Aw, A. J. | Search bioRxiv

bioRxiv2023

GPN-MSA: an alignment-based DNA language model for genome-wide variant effect prediction

Whereas protein language models have demonstrated remarkable efficacy in predicting the effects of missense variants, DNA counterparts have not yet achieved a similar competitive edge for genome-wide variant effect predictions, especially in complex genomes such as that of humans. To address this challenge, we here introduce GPN-MSA, a novel framework for DNA language models that leverages whole-genome sequence alignments across multiple species and takes only a few hours to train. Across several benchmarks on clinical databases (ClinVar, COSMIC, OMIM), experimental functional assays (DMS, DepMap), and population genomic data (gnomAD), our model for the human genome achieves outstanding performance on deleteriousness prediction for both coding and non-coding variants.

bioinformatics↗

bioRxiv2021

Comprehensive mapping of SARS-CoV-2 interactions in vivo reveals functional virus-host interactions

SARS-CoV-2 has emerged as a major threat to global public health, resulting in global societal and economic disruptions. Here, we investigate the intramolecular and intermolecular RNA interactions of wildtype (WT) and a mutant ({Delta}382) SARS-CoV-2 virus in cells using high throughput structure probing on Illumina and Nanopore platforms. We identified twelve potentially functional structural elements within the SARS-CoV-2 genome, observed that identical sequences can fold into divergent structures on different subgenomic RNAs, and that WT and {Delta}382 virus genomes can fold differently. Proximity ligation sequencing experiments identified hundreds of intramolecular and intermolecular pair-wise interactions within the virus genome and between virus and host RNAs. SARS-CoV-2 binds strongly to mitochondrial and small nucleolar RNAs and is extensively 2-O-methylated. 2-O-methylation sites in the virus genome are enriched in the untranslated regions and are associated with increased pair-wise interactions. SARS-CoV-2 infection results in a global decrease of 2-O-methylation sites on host mRNAs, suggesting that binding to snoRNAs could be a pro-viral mechanism to sequester methylation machinery from host RNAs towards the virus genome. Collectively, these studies deepen our understanding of the molecular basis of SARS-CoV-2 pathogenicity, cellular factors important during infection and provide a platform for targeted therapy.

genomics↗