Biology subjects

van der Lee, S.

Publications and source records attributed to van der Lee, S..

4 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↗

bioRxiv2022

What does heritability of Alzheimer's disease represent?

INTRODUCTIONBoth Alzheimers disease (AD) and ageing have a strong genetic component. In each case, many associated variants have been discovered, but how much missing heritability remains to be discovered is debated. Variability in the estimation of SNP-based heritability could explain the differences in reported heritability. METHODSWe compute heritability in five large independent cohorts (N=7,396, 1,566, 803, 12,528 and 3,963) to determine whether a consensus for the AD heritability estimate can be reached. These cohorts vary by sample size, age of cases and controls and phenotype definition. We compute heritability a) for all SNPs, b) excluding APOE region, c) excluding both APOE and genome-wide association study hit regions, and d) SNPs overlapping a microglia gene-set. RESULTSSNP-based heritability of Alzheimers disease is between 38 and 66% when age and genetic disease architecture are correctly accounted for. The heritability estimates decrease by 12% [SD=8%] on average when the APOE region is excluded and an additional 1% [SD=3%] when genome-wide significant regions were removed. A microglia gene-set explains 69-84% of our estimates of SNP-based heritability using only 3% of total SNPs in all cohorts. CONCLUSIONThe heritability of neurodegenerative disorders cannot be represented as a single number, because it is dependent on the ages of cases and controls. Genome-wide association studies pick up a large proportion of total AD heritability when age and genetic architecture are correctly accounted for. Around 13% of SNP-based heritability can be explained by known genetic loci and the remaining heritability likely resides around microglial related genes. Author SummaryEstimates of heritability in Alzheimers disease, the proportion of phenotypic variance explained by genetics, are very varied across different studies, therefore, the amount of missing heritability not yet captured by current genome-wide association studies is debated. We investigate this in five independent cohorts, provide estimates based on these cohorts and detail necessary suggestions to accurately calculate heritability in age-related disorders. We also confirm the importance of microglia relevant genetic markers in Alzheimers disease. This manuscript provides suggestions for other researchers computing heritability in late-onset disorders and the microglia gene-set used in this study will be published alongside this manuscript and made available to other researchers. The correct assessment of disease heritability will aid in better understanding the amount of missing heritability in Alzheimers disease.

genetics↗

bioRxiv2017

A common haplotype lowers SPI1 (PU.1) expression in myeloid cells and delays age at onset for Alzheimer’s disease

In this study we used age at onset of Alzheimers disease (AD), cerebrospinal fluid (CSF) biomarkers, and cis-expression quantitative trait loci (cis-eQTL) datasets to identify candidate causal genes and mechanisms underlying AD GWAS loci. In a genome-wide survival analysis of 40,255 samples, eight of the previously reported AD risk loci are significantly (P < 5x10-8) or suggestively (P < 1x10-5) associated with age at onset-defined survival (AAOS) and a further fourteen novel loci reached suggestive significance. Using stratified LD score regression we demonstrated a significant enrichment of AD heritability in hematopoietic cells of the myeloid and B-lymphoid lineage. We then investigated the impact of these 22 AAOS-associated variants on CSF biomarkers and gene expression in cells of the myeloid lineage. In particular, the minor allele of rs1057233 (G), within the previously reported CELF1 AD risk locus, shows association with higher age at onset of AD (P=8.40x10-6), higher CSF levels of A{beta}42 (P=1.2x10-4), and lower expression of SPI1 in monocytes (P=1.50x10-105) and macrophages (P=6.41x10-87). SPI1 encodes PU.1, a transcription factor critical for myeloid cell development and function. AD heritability is enriched within the SPI1 cistromes of monocytes and macrophages, implicating a myeloid PU.1 target gene network in the etiology of AD. Finally, experimentally altered PU.1 levels are correlated with phagocytic activity of BV2 mouse microglial cells and specific changes in the expression of multiple myeloid-expressed genes, including the mouse orthologs of AD-associated genes, APOE, CLU/APOJ, CD33, MS4A4A/MS4A6A, and TYROBP. Our results collectively suggest that lower SPI1 expression reduces AD risk by modulating myeloid cell gene expression and function.

neuroscience↗