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Biology subjects

Scandura, M.

Publications and source records attributed to Scandura, M..

3 recordsLinked to original sources

Wolves in black: multiple introgressions and natural selection may explain melanism in Italian wolves

Hybridisation between wild and domestic taxa can favour the spread of domestic alleles into wild populations through backcrossing. The complex interplay of random genetic drift, recombination, and selection can shape the fate of introgressed alleles. Maladaptive domestic variants are likely to be purged by natural selection, but others may persist across generations. It has long been known that the Apennine Italian wolf population, exposed to large numbers of free-ranging dogs, has experienced extensive introgression. The unusually high frequency of black wolves observed in Italy, compared to other European populations, may parallel patterns documented in North American wolves, where the melanistic KB allele at the CBD103 gene, of domestic origin, has spread over thousands of years of introgression. We tested whether the KB mutation entered the peninsular Italian wolf population via hybridisation and spread through adaptive introgression. Genome-wide analyses of black and wild-type (grey-coated) Apennine wolves showed no clear signatures of recent dog ancestry in most melanistic animals. Our ancestry reconstruction approaches identified two distinct KB haplogroups of domestic origin, suggesting multiple introgression events. Notably, we found molecular evidence consistent with balancing selection on the KB haplotypes, whose functional role, nonetheless, warrants further research. Therefore, the microevolutionary genomic and ecological consequences of wolf-dog hybridisation in Italy should be carefully investigated to inform appropriate science-based conservation management strategies.

genomics↗

Dysregulation of Hippo Signaling Pathway as a Convergent Mechanism Underlying Choroid Plexus Defects in Bipolar Disorder

Bipolar disorder (BD) is a prevalent and highly heritable psychiatric condition. Developmental mechanisms are implicated but the specific molecular origins remain unclear. The choroid plexus (ChP), which regulates cerebrospinal fluid (CSF) and brain homeostasis, has been implicated in BD, but its role is poorly understood. Here, we identify aberrant expansion of ChP in human cortical (hCOs) and ChP organoids (hChPOs) derived from, and in vivo structural magnetic resonance imaging (sMRI) scans of, individuals with BD compared to healthy comparison individuals. Single-cell transcriptomics revealed a lineage bias toward ChP fate in BD hCOs, accompanied by structural enlargement observed in both BD hChPOs and ChP in sMRI scans from individuals with BD. Comprehensive transcriptomic profiling implicates early hyperactivation of the Hippo signaling pathway in neural progenitor cells as a convergent mechanism driving ChP overgrowth. Whole-genome and genome-wide association study analyses highlight recurrent genetic variants in Hippo regulators, including STK4 and YAP1, suggesting genetic priming. BD hChPOs exhibit disrupted epithelial junctions and altered in vitro CSF secretion. These findings position the ChP as a genetically and developmentally predisposed to pathology in BD and highlight organoids as a platform for translational discovery in diagnostics and therapeutics.

developmental biology↗

Expression of NMNAT1 in the Photoreceptors is Sufficient to Prevent NMNAT1-Associated Disease

Nicotinamide nucleotide adenylyltransferase 1 (NMNAT1) is a ubiquitously expressed enzyme involved in nuclear NAD+ production throughout the body. However, mutations in the NMNAT1 gene lead to retina-specific disease with few reports of systemic effects. We have previously demonstrated that AAV-mediated gene therapy using self-complimentary AAV (scAAV) to ubiquitously express NMNAT1 throughout the retina prevents retinal degeneration in a mouse model of NMNAT1-associated disease. We aimed to develop a better understanding of the cell types in the retina that contribute to disease pathogenesis in NMNAT1-associated disease, and to identify the cell types that require NMNAT1 expression for therapeutic benefit. To achieve this goal, we treated Nmnat1V9M/V9M mice with scAAV using cell type-specific promoters to restrict NMNAT1 expression to distinct retinal cell types. We hypothesized that photoreceptors are uniquely vulnerable to NAD+ depletion due to mutations in NMNAT1. Consistent with this hypothesis, we identified that treatments that drove NMNAT1 expression in the photoreceptors led to preservation of retinal morphology. These findings suggest that gene therapies for NMNAT1-associated disease should aim to express NMNAT1 in the photoreceptor cells.

molecular biology↗