Deleterious mutations accumulating on non-recombining Y chromosomes can drive XY to XY turnovers, as they allow to replace the old mutation-loaded Y by a new mutation-free one. The same process is thought to prevent XY to ZW turnovers, because the latter requires fixation of the ancestral Y, assuming dominance of the emergent feminizing mutation. Using individual-based simulations, we explored whether and how an epistatically dominant W allele can spread in a young XY system that gradually accumulates deleterious mutations. We also investigated how sexually antagonistic (SA) polymorphism on the ancestral sex chromosomes and the mechanism controlling X-Y recombination suppression affect these transitions. In contrast with XY to XY turnovers, XY to ZW turnovers cannot be favored by Y chromosome mutation load. If the arrest of X-Y recombination depends on genotypic sex, transitions are strongly hindered by deleterious mutations, and totally suppressed by very small SA cost, because deleterious mutations and female-detrimental SA alleles would have to fix with the Y. If, however, the arrest of X-Y recombination depends on phenotypic sex, X and Y recombine in XY ZW females, allowing for the purge of Y-linked deleterious mutations and loss of the SA polymorphism, causing XY to ZW turnovers to occur at the same rate as in the absence of deleterious and sex-antagonistic mutations. We generalize our results to other types of turnovers (e.g., triggered by non-dominant sex-determining mutations) and discuss their empirical relevance.
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http://dx.doi.org/10.1038/s41437-019-0225-z | DOI Listing |
Sci Transl Med
January 2025
Graduate Program in Human Genetics, University of Miami Miller School of Medicine, 1501 NW 10th Avenue (M-860), Miami, FL 33136, USA.
Primary mitochondrial disorders are most often caused by deleterious mutations in the mitochondrial DNA (mtDNA). Here, we used a mitochondrial DddA-derived cytosine base editor (DdCBE) to introduce a compensatory edit in a mouse model that carries the pathological mutation in the mitochondrial transfer RNA (tRNA) alanine (mt-tRNA) gene. Because the original m.
View Article and Find Full Text PDFCancer
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Department of Medical Oncology, Cancer Center, West China Hospital, Sichuan University, Chengdu, Sichuan Province, China.
Background: This study aims to explore the genetic characteristics of biliary tract cancer (BTC), with a particular focus on the impact of DNA damage response and repair (DDR) genes on clinical outcomes.
Methods: A total of 180 patients with BTC and next-generation sequencing data were retrospectively analyzed. Clinical outcomes were compared between DDR-positive and DDR-negative groups.
Proc Natl Acad Sci U S A
February 2025
Department of Agricultural Biotechnology, and Research Institute of Agriculture and Life Sciences, CALS, Seoul National University, Seoul 08826, Republic of Korea.
The formation of superoxide dismutase 1 (SOD1) filaments has been implicated in amyotrophic lateral sclerosis (ALS). Although the disulfide bond formed between Cys57 and Cys146 in the active state has been well studied, the role of the reduced cysteine residues, Cys6 and Cys111, in SOD1 filament formation remains unclear. In this study, we investigated the role of reduced cysteine residues by determining and comparing cryoelectron microscopy (cryo-EM) structures of wild-type (WT) and C6A/C111A SOD1 filaments under thiol-based reducing and metal-depriving conditions, starting with protein samples possessing enzymatic activity.
View Article and Find Full Text PDFEMBO Rep
January 2025
Department of Biochemistry, University of Toronto, 1 King's College Circle, Toronto, ON, M5S 1A8, Canada.
Homologous recombination is a largely error-free DNA repair mechanism conserved across all domains of life and is essential for the maintenance of genome integrity. Not only are the mutations in homologous recombination repair genes probable cancer drivers, some also cause genetic disorders. In particular, mutations in the Bloom (BLM) helicase cause Bloom Syndrome, a rare autosomal recessive disorder characterized by increased sister chromatid exchanges and predisposition to a variety of cancers.
View Article and Find Full Text PDFCurr Pharm Des
January 2025
Department of Physiology, Medical School, Selcuk University, Konya, Turkey.
Introduction: Brain ischemia-reperfusion can cause serious and irreversible health problems. Recent studies have suggested that certain flavonoids may help stabilize the correctly folded structure of the visual photoreceptor protein rhodopsin and offset the deleterious effect of retinitis pigmentosa mutations.
Objective: The current study aimed to determine the effect of 3',4'-Dihydroxyflavonol (DiOHF) supplementation for 1 week on lipid peroxidation in the retina tissue following focal brain ischemia-reperfusion in rats.
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