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The persistence of SARS-CoV-2 despite the development of vaccines and a degree of herd immunity is partly due to viral evolution reducing vaccine and treatment efficacy. Serial infections of wild-type (WT) SARS-CoV-2 in Balb/c mice yield mouse-adapted strains with greater infectivity and mortality. We investigate if passaging unmodified B.1.351 (Beta) and B.1.617.2 (Delta) 20 times in K18-ACE2 mice, expressing the human ACE2 receptor, in a BSL-3 laboratory without selective pressures, drives human health-relevant evolution and if evolution is lineage-dependent. Late-passage virus causes more severe disease, at organism and lung tissue scales, with late-passage Delta demonstrating antibody resistance and interferon suppression. This resistance co-occurs with a de novo spike S371F mutation, linked with both traits. S371F, an Omicron-characteristic mutation, is co-inherited at times with spike E1182G per Nanopore sequencing, existing in different within-sample viral variants at others. Both S371F and E1182G are linked to mammalian GOLGA7 and ZDHHC5 interactions, which mediate viral-cell entry and antiviral response. This study demonstrates SARS-CoV-2’s tendency to evolve with phenotypic consequences, its evolution varying by lineage, and suggests non-dominant quasi-species contribution. Short-term repeated SARS-CoV-2 passaging in immune-naïve mice leads to the virus acquiring lineage-specific differences in antibody resistance, interferon suppression and infection phenotypes.

Basal breast cancer subtype is enriched for triple-negative breast cancer (TNBC) and exhibits a recurrent large chromosomal deletion in chromosome 4p (chr4p). Chr4p loss is associated with poor survival, evolves early in tumorigenesis and confers on cells a proliferative state. Here, we map the integrated metabolic complex genetic interaction network of chr4p in basal breast cancer to identify targetable vulnerabilities. Differential gene expression analysis of patient derived xenografts and cancer cell models revealed that chr4p loss is associated with changes in cellular energetics and reduction/oxidation balance. Analysis of DepMap pooled genome-wide CRISPR-Cas9 screens identified complex genetic interactions specific to chr4p deletion in basal breast cancer cell models. Functional assays revealed that chr4p loss is associated with disrupted mitochondrial respiratory function and reduced glycolytic capacity, suggesting metabolic rewiring. Increased reactive oxygen species and lipid peroxidation compromised antioxidant defense mechanisms. Ultimately, this study sheds light on targeted therapies for basal breast cancer harboring large chromosomal deletions.

The persistence of COVID-19 is partly due to viral evolution reducing vaccine and treatment efficacy. Serial infections of Wuhan-like SARS-CoV-2 in Balb/c mice yielded mouse-adapted strains with greater infectivity and mortality. We investigated if passaging unmodified B.1.351 (Beta) and B.1.617.2 (Delta) 20 times in K18-ACE2 mice, expressing human ACE2 receptor, in a BSL-3 laboratory without selective pressures, would drive human health-relevant evolution and if evolution was lineage-dependent. Late-passage virus caused more severe disease, at organism and lung tissue scales, with late-passage Delta demonstrating antibody resistance and interferon suppression. This resistance co-occurred with a de novo spike S371F mutation, linked with both traits. S371F, an Omicron-characteristic mutation, was co-inherited at times with spike E1182G per Nanopore sequencing, existing in different quasi-species at others. Both are linked to mammalian GOLGA7 and ZDHHC5 interactions, which mediate viral-cell entry and antiviral response. This study demonstrates SARS-CoV-2’s tendency to evolve with phenotypic consequences, its evolution varying by lineage, and suggests non-dominant quasi-species contribute.

Flooding insect pest populations with huge numbers of sterilized males is an effective mean of biological control as they mate with, but cannot fertilize, wild females. The greatest challenge of the sterile insect technique (SIT) is the removal of unrequired factory reared females prior to sterilization and release. Spontaneous white-pupae (wp−) color mutations have been integrated as a dimorphic selectable marker into historical SIT strains for three major tephritid fruit fly pests, Bactrocera dorsalis, Ceratitis capitata and Zeugodacus cucurbitae. Here we identify parallel genetic mutations causing the phenotype in all three species using diverse experimental approaches. The B. dorsalis wp− locus was introgressed into a related species, Bactrocera tryoni, and whole-genome sequencing identified a 37 bp truncating mutation within a gene containing a Major Facilitator Superfamily domain (MFS). In C. capitata and Z. cucurbitae, cytogenetics, comparative genomics and transcriptomic analysis of strains carrying brown and white pupae phenotypes identified an 8,150 bp insertion of a putative transposon into the C. capitata MFS ortholog and a 13 bp deletion in the Z. cucurbitae ortholog. In B. tryoni CRISPR/Cas9-mediated knock-out of the putative Bt_wp developed mosaic white and brown puparium colors in G0, and G1 progeny with recessive white pupae phenotypes. In C. capitata, complementation crosses of CRISPR-induced wp− mutants to flies carrying the naturally occurring recessive wp− mutation confirmed the role of the gene. Gene editing technology carries the potential for engineering white pupae phenotypes and generating dimorphic SIT strains in other tephritids or insect pest species. Competing Interest Statement The authors have declared no competing interest.