Biology subjects

Varadarajan, A.

Publications and source records attributed to Varadarajan, A..

3 recordsLinked to original sources

bioRxiv2022

Longitudinal fundus imaging and its genome-wide association analysis provide evidence for a human retinal aging clock

Biological age, distinct from an individuals chronological age, has been studied extensively through predictive aging clocks. However, these clocks have limited accuracy in short time-scales. Deep learning approaches on imaging datasets of the eye have proven powerful for a variety of quantitative phenotype inference tasks and provide an opportunity to explore organismal aging and tissue health. Here we trained deep learning models on fundus images from the EyePACS dataset to predict individuals chronological age. These predictions led to the concept of a retinal aging clock, "eyeAge", which we employed for a series of downstream longitudinal analyses. eyeAge was used to predict chronological age on timescales under a year using longitudinal fundus imaging data from a subset of patients. To further validate the model, it was applied to a separate cohort from the UK Biobank. The difference between individuals eyeAge and their chronological age, hereafter "eyeAgeAccel", was computed and used for genome-wide association analysis (GWAS). EyeAge predicted chronological age more accurately than other aging clocks (mean absolute error of 2.86 and 3.30 years on quality-filtered data from EyePACS and UKBiobank, respectively). Additionally, eyeAgeAccel was highly independent of blood marker-based measures of biological age (e.g. "phenotypic age"), maintaining an all-cause mortality hazard ratio of 1.026 even in the presence of phenotypic age. Longitudinal studies showed that the resulting models were able to predict individuals aging, in time-scales less than a year, with 71% accuracy. The individual-specific component to this prediction was confirmed with the identification of multiple GWAS hits in the independent UK Biobank cohort. The knockdown of the fly homolog to the top hit, ALKAL2, which was previously shown to extend lifespan in flies, also slowed age-related decline in vision in flies. In conclusion, predicted age from retinal images can be used as a biomarker of biological aging that is independent from assessment based on blood markers. This study demonstrates the potential utility of a retinal aging clock for studying aging and age-related diseases and quantitatively measuring aging on very short time-scales, opening avenues for quick and actionable evaluation of gero-protective therapeutics.

bioinformatics↗

bioRxiv2022

Integrative single-cell analysis of cardiogenesis identifies developmental trajectories and non-coding mutations in congenital heart disease

Congenital heart defects, the most common birth disorders, are the clinical manifestation of anomalies in fetal heart development - a complex process involving dynamic spatiotemporal coordination among various precursor cell lineages. This complexity underlies the incomplete understanding of the genetic architecture of congenital heart diseases (CHDs). To define the multi-cellular epigenomic and transcriptional landscape of cardiac cellular development, we generated single-cell chromatin accessibility maps of human fetal heart tissues. We identified eight major differentiation trajectories involving primary cardiac cell types, each associated with dynamic transcription factor (TF) activity signatures. We identified similarities and differences of regulatory landscapes of iPSC-derived cardiac cell types and their in vivo counterparts. We interpreted deep learning models that predict cell-type resolved, base-resolution chromatin accessibility profiles from DNA sequence to decipher underlying TF motif lexicons and infer the regulatory impact of non-coding variants. De novo mutations predicted to affect chromatin accessibility in arterial endothelium were enriched in CHD cases versus controls. We used CRISPR-based perturbations to validate an enhancer harboring a nominated regulatory CHD mutation, linking it to effects on the expression of a known CHD gene JARID2. Together, this work defines the cell-type resolved cis-regulatory sequence determinants of heart development and identifies disruption of cell type-specific regulatory elements as a component of the genetic etiology of CHD.

genomics↗

bioRxiv2020

Rapid diffusion of large TatA complexes detected using single particle tracking microscopy

The twin-arginine translocation (Tat) system transports folded proteins across the cytoplasmic membrane of most bacteria and archaea. TatA, which contains a single membrane-spanning helix, is believed to be responsible for the actual translocation. According to the prevalent model, multiple TatA subunits form a transient protein-conducting pore, which disassembles after each translocation event. An alternative model exists, in which TatA proteins locally weaken the lipid bilayer to translocate folded proteins. Here, we imaged eGFP-fused TatA expressed from the genome in live E. coli cells. Images showed TatA occuring both in highly mobile monomers or small oligomers and in large, stable complexes that do not dissociate. Single-particle tracking revealed that large TatA complexes switch between fast and slow diffusion. The fast diffusion is too fast for a transmembrane protein complex consisting of multiple TatA monomers. In line with recent data on rhomboid proteases, we propose that TatA complexes switch between a slowly diffusing transmembrane conformation and a rapidly diffusing membrane-disrupting state that enables folded proteins to cross the membrane, in accordance with the membrane-weakening model.

microbiology↗