Biology subjects

Sexton, C. E.

Publications and source records attributed to Sexton, C. E..

6 recordsLinked to original sources

bioRxiv2026

Recurrent mitotic error and purifying selection shape chromosomal mosaicism across human tissues

Mosaic chromosomal alterations (mCAs) have been extensively studied in cancer and clonal hematopoiesis but less so in healthy solid tissues. Here, we characterized mCAs in 19 tissues across 25 donors (aged 42-89+ years) by analyzing >200x whole-genome sequencing data generated by the Somatic Mosaicism across Human Tissues (SMaHT) Network. Across 722 tissue samples, we identified 1,008 autosomal mCAs >1 Mb in length and ubiquitous losses of sex chromosomes. Surprisingly, the highest levels of Y chromosome loss in males (5-10% cell fraction in elderly donors) were observed in the lung, adrenal gland, and heart. These tissues also tended to experience more X loss in females, revealing a gradient of mitotic error burden across human tissues. Autosomal aneuploidies displayed distinct tissue-specific patterns indicative of negative selection against most events, except in the adrenal gland, in which low-level aneuploidy was pervasive. In contrast to the adrenal gland, testis rarely harbored aneuploidies but frequently experienced low-level copy-neutral loss of heterozygosity (CN-LOH), suggesting increased mitotic recombination in spermatogonial stem cells. Recurrent X chromosome losses within tissues of female donors exhibited allelic skews explained by a combination of genetic and epigenetic effects. Together, these results show that the chromosomal landscape of aging human tissues is shaped by genetics and recurrent mutations, most but not all of which are held in check by purifying selection.

genomics↗

bioRxiv2025

Multi-platform framework for mapping somatic retrotransposition in human tissues

Mobile element insertions (MEI) shape the human genome in both germline and somatic tissues. While inherited MEIs are well characterized, mapping somatic MEIs (sMEI) in non-cancer tissues remains challenging due to their low allelic fraction and repetitive nature. We established an integrative framework for sMEI analysis leveraging modern sequencing technologies and analytical innovations. We first benchmarked sMEI detection and demonstrated advantages of long-read and MEI-targeted sequencing for ultra-low-frequency events using a mixture of well-established cell lines. We then showed that haplotype phasing and donor-specific assemblies refine sMEI detection, effectively distinguishing from germline and false signals in in-silico tumor-normal mixtures. We further developed a source-tracing strategy based on internal sequence variation, expanding the catalogue of active source elements beyond traditional transduction-based methods. Applying this framework to donor tissues, we identified 18 rare somatic L1 insertions, revealing structural and source diversity. Our work provides a foundational framework and biological insight into sMEIs.

genomics↗

bioRxiv2023

Genome wide clustering on integrated chromatin states and Micro-C contacts reveals chromatin interaction signatures

Chromatin states based on various histone modifications are a common annotation for genomes, and have been shown to correspond to regulatory functions such as enhancers and transcription start sites. With the advent of Hi-C and other chromatin conformation capture technologies, we now have the ability to analyze 3-dimensional physical interactions of chromatin regions, in addition to the 1-dimensional regulatory annotation, but methods to integrate this information are lacking. We present a framework for integrating the chromatin state of interacting regions into a numeric vector through the contact-weighted sum of chromatin states. Unsupervised clustering on integrated chromatin states and Micro-C contacts reveals common patterns of chromatin interaction which we call chromatin interaction signatures. Our results indicate that most chromatin interaction signatures are found in all four cell types investigated here. Between 12-40% of the regions change chromatin interaction signatures between the cell types despite maintaining chromatin state, hinting at the dynamic nature of chromatin conformation. Although regions with similar chromatin states are often in contact as expected, subcategories of enhancers and transcription start sites have distinct chromatin interaction signatures that are associated with gene expression. The integrated information on the chromatin states that the region is in contact with adds another layer of annotation beyond chromatin state or Hi-C contact separately. In summary, we present the first set of chromatin interaction signatures for the human genome that provides an integrated view of the complex dynamics of concurrent change occurring in chromatin state and in chromatin interaction.

bioinformatics↗

bioRxiv2020

Sleep Efficiency Relates to Hippocampal Integrity Decline in β-Amyloid Positive Adults

BackgroundTo test the hypothesis that worse self-reported sleep relates to memory decay and reduced hippocampal integrity as indexed by increased intra-hippocampal water diffusion, and that the relations are stronger in the presence of {beta}-amyloid (A{beta}) accumulation, a marker of Alzheimers disease (AD) pathology. MethodsTwo-hundred and forty-three cognitively healthy participants, aged 19-81 years, completed the Pittsburgh Sleep Quality Index, and 2 diffusion tensor imaging sessions, on average 3 years apart, allowing measures of decline in hippocampal microstructural integrity as indexed by increased mean diffusivity. We measured memory decay using delayed recall from the California Verbal Learning Test. 18F-Flutemetamol positron emission tomography, in 108 participants above 44 years of age, yielded 23 A{beta} positive. Genotyping enabled controlling for APOE {varepsilon}4 status, and polygenic scores for sleep efficiency and AD. ResultsWorse global sleep quality and sleep efficiency related to more rapid reduction in hippocampal microstructural integrity over time. Focusing on sleep efficiency, the relation was stronger in presence of A{beta} accumulation. Sleep efficiency related to memory decay indirectly via hippocampal integrity decline. The results were not explained by genetic risk for sleep efficiency and AD. ConclusionsPoor self-reported sleep efficiency related to decline in hippocampal integrity, especially in the presence of A{beta} accumulation. Poor sleep and hippocampal microstructural decline may partly explain memory decline in older adults with A{beta} pathology. The relationships were not explained by genetic risk. Poor self-reported sleep efficiency might constitute a risk factor for AD, although the causal mechanisms driving the of observed associations remain unknown.

neuroscience↗

bioRxiv2020

Mid-life and late life activities and their relationship with MRI measures of brain structure and functional connectivity in the UK Biobank cohort

INTRODUCTIONThis study aimed to evaluate whether mid-life and late life participation in leisure activities is linked to measures of brain structure, functional connectivity and cognition in early old age. METHODSWe examined data collected from 7,152 participants of the UK Biobank study. Weekly participation in six leisure activities was assessed twice. A cognitive battery and 3T MRI brain scan were administered at the second visit. RESULTSWeekly computer use at mid-life associated with larger volumes of the left putamen and higher scores for fluid intelligence, alphanumeric and numeric trail making tasks and prospective memory. Frequent attendance at a sports club or gym at mid-life was associated with stronger connectivity of the sensorimotor network with the lateral visual and cerebellar networks. No other associations were significant. DISCUSSIONThis study demonstrates that not all leisure activities contribute to cognitive health equally, nor is there one unifying neural signature across leisure activities.

neuroscience↗

bioRxiv2019

Paired-end Mappability of Transposable Elements in the Human Genome

Though transposable elements make up around half of the human genome, the repetitive nature of their sequences makes it difficult to accurately align conventional sequencing reads. However, in light of new advances in sequencing technology, such as increased read length and paired-end libraries, these repetitive regions are now becoming easier to align to. This study investigates the mappability of transposable elements with 50bp, 76bp and 100bp paired-end read libraries. With respect to those read lengths and allowing for 3 mismatches during alignment, over 68%, 85%, and 88% of all transposable elements in the RepeatMasker database are uniquely mappable, suggesting that accurate locus-specific mapping of older transposable elements is well within reach.

genomics↗