Biology subjects

Lash, A.

Publications and source records attributed to Lash, A..

6 recordsLinked to original sources

bioRxiv2024

Sharing Data from the Human Tumor Atlas Network through Standards, Infrastructure, and Community Engagement

The Data Coordinating Center (DCC) of the Human Tumor Atlas Network (HTAN) has played a crucial role in enabling the broad sharing and effective utilization of HTAN data within the scienti[fi]c community. Data from the [fi]rst phase of HTAN are now available publicly. We describe the diverse datasets and modalities shared, multiple access routes to HTAN assay data and metadata, data standards, technical infrastructure and governance approaches, as well as our approach to sustained community engagement. HTAN data can be accessed via the HTAN Portal, explored in visualization tools--including CellxGene, Minerva, and cBioPortal--and analyzed in the cloud through the NCI Cancer Research Data Commons nodes. We have developed a streamlined infrastructure to ingest and disseminate data by leveraging the Synapse platform. Taken together, the HTAN DCCs approach demonstrates a successful model for coordinating, standardizing, and disseminating complex cancer research data via multiple resources in the cancer data ecosystem, offering valuable insights for similar consortia, and researchers looking to leverage HTAN data.

cancer biology↗

bioRxiv2024

The Genotype and Phenotypes in Families (GPF) platform manages the large and complex data at SFARI

The exploration of genotypic variants impacting phenotypes is a cornerstone in genetics research. The emergence of vast collections containing deeply genotyped and phenotyped families has made it possible to pursue the search for variants associated with complex diseases. However, managing these large-scale datasets requires specialized computational tools tailored to organize and analyze the extensive data. GPF (Genotypes and Phenotypes in Families) is an open-source platform (https://github.com/iossifovlab/gpf) that manages genotypes and phenotypes derived from collections of families. The GPF interface allows interactive exploration of genetic variants, enrichment analysis for de novo mutations, and phenotype/genotype association tools. In addition, GPF allows researchers to share their data securely with the broader scientific community. GPF is used to disseminate two large-scale family collection datasets (SSC, SPARK) for the study of autism funded by the SFARI foundation. However, GPF is versatile and can manage genotypic data from other small or large family collections. Our GPF-SFARI GPF instance (https://gpf.sfari.org/) provides protected access to comprehensive genotypic and phenotypic data for the SSC and SPARK. In addition, GPF-SFARI provides public access to an extensive collection of de novo mutations identified in individuals with autism and related disorders and to gene-level statistics of the protected datasets characterizing the genes roles in autism. Here, we highlight the primary features of GPF within the context of GPF-SFARI.

bioinformatics↗

bioRxiv2023

Cell specificity of adeno-associated virus (AAV) serotypes in human cortical organoids

Human-derived cortical organoids (hCOs) recapitulate cell diversity and 3D structure found in the human brain and offer a promising model for discovery of new gene therapies targeting neurological disorders. Adeno-associated viruses (AAVs) are the most promising vehicles for non-invasive gene delivery to the central nervous system (CNS), but reliable and reproducible in vitro models to assess their clinical potential are lacking. hCOs can take on these issues as they are a physiologically relevant model to assess AAV transduction efficiency, cellular tropism, and biodistribution within the tissue parenchyma, all of which could significantly modulate therapeutic efficacy. Here, we examine a variety of naturally occurring AAV serotypes and measure their ability to transduce neurons and glia in hCOs from multiple donors. We demonstrate cell tropism driven by AAV serotype and hCO donor and quantify fractions of neurons and astrocytes transduced with GFP as well as overall hCO health.

neuroscience↗

bioRxiv2023

Neuroimmune cortical organoids overexpressing C4A exhibit multiple schizophrenia endophenotypes

Elevated expression of the complement component 4A (C4A) protein has been linked to an increased risk of schizophrenia (SCZ). However, there are few human models available to study the mechanisms by which C4A contributes to the development of SCZ. In this study, we established a C4A overexpressing neuroimmune cortical organoid (NICO) model, which includes mature neuronal cells, astrocytes, and functional microglia. The C4A NICO model recapitulated several neuroimmune endophenotypes observed in SCZ patients, including modulation of inflammatory genes and increased cytokine secretion. C4A expression also increased microglia-mediated synaptic uptake in the NICO model, supporting the hypothesis that synapse and brain volume loss in SCZ patients may be due to excessive microglial pruning. Our results highlight the role of C4A in the immunogenetic risk factors for SCZ and provide a human model for phenotypic discovery and validation of immunomodulating therapies.

neuroscience↗

bioRxiv2020

Optimization and scaling of patient-derived brain organoids uncovers deep phenotypes of disease

Cerebral organoids provide unparalleled access to human brain development in vitro. However, variability induced by current culture methodologies precludes using organoids as robust disease models. To address this, we developed an automated Organoid Culture and Assay (ORCA) system to support longitudinal unbiased phenotyping of organoids at scale across multiple patient lines. We then characterized organoid variability using novel machine learning methods and found that the contribution of donor, clone, and batch is significant and remarkably consistent over gene expression, morphology, and cell-type composition. Next, we performed multi-factorial protocol optimization, producing a directed forebrain protocol compatible with 96-well culture that exhibits low variability while preserving tissue complexity. Finally, we used ORCA to study tuberous sclerosis, a disease with known genetics but poorly representative animal models. For the first time, we report highly reproducible early morphological and molecular signatures of disease in heterozygous TSC+/- forebrain organoids, demonstrating the benefit of a scaled organoid system for phenotype discovery in human disease models.

neuroscience↗

bioRxiv2017

Damaging Mutations are Associated with Diminished Motor Skills and IQ in Children on the Autism Spectrum

In individuals with Autism Spectrum Disorder (ASD), de novo mutations have previously been shown to be significantly correlated with lower IQ, but not with the core characteristics of ASD: deficits in social communication and interaction, and restricted interests and repetitive patterns of behavior. We extend these findings by demonstrating in the Simons Simplex Collection that damaging de novo mutations in ASD individuals are also significantly and convincingly correlated with measures of impaired motor skills. This correlation is not explained by a correlation between IQ and motor skills. We find that IQ and motor skills are distinctly associated with damaging mutations and, in particular, that motor skills are a more sensitive indicator of mutational severity, as judged by the type and its gene target. We use this finding to propose a combined classification of phenotypic severity: mild (little impairment of both), moderate (impairment mainly to motor skills) and severe (impairment of both).

genetics↗