Biology subjects

Diehl, A. G.

Publications and source records attributed to Diehl, A. G..

5 recordsLinked to original sources

bioRxiv2026

Fiber-TEnCATS reveals haplotype-specific chromatin accessibility and DNA methylation at human L1HS loci

Human-specific long interspersed nuclear element-1 (L1HS) is an active and autonomous retrotransposon in the human genome. Changes in its transcription and transposition are known to affect cellular processes involved in development and aging, and diseases such as neurological disorders and cancer. To better understand natural variability in epigenetic patterns that affect L1HS regulation, we developed a targeted long-read method to simultaneously profile individual haplotypes for DNA methylation and chromatin accessibility across L1HS loci in a healthy human cell line trio. We show that the intronic L1HS in the ZNF638 gene consistently displays high chromatin accessibility and DNA hypomethylation with bidirectional transcription. Our approach also reveals additional intronic and intergenic L1HS copies with allele-specific chromatin accessibility and methylation, and instances of reduced promoter DNA methylation that does not correspond with increased chromatin accessibility. We also identify potential cases of non-Mendelian inheritance of DNA methylation patterns over a subset of L1HS promoters. Our methods high coverage over L1HS loci enables detection and profiling of loci that are missed even by long-read-based assemblies and enables more accurate inheritance tracing of L1HS insertions. Overall, our results offer new insights into the locus-specific regulation of both reference and non-reference L1HS within the human genome.

genomics↗

bioRxiv2023

LRphase: an efficient method for assigning haplotype identity to long reads

MotivationUnderstanding the functional effects of sequence variation is among the primary goals of contemporary genomics. Individual human genomes contain millions of variants which are thought to contribute to phenotypic variability and differential disease risks at the population level. However, because variants rarely act in isolation, we cannot accurately predict functional effects without first considering the potential effects of other interacting variants on the same chromosome. This information can be obtained by phasing the read data from sequencing experiments. However, no standalone tools are available to simply phase reads based on known haplotypes. Here we present LRphase: a user-friendly utility for simple phasing of long sequencing reads. Availability and ImplementationLRphase is implemented in Python, and is freely available at https://github.com/Boyle-Lab/LRphase, under the MIT license. Version 1.1.0, described in this manuscript, is available through the pip and Bioconda repositories (e.g., "pip install lrphase==1.1.0"). Contactapboyle@umich.edu Supplementary InformationSupplementary methods are available as part of the online version of this publication.

bioinformatics↗

bioRxiv2022

Challenges in screening for de novo noncoding variants contributing to genetically complex phenotypes

Understanding the genetic basis for complex, heterogeneous disorders, such as autism spectrum disorder (ASD), is a persistent challenge in human medicine. Owing to their phenotypic complexity, the genetic mechanisms underlying these disorders may be highly variable across individual patients. Furthermore, much of their heritability is unexplained by known regulatory or coding variants. Indeed, there is evidence that much of the causal genetic variation stems from rare and de novo variants arising from ongoing mutation. These variants occur mostly in noncoding regions, likely affecting regulatory processes for genes linked to the phenotype of interest. However, because there is no uniform code for assessing regulatory function, it is difficult to separate these mutations into likely functional and nonfunctional subsets. This makes finding associations between complex diseases and potentially causal de novo single-nucleotide variants (dnSNVs) a difficult task. To date, all but one published study in this area has failed to find any significant associations between dnSNVs from ASD patients and any class of known regulatory elements. We sought to identify the underlying reasons for this and present strategies for overcoming these challenges. We show that, contrary to previous claims, the main reason for failure to find robust statistical enrichments is not the number of families sampled, but the quality and relevance to ASD of the annotations used to prioritize dnSNVs, and the reliability of the set of dnSNVs itself. We present a list of recommendations for designing future studies of this sort that will help researchers avoid common pitfalls.

genetics↗

bioRxiv2019

Transposable elements strongly contribute to cell-specific and species-specific looping diversity in mammalian genomes.

BackgroundChromatin looping is exceedingly important to gene regulation and a host of other nuclear processes. Many recent insights into 3D chromatin structure across species and cell types have contributed to our understanding of the principles governing chromatin looping. However, 3D genome evolution and how it relates to Mendelian selection remain largely unexplored. CTCF, an insulator protein found at most loop anchors, has been described as the \"master weaver\" of mammalian genomes, and variations in CTCF occupancy are known to influence looping divergence. A large fraction of mammalian CTCF binding sites fall within transposable elements (TEs) but their contributions to looping variation are unknown. Here we investigated the effect of TE-driven CTCF binding site expansions on chromatin looping in human and mouse.\n\nResultsTEs have broadly contributed to CTCF binding and loop boundary specification, primarily forming variable loops across species and cell types and contributing nearly 1/3 of species-specific and cell-specific loops.\n\nConclusionsOur results demonstrate that TE activity is a major source of looping variability across species and cell types. Thus, TE-mediated CTCF expansions explain a large fraction of population-level looping variation and may play a role in adaptive evolution.

genomics↗

bioRxiv2017

Transcription factor co-binding patterns drive conserved regulatory outcomes

The mouse has been widely used as a model system in which to study human genetic mechanisms. However, part of the difficulty in translating findings from mouse is that, despite high levels of gene conservation, regulatory control networks between human and mouse have been extensively rewired. To understand common themes of regulatory control we look beyond physical sharing of regulatory sequence, where extensive turnover of individual transcription factor binding sites complicates cross-species prediction of specific functions, and instead look at conserved properties of the regulatory code itself. We define regulatory conservation in terms of a grammar with shared, species-specific, and tissue-specific segments, and show that this grammar is more predictive of shared chromatin states and gene expression profiles than shared occupancy alone. Furthermore, we demonstrate a marked enrichment of disease associated variation in conserved grammatical patterns. These findings offer new understanding of transcriptional regulatory mechanisms shared between human and mouse.

genomics↗