Characterization of Vps13b-mutant mice reveals neuroanatomical and behavioral phenotypes with females less affected.

The vacuolar protein sorting-associated protein 13B (VPS13B) is a large and highly conserved protein. Disruption of VPS13B causes the autosomal recessive Cohen syndrome, a rare disorder characterized by microcephaly and intellectual disability among other features, including developmental delay, hypotonia, and friendly-personality. However, the underlying mechanisms by which VPS13B disruption leads to brain dysfunction still remain unexplained. To gain insights into the neuropathogenesis of Cohen syndrome, we systematically characterized brain changes in Vps13b-mutant mice and compared murine findings to 235 previously published and 17 new patients diagnosed with VPS13B-related Cohen syndrome. We showed that Vps13b is differentially expressed across brain regions with the highest expression in the cerebellum, the hippocampus and the cortex with postnatal peak. Half of the Vps13b-/- mice die during the first week of life. The remaining mice have a normal lifespan and display the core phenotypes of the human disease, including microcephaly, growth delay, hypotonia, altered memory, and enhanced sociability. Systematic 2D and 3D brain histo-morphological analyses reveal specific structural changes in the brain starting after birth. The dentate gyrus is the brain region with the most prominent reduction in size, while the motor cortex is specifically thinner in layer VI. The fornix, the fasciculus retroflexus, and the cingulate cortex remain unaffected. Interestingly, these neuroanatomical changes implicate an increase of neuronal death during infantile stages with no progression in adulthood suggesting that VPS13B promotes neuronal survival early in life. Importantly, whilst both sexes were affected, some neuroanatomical and behavioral phenotypes were less pronounced or even absent in females. We evaluate sex differences in Cohen patients and conclude that females are less affected both in mice and patients. Our findings provide new insights about the neurobiology of VPS13B and highlight previously unreported brain phenotypes while defining Cohen syndrome as a likely new entity of non-progressive infantile neurodegeneration.

Functional constraints channel mandible shape ontogenies in rodents.

In mammals, postnatal growth plays an essential role in the acquisition of the adult shape. During this period, the mandible undergoes many changing functional constraints, leading to spatialization of bone formation and remodelling to accommodate various dietary and behavioural changes. The interactions between the bone, muscles and teeth drive this developmental plasticity, which, in turn, could lead to convergences in the developmental processes constraining the directionality of ontogenies, their evolution and thus the adult shape variation. To test the importance of the interactions between tissues in shaping the ontogenetic trajectories, we compared the mandible shape at five postnatal stages on three rodents: the house mouse, the Mongolian gerbil and the golden hamster, using geometric morphometrics. After an early shape differentiation, by both longer gestation and allometric scaling in gerbils or early divergence of postnatal ontogeny in hamsters in comparison with the mouse, the ontogenetic trajectories appear more similar around weaning. The changes in muscle load associated with new food processing and new behaviours at weaning seem to impose similar physical constraints on the mandible, driving the convergences of the ontogeny at that stage despite an early anatomical differentiation. Nonetheless, mice present a rather different timing compared with gerbils or hamsters.

Commonalities and evolutionary divergences of mandible shape ontogenies in rodents.

In mammals, significant changes take place during postnatal growth, linked to changes in diet (from sucking to gnawing). During this period, mandible development is highly interconnected with muscle growth and the epigenetic interactions between muscle and bone control the spatialization of bone formation and remodelling in response to biomechanical strain. This mechanism contributes to postnatal developmental plasticity and may have influenced the course of evolutionary divergences between species and clades. We sought to model postnatal changes at a macroevolutionary scale by analysing ontogenetic trajectories of mandible shape across 16 species belonging mainly to two suborders of Rodents, Myomorpha and Hystricomorpha, which differ in muscle attachments, tooth growth and life-history traits. Myomorpha species present a much stronger magnitude of changes over a shorter growth period. Among Hystricomorpha, part of the observed adult shape is set up prenatally, and most postnatal trajectories are genus-specific, which agrees with nonlinear developmental trajectories over longer gestational periods. Beside divergence at large scale, we find some collinearities between evolutionary and developmental trajectories. A common developmental trend was also observed, leading to enlargement of the masseter fossa during postnatal growth. The tooth growth, especially hypselodonty, seems to be a major driver of divergences of postnatal trajectories. These muscle- and tooth-related effects on postnatal trajectories suggest opportunities for developmental plasticity in the evolution of the mandible shape, opportunities that may have differed across Rodent clades.

A GWAS in Latin Americans identifies novel face shape loci, implicating VPS13B and a Denisovan introgressed region in facial variation.

To characterize the genetic basis of facial features in Latin Americans, we performed a genome-wide association study (GWAS) of more than 6000 individuals using 59 landmark-based measurements from two-dimensional profile photographs and ~9,000,000 genotyped or imputed single-nucleotide polymorphisms. We detected significant association of 32 traits with at least 1 (and up to 6) of 32 different genomic regions, more than doubling the number of robustly associated face morphology loci reported until now (from 11 to 23). These GWAS hits are strongly enriched in regulatory sequences active specifically during craniofacial development. The associated region in 1p12 includes a tract of archaic adaptive introgression, with a Denisovan haplotype common in Native Americans affecting particularly lip thickness. Among the nine previously unidentified face morphology loci we identified is the VPS13B gene region, and we show that variants in this region also affect midfacial morphology in mice.