Biology subjects

Wheeler, J.

Publications and source records attributed to Wheeler, J..

5 recordsLinked to original sources

bioRxiv2026

Novel Co-expression of Group I Metabotropic Glutamate Receptor During Mouse Cochlear Nucleus Development

Metabotropic glutamate receptors (mGluR) are G-protein coupled receptors that regulate neuroplasticity and have been shown to play a role in auditory processing. However, not much is known about the expression of mGluRs during cochlear nucleus development in the context of Fragile X syndrome (FXS). FXS is the most common heritable form of intellectual disability and autism and is associated with auditory processing deficits including hypersensitivity. Audiogenic seizure is a notable feature of the Fmr1 knock-out (KO) mouse model for FXS, in which mGluR5 has been shown to be necessary. In this study, we investigated the expression of eight metabotropic glutamate receptors (mGluRs) in the cochlear nucleus at both young and adult ages and in wildtype and Fmr1 KO mice. While it is established that mGluR1 is the predominantly expressed mGluR in adult cochlear nucleus, we report the following new finding that mGluR5 is the more abundant receptor during early development. The expression of Group II and III mGluRs (2,3,4,6,7,8) was relatively stable during development. We show that mGluR1 and mGluR5 are co-expressed across multiple neuron types. Fmr1 genotype did not have statistically significant impact on the expression pattern of mGluRs in cochlear nucleus. Although hearing onset occurs during this mGluR5 to 1 transition period, mGluR expression patterns were not impacted by cochlear activity. We conclude that there is an mGluR5 is to mGluR1 transition that occurs within cochlear nucleus neurons during the critical period closure that is intrinsic to neuronal development.

neuroscience↗

bioRxiv2024

The maize recombination landscape evolved during domestication.

Meiotic recombination is an important evolutionary process because it can increase the amount of genetic variation within populations through the breakage of unfavorable linkages and creation of novel allelic combinations. Despite the plethora of knowledge about population-level benefits of recombination and numerous theoretical studies examining how recombination rates can evolve over time, there is a lack of empirical evidence for any hypotheses that have been put forward. To alleviate this gap in knowledge, we characterized the evolution of the recombination landscape in Zea mays ssp. mays (maize) during its domestication from Zea mays ssp. parviglumis (teosinte), explored hypotheses that permitted the evolution of the maize recombination landscape and tied these alterations to changes in the genetic basis of recombination. Using experimental populations and the population genomics approach of ancestral recombination graph (ARG) inference, our data demonstrated that maize had a 12% increase in its genome-wide recombination rate during domestication. Although the maize and teosinte recombination landscapes are highly correlated, r = 0.85 at 1Mb resolution, maize has evolved to have higher recombining regions in interstitial chromosome regions, compared to teosinte which only harbors high recombining regions sub-telomerically. Our data show that the re-patterning of COs towards interstitial chromosome regions came from reduced CO interference levels within maize. Supporting the idea that CO interference is reduced within maize, we found evidence for selection acting on trans-acting recombination-modifiers that participate in the class I CO pathway or CO interference directly. Lastly, we showed that the re-patterning of COs was beneficial to maize evolution because regions that significantly increased in recombination were targeted to gene-rich regions harboring domestication related loci. Because we found regions with significant increases in recombination had a lower deleterious mutation load, compared to regions with decreases in recombination, we concluded that the domestication-related variation in these regions, in which selection acted upon during domestication, was shielded from the Hill-Robertson effect. In conclusion, the re-patterning of CO events during domestication allowed maize to adapt and evolve at a faster rate than previously understood.

evolutionary biology↗

bioRxiv2020

Genomic diversity, population structure and accessory genome analysis of Pasteurella multocida: New Insights into host adaptation and disease specialization

Pasteurella multocida is a multi-host pathogen that infects a wide spectrum of domestic and wild animals including humans. Despite its impact on health and economics, P. multocida is considered an enigmatic pathogen and the genetic basis of its pathogenicity and host adaptation still remains unclear. Here we present a detailed genomic framework based on 336 whole-genome sequences of P. multocida isolates from different animal species and countries. Our data provide genomic support of the existence of two very divergent phylogroups (PmI and PmII), which present a barrier to homologous recombination suggesting genetic isolation. Additionally, a torCAD operon, which reduces TMAO (trimethylamine N-oxide) to produce energy during bacterial anaerobic respiration, is present only in PmI and can act as a hypothetical driver of niche segregation between phylogroups. The PmI phylogroup harbors strains that infect a wider range of hosts than PmII, and shows a highly diverse phylogeny and accessory genome. We identified nine clonal lineages for PmI, seven of which are associated with specific hosts or diseases and contain distinct accessory gene pools that can confer ecologically relevant phenotypes. We found differential presence of a trehalose metabolism operon in the bovine lineage associated with pneumonic pasteurellosis; while, citrate, L-arabinose, L-fucose, and D-allose operons are only present in avian lineages. These findings suggest that alternative metabolic pathways may facilitate the establishment of P. multocida during host colonization in the early stages of infection promoting the adaptation of P. multocida lineages to certain hosts.

microbiology↗

bioRxiv2020

Neuroinvasive potential of SARS-CoV-2 revealed in a human brain organoid model

Although COVID-19 is considered to be primarily a respiratory disease, SARS-CoV-2 affects multiple organ systems including the central nervous system (CNS). Yet, there is no consensus whether the virus can infect the brain, or what the consequences of CNS infection are. Here, we used three independent approaches to probe the capacity of SARS-CoV-2 to infect the brain. First, using human brain organoids, we observed clear evidence of infection with accompanying metabolic changes in the infected and neighboring neurons. However, no evidence for the type I interferon responses was detected. We demonstrate that neuronal infection can be prevented either by blocking ACE2 with antibodies or by administering cerebrospinal fluid from a COVID-19 patient. Second, using mice overexpressing human ACE2, we demonstrate in vivo that SARS-CoV-2 neuroinvasion, but not respiratory infection, is associated with mortality. Finally, in brain autopsy from patients who died of COVID-19, we detect SARS-CoV-2 in the cortical neurons, and note pathologic features associated with infection with minimal immune cell infiltrates. These results provide evidence for the neuroinvasive capacity of SARS-CoV2, and an unexpected consequence of direct infection of neurons by SARS-CoV-2.

microbiology↗

bioRxiv2017

High Frequency Actionable Pathogenic Exome Mutations in an Average-Risk Cohort

Whole exome sequencing (WES) is increasingly utilized in both clinical and non-clinical settings, but little is known about the utility of WES in healthy individuals. In order to determine the frequency of both medically actionable and non-actionable but medically relevant exome findings in the general population we assessed the exomes of 70 participants who have been extensively characterized over the past several years as part of a longitudinal integrated multi-omics profiling study at Stanford University. We assessed exomes for rare likely pathogenic and pathogenic variants in genes associated with Mendelian disease in the Online Mendelian Inheritance in Man (OMIM) database. We used American College of Medical Genetics (ACMG) guidelines were used for the classification of rare sequence variants, and additionally we assessed pharmacogenetic variants. Twelve out of 70 (17%) participants had medically actionable findings in Mendelian disease genes, including 6 (9%) with mutations in genes not currently included in the ACMGs list of 59 actionable genes. This number is higher than that reported in previous studies and suggests added benefit from utilizing expanded gene lists and manual curation to assess actionable findings. A total of 60 participants (89%) had non-actionable findings identified including 57 who were found to be mutation carriers for recessive diseases and 21 who have increased Alzheimers disease risk due to heterozyg ous or homozygous APOE e4 alleles (18 participants had both). These results suggest that exome sequencing may have considerably more utility for health management in the general population than previously thought.

genomics↗