Silva, D. M. | Search bioRxiv

bioRxiv2026

Rapid chromosomal rearrangements and sex chromosome turnover underlie the evolution of parapatric Pacific Scomber mackerels

Teleost display remarkable species diversity despite relatively conserved karyotypes, suggesting an important role for chromosomal rearrangements in speciation. Yet this hypothesis remains poorly tested in pelagic marine fishes, as genomic studies have predominantly focused on freshwater and coastal taxa. In this study, we investigated the genomic basis of hybrid incompatibility between two parapatric Pacific mackerels, Scomber japonicus and S. australasicus, hypothesizing chromosomal rearrangements as the major driving forces. We generated haplotype-resolved de novo genome assemblies for both Pacific species and assessed genomic rearrangements along with the genome of the Atlantic species, S. scombrus, reconstructed from publicly available data. Comparative genomic analyses revealed extensive chromosomal rearrangements across the genomes. Notably, the rate of chromosomal inversions was approximately sevenfold higher between the two Pacific species than between allopatric lineages. These rearrangements included complex structural changes involving megabase-scale inversions and associated translocations. Our analyses also showed that the sex chromosomes of the three species evolved independently. In the two Pacific species, large recombination-suppression regions (>10 Mb) arose convergently but through distinct mechanisms: tandem chromosomal inversions in S. japonicus and, most likely, transposable element-mediated sequence divergence in S. australasicus. By contrast, recombination suppression in S. scombrus is restricted to a [~]14 kb hemizygous region containing amhr2Y, generated by duplication and translocation. Population-level analyses further revealed ongoing evolution of recombination-suppressed regions in the Pacific species and uncovered multiple Y chromosome lineages in S. australasicus that differ markedly in the extent of recombination suppression. Together, these results demonstrate rapid structural genome evolution in Scomber and provide a genomic framework for understanding how chromosomal rearrangements contribute to reproductive isolation, sex chromosome turnover, and the diversification of pelagic marine fishes.

evolutionary biology↗

bioRxiv2020

Identification of repurposable cytoprotective drugs for Vanishing White Matter Disease

Vanishing white matter disease (VWMD) is a rare leukodystrophy involving loss of function mutations of the guanine exchange factor eIF2B and typically presenting with juvenile onset. We aimed to identify repurposable FDA approved drugs in an in vitro drug screen using patient-derived fibroblasts and induced pluripotent stem cell (iPSC)-derived astrocytes. Dysregulated GADD34 and CHOP were identified in patient fibroblasts and iPSC-derived astrocytes under proteasomal stress conditions. A drug screen from a 2400 FDA approved drug library with EIF2B5 disease patient fibroblasts identified 113 anti-inflammatory drugs as a major class of hits with cytoprotective effects. A panel of potential candidate drugs including berberine, deflazacort, ursodiol, zileuton, guanabenz and Anavex 2-73, and preclinical ISRIB, increased cell survival of MG132-stressed EIF2B2 and EIF2B5 disease VWMD astrocytes, and were further investigated for their effect on the integrated stress response and mitochondrial stress. ISRIB but not other drugs significantly affected eIF2 phosphorylation and GADD34 expression. Ursodiol demonstrated capacity to reduce complex I subunit upregulation, ameliorate oxidative stress, loss of mitochondrial membrane potential and upregulation of eIF2B subunits in VWMD astrocytes, highlighting its potential as a cytoprotective compound for VWMD.

neuroscience↗