Biology subjects

Mordaunt, C. E.

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

9 recordsLinked to original sources

bioRxiv2021

Comethyl: A network-based methylome approach to investigate the multivariate nature of health and disease

Health outcomes are frequently shaped by difficult to dissect inter-relationships between biological, behavioral, social, and environmental factors. DNA methylation patterns reflect such multi-variate intersections, providing a rich source of novel biomarkers and insight into disease etiologies. Recent advances in whole-genome bisulfite sequencing (WGBS) enable investigation of DNA methylation over all genomic CpGs, but existing bioinformatic approaches lack accessible system-level tools. Here, we develop the R package Comethyl, for weighted gene correlation network analysis (WGCNA) of user-defined genomic regions that generates modules of comethylated regions, which are then tested for correlations with sample traits. First, regions are defined by CpG genomic location or regulatory annotation and filtered based on CpG count, sequencing depth, and variability. Next, correlation networks are used to find modules of interconnected nodes using methylation values within the selected regions. Each module containing multiple comethylated regions is reduced in complexity to a single eigennode value, which is then tested for correlations with experimental metadata. Comethyl has the ability to cover the noncoding regulatory regions of the genome with high relevance to interpretation of genome-wide association studies and integration with other types of epigenomic data. We demonstrate the utility of Comethyl on a dataset of male cord blood samples from newborns later diagnosed with autism spectrum disorder (ASD) versus typical development. Comethyl successfully identified an ASD-associated module containing gene regions with brain glial functions. Comethyl is expected to be useful in uncovering the multi-variate nature of health disparities for a variety of common disorders. Comethyl is available at github.com/cemordaunt/comethyl. Description of the AuthorsCharles E. Mordaunt, Ph.D. developed Comethyl while a postdoctoral fellow in the department of Medical Microbiology and Immunology at UC Davis. He is currently a Computational Biologist at GSK. Julia S. Mouat is a doctoral student in the Integrative Genetics and Genomics graduate group at UC Davis with interests in health disparities and intergenerational epigenetic risk factors for autism spectrum disorders. Rebecca J. Schmidt, Ph.D. is an Associate Professor of Public Health Sciences at UC Davis, with expertise in the use of epigenetics in epidemiology and neurodevelopmental disorders. Janine M. LaSalle, Ph.D. is a Professor of Medical Microbiology and Immunology, Co-Director of the Perinatal Origins of Disparities Center, and Deputy Director of the Environmental Health Sciences Center at UC Davis, with expertise in epigenomics and neurodevelopmental disorders.

bioinformatics↗

bioRxiv2020

Low-Pass Whole Genome Bisulfite Sequencing of Neonatal Dried Blood Spots Identifies a Role for RUNX1 in Down Syndrome DNA Methylation Profiles

Neonatal dried blood spots (NDBS) are a widely banked sample source that enable retrospective investigation into early-life molecular events. Here, we performed low-pass whole genome bisulfite sequencing (WGBS) of 86 NDBS DNA to examine early-life Down syndrome (DS) DNA methylation profiles. DS represents an example of genetics shaping epigenetics, as multiple array-based studies have demonstrated that trisomy 21 is characterized by genome-wide alterations to DNA methylation. By assaying over 24 million CpG sites, thousands of genome-wide significant (q < 0.05) DMRs that distinguished DS from typical development (TD) and idiopathic developmental delay (DD) were identified. Machine learning feature selection refined these DMRs to 22 loci. The DS DMRs mapped to genes involved in neurodevelopment, metabolism, and transcriptional regulation. Based on comparisons to previous DS methylation studies and reference epigenomes, the hypermethylated DS DMRs were significantly (q < 0.05) enriched across tissues while the hypomethylated DS DMRs were significantly (q < 0.05) enriched for blood-specific chromatin states. A [~]28 kb block of hypermethylation was observed on chromosome 21 in the RUNX1 locus, which encodes a hematopoietic transcription factor whose binding motif was the most significantly enriched (q < 0.05) overall and specifically within the hypomethylated DMRs. Finally, we also identified DMRs that distinguished DS NDBS based on the presence or absence of congenital heart disease (CHD). Together, these results not only demonstrate the utility of low-pass WGBS on NDBS samples for epigenome-wide association studies, but also provide new insights into the early-life mechanisms of epigenomic dysregulation resulting from trisomy 21.

genomics↗

bioRxiv2020

Expression changes in immune and epigenetic gene pathways associated with nutritional metabolites in maternal blood from pregnancies resulting in autism and atypical neurodevelopment

BackgroundThe prenatal period is a critical window to study factors involved in the development of autism spectrum disorder (ASD). Environmental factors, especially in utero nutrition, can interact with genetic risk for ASD, but how specific prenatal nutrients in mothers of children later diagnosed with ASD or non-typical development (Non-TD) associate with gestational gene expression is poorly understood. Maternal blood collected prospectively during pregnancy provides a new opportunity to gain insights into nutrition, particularly one-carbon metabolites, on gene pathways and neurodevelopment. MethodsGenome-wide transcriptomes were measured using microarrays in 300 maternal blood samples from all three trimesters in the Markers of Autism Risk in Babies - Learning Early Signs (MARBLES) study. Sixteen different one-carbon metabolites, including folic acid, betaine, 5-methyltretrahydrofolate (5-MeTHF), and dimethylglycine (DMG) were measured. Differential expression analysis and weighted gene correlation network analysis (WGCNA) were used to compare gene expression between children later diagnosed as typical development (TD), Non-TD and ASD, and to nutrient metabolites. ResultsUsing differential gene expression analysis, six transcripts associated with four genes (TGR-AS1, SQSTM1, HLA-C and RFESD) showed genome-wide significance (FDR q < 0.05) with child outcomes. Genes nominally differentially expressed compared to TD specifically in ASD, but not Non-TD, significantly overlapped with seven high confidence ASD genes. 218 transcripts in common to ASD and Non-TD differential expression compared to TD were significantly enriched for functions in immune response to interferon-gamma, apoptosis, and metal ion transport. WGCNA identified co-expressed gene modules significantly correlated with 5-MeTHF, folic acid, DMG, and betaine. A module enriched in DNA methylation functions showed a protective association with folic acid/5-MeTHF concentrations and ASD risk. Independent of child outcome, maternal plasma betaine and DMG concentrations associated with a block of co-expressed genes enriched for adaptive immune, histone modification, and RNA processing functions. LimitationsBlood contains a heterogeneous mixture of cell types, and many WGCNA modules correlated with cell type and/or nutrient concentrations, but not child outcome. Gestational age correlated with some co-expressed gene modules in addition to nutrients. ConclusionsThese results support the premise that the prenatal maternal blood transcriptome is a sensitive indicator of gestational nutrition and childrens later neurodevelopmental outcomes.

bioinformatics↗

bioRxiv2019

Cord blood DNA methylome in newborns later diagnosed with autism spectrum disorder reflects early dysregulation of neurodevelopmental and X-linked genes

BackgroundAutism spectrum disorder (ASD) is a neurodevelopmental disorder with complex heritability and higher prevalence in males. Since the neonatal epigenome has the potential to reflect past interactions between genetic and environmental factors during early development, we performed whole-genome bisulfite sequencing of 152 umbilical cord blood samples from the MARBLES and EARLI high-familial risk prospective cohorts to identify an epigenomic signature of ASD at birth. ResultsWe identified differentially-methylated regions (DMRs) stratified by sex that discriminated ASD from control cord blood samples in discovery and replication sets. At a region level, 7 DMRs in males and 31 DMRs in females replicated across two independent groups of subjects, while 537 DMR genes in males and 1762 DMR genes in females replicated by gene association. These DMR genes were significantly enriched for brain and embryonic expression, X chromosome location, and identification in prior epigenetic studies of ASD in post-mortem brain. In males and females, autosomal ASD DMRs were significantly enriched for promoter and bivalent chromatin states across most cell types, while sex differences were observed for X-linked ASD DMRs. Lastly, these DMRs identified in cord blood were significantly enriched for binding sites of methyl-sensitive transcription factors relevant to fetal brain development. ConclusionsAt birth, prior to the diagnosis of ASD, a distinct DNA methylation signature was detected in cord blood over regulatory regions and genes relevant to early fetal neurodevelopment. Differential cord methylation in ASD supports the developmental and sex-biased etiology of ASD, and provides novel insights for early diagnosis and therapy.

genomics↗

bioRxiv2018

Placental DNA methylation levels at CYP2E1 and IRS2 are associated with child outcome in a prospective autism study

DNA methylation acts at the interface of genetic and environmental factors relevant for autism spectrum disorder (ASD). Placenta, normally discarded at birth, is a potentially rich source of DNA methylation patterns predictive of ASD in the child. Here, we performed whole methylome analyses of placentas from a prospective study of high-risk pregnancies. 400 differentially methylated regions (DMRs) discriminated placentas stored from children later diagnosed with ASD compared to typical controls. These ASD DMRs were significantly enriched at promoters, mapped to 596 genes functionally enriched in neuronal development, and overlapped genetic ASD risk. ASD DMRs at CYP2E1 and IRS2 reached genome-wide significance, replicated by pyrosequencing, and correlated with expression. Methylation at CYP2E1 associated with both ASD diagnosis and cis genotype, while methylation at IRS2 was unaffected by cis genotype but modified by preconceptional maternal prenatal vitamin use. This study therefore identified two potentially useful early epigenetic markers for ASD in placenta.

genetics↗

bioRxiv2018

A meta-analysis of two high-risk prospective cohort studies reveals autism-specific transcriptional changes to chromatin, autoimmune, and environmental response genes in umbilical cord blood

BackgroundAutism spectrum disorder (ASD) is a neurodevelopmental disorder that affects more than 1% of children in the United States. ASD risk is thought to arise from a combination of genetic and environmental factors, with the perinatal period as a critical window. Understanding early transcriptional changes in ASD would assist in clarifying disease pathogenesis and identifying biomarkers and treatments. However, little is known about umbilical cord blood gene expression profiles in babies later diagnosed with ASD compared to non-typically developing (Non-TD) or neurotypical children.\n\nMethodsGenome-wide transcript levels were measured by Affymetrix Human Gene 2.0 array in RNA from umbilical cord blood samples from both the Markers of Autism Risk in Babies--Learning Early Signs (MARBLES) and the Early Autism Risk Longitudinal Investigation (EARLI) high-risk pregnancy cohorts that enroll younger siblings of a child previously diagnosed with ASD. An algorithm-based diagnosis from 36 month assessments categorized the younger sibling as either ASD, typically developing (TD), or not ASD but non-typically developing (Non-TD). 59 ASD, 92 Non-TD, and 120 TD subjects were included and differences were identified in ASD versus TD subjects, with Non-TD versus TD as a specificity control. Meta-analysis was used to combine the results from both studies. Functional enrichments of differentially-expressed genes were examined across diagnostic groups.\n\nResultsWhile cord blood gene expression differences comparing either ASD or Non-TD to TD did not reach genome-wide significance when adjusting for multiple comparisons, 172 genes were nominally differentially-expressed between ASD and TD cord blood (log2(fold change) > 0.1, p < 0.01). These genes were significantly enriched for toxic substance response and xenobiotic metabolism functions, and gene sets involved in chromatin regulation and systemic lupus erythematosus were significantly upregulated (FDR q < 0.05). In contrast, 66 genes were differentially-expressed between Non-TD and TD cord blood, including only 8 genes that were also differentially-expressed in ASD.\n\nConclusionsThis is the first study to identify perinatal gene expression differences in umbilical cord blood specific to ASD. The results of this meta-analysis across two prospective ASD cohorts support involvement of environmental, immune, and epigenetic mechanisms in ASD etiology.

genomics↗

bioRxiv2018

Whole genome bisulfite sequencing of Down syndrome brain reveals regional DNA hypermethylation and novel disease insights

Down Syndrome (DS) is the most common genetic cause of intellectual disability, in which an extra copy of human chromosome 21 (HSA21) affects regional DNA methylation profiles across the genome. Although DNA methylation has been previously examined at select regulatory regions across the genome in a variety of DS tissues and cells, differentially methylated regions (DMRs) have yet to be examined in an unbiased sequencing-based approach. Here, we present the first analysis of DMRs from whole genome bisulfite sequencing (WGBS) data of human DS and matched control brain, specifically frontal cortex. While no global differences in DNA methylation were observed, we identified 3,152 DS-DMRs across the entire genome, the majority of which were hypermethylated in DS. DS-DMRs were significantly enriched at CpG islands and de-enriched at specific gene body and regulatory regions. Functionally, the hypermethylated DS-DMRs were enriched for one-carbon metabolism, membrane transport, and glutamatergic synaptic signaling, while the hypomethylated DMRs were enriched for proline isomerization, glial immune response, and apoptosis. Furthermore, in a cross-tissue comparison to previous studies of DNA methylation from diverse DS tissues and reference epigenomes, hypermethylated DS-DMRs showed a strong cross-tissue concordance, while a more tissue-specific pattern was observed for the hypomethylated DS-DMRs. Overall, this approach highlights that low-coverage WGBS of clinical samples can identify epigenetic alterations to known biological pathways, which are potentially relevant to therapeutic treatments and include metabolic pathways. These results also provide new insights into the genome-wide effects of genetic alterations on DNA methylation profiles indicative of altered neurodevelopment and brain function.

genomics↗

bioRxiv2018

Epigenomic convergence of genetic and immune risk factors in autism brain

Neurodevelopmental disorders (NDDs) impact 7% to 14% of all children in developed countries and are one of the leading causes of lifelong disability. Epigenetic modifications are poised at the interface between genes and environment and are predicted to reveal insight into the gene networks, cell types, and developmental timing of NDD etiology. Whole-genome bisulfite sequencing was used to examine DNA methylation in 49 human cortex samples from three different NDDs (autism spectrum disorder, Rett syndrome, and Dup15q syndrome) and matched controls. Integration of methylation differences across NDDs with relevant genomic and genetic datasets revealed differentially methylated regions (DMRs) unique to each type of NDD but with shared regulatory functions in neurons and microglia. DMRs were significantly enriched for known NDD genetic risk factors, including both common inherited and rare de novo variants. Weighted region co-methylation network analysis revealed a module related to NDD diagnosis and enriched for microglial regulatory regions. Together, these results demonstrate an epigenomic signature of NDDs in human cortex shared with known genetic and immune etiological risk. Epigenomic insights into cell types and gene regulatory regions will aid in defining therapeutic targets and early biomarkers at the interface of genetic and environmental NDD risk factors.

genomics↗

bioRxiv2017

Experience-dependent neuroplasticity of the developing hypothalamus: integrative epigenomic approaches

BackgroundMaternal care during early-life plays a crucial role in the sculpting of the mammalian brain. Augmented maternal care during the first postnatal week promotes life-long stress resilience and improved memory compared with the outcome of routine rearing conditions. Recent evidence suggests that this potent phenotypic change commences with altered synaptic connectivity of stress sensitive hypothalamic neurons. However, the epigenomic basis of the long-lived consequences is not well understood.\n\nMethodsHere, we employed whole-genome bisulfite sequencing (WGBS), RNA-sequencing (RNA-seq), and a multiplex microRNA (miRNA) assay to examine the effects of augmented maternal care on DNA cytosine methylation, gene expression, and miRNA expression.\n\nResultsA significant decrease in global DNA methylation was observed in offspring hypothalamus following a week of augmented maternal care, corresponding to differential methylation and expression of thousands of genes. Differentially methylated and expressed genes were enriched for functions in neurotransmission, neurodevelopment, protein synthesis, and oxidative phosphorylation, as well as known stress response genes. Twenty prioritized genes with three lines of evidence (methylation, expression, and altered miRNA target) were identified as highly relevant to the stress resiliency phenotype.\n\nConclusionsThis combined unbiased approach enabled the discovery of novel genes and gene pathways that advance our understanding of the central epigenomic mechanisms underlying the profound effects of maternal care on the developing brain.

neuroscience↗