@article{19626,
  abstract     = {Active regulation of gene expression, orchestrated by complex interactions of activators and repressors at promoters, controls the fate of organisms. In contrast, basal expression at uninduced promoters is considered to be a dynamically inert mode of nonfunctional “promoter leakiness,” merely a byproduct of transcriptional regulation. Here, we investigate the basal expression mode of the mar operon, the main regulator of intrinsic multiple antibiotic resistance in Escherichia coli, and link its dynamic properties to the noncanonical, yet highly conserved start codon of marR across Enterobacteriaceae. Real-time, single-cell measurements across tens of generations reveal that basal expression consists of rare stochastic gene expression pulses, which maximize variability in wildtype and, surprisingly, transiently accelerate cellular elongation rates. Competition experiments show that basal expression confers fitness advantages to wildtype across several transitions between exponential and stationary growth by shortening lag times. The dynamically rich basal expression of the mar operon has likely been evolutionarily maintained for its role in growth homeostasis of Enterobacteria within the gut environment, thereby allowing other ancillary gene regulatory roles to evolve, e.g., control of costly-to-induce multidrug efflux pumps. Understanding the complex selection forces governing genetic systems involved in intrinsic multidrug resistance is crucial for effective public health measures.},
  author       = {Jain, Kirti and Hauschild, Robert and Bochkareva, Olga and Römhild, Roderich and Tkačik, Gašper and Guet, Calin C},
  issn         = {1091-6490},
  journal      = {Proceedings of the National Academy of Sciences},
  number       = {15},
  publisher    = {National Academy of Sciences},
  title        = {{Pulsatile basal gene expression as a fitness determinant in bacteria}},
  doi          = {10.1073/pnas.2413709122},
  volume       = {122},
  year         = {2025},
}

@article{15362,
  abstract     = {Constitutional heterozygous pathogenic variants in the exonuclease domain of POLE and POLD1, which affect the proofreading activity of the corresponding polymerases, cause a cancer predisposition syndrome characterized by increased risk of gastrointestinal polyposis, colorectal cancer, endometrial cancer and other tumor types. The generally accepted explanation for the connection between the disruption of the proofreading activity of polymerases epsilon and delta and cancer development is through an increase in the somatic mutation rate. Here we studied an extended family with multiple members heterozygous for the pathogenic POLD1 variant c.1421T>C p.(Leu474Pro), which segregates with the polyposis and cancer phenotypes. Through the analysis of mutational patterns of patient-derived fibroblasts colonies and de novo mutations obtained by parent-offspring comparisons, we concluded that heterozygous POLD1 L474P just subtly increases the somatic and germline mutation burden. In contrast, tumors developed in individuals with a heterozygous mutation in the exonuclease domain of POLD1, including L474P, have an extremely high mutation rate (>100 mut/Mb) associated with signature SBS10d. We solved this contradiction through the observation that tumorigenesis involves somatic inactivation of the wildtype POLD1 allele. These results imply that exonuclease deficiency of polymerase delta has a recessive effect on mutation rate.},
  author       = {Andrianova, Maria A. and Seplyarskiy, Vladimir B. and Terradas, Mariona and Sánchez-Heras, Ana Beatriz and Mur, Pilar and Soto, José Luis and Aiza, Gemma and Borràs, Emma and Kondrashov, Fyodor and Kondrashov, Alexey S. and Bazykin, Georgii A. and Valle, Laura},
  issn         = {1476-5438},
  journal      = {European Journal of Human Genetics},
  pages        = {837--845},
  publisher    = {Springer Nature},
  title        = {{Discovery of recessive effect of human polymerase δ proofreading deficiency through mutational analysis of POLD1-mutated normal and cancer cells}},
  doi          = {10.1038/s41431-024-01598-8},
  volume       = {32},
  year         = {2024},
}

@article{11344,
  abstract     = {Until recently, Shigella and enteroinvasive Escherichia coli were thought to be primate-restricted pathogens. The base of their pathogenicity is the type 3 secretion system (T3SS) encoded by the pINV virulence plasmid, which facilitates host cell invasion and subsequent proliferation. A large family of T3SS effectors, E3 ubiquitin-ligases encoded by the ipaH genes, have a key role in the Shigella pathogenicity through the modulation of cellular ubiquitination that degrades host proteins. However, recent genomic studies identified ipaH genes in the genomes of Escherichia marmotae, a potential marmot pathogen, and an E. coli extracted from fecal samples of bovine calves, suggesting that non-human hosts may also be infected by these strains, potentially pathogenic to humans. We performed a comparative genomic study of the functional repertoires in the ipaH gene family in Shigella and enteroinvasive Escherichia from human and predicted non-human hosts. We found that fewer than half of Shigella genomes had a complete set of ipaH genes, with frequent gene losses and duplications that were not consistent with the species tree and nomenclature. Non-human host IpaH proteins had a diverse set of substrate-binding domains and, in contrast to the Shigella proteins, two variants of the NEL C-terminal domain. Inconsistencies between strains phylogeny and composition of effectors indicate horizontal gene transfer between E. coli adapted to different hosts. These results provide a framework for understanding of ipaH-mediated host-pathogens interactions and suggest a need for a genomic study of fecal samples from diseased animals.},
  author       = {Dranenko, NO and Tutukina, MN and Gelfand, MS and Kondrashov, Fyodor and Bochkareva, Olga},
  issn         = {2045-2322},
  journal      = {Scientific Reports},
  publisher    = {Springer Nature},
  title        = {{Chromosome-encoded IpaH ubiquitin ligases indicate non-human enteroinvasive Escherichia}},
  doi          = {10.1038/s41598-022-10827-3},
  volume       = {12},
  year         = {2022},
}

@article{11447,
  abstract     = {Empirical essays of fitness landscapes suggest that they may be rugged, that is having multiple fitness peaks. Such fitness landscapes, those that have multiple peaks, necessarily have special local structures, called reciprocal sign epistasis (Poelwijk et al. in J Theor Biol 272:141–144, 2011). Here, we investigate the quantitative relationship between the number of fitness peaks and the number of reciprocal sign epistatic interactions. Previously, it has been shown (Poelwijk et al. in J Theor Biol 272:141–144, 2011) that pairwise reciprocal sign epistasis is a necessary but not sufficient condition for the existence of multiple peaks. Applying discrete Morse theory, which to our knowledge has never been used in this context, we extend this result by giving the minimal number of reciprocal sign epistatic interactions required to create a given number of peaks.},
  author       = {Saona Urmeneta, Raimundo J and Kondrashov, Fyodor and Khudiakova, Kseniia},
  issn         = {1522-9602},
  journal      = {Bulletin of Mathematical Biology},
  keywords     = {Computational Theory and Mathematics, General Agricultural and Biological Sciences, Pharmacology, General Environmental Science, General Biochemistry, Genetics and Molecular Biology, General Mathematics, Immunology, General Neuroscience},
  number       = {8},
  publisher    = {Springer Nature},
  title        = {{Relation between the number of peaks and the number of reciprocal sign epistatic interactions}},
  doi          = {10.1007/s11538-022-01029-z},
  volume       = {84},
  year         = {2022},
}