HIF) stability, are associated with familial erythrocytosis type 3 (ECYT3). In patients with idiopathic erythrocytosis we previously identified two novel EGLN1 variants, c.1072C>T (p.(Pro358Ser)) and c.1124A>G (p.(Glu375Gly)), classified as variants of uncertain significance. Herein, we performed in silico and in vitro analyses to assess their structural and functional effects, using the known pathogenic variant p.(His374Arg) as a positive control. AlphaFold3 predictions revealed minimal conformational changes in the protein core for all variants, while stability predictions suggested reduced protein stability. Functional assays in HEK293 cells demonstrated significantly decreased protein levels and stability for p.(Pro358Ser) and p.(Glu375Gly), comparable to p.(His374Arg). However, luciferase reporter assays showed that, unlike p.(His374Arg), the novel variants did not substantially impair EGLN1 enzymatic activity or activate HIF signalling. Our results suggest that the novel variants may contribute to erythrocytosis through destabilization of EGLN1, supporting further studies to elucidate their precise impact on hypoxia regulation. This study highlights the complexity of studying EGLN1 variants and the importance of functional evaluation for clinical interpretation.

Molecular Biology↗

bioRxiv2022

Like mother, like daughter? Phenotypic plasticity, environmental covariation, and heritability of size in a parthenogenetic wasp

Dinocampus coccinellae (Hymenoptera:Braconidae, Euphorinae) is a solitary, generalist Braconid parasitoid wasp that reproduces through thelytokous parthenogenesis, an asexual process in which diploid daughters emerge from unfertilized eggs, and parasitizes over fifty diverse species of coccinellid ladybeetles worldwide as hosts. Here we utilized a common garden and reciprocal transplant experiment using parthenogenetic lines of D. coccinellae presented with three different host ladybeetle species of varying sizes, across multiple generations to investigate heritability, plasticity, and environmental covariation of body size in D. coccinellae. We expected positively correlated parent-offspring parasitoid regressions, indicative of heritable size variation, from unilineal (parent and offspring reared on same host species) lines, since these restrict environmental variation in phenotypes. In contrast, because multilineal (parent and offspring reared on different host species) lines would induce phenotypic plasticity of clones reared in varying environments, we expected negatively correlated parent-offspring parasitoid regressions. Our results indicate (1) little heritable variation in body size, (2) strong independence of offspring size on the host environment, (3) a consistent signal of size-host tradeoff wherein small mothers produced larger offspring, and vice versa, independent of host environment. We then model the evolution of size and host-shifting under a constrained fecundity advantage model of Copes Law using a Hidden Markov Model, showing that D. coccinellae likely has considerable fitness advantage to maintain phenotypic plasticity in body size despite parthenogenetic reproduction.

evolutionary biology↗