Macdonald, K. | Search bioRxiv

bioRxiv2026

The crabeater seal reference genome reveals hallmarks of persistently large effective population size and sustained population expansion in the World's most abundant pinniped

Population genetic theory predicts that a species demographic history shapes patterns of genome-wide variation. However, conservation genomic studies have disproportionately focused on small or declining species, where low genetic diversity and inbreeding are major concerns, while highly abundant species have attracted comparatively less attention. Here, we investigate the crabeater seal (Lobodon carcinophaga) which, despite being one of the most numerous large mammals on Earth, remains largely uncharacterised in terms of its genomic diversity and demographic history. We assembled a high-quality crabeater seal reference genome from a combination of Illumina and PacBio HiFi reads, generating a 2.44 Gb assembly spanning 138 scaffolds with high completeness. To evaluate genomic diversity in a comparative context, we whole-genome resequenced 20 crabeater seals alongside 20 individuals each of three Antarctic phocids spanning a population size gradient: the Weddell seal (Leptopnychotes weddellii), leopard seal (Hydrurga leptonyx) and southern elephant seal (Mirounga leonina). Crabeater seals carried 61.5 million SNPs compared to 12-16 million in the other species and exhibited markedly higher nucleotide diversity and negligible genomic inbreeding. We observed an excess of rare alleles, with nearly half of all variants segregating at frequencies below 5%. Demographic reconstruction revealed persistently large effective population sizes over the past million years and sustained population expansion, paralleling inferred increases in Antarctic krill associated with sea-ice expansion during the late Pleistocene. This study provides a new genomic resource and sheds new light on the evolutionary dynamics of the worlds most abundant pinniped.

genomics↗

bioRxiv2025

Remodelling of supernumerary leaflet primordia leads to bicuspid aortic valve (BAV) caused by loss of primary cilia

AimsBicuspid aortic valve (BAV), where two valve leaflets are found instead of the usual three, affects 1-2% of the general population and is associated with significant morbidity and mortality. Despite its frequency, the majority of cases remain unexplained. This is, at least in part, because there are two types of valve leaflet primordia: endocardial cushions and intercalated valve swellings (ICVS). Moreover, multiple progenitors make distinct contribution to the formation of these primordia. Genomic studies in mouse and human have suggested a correlation between BAV and malfunctional primary cilia. However, the precise requirement for cilia during early embryonic valvulogenesis remains unknown. Methods and resultsHere, we disrupted primary cilia by deleting the ciliary gene Ift88 in the main progenitor cells forming the aortic valve using specific Cre drivers: Wnt1-Cre for neural crest cells, Isl1-Cre for second heart field cells (SHF); Tie2-Cre for endocardial-derived cells and Tnnt2-Cre for direct-differentiating SHF in the ICVS. Loss of Ift88, and thus primary cilia, from neural crest cells and endocardium did not impact aortic valve formation. However, primary cilia are essential in SHF cells for aortic valve leaflet formation, with over half of Ift88f/f;Isl1-Cre mutants presenting with BAV. As the valve leaflets are forming, 50% of the Ift88f/f;Isl1-Cre mutants have two small leaflets in the position of the usual posterior leaflet, meaning that at this stage the aortic valve is quadricuspid, which then remodels to BAV by E15.5. Mechanistic studies demonstrate premature differentiation of SHF cells as the ICVS form, leading to the formation of a broadened ICVS that forms two posterior leaflet precursors. This abnormality in the formation of the ICVS is associated with disruption of Notch-Jag1 signalling pathway, with Jag1f/f;Isl1-Cre mutants presenting with a similar phenotype. ConclusionsThese data show that primary cilia, via the Notch-Jag1 signalling pathway, regulate differentiation of SHF cells in the aortic valve primordia. Additionally, we identify a mechanistic link between the developmental basis of quadricuspid and bicuspid arterial valve leaflets. Translational PerspectiveSeveral genomic studies in human and mouse have suggested that disruption of cilia-related genes may be a significant cause of CHD. Although there is limited data from animal models to suggest a link between cilia and bicuspid aortic valve (BAV), the mechanisms underpinning BAV formation during early valvulogenesis have not been described. Here, we established a potential mechanism underpinning BAV formation, highlighting a role for primary cilia in a subset of valve interstitial cells (VIC) derived from second heart field progenitors. Loss of cilia altered VIC differentiation and valvulogenesis. This study confirms that disruption of cilial formation and/or function can lead to arterial valve defects and could pave the way to finding therapies for patient benefit.

developmental biology↗