Biology subjects

Quinn, J. P.

Publications and source records attributed to Quinn, J. P..

8 recordsLinked to original sources

bioRxiv2026

Long-read sequencing maps transposable element variation and its regulatory and epigenetic effects in the human brain

Transposable elements (TEs) are mobile DNA sequences that shape genome architecture and gene regulation, yet their roles in the human brain remain largely unresolved. Short-read sequencing lacks the resolution to accurately map TE insertions, detect associated structural variants, and resolve highly repetitive regions. Here, we leverage long-read whole-genome sequencing to profile germline TE insertions in postmortem brain tissue from two ancestrally diverse cohorts: the North American Brain Expression Consortium (NABEC; European ancestry, n = 205) and the Human Brain Collection Core (HBCC; African and African-admixed ancestry, n = 146). We identified 2,842 and 1,660 high-confidence non-reference insertions in HBCC and NABEC, respectively, spanning Alu, LINE-1, and SVA elements. We then also further characterized complex short tandem repeat and variable number tandem repeat variation within reference SVA and Alu loci. Reference TEs were also found to mediate complex structural variants at loci implicated in brain development and neurodegenerative disease, with several showing ancestry-specific patterns. Integration of bulk RNA-sequencing data identified TE expression quantitative trait loci, including insertions that modulate neuronal gene expression. Single-nucleus RNA sequencing revealed cell-type-specific effects of TE regulation across cortical populations. Long-read methylation profiling further demonstrated age-associated epigenetic regulation of both reference and non-reference Alu elements. As a community resource, we release a catalog of TE insertions, allele frequencies, and ancestry-specific distributions to enable future functional and disease-focused investigations. Together, these findings highlight the widespread regulatory and epigenetic influence of TEs in the human brain and establish long-read sequencing as a powerful approach for uncovering cell-type- and population-specific TE dynamics.

genomics↗

bioRxiv2025

Systematic comparative benchmarking of computational methods for the detection of transposable elements in long-read sequencing data

BackgroundMobile element insertions, particularly transposable elements (TEs) such as Alu, LINE-1 (L1), SVA, and endogenous retroviruses (ERVs), represent a major source of human genetic variation and have been implicated in evolution, genomic instability, and disease. Although long-read sequencing generally outperforms short-read sequencing for the characterisation of such elements, their accurate detection with long-reads remains challenging, with different computational tools adopting varying approaches and producing divergent call sets. As gold standards currently do not exist for TE detection, benchmarking these methods is essential to understand their strengths, limitations, and biases. Here, we systematically evaluate the performance of available state-of-the-art TE detection tools on both simulated and real human genome data using highly characterised samples from the Genome in a Bottle consortium, population level reference databases and an in-house collection for which matching short-read sequencing data are available. ResultsOur results show significant differences in calling strategies, leading to substantial variation in precision, recall, and the spectrum of TE families detected across tools. Our benchmark also displays the differences between short-read and long-read calls, highlighting the importance of appropriate method selection. ConclusionsThe benchmarking results presented here will aid TE researchers make better informed decisions on which tool to use in their long-read TE analyses. Strengths and limitations of different tools have been highlighted in depth as well as their computational requirements, which will result in less time spent finding the best tool for the job and promote faster TE research.

bioinformatics↗

bioRxiv2022

Mitochondrial function determines severity but not risk of amyotrophic lateral sclerosis

Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease. Selective vulnerability of energy-intensive motor neurons (MNs) has fostered speculation that mitochondrial function is a determinant of ALS. Previously, the position of mitochondrial function in the pathogenic cascade leading to neurotoxicity has been unclear. We separated upstream genetic determinants of mitochondrial function, including genetic variation within the mitochondrial genome or autosomes; from downstream changeable factors including mitochondrial copy number (mtCN) and MN gene expression. We discovered that functionally validated mitochondrial haplotypes are a determinant of ALS survival but not ALS risk. Loss-of-function genetic variants within, and reduced MN expression of, ACADM and DNA2 lead to shorter ALS survival; both genes impact mitochondrial function. MtCN responds dynamically to the onset of ALS independent of mitochondrial haplotype, and is also significantly correlated with disease severity. We conclude that mitochondrial function impacts ALS progression but not risk; our findings have therapeutic implications.

genetics↗

bioRxiv2022

RetroSnake: a Modular End-to-End Pipeline for Detection of Human Endogenous Retrovirus (HERV) Transposable Elements in Next Generation Sequencing (NGS) Data

Human Endogenous Retroviruses (HERVs) integrated into the genome of vertebrates as a result of ancient exogenous infections and currently comprise [~]8% of our genome. The majority of these elements have accumulated mutations rendering them inactive. The most recently acquired members, HERV-K have potential to produce viral particles and have been linked to a wide range of diseases including cancer and neurodegeneration. Although a range of tools for HERV discovery exist, most of them lack wet-lab validation of their results and are not end-to-end as they do not cover all steps of the analysis. These factors greatly limit their use. Here we describe RetroSnake, an end-to-end, modular, computationally efficient and customisable pipeline for the discovery of HERVs in short-read NGS data. RetroSnake presents important advantages with respect to other available tools. For instance, it is the only pipeline based on an extensively wet-lab validated protocol, and it is the most complete transposable elements detection pipeline, producing annotated insertions presented as an interactive html file, easy enough to use by life scientists without substantial computational training. Availability and implementationThe Pipeline and an extensive documentation are available at https://github.com/KHP-Informatics/RetroSnake Contactalfredo.iacoangeli@kcl.ac.uk

genomics↗

bioRxiv2022

An assessment of bioinformatics tools for the detection of human endogenous retroviral insertions in short-read genome sequencing data

There is a growing interest in the study of human endogenous retroviruses (HERVs) given the substantial body of evidence that implicates them in many human diseases. Although their genomic characterization presents numerous technical challenges, next-generation sequencing (NGS) has shown potential to detect HERV insertions and their polymorphisms in humans, and a number of computational tools to detect them in short-read NGS data exist. In order to design optimal analysis pipelines, an independent evaluation of the currently available tools is required. We evaluated the performance of a set of such tools using a variety of experimental designs and types of NGS datasets. These included 50 human short read whole-genome sequencing samples, matching long and short read NGS data, and simulated short-read NGS data. Our results highlight the performance variability of the tools across the datasets and suggest that different tools might be suitable for different study designs. Using multiple tools and a consensus approach is advisable if computationally feasible and wet-lab validation via PCR is advisable where biological samples are available.

bioinformatics↗

bioRxiv2019

The potential for polyphosphate metabolism in Archaea and anaerobic polyphosphate formation in Methanosarcina mazei.

Inorganic polyphosphate (polyP) is ubiquitous across all forms of life, but the study of its metabolism has been mainly confined to bacteria and yeasts. Few reports detail the presence and accumulation of polyP in Archaea, and little information is available on its functions and regulation. Here, we report that homologs of bacterial polyP metabolism proteins are present across the major taxa in the Archaea, suggesting that archaeal populations may have a greater contribution to global phosphorus cycling than has previously been recognised. We also demonstrate that polyP accumulation can be induced under strictly anaerobic conditions, in response to changes in phosphate (Pi) availability, i.e. Pi starvation, followed by incubation in Pi replete media (overplus), in cells of the methanogenic archaeon Methanosarcina mazei. Pi-starved M. mazei cells increased transcript abundance of the PHO-regulated alkaline phosphatase (phoA) gene and of the high-affinity phosphate transport (pstSCAB-phoU) operon: no increase in polyphosphate kinase 1 (ppk1) transcript abundance was observed. Subsequent incubation of Pi-starved M. mazei cells under Pi replete conditions, led to a 237% increase in intracellular polyphosphate content and a >5.7-fold increase in ppk1 gene transcripts. Ppk1 expression in M. mazei thus appears not to be under classical PHO regulon control.

microbiology↗

bioRxiv2018

Genetic variation within genes associated with mitochondrial function is significantly associated with later age at onset of Parkinson disease and contributes to disease risk

Mitochondrial dysfunction has been implicated in the aetiology of monogenic Parkinsons disease (PD). Yet the role that mitochondrial processes play in the most common form of the disease; sporadic PD, is yet to be fully established. Here we comprehensively assessed the role of mitochondrial function associated genes in sporadic PD by leveraging improvements in the scale and analysis of PD GWAS data with recent advances in our understanding of the genetics of mitochondrial disease. First, we identified that a proportion of the \"missing heritability\" of the PD can be explained by common variation within genes implicated in mitochondrial disease (primary gene list) and mitochondrial function (secondary gene list). Next we calculated a mitochondrial-specific polygenic risk score (PRS) and showed that cumulative small effect variants within both our primary and secondary gene lists are significantly associated with increased PD risk. Most significantly we further report that the PRS of the secondary mitochondrial gene list was significantly associated with later age at onset. Finally, to identify possible functional genomic associations we implemented Mendelian randomisation, which showed that 14 of these mitochondrial function associated genes showed functional consequence associated with PD risk. Further analysis suggested that the 14 identified genes are not only involved in mitophagy but implicate new mitochondrial processes. Our data suggests that therapeutics targeting mitochondrial bioenergetics and proteostasis pathways distinct from mitophagy could be beneficial to treating the early stage of PD.

genetics↗

bioRxiv2017

Maternal depression and child behaviours: sex-dependent mediation by glucocorticoid receptor gene methylation in a longitudinal study from pregnancy to age 5 years

BackgroundEvolutionary hypotheses predict that male fetuses are more vulnerable to poor maternal conditions than females (Sex-biased Maternal Investment), but that the adaptive female fetus, with a more responsive hypothalamic-pituitary-adrenal (HPA) axis, is put at later risk of glucocorticoid mediated disorders where there is a mismatch between fetal and postnatal environments (Predictive Adaptive Response). Self-report measures of prenatal and postnatal depression and maternal report of child anxious depressed symptoms at 2.5, 3.5 and 5.0 years were obtained from an extensive sample of first time mothers recruited from the general population (N = 794). Salivary NR3C1 1-F promoter methylation was assayed at 14 months in an intensive subsample (N = 176) stratified during pregnancy by psychosocial risk. Generalised structural equation models (SEM) were fitted and estimated by maximum likelihood to allow inclusion of participants from both intensive and extensive samples.\n\nResultsPostnatal depression was associated with NR3C1 methylation and with anxious-depressed symptoms in the daughters of mothers lacking the hypothesised protective effect of high prenatal depression (prenatal-postnatal depression interaction for methylation, p =.00001; for child symptoms, p = .011). In girls, NR3C1 methylation mediated the association between maternal depression and child anxious-depressed symptoms. The effects were greater in girls than boys, and the test of the sex differences in the effect of the prenatal-postnatal depression interaction on both outcomes gave {chi}2(2) = 5.95 (p=.051).\n\nConclusionsThis is the first study to show in humans that, as a result of sex-biased reproductive investment and fetal adaptation, epigenetic and early behavioural outcomes may arise through different mechanisms in males and females. Epigenetic effects at the NR3C1 promoter mediated mismatch between prenatal and postnatal maternal conditions and child anxious-depressed symptoms, specifically in females.

genetics↗