Biology subjects

Majithia, A.

Publications and source records attributed to Majithia, A..

3 recordsLinked to original sources

bioRxiv2024

Mechanistic genotype-phenotype translation using hierarchical transformers

Genome-wide association studies have linked millions of genetic variants to biomedical phenotypes, but their utility has been limited by lack of mechanistic understanding and widespread epistatic interactions. Recently, Transformer models have emerged as powerful machine learning architectures with potential to address these and other challenges. Here we introduce the Genotype-to-Phenotype Transformer (G2PT), a framework for modeling hierarchical information flow among variants, genes, multigenic systems, and phenotypes. As proof-of-concept, we train G2PT to model the genetics of metabolic traits including insulin resistance (serum triglycerides-to-HDL ratio), LDL and type-2 diabetes. G2PT predicts these traits with accuracy exceeding state-of-the-art and, unlike other polygenic models, extends to distinct populations not used for training. Predictions of insulin resistance are based on >1,395 variants within 20 systems and include epistatic interactions among variants, e.g. between APOA4 and CETP in phospholipid transfer. This work positions hierarchical graph transformers as a next-generation approach to polygenic risk.

bioinformatics↗

bioRxiv2021

Glycocalyx engineering with heparan sulfate mimetics attenuates Wnt activity during adipogenesis to promote glucose uptake and metabolism.

Adipose tissue (AT) plays a crucial role in maintaining me tabolic homeostasis by storing lipids and glucose from circulation as intracellular fat. As peripheral tissues like AT become insulin resistant, decompensation of blood glucose levels occurs causing type 2 diabetes (T2D). Currently, glycocalyx modulating as a pharmacological treatment strategy to improve glucose homeostasis in T2D patients is underexplored. Here, we show a novel role for cell surface heparan sulfate (HS) in establishing glucose uptake capacity and metabolic utilization in differentiated adipocytes. Using a combination of chemical and genetic interventions, we identified that HS modulates this metabolic phenotype by attenuating levels of Wnt signaling during adipogenesis. By engineering the glycocalyx of preadipocytes with exogenous synthetic HS mimetics, we were able to enhance glucose clearance capacity after differentiation through modulation of Wnt ligand availability. These findings establish the cellular glycocalyx as a possible new target for therapeutic intervention in T2D patients by enhancing glucose clearance capacity independent of insulin secretion. SIGNIFICANCEMetabolic disorders associated with the Western-style diet, such as type 2 diabetes, are among the main drivers of mortality in the US and globally, with more than 380 million people currently affected by this disease worldwide. However, treatment options for type 2 diabetes are currently limited to management of caloric uptake and expenditure, with none able to reverse the condition long-term. The ability to reprogram adipose tissues to improve their overall capacity to clear glucose may provide one such opportunity. Here we provide evidence that glycocalyx remodeling in pre-adipocytes with heparan sulfate mimetics will alter their differentiation program by modulating Wnt signaling to produce adipocytes with increased glucose uptake and utilization.

cell biology↗

bioRxiv2017

Gene family information facilitates variant interpretation and identification of disease-associated genes

Differentiating risk-conferring from benign missense variants, and therefore optimal calculation of gene-variant burden, represent a major challenge in particular for rare and genetic heterogeneous disorders. While orthologous gene conservation is commonly employed in variant annotation, approximately 80% of known disease-associated genes are paralogs and belong to gene families. It has not been thoroughly investigated how gene family information can be utilized for disease gene discovery and variant interpretation. We developed a paralog conservation score to empirically evaluate whether paralog conserved or nonconserved sites of in-human paralogs are important for protein function. Using this score, we demonstrate that disease-associated missense variants are significantly enriched at paralog conserved sites across all disease groups and disease inheritance models tested. Next, we assessed whether gene family information could assist in discovering novel disease-associated genes. We subsequently developed a gene family de novo enrichment framework that identified 43 exome-wide enriched gene families including 98 de novo variant carrying genes in more than 10k neurodevelopmental disorder patients. 33 gene family enriched genes represent novel candidate genes which are brain expressed and variant constrained in neurodevelopmental disorders.

genetics↗