Biology subjects

Knoop, L.

Publications and source records attributed to Knoop, L..

3 recordsLinked to original sources

bioRxiv2024

Characterising tandem repeat complexities across long-read sequencing platforms with TREAT

Tandem repeats (TR) play important roles in genomic variation and disease risk in humans. Long-read sequencing allows for the accurate characterisation of TRs, however, the underlying bioinformatics perspectives remain challenging. We present otter and TREAT: otter is a fast targeted local assembler, cross-compatible across different sequencing platforms. It is integrated in TREAT, an end-to-end workflow for TR characterisation, visualisation and analysis across multiple genomes. In a comparison with existing tools based on long-read sequencing data from both Oxford Nanopore Technology (ONT, Simplex and Duplex) and PacBio (Sequel 2 and Revio), otter and TREAT achieved state-of-the-art genotyping and motif characterisation accuracy. Applied to clinically relevant TRs, TREAT/otter significantly identified individuals with pathogenic TR expansions. When applied to a case-control setting, we significantly replicated previously reported associations of TRs with Alzheimers Disease, including those near or within APOC1 (p=2.63x10-9), SPI1 (p=6.5x10-3) and ABCA7 (p=0.04) genes. We finally used TREAT/otter to systematically evaluate potential biases when genotyping TRs using diverse ONT and PacBio long-read sequencing datasets. We showed that, in rare cases (0.06%), long-read sequencing suffers from coverage drops in TRs, including the disease-associated TRs in ABCA7 and RFC1 genes. Such coverage drops can lead to TR mis-genotyping, hampering the accurate characterisation of TR alleles. Taken together, our tools can accurately genotype TR across different sequencing technologies and with minimal requirements, allowing end-to-end analysis and comparisons of TR in human genomes, with broad applications in research and clinical fields.

bioinformatics↗

bioRxiv2024

MotifScope: a multi-sample motif discovery and visualization tool for tandem repeats

Tandem repeats (TRs) constitute a significant portion of the human genome, exhibiting high levels of polymorphism due to variations in size and motif composition. These variations have been associated with various neuropathological disorders, underscoring the clinical importance of TRs. Furthermore, the motif structure of these repeats can offer valuable insights into evolutionary dynamics and population structure. However, analysis of TRs has been hampered by the limitations of short-read sequencing technology, which lacks the ability to fully capture the complexity of these sequences. With long-read data becoming more accessible, there is now also a need for tools to explore and characterize these TRs. In this study, we introduce MotifScope, a novel algorithm for visualization of TRs in their population context based on a de novo k-mer approach for motif discovery. Comparative analysis against three established tools, uTR, TRF, and vamos, reveals that MotifScope can identify a greater number of motifs and more accurately represent the actual repeat sequence. Additionally, MotifScope enables comparison of sequencing reads within an individual and assemblies across different individuals, showing its applicability in diverse genomic contexts. We demonstrate potential applications of MotifScope in diverse fields, including population genetics, clinical settings, and forensic analyses.

genomics↗

bioRxiv2020

Meningeal inflammation in multiple sclerosis induces phenotypic changes in cortical microglia that differentially associate with neurodegeneration

Meningeal inflammation strongly associates with demyelination and neuronal loss in the underlying cortex of progressive MS patients, contributing to clinical disability. However, the pathological mechanisms of meningeal inflammation-induced cortical pathology are still largely elusive. Using extensive analysis of human post-mortem tissue, we identified two distinct microglial phenotypes, termed MS1 and MS2, in the cortex of progressive MS patients. These phenotypes differed in morphology and protein expression, but both associated with inflammation of the overlying meninges. We could replicate the MS-specific microglial phenotypes in a novel in vivo rat model for progressive MS-like meningeal inflammation, with microglia present at 1 month post-induction resembling MS1 microglia whereas those at 2 months acquired an MS2-like phenotype. Interestingly, MS1 microglia were involved in presynaptic displacement and phagocytosis and associated with a relative sparing of neurons in the MS and animal cortex. In contrast, the presence of MS2 microglia coincided with substantial neuronal loss. Taken together, we uncovered that in response to meningeal inflammation, microglia acquire two distinct phenotypes that differentially associate with neurodegeneration in the progressive MS cortex. Our data suggests that these phenotypes occur sequentially and that microglia may lose their protective properties over time, contributing to neuronal loss.

neuroscience↗