Biology subjects

Aylor, D. L.

Publications and source records attributed to Aylor, D. L..

7 recordsLinked to original sources

bioRxiv2026

Inferring toxicant susceptibility in global populations from gene-environment interactions involving the Aryl Hydrocarbon Receptor

Gene-environment interaction (GxE) studies comprise a very small part of the genetics or environmental epidemiology literature, and most existing studies are in populations of European ancestry. We made predictions about GxE in global populations by combining existing GxE studies with genetic data from the 1000 Genomes Project (1kGP), which captured genetic variation in diverse populations worldwide. We modeled susceptibility of 1kGP populations to 2, 3, 7, 8-tetrachlorodibenzo-p-dioxin (TCDD) exposures based on variation in the aryl hydrocarbon receptor (AHR) gene. The premise of our approach is that the risk variants involved in GxE are shared across global super-populations but vary in frequency by population. We built our model upon GxE estimates from a study in Seveso, Italy, where offspring birthweight was influenced by AHR variants after TCDD exposure. Our simulations predicted that GxE would result in different outcomes across global populations. This framework can be extended to model population susceptibility to a broad range of toxicants that impact public health, including common AHR ligands like the polycyclic aromatic hydrocarbons found in cigarette smoke and diesel exhaust.

genetics↗

bioRxiv2025

Comprehensive Transcriptomic and Epigenomic Insights into Environmental Toxicant Exposures: The TaRGET II Resource

Environmental exposures to toxic chemicals can profoundly alter the transcriptome and epigenome in both humans and animals, contributing to disease development across the lifespan. To elucidate how early-life exposure to toxicants exerts such persistent effects, the Toxicant Exposures and Responses by Genomic and Epigenomic Regulators of Transcription II (TaRGET II) Consortium generated a landmark resource comprising 2,564 epigenomes and 1,043 transcriptomes from longitudinal studies in mice. All data are publicly available through the TaRGET II data portal and the WashU Epigenome Browser. This resource from target (liver, brain, lung, heart) and surrogate (blood) tissues at weaning (3 weeks) and two adult time-points (5 and 10 months) characterized the molecular response to arsenic (As), lead (Pb), bisphenol-A (BPA), di-2-ethylhexyl phthalate(DEHP), tributyltin (TBT), tetrachlorodibenzo-p-dioxin (TCDD), and particulate matter with a diameter of <2.5m (PM2.5). The findings revealed persistent, toxicant-specific, sex-dependent epigenomic and transcriptomic perturbations, resulting in disrupted expression of 14,908 genes, altered chromatin accessibility at 87,409 regulatory elements, DNA methylation changes at 113,186 genomic regions, and chromatin state switching of histone modifications. The resulting high-resolution map of how environmental exposures reprogram the epigenome and transcriptome is broadly accessible via ToxiTaRGET database, offering unparalleled opportunities for the scientific community to investigate the molecular underpinnings of environmental toxicant exposures and their contributions to disease pathogenesis.

pharmacology and toxicology↗

bioRxiv2025

Early-Life Environmental Exposures Reprogram Epigenomic Aging to Alter Gene Expression Trajectories

To understand how early-life environmental exposures shape health and disease risk across the lifecourse, the TaRGET II Consortium exposed mice to diverse toxicants from pre-conception through weaning, and followed individual animals into adulthood, generating over 800 epigenomic and transcriptomic profiles. These profiles revealed that early-life exposures induced persistent epigenomic reprogramming and significantly disrupted the adult transcriptome. Notably, despite their diverse mechanisms of action, the exposure signatures of the xenoestrogen BPA, obesogen TBT, dioxin TCDD, and air pollutant PM2.5, were all largely comprised of genes normally differentially expressed during liver aging. Epigenetic histone modifications at enhancers--and, to a lesser extent, promoters--emerged as key targets for this reprogramming. Despite differing mechanisms of action, these four toxicants imparted similar "fingerprints" on the adult liver, characterized by direction-and cell type-specific polarization of the transcriptome. Hepatocyte genes that typically increase with age, particularly those in metabolic pathways, were downregulated, while conversely, non-parenchymal cell genes that typically decrease with age, such as those involved in extracellular matrix production, were upregulated. A similar signature of anti-correlation with programmed aging aging was also found in the transcriptome of patients with liver disease and hepatocellular carcinoma (HCC), and was effective at distinguishing healthy from diseased human livers. These findings demonstrate that the plasticity of epigenomic aging is vulnerable to early-life environmental exposures, which can reprogram the epigenome with lasting impacts on the transcriptome, and disease risk, later in life.

genomics↗

bioRxiv2020

A neuroprotective locus modulates ischemic stroke infarction independent of collateral vessel anatomy

Ischemic stroke is caused by a disruption of the blood supply to the brain leading to neuronal cell death. Genetic studies of ischemic stroke have identified numerous gene variants that increase the risk to develop stroke. In stark contrast, genetic studies of stroke outcomes, such as the infarct territory size, are confounded by many uncontrollable variables, leading to a paucity of gene targets for treatment of an incipient stroke. Using genetically diverse inbred strains of mice and a surgically-induced model of ischemic stroke, we used quantitative trait locus mapping to identify novel gene targets modulating infarct size, which varies greatly across inbred strains. Although infarct size is largely determined by the extent of collateral vessel connection between arteries in the brain that enables reperfusion of the ischemic territory, we have identified strain pairs that do not vary in this phenotype, but which nonetheless exhibit large differences in infarct size. In this study we performed QTL mapping in mice from an intercross between two such strains, WSB/EiJ and C57BL/6J. We identified a strong locus on chromosome 8 that overlaps with a locus of similar direction and effect previously mapped in an intercross between C3H/HeJ and C57BL/6J strains. To identify causative genes within the overlapping genetic interval, we surveyed nonsynonymous coding SNPs and performed RNA sequencing data analysis for all three mapping strains. We identified Macrophage Scavenger Receptor 1 (Msr1) as a strong candidate gene that harbors multiple coding SNPs predicted to be damaging. Using Msr1-deficient mice, we demonstrated that cerebral infarct volume after stroke induction is dramatically increased in a strain background where reperfusion effects due to collateral vessels is blunted. Significantly, the identification of neuroprotective genes such as Msr1 provides new genes for future mechanistic studies of infarction following ischemic stroke and provides novel gene/protein targets for therapeutic development. Author summaryThe most common form of stroke arises when a blockage occurs in a blood vessel of the brain, thereby preventing delivery of oxygen and nutrients to areas supplied by the affected vessel, leading to tissue death. The main treatment for this form of stroke is medication to dissolve the blockage; however, more treatment options are required to better reduce the death and disability associated with stroke. In this study, we sought to identify genes that can decrease the amount of damage to brain tissue following a stroke, with a specific focus on examining genes that work to directly protect the neurons, rather than returning blood flow to the affected area. Since it is impossible to precisely control the nature of stroke and the genetic variability in humans, we used mice identify a genetic region that is associated with the amount of tissue damage following stroke. Within this genetic region, we identified a list of candidate genes, including the gene Msr1, which we found is important for controlling tissue damage in one genetic population of mice after stroke. The genes identified here require further follow-up to determine the impact on stroke outcomes and the usefulness of these candidates as therapeutic targets.

genetics↗

bioRxiv2020

Age and genetic background modify hybrid male sterility in house mice

Hybrid male sterility (HMS) contributes to reproductive isolation commonly observed among house mouse (Mus musculus) subspecies, both in the wild and in laboratory crosses. Incompatibilities involving specific Prdm9 alleles and certain Chromosome (Chr) X genotypes are known determinants of fertility and HMS, and previous work in the field has demonstrated that genetic background modifies these two major loci. We constructed hybrids that have identical genotypes at Prdm9 and identical X chromosomes, but differ widely across the rest of the genome. In each case, we crossed female PWK/PhJ mice representative of the M. m. musculus subspecies to males from a classical inbred strain representative of M. m. domesticus: 129S1/SvImJ, A/J, C57BL/6J, or DBA/2J. We detected three distinct trajectories of fertility among the hybrids using breeding experiments. The PWK129S1 males were always infertile. PWKDBA2 males were fertile, despite their genotypes at the major HMS loci. We also observed age-dependent changes in fertility parameters across multiple genetic backgrounds. The PWKB6 and PWKAJ males were always infertile before 15 weeks and after 35 weeks, yet some PWKB6 and PWKAJ males were fertile between fifteen and 35 weeks. This observation could resolve previous contradictory reports about the fertility of PWKB6. Taken together, these results point to multiple segregating HMS modifier alleles, some of which have age-related modes of action. The ultimate identification of these alleles and their age-related mechanisms will advance understanding both of the genetic architecture of HMS and of how reproductive barriers are maintained between house mouse subspecies.

genetics↗

bioRxiv2019

Identification of novel neuroprotective loci modulating ischemic stroke volume in a cross between wild-derived inbred mouse strains

To identify genes involved in cerebral infarction we have employed a forward genetic approach in inbred mouse strains, using quantitative trait locus (QTL) mapping for cerebral infarct volume after middle cerebral artery occlusion. We had previously observed that infarct volume is inversely correlated with cerebral collateral vessel density in the strains. In this study, we expanded the pool of allelic variation among classical inbred mouse strains by utilizing the eight founder strains of the Collaborative Cross and found a wild-derived strain, WSB/EiJ, that breaks this general rule that collateral vessel density inversely correlates with infarct volume. WSB/EiJ and another wild-derived strain, CAST/EiJ, show the highest collateral vessel densities of any inbred strain, but infarct volume of WSB/EiJ mice is 8.7-fold larger than that of CAST/EiJ mice. QTL mapping between these strains identified four new neuroprotective loci modulating cerebral infarct volume while not affecting collateral vessel phenotypes. To identify causative variants in genes we surveyed non-synonymous coding SNPs between CAST/EiJ and WSB/EiJ and found 96 genes harboring coding SNPs predicted to be damaging and mapping within one of the four intervals. In addition, we performed RNA sequencing for brain tissue of CAST/EiJ and WSB/EiJ mice and identified 79 candidate genes mapping in one of the four intervals showing strain-specific differences in expression. The identification of the genes underlying these neuroprotective loci will provide new understanding of genetic risk factors of ischemic stroke which may provide novel targets for future therapeutic intervention of human ischemic stroke.

genetics↗

bioRxiv2018

Age and genetic background determine hybrid male sterility in house mice

Hybrid male sterility (HMS) is a unique type of reproductive isolation commonly observed between house mouse (Mus musculus) subspecies in the wild and in laboratory crosses. We identified hybrids that display three distinct trajectories of fertility despite having identical genotypes at the major HMS gene Prdm9 and the X Chromosome. In each case, we crossed female PWK/PhJ mice representative of the M.m.musculus subspecies to males from classical inbred strains representative of M.m.domesticus: 129S1/SvImJ, A/J, C57BL/6J, and DBA/2J. PWK129S1 males are always sterile, while PWKDBA2 males escape HMS. In addition, we observe age-dependent sterility in PWKB6 and PWKAJ males. These males are fertile between 15 and 35 weeks with moderate penetrance. These results point to multiple segregating HMS modifier alleles, some of which have an age-dependent mode of action. Age-dependent mechanisms could have broad implications for the maintenance of reproductive barriers in nature.\n\nAuthor SummaryTwo subspecies of house mice show partial reproductive barriers in nature, and may be in the process of speciation. We used mice derived from each subspecies to replicate hybrid male sterility (HMS) in laboratory mice. Two major genetic factors are well established as playing a role in mouse HMS, but the number of additional factors and their mechanisms are unknown. We characterized reproductive trait variation in a set of hybrid male mice that were specifically designed to eliminate the effects of known genetic factors. We discovered that age played an important role in fertility of some hybrids. These hybrid males showed a delayed onset of fertility, then became fertile for only a few weeks. Across all hybrids males in our study, we observed three distinct trajectories of fertility: complete fertility, complete sterility, and age-dependent fertility. These results point to two or more critical HMS variants with large enough effects to completely restore fertility. This study advances our understanding of the genetic architecture and biological mechanisms of reproductive isolation in mice.

genetics↗