Biology subjects

O'Neill, L.

Publications and source records attributed to O'Neill, L..

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↗

bioRxiv2021

Scalable Clustering with Supervised Linkage Methods

Data clustering plays a significant role in biomedical sciences, particularly in single-cell data analysis. Researchers use clustering algorithms to group individual cells into populations that can be evaluated across different levels of disease progression, drug response, and other clinical statuses. In many cases, multiple sets of clusters must be generated to assess varying levels of cluster specificity. For example, there are many subtypes of leukocytes (e.g. T cells), whose individual preponderance and phenotype must be assessed for statistical/functional significance. In this report, we introduce a novel hierarchical density clustering algorithm (HAL-x) that uses supervised linkage methods to build a cluster hierarchy on raw single-cell data. With this new approach, HAL-x can quickly predict multiple sets of labels for immense datasets, achieving a considerable improvement in computational efficiency on large datasets compared to existing methods. We also show that cell clusters generated by HAL-x yield near-perfect F1-scores when classifying different clinical statuses based on single-cell profiles. Our hierarchical density clustering algorithm achieves high accuracy in single cell classification in a scalable, tunable and rapid manner. We make HAL-x publicly available at: https://pypi.org/project/hal-x/

bioinformatics↗

bioRxiv2020

Causal Understanding of the Stone Dropping Task in Two Species of Macaw

Causal understanding in animal cognition can be divided into two broad categories (Woodward, 2011): learned associations between cause and effect (Le Pelley et al., 2017) and understanding based on underlying mechanisms (Johnson and Ahn, 2017). One experiment that gives insight to animals use of causal mechanisms is the stone-dropping task. In this, subjects are given an opportunity to push a platform to make it collapse and are then required to innovate dropping a stone tool to recreate the platform collapsing (von Bayern et al., 2009). We describe how 16/18 subjects of two species of macaw (n=18; Ara ambiguus (n=9) & Ara glaucogularis (n=9)) were able to innovate the solution in this task. Many of the subjects were able to innovate the behaviour through exploratory object combination, but it is also possible that a mechanistic understanding of the necessity for contact with the platform influenced some subjects behaviour. All the successful subjects were able to recreate their novel stone-dropping behaviour in the first or second trial after innovation (and all trials thereafter) and they were also able to do the behaviour increasingly faster. This suggests they also rely on learned associations of cause and effect. However, in a transfer task in which subjects had to guide a stick tool to make it touch a differently positioned platform, all but one of the subjects failed. This would suggest that the majority of the subjects were not using an understanding of platform contact to solve the task, although the subjects difficulty with using stick tools may have also affected their performance in this transfer.

animal behavior and cognition↗

bioRxiv2018

The landscape of somatic mutation in normal colorectal epithelial cells

The colorectal adenoma-carcinoma sequence has provided a paradigmatic framework for understanding the successive somatic genetic changes and consequent clonal expansions leading to cancer. As for most cancer types, however, understanding of the earliest phases of colorectal neoplastic change, which may occur in morphologically normal tissue, is comparatively limited because of the difficulty of detecting somatic mutations in normal cells. Each colorectal crypt is a small clone of cells derived from a single recently-existing stem cell. Here, we whole genome sequenced hundreds of normal crypts from 42 individuals. Signatures of multiple mutational processes were revealed, some ubiquitous and continuous, others only found in some individuals, in some crypts or during some phases of the cell lineage from zygote to adult cell. Likely driver mutations were present in [~]1% of normal colorectal crypts in middle-aged individuals, indicating that adenomas and carcinomas are rare outcomes of a pervasive process of neoplastic change across morphologically normal colorectal epithelium.

cancer biology↗