Inbreeding (the mating between closely related individuals) often has detrimental effects that are associated with loss of heterozygosity at overdominant loci, and the expression of deleterious recessive alleles. However, determining which loci are detrimental when homozygous, and the extent of their phenotypic effects, remains poorly understood. Here, we utilize a unique inbred population of clonal (thelytokous) honey bees, Apis mellifera capensis, to determine which loci reduce individual fitness when homozygous. This asexual population arose from a single worker ancestor approximately 20 years ago and has persisted for at least 100 generations. Thelytokous parthenogenesis results in a 1/3 of loss of heterozygosity with each generation. Yet, this population retains heterozygosity throughout its genome due to selection against homozygotes. Deep sequencing of one bee from each of the three known sub-lineages of the population revealed that 3,766 of 10,884 genes (34%) have retained heterozygosity across all sub-lineages, suggesting that these genes have heterozygote advantage. The maintenance of heterozygosity in the same genes and genomic regions in all three sub-lineages suggests that nearly every chromosome carries genes that show sufficient heterozygote advantage to be selectively detrimental when homozygous.
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Cancer Metastasis Rev
December 2024
Institute of Chemical Biology and Fundamental Medicine, Novosibirsk, 630090, Russia.
Homologous recombination deficiency (HRD) is considered a universal and effective sign of a tumor's sensitivity to poly(ADP-ribose) polymerase (PARP) inhibitors. HRD diagnostics have undergone several stages of transformations: from detection of point mutations in HR-related genes and large regions with loss of heterozygosity detected using single-nucleotide polymorphism arrays to whole-genome signatures of single-nucleotide variants, large genomic rearrangements (LGRs), and copy number alterations. All these methods have their own advantages and limitations.
View Article and Find Full Text PDFInt J Cancer
December 2024
Pediatric Cancer Research Center, National Clinical Research Center for Child Health, Children's Hospital Zhejiang University School of Medicine, Hangzhou, China.
Wilms tumor (WT) is the most common kidney cancer in infants and young children. The determination of the clonality of bilateral WTs is critical to the treatment, because lineage-independent and metastatic tumors may require different treatment strategies. Here we found synchronous bilateral WT (n = 24 tumors from 12 patients) responded differently to preoperative chemotherapy.
View Article and Find Full Text PDFTransplant Cell Ther
December 2024
Fred Hutchinson Cancer Center, Seattle, WA; University of Washington, Seattle, WA. Electronic address:
Background: Despite its known superior diagnostic yield for chromosomal anomalies compared to karyotype and FISH studies, Chromosome Genomic Array Testing (CGAT) is not used as a routine clinical test for myelofibrosis. Meanwhile, although many prognostic systems exist that risk stratify patients at diagnosis, limited tools are available to prognosticate transplant outcome.
Objective: The current study aimed at testing if CGAT results obtained before transplantation improves prognosis of post-transplant outcome in myelofibrosis patients compared with current risk categorization systems namely DIPSS plus.
BMC Res Notes
December 2024
School of Biomedical Sciences, The University of Queensland, Brisbane, QLD, 4072, Australia.
Objective: The Polycomb Repressive Complex 2 (PRC2) regulates neural stem cell behaviour during development of the cerebral cortex, yet how the loss of PRC2 developmentally influences cell identity in the mature brain is poorly defined. Using a mouse model in which the PRC2 gene Embryonic ectoderm development (Eed) was conditionally deleted from the developing mouse dorsal telencephalon, we performed single nuclei RNA sequencing (snRNA-seq) on the cortical plate of an adult heterozygote Eed knockout mouse and an adult homozygote Eed knockout mouse compared to a littermate control. This work was part of a larger effort to understand consequences of mutations to PRC2 within the mature brain.
View Article and Find Full Text PDFCancer Metab
December 2024
Department of Biochemistry and Molecular Biology, Mayo Clinic College of Medicine and Science, 200 First St. SW, Rochester, MN, 55905, USA.
Heterozygosity for loss-of-function alleles of the genes encoding the four subunits of succinate dehydrogenase (SDHA, SDHB, SDHC, SDHD), as well as the SDHAF2 assembly factor predispose affected individuals to pheochromocytoma and paraganglioma (PPGL), two rare neuroendocrine tumors that arise from neural crest-derived paraganglia. Tumorigenesis results from loss of the remaining functional SDHx gene copy, leading to a cell with no functional SDH and a defective tricarboxylic acid (TCA) cycle. It is believed that the subsequent accumulation of succinate competitively inhibits multiple dioxygenase enzymes that normally suppress hypoxic signaling and demethylate histones and DNA, ultimately leading to increased expression of genes involved in angiogenesis and cell proliferation.
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