Biology subjects

Machado, H. E.

Publications and source records attributed to Machado, H. E..

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↗

bioRxiv2025

Somatic TYK2 activating mutations in tumor-infiltrating T cells promote anti-cancer immunity

Cancer cells evolve to increase fitness and evade the immune system, but it is not clear if tumor infiltrating lymphocytes (TILs) undergo selection for somatic mutations that augment anti-cancer immunity. Using single molecule whole exome sequencing in TILs, we identified somatic mutations in Tyrosine-protein kinase 2 (TYK2), several of which increased TYK2 phosphorylation, JAK-STAT signaling, and interferon gamma signaling. Among these mutations, TYK2D810V was recurrently observed in patients with diverse cancer types. In vitro, TYK2D810V enhanced T cells effector functions and cytokine production. We generated mice with a germline Tyk2D807V mutation that recapitulated the human TYK2D810Vmutation. These mice were healthy and did not develop autoimmune disorders. However, they possessed enhanced anti-tumor effects in the context of syngeneic and autochthonous cancer models. Adoptive therapy with Tyk2D807V CD8 T cells also decreased cancer growth. Thus, naturally occurring mutations in non-malignant lymphocytes can antagonize cancer and inspire new immunotherapies strategies.

cancer biology↗

bioRxiv2024

The long-term effects of chemotherapy on normal blood cells

In developed countries, [~]10% of individuals are exposed to systemic chemotherapy for cancer and other diseases. Many chemotherapeutic agents act by increasing DNA damage in cancer cells, triggering cell death. However, there is limited understanding of the extent and long-term consequences of collateral DNA damage to normal tissues. To investigate the impact of chemotherapy on mutation burdens and cell population structure of a normal tissue we sequenced blood cell genomes from 23 individuals, aged 3-80 years, treated with a range of chemotherapy regimens. Substantial additional mutation loads with characteristic mutational signatures were imposed by some chemotherapeutic agents, but there were differences in burden between different classes of agent, different agents of the same class and different blood cell types. Chemotherapy also induced premature changes in the cell population structure of normal blood, similar to those of normal ageing. The results constitute an initial survey of the long-term biological consequences of cytotoxic agents to which a substantial fraction of the population is exposed during the course of their disease management, raising mechanistic questions and highlighting opportunities for mitigation of adverse effects.

cell biology↗

bioRxiv2017

Strong purifying selection on codon usage bias

1Codon usage bias (CUB), where certain codons are used more frequently than expected by chance, is a ubiquitous phenomenon and occurs across the tree of life. The dominant paradigm is that the proportion of preferred codons is set by weak selection. While experimental changes in codon usage have at times shown large phenotypic effects in contrast to this paradigm, genome-wide population genetic estimates have supported the weak selection model. Here we use deep genomic sequencing of two Drosophila melanogaster populations to measure selection on synonymous sites in a way that allowed us to estimate the prevalence of both weak and strong selection. We find that selection in favor of preferred codons ranges from weak (|Nes| [~] 1) to strong (|Nes| > 10). While previous studies indicated that selection at synonymous sites could be strong, this is the first study to detect and quantify strong selection specifically at the level of CUB. We suggest that the level of CUB in the genome is determined by the proportion of synonymous sites under no, weak, and strong selection. This model challenges the standard Li-Bulmer model and explains some of the longest-standing puzzles in the field.

evolutionary biology↗