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1. Mitochondrial haplotype and mito-nuclear matching drive somatic mutation and selection throughout ageing

   https://doi.org/10.1038/s41559-024-02338-3  

   Serrano, Isabel M. ; Hirose, Misa ; Valentine, Charles C. ; Roesner, Sharon ; Schmidt, Elizabeth ; Pratt, Gabriel ; Williams, Lindsey ; Salk, Jesse ; Ibrahim, Saleh ; Sudmant, Peter H. ( February 2024 , Nature Ecology & Evolution)

   Mitochondrial genomes co-evolve with the nuclear genome over evolutionary timescales and are shaped by selection in the female germline. Here we investigate how mismatching between nuclear and mitochondrial ancestry impacts the somatic evolution of the mitochondrial genome in different tissues throughout ageing. We used ultrasensitive duplex sequencing to profile ~2.5 million mitochondrial genomes across five mitochondrial haplotypes and three tissues in young and aged mice, cataloguing ~1.2 million mitochondrial somatic and ultralow-frequency inherited mutations, of which 81,097 are unique. We identify haplotype-specific mutational patterns and several mutational hotspots, including at the light strand origin of replication, which consistently exhibits the highest mutation frequency. We show that rodents exhibit a distinct mitochondrial somatic mutational spectrum compared with primates with a surfeit of reactive oxygen species-associated G > T/C > A mutations, and that somatic mutations in protein-coding genes exhibit signatures of negative selection. Lastly, we identify an extensive enrichment in somatic reversion mutations that ‘re-align’ mito-nuclear ancestry within an organism’s lifespan. Together, our findings demonstrate that mitochondrial genomes are a dynamically evolving subcellular population shaped by somatic mutation and selection throughout organismal lifetimes.

    

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2. A catalogue of somatic NRF2 gain-of-function mutations in cancer

   https://doi.org/10.1038/s41598-018-31281-0  

   Kerins, Michael John ; Ooi, Aikseng ( August 2018 , Scientific Reports)

   Identification and characterization of somatic mutations in cancer have important prognostication and treatment implications. Genes encoding the Nuclear factor (erythroid-derived 2)-like 2 (NRF2) transcription factor and its negative regulator, Kelch-like ECH-associated protein 1 (KEAP1), are frequently mutated in cancer. These mutations drive constitutive NRF2 activation and correlate with poor prognosis. Despite its apparent significance, a comprehensive catalogue of somatic NRF2 mutations across different tumor types is still lacking. Here, we catalogue NRF2 mutations in The Cancer Genome Atlas (TCGA) database. 226 unique NRF2-mutant tumors were identified from 10,364 cases. NRF2 mutations were found in 21 out of the 33 tumor types. A total of 11 hotspots were identified. Of these, mutation to the R34 position was most frequent. Notably, R34 and D29 mutations were overrepresented in bladder, lung, and uterine cancers. Analyses of corresponding RNA sequencing data using a de novo derived gene expression classifier showed that the R34 mutations drive constitutive NRF2 activation with a selection pressure biased against the formation of R34L. Of all R34 mutants, R34L conferred the least degree of protein stabilization, suggesting a pro-tumor NRF2 half-life threshold. Our findings offer a comprehensive catalogue of NRF2 mutations in cancer that can help prognostication and NRF2 research.

    

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3. Literature-Based Discovery to Elucidate the Biological Links between Resistant Hypertension and COVID-19

   https://doi.org/10.3390/biology12091269  

   Kartchner, David ; McCoy, Kevin ; Dubey, Janhvi ; Zhang, Dongyu ; Zheng, Kevin ; Umrani, Rushda ; Kim, James J. ; Mitchell, Cassie S. ( September 2023 , Biology)

   Multiple studies have reported new or exacerbated persistent or resistant hypertension in patients previously infected with COVID-19. We used literature-based discovery to identify and prioritize multi-scalar explanatory biology that relates resistant hypertension to COVID-19. Cross-domain text mining of 33+ million PubMed articles within a comprehensive knowledge graph was performed using SemNet 2.0. Unsupervised rank aggregation determined which concepts were most relevant utilizing the normalized HeteSim score. A series of simulations identified concepts directly related to COVID-19 and resistant hypertension or connected via one of three renin–angiotensin–aldosterone system hub nodes (mineralocorticoid receptor, epithelial sodium channel, angiotensin I receptor). The top-ranking concepts relating COVID-19 to resistant hypertension included: cGMP-dependent protein kinase II, MAP3K1, haspin, ral guanine nucleotide exchange factor, N-(3-Oxododecanoyl)-L-homoserine lactone, aspartic endopeptidases, metabotropic glutamate receptors, choline-phosphate cytidylyltransferase, protein tyrosine phosphatase, tat genes, MAP3K10, uridine kinase, dicer enzyme, CMD1B, USP17L2, FLNA, exportin 5, somatotropin releasing hormone, beta-melanocyte stimulating hormone, pegylated leptin, beta-lipoprotein, corticotropin, growth hormone-releasing peptide 2, pro-opiomelanocortin, alpha-melanocyte stimulating hormone, prolactin, thyroid hormone, poly-beta-hydroxybutyrate depolymerase, CR 1392, BCR-ABL fusion gene, high density lipoprotein sphingomyelin, pregnancy-associated murine protein 1, recQ4 helicase, immunoglobulin heavy chain variable domain, aglycotransferrin, host cell factor C1, ATP6V0D1, imipramine demethylase, TRIM40, H3C2 gene, COL1A1+COL1A2 gene, QARS gene, VPS54, TPM2, MPST, EXOSC2, ribosomal protein S10, TAP-144, gonadotropins, human gonadotropin releasing hormone 1, beta-lipotropin, octreotide, salmon calcitonin, des-n-octanoyl ghrelin, liraglutide, gastrins. Concepts were mapped to six physiological themes: altered endocrine function, 23.1%; inflammation or cytokine storm, 21.3%; lipid metabolism and atherosclerosis, 17.6%; sympathetic input to blood pressure regulation, 16.7%; altered entry of COVID-19 virus, 14.8%; and unknown, 6.5%.

    

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4. COLD-PCR Enrichment of Rare Cancer Mutations prior to Targeted Amplicon Resequencing

   https://doi.org/10.1373/clinchem.2011.176198  

   Milbury, Coren A. ; Correll, Mick ; Quackenbush, John ; Rubio, Renee ; Makrigiorgos, G. Mike ( January 2020 , Clinical Chemistry)

   Despite widespread interest in next-generation sequencing (NGS), the adoption of personalized clinical genomics and mutation profiling of cancer specimens is lagging, in part because of technical limitations. Tumors are genetically heterogeneous and often contain normal/stromal cells, features that lead to low-abundance somatic mutations that generate ambiguous results or reside below NGS detection limits, thus hindering the clinical sensitivity/specificity standards of mutation calling. We applied COLD-PCR (coamplification at lower denaturation temperature PCR), a PCR methodology that selectively enriches variants, to improve the detection of unknown mutations before NGS-based amplicon resequencing.

   We used both COLD-PCR and conventional PCR (for comparison) to amplify serially diluted mutation-containing cell-line DNA diluted into wild-type DNA, as well as DNA from lung adenocarcinoma and colorectal cancer samples. After amplification of TP53 (tumor protein p53), KRAS (v-Ki-ras2 Kirsten rat sarcoma viral oncogene homolog), IDH1 [isocitrate dehydrogenase 1 (NADP+), soluble], and EGFR (epidermal growth factor receptor) gene regions, PCR products were pooled for library preparation, bar-coded, and sequenced on the Illumina HiSeq 2000.

   In agreement with recent findings, sequencing errors by conventional targeted-amplicon approaches dictated a mutation-detection limit of approximately 1%–2%. Conversely, COLD-PCR amplicons enriched mutations above the error-related noise, enabling reliable identification of mutation abundances of approximately 0.04%. Sequencing depth was not a large factor in the identification of COLD-PCR–enriched mutations. For the clinical samples, several missense mutations were not called with conventional amplicons, yet they were clearly detectable with COLD-PCR amplicons. Tumor heterogeneity for the TP53 gene was apparent.

   As cancer care shifts toward personalized intervention based on each patient's unique genetic abnormalities and tumor genome, we anticipate that COLD-PCR combined with NGS will elucidate the role of mutations in tumor progression, enabling NGS-based analysis of diverse clinical specimens within clinical practice.

    

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5. The cost of evolved constitutive lac gene expression is usually, but not always, maintained during evolution of generalist populations

   https://doi.org/10.1002/ece3.7994  

   Phillips, Kelly N. ; Cooper, Tim F. ( August 2021 , Ecology and Evolution)

   Beneficial mutations can become costly following an environmental change. Compensatory mutations can relieve these costs, while not affecting the selected function, so that the benefits are retained if the environment shifts back to be similar to the one in which the beneficial mutation was originally selected. Compensatory mutations have been extensively studied in the context of antibiotic resistance, responses to specific genetic perturbations, and in the determination of interacting gene network components. Few studies have focused on the role of compensatory mutations during more general adaptation, especially as the result of selection in fluctuating environments where adaptations to different environment components may often involve trade‐offs. We examine whether costs of a mutation inlacI,which deregulated the expression of thelacoperon in evolving populations ofEscherichia colibacteria, were compensated. This mutation occurred in multiple replicate populations selected in environments that fluctuated between growth on lactose, where the mutation was beneficial, and on glucose, where it was deleterious. We found that compensation for the cost of thelacImutation was rare, but, when it did occur, it did not negatively affect the selected benefit. Compensation was not more likely to occur in a particular evolution environment. Compensation has the potential to remove pleiotropic costs of adaptation, but its rarity indicates that the circumstances to bring about the phenomenon may be peculiar to each individual or impeded by other selected mutations.

    

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