Biology subjects

Rubin, B.

Publications and source records attributed to Rubin, B..

3 recordsLinked to original sources

bioRxiv2023

Intra-Host Mutation Rate of Acute SARS-CoV-2 Infection During the Initial Pandemic Wave

BackgroundOur understanding of SARS-CoV-2 evolution and mutation rate is limited. The rate of SARS-CoV-2 evolution is minimized through a proofreading function encoded by NSP-14 and may be affected by patient comorbidity. Current understanding of SARS-CoV-2 mutational rate is through population based analysis while intra-host mutation rate remains poorly studied. MethodsViral genome analysis was performed between paired samples and mutations quantified at allele frequencies (AF) [≥]0.25, [≥]0.5 and [≥]0.75. Mutation rate was determined employing F81 and JC69 evolution models and compared between isolates with ({Delta}NSP-14) and without (wtNSP-14) non-synonymous mutations in NSP-14 and by patient comorbidity. ResultsForty paired samples with median interval of 13 days [IQR 8.5-20] were analyzed. The estimated mutation rate by F81 modeling was 93.6 (95%CI:90.8-96.4], 40.7 (95%CI:38.9-42.6) and 34.7 (95%CI:33.0-36.4) substitutions/genome/year at AF [≥]0.25, [≥]0.5, [≥]0.75 respectively. Mutation rate in {Delta}NSP-14 were significantly elevated at AF>0.25 vs wtNSP-14. Patients with immune comorbidities had higher mutation rate at all allele frequencies. DiscussionIntra-host SARS-CoV-2 mutation rates are substantially higher than those reported through population analysis. Virus strains with altered NSP-14 have accelerated mutation rate at low AF. Immunosuppressed patients have elevated mutation rate at all AF. Understanding intra-host virus evolution will aid in current and future pandemic modeling.

evolutionary biology↗

bioRxiv2022

The oncogenic fusion protein TAZ-CAMTA1 promotes genomic instability and senescence through hypertranscription

TAZ-CAMTA1 is a fusion protein found in over 90% of Epithelioid Hemangioendothelioma (EHE), a rare vascular sarcoma with an unpredictable disease course. To date, how TAZ-CAMTA1 initiates tumour formation remains unexplained. To study the oncogenic mechanism leading to EHE initiation, we developed a model system whereby TAZ-CAMTA1 expression is induced by doxycycline in primary endothelial cells. Using this model, we establish that upon TAZ-CAMTA1 expression endothelial cells rapidly enter a hypertranscription state, triggering considerable DNA damage. As a result, TC-expressing cells become trapped in S phase. Additionally, TAZ-CAMTA1-expressing endothelial cells have impaired homologous recombination, as shown by reduced BRCA1 and RAD51 foci formation. Consequently, the DNA damage remains unrepaired and TAZ-CAMTA1-expressing cells enter senescence. Knockout of Cdkn2a, the most common secondary mutation found in EHE, allows senescence bypass and uncontrolled growth. Together, this provides a mechanistic explanation for the clinical course of EHE and offers novel insight into therapeutic options.

cancer biology↗

bioRxiv2017

Positively Selected Enhancer Elements Endow Tumor Cells with MetastaticCompetence

Metastasis results from a complex set of traits acquired by tumor cells, distinct from those necessary for tumorigenesis. Here, we investigate the contribution of enhancer elements to the metastatic phenotype of osteosarcoma. Through epigenomic profiling, we identify substantial differences in enhancer activity between primary and metastatic tumors in human patients as well as nearisogenic pairs of high and low lung-metastatic osteosarcoma cells. We term these regions Metastatic Variant Enhancer Loci (Met-VELs). We demonstrate that these Met-VELs drive coordinated waves of gene expression during metastatic colonization of the lung. Met-VELs cluster non-randomly, indicating that activity of these enhancers and their associated gene targets are positively selected. As evidence of this causal association, osteosarcoma lung metastasis is inhibited by global interruptions of Met-VEL-associated gene expression via pharmacologic BET inhibition, by knockdown of AP-1 transcription factors that occupy Met-VELs, and by knockdown or functional inhibition of individual genes activated by Met-VELs, such as F3. We further show that genetic deletion of a single Met-VEL at the F3 locus blocks metastatic cell outgrowth in the lung. These findings indicate that Met-VELs and the genes they regulate play a functional role in metastasis and may be suitable targets for anti-metastatic therapies.

cancer biology↗