Biology subjects

Mendonca, D.

Publications and source records attributed to Mendonca, D..

3 recordsLinked to original sources

bioRxiv2021

scMARK an 'MNIST' like benchmark to evaluate and optimize models for unifying scRNA data

Todays single-cell RNA analysis tools provide enormous value in enabling researchers to make sense of large single-cell RNA (scRNA) studies, yet their ability to integrate different studies at scale remains untested. Here we present a novel benchmark dataset (scMARK), that consists of 100,000 cells over 10 studies and can test how well models unify data from different scRNA studies. We also introduce a two-step framework that uses supervised models, to evaluate how well unsupervised models integrate scRNA data from the 10 studies. Using this framework, we show that the Variational Autoencoder, scVI, represents the only tool tested that can integrate scRNA studies at scale. Overall, this work paves the way to creating large scRNA atlases and off-the-shelf analysis tools.

bioinformatics↗

bioRxiv2021

Developmental and behavioral phenotypes in a new mouse model of DDX3X syndrome

BackgroundMutations in the X-linked gene DDX3X account for ~2% of intellectual disability in females, often co-morbid with behavioral problems, motor deficits, and brain malformations. DDX3X encodes an RNA helicase with emerging functions in corticogenesis and synaptogenesis. MethodsWe generated a Ddx3x haploinsufficient mouse (Ddx3x+/-) with construct validity for DDX3X loss-of-function mutations. We used standardized batteries to assess developmental milestones and adult behaviors, as well as magnetic resonance imaging and immunostaining of cortical projection neurons to capture early postnatal changes in brain development. ResultsDdx3x+/- mice show physical, sensory, and motor delays that evolve into behavioral anomalies in adulthood, including hyperactivity, anxiety-like behaviors, cognitive impairments, and motor deficits. Motor function further declines with age. These behavioral changes are associated with a reduction in brain volume, with some regions (e.g., cortex and amygdala) disproportionally affected. Cortical thinning is accompanied by defective cortical lamination, indicating that Ddx3x regulates the balance of glutamatergic neurons in the developing cortex. ConclusionsThese data shed new light on the developmental mechanisms driving DDX3X syndrome and support face validity of this novel pre-clinical mouse model.

neuroscience↗

bioRxiv2020

Episignatures stratifying ADNP syndrome show modest correlation with phenotype

ADNP syndrome, also known as Helsmoortel-van Der Aa syndrome, is a neurodevelopmental condition associated with intellectual disability/developmental delay, autism spectrum disorder, and multiple medical comorbidities. ADNP syndrome is caused by mutations in the activity-dependent neuroprotective protein (ADNP). A recent study identified genome-wide DNA methylation changes in 22 individuals with ADNP syndrome, adding to the group of neurodevelopmental disorders with an epigenetic signature. This methylation signature segregated those with ADNP syndrome into two groups, based on the location of the mutations. Here, we conducted an independent study on 24 individuals with ADNP syndrome and replicated the existence of the two, mutation-dependent ADNP episignatures. To probe whether the two distinct episignatures correlate with clinical outcomes, we used deep behavioral and neurobiological data from two prospective cohorts of individuals with a genetic diagnosis of ADNP syndrome. We found limited phenotypic differences between the two ADNP groups, and no evidence that individuals with more widespread methylation changes are more severely affected. Also, in spite of the methylation changes, we observed no profound alterations in the blood transcriptome of individuals with ADNP syndrome. Our data warrant caution in harnessing methylation signatures in ADNP syndrome as a tool for clinical stratification, at least with regards to behavioral phenotypes.

developmental biology↗