Biology subjects

Brzozowska, N.

Publications and source records attributed to Brzozowska, N..

4 recordsLinked to original sources

bioRxiv2026

A comprehensive atlas of somatic mutation rates and mutational signatures in normal human cells

Over the course of a lifetime, somatic mutations accrue in normal human cells, causing variation in cell phenotype and engendering somatic evolution with outcomes ranging from the adaptive immune system to cancer. To inform understanding of somatic evolution in the human body we report the mutation rates and mutational signatures of 53 normal cell types. Most show evidence of linear mutation accumulation over time with single base substitution mutation rates ranging from ~3.5/year/diploid genome in spermatogonia and sperm, to ~20/year in postmitotic neurons, ~50/year in mitotically active colorectal epithelial cells, ~60/year in kidney proximal tubule cells and hepatocytes, 100s/year in sun-exposed skin epidermal cells and 10-50/year in the remainder. Certain cell types, including skin epidermis, cardiac myocytes, bladder urothelium, kidney proximal tubule cells, and hepatocytes, show substantial variability in mutation burdens around the linear age trend, indicating the influence of additional factors which differ between individuals and modulate mutation accumulation, including exogenous mutagen exposures. At least 18 single-base substitution and nine small insertion and deletion mutational signatures are present, some in all cell types, some in a subset and others in a single cell type. Known exogenous mutagen exposures and endogenous mutational processes account for some mutational signatures, but the origins and mechanisms underlying many are uncertain. This comprehensive survey of mutagenesis provides a foundation for understanding somatic evolution of human cell populations in health and disease.

genomics↗

bioRxiv2024

Convergent evolution of somatic escape variants in SERPINA1 in the liver in alpha-1 anti-trypsin deficiency

Somatic variants accumulate in non-malignant tissues with age1,2. Functional variants leading to clonal advantage of hepatocytes accumulate in the liver from patients with acquired chronic liver disease (CLD)3-5. Whether these somatic variants are common to CLD from differing aetiologies is unknown. We analysed somatic variants in the liver from patients with genetic CLD from alpha-1 anti-trypsin (A1AT) deficiency or haemochromatosis. We show that somatic variants in SERPINA1, the gene encoding A1AT, are strongly selected for in A1AT deficiency, with evidence of convergent evolution. Acquired variants cluster at the 3 end of SERPINA1 leading to C-terminal missense or truncation variants of A1AT. In vitro, C-terminal truncation variants abrogate disease-associated A1AT polymerisation and retention in the endoplasmic reticulum, supporting the C-terminal domain swap mechanism. Therefore, somatic escape variants from a deleterious germline variant are selected for in A1AT deficiency, suggesting adaptive functional somatic variants are disease-specific in CLD and point to disease-associated mechanisms.

genomics↗

bioRxiv2021

Somatic mutation rates scale with lifespan across mammals

The rates and patterns of somatic mutation in normal tissues are largely unknown outside of humans. Comparative analyses can shed light on the diversity of mutagenesis across species and on long-standing hypotheses regarding the evolution of somatic mutation rates and their role in cancer and ageing. Here, we used whole-genome sequencing of 208 intestinal crypts from 56 individuals to study the landscape of somatic mutation across 16 mammalian species. We found somatic mutagenesis to be dominated by seemingly endogenous mutational processes in all species, including 5-methylcytosine deamination and oxidative damage. With some differences, mutational signatures in other species resembled those described in humans, although the relative contribution of each signature varied across species. Remarkably, the somatic mutation rate per year varied greatly across species and exhibited a strong inverse relationship with species lifespan, with no other life-history trait studied displaying a comparable association. Despite widely different life histories among the species surveyed, including [~]30-fold variation in lifespan and [~]40,000-fold variation in body mass, the somatic mutation burden at the end of lifespan varied only by a factor of [~]3. These data unveil common mutational processes across mammals and suggest that somatic mutation rates are evolutionarily constrained and may be a contributing factor in ageing.

genomics↗

bioRxiv2018

Characterizing Genetic Circuit Components in E. coli towards a Campylobacter jejuni Biosensor.

Campylobacter jejuni is responsible for most cases of bacterial gastroenteritis (food poisoning) in the United Kingdom. The most common routes of transmission are by contact with raw poultry. Current detection systems for the pathogen are time-consuming, expensive or inaccessible for everyday users. In this article we propose a cheaper and faster system for detection of C. jejuni using a synthetic biology approach. We aimed to detect C. jejuni by the presence of xylulose, an uncommon bacterial capsular saccharide. We characterized two sugar-based regulatory systems that displayed potential to act as tools for detection of xylulose. Using a two-plasmid reporter system in Escherichia coli, we investigated the regulatory protein component (MtlR) of the mannitol operon from Pseudomonas fluorescens. Our findings suggest that the promoter of mtlE is activated by MtlR in the presence of a variety of sugar inducer molecules, and may exhibit cross-activity with a native regulator of E. coli. Additionally, we engineered the L-arabinose transcriptional activator (AraC) of E. coli for altered ligand specificity. We performed site-specific saturation mutagenesis to generate AraC variants with altered effector specificity, with an aim to generate a mutant activated by xylulose. We characterized several mutant AraC variants which have lost the ability to respond specifically to the native L-arabinose effector. We promote this technique as a powerful tool for future iGEM teams to create regulatory circuits activated by novel small molecule ligands.

synthetic biology↗