Biology subjects

Matelska, D.

Publications and source records attributed to Matelska, D..

6 recordsLinked to original sources

bioRxiv2024

Diverse ancestral representation improves genetic intolerance metrics

Rapidly expanding genomic databases have enabled the identification of regions in the human genome intolerant to variation and thus likely relevant to human disease. However, despite their unprecedented scale, these datasets remain constrained by limited ancestral diversity. Here, we systematically evaluate how genetic diversity impacts gene- and sub-genic intolerance metrics by analyzing whole-exome sequencing data from 460,551 UK Biobank participants and 125,748 gnomAD participants across diverse ancestral backgrounds. Through comprehensive analysis of randomly sampled datasets with varying ancestral compositions, we demonstrate that genetic diversity, rather than sample size alone, drives the performance of intolerance metrics in identifying functionally critical genes and genic sub-regions. Notably, scores trained on variation observed in African and Admixed American ancestral groups showed superior resolution in detecting neurodevelopmental disease risk genes and haploinsufficient genes compared to scores trained on variation observed in European ancestry cohorts. Most strikingly, the Missense Tolerance Ratio (MTR) trained on 43,000 multi-ancestry exomes demonstrated greater predictive power than when trained on a nearly 10-fold larger dataset of 440,000 non-Finnish European exomes, indicating that European ancestry-based scores are approaching saturation. These findings establish ancestral diversity as the fundamental determinant for advancing intolerance metrics and underscore the urgent scientific and ethical imperative for enhanced population representation in genomic resources to fully realize the potential of precision medicine and drug discovery.

genetics↗

bioRxiv2022

Influences of rare protein-coding genetic variants on the human plasma proteome in 50,829 UK Biobank participants

Combining human genomics with proteomics is becoming a powerful tool for drug discovery. Associations between genetic variants and protein levels can uncover disease mechanisms, clinical biomarkers, and candidate drug targets. To date, most population-level proteogenomic studies have focused on common alleles through genome-wide association studies (GWAS). Here, we studied the contribution of rare protein-coding variants to 1,472 plasma proteins abundances measured via the Olink Explore 1536 assay in 50,829 UK Biobank human exomes. Through a variant-level exome-wide association study (ExWAS), we identified 3,674 rare and significant protein quantitative trait loci (pQTLs), of which 76% were undetected in a prior GWAS performed on the same cohort, and we found that rare pQTLs are less likely to be random in their variant effect annotation. In gene-based collapsing analyses, we identified an additional 166 significant gene-protein pQTL signals that were undetected through single-variant analyses. Of the total 456 protein-truncating variant (PTV)-driven cis-pQTLs in the gene-based collapsing analysis, 99.3% were associated with decreased protein levels. We demonstrate how this resource can identify allelic series and propose biomarkers for several candidate therapeutic targets, including GRN, HSD17B13, NLRC4, and others. Finally, we introduce a new collapsing analysis framework that combines PTVs with missense cis-pQTLs that are associated with decreased protein abundance to bolster genetic discovery statistical power. Our results collectively highlight a considerable role for rare variation in plasma protein abundance and demonstrate the utility of plasma proteomics in gene discovery and unravelling mechanisms of action.

genomics↗

bioRxiv2022

Cancer-driving mutations are enriched in genic regions intolerant to germline variation

Large reference datasets of protein-coding variation in human populations have allowed us to determine which genes and genic sub-regions are intolerant to germline genetic variation. There is also a growing number of genes implicated in severe Mendelian diseases that overlap with genes implicated in cancer. Here, we hypothesized that mitotically mutable genic sub-regions that are intolerant to germline variation are enriched for cancer-driving mutations. We introduce a new metric, OncMTR, which uses 125,748 exomes in the gnomAD database to identify genic sub-regions intolerant to germline variation but enriched for hematologic somatic variants. We demonstrate that OncMTR can significantly predict driver mutations implicated in hematologic malignancies. Divergent OncMTR regions were enriched for cancer-relevant protein domains, and overlaying OncMTR scores on protein structures identified functionally important protein residues. Finally, we performed a rare variant, gene-based collapsing analysis on an independent set of 394,694 exomes from the UK Biobank and find that OncMTR dramatically improves genetic signals for hematologic malignancies. Our web app enables easy visualization of OncMTR scores for each protein-coding gene (https://astrazeneca-cgr-publications.github.io/OncMTR-Viewer/).

genomics↗

bioRxiv2021

The determinants of African Swine Fever Virus Virulence - the Georgia 2007/1 strain and the host macrophage response

African swine fever virus (ASFV) has a major global economic impact. With a case fatality in domestic pigs approaching 100%, it currently presents the largest threat to animal farming. Although genomic differences between attenuated and highly virulent ASFV strains have been identified, the molecular determinants for virulence at the level of gene expression have remained opaque. Here we characterise the transcriptome of ASFV genotype II Georgia 2007/1 (GRG) during infection of the physiologically relevant host cells, porcine macrophages. In this study we applied Cap Analysis Gene Expression sequencing (CAGE-seq) to map the 5 ends of viral mRNAs at 5 and 16 hours post-infection. A bioinformatics analysis of the sequence context surrounding the transcription start sites (TSSs) enabled us to characterise the global early and late promoter landscape of GRG. We compared transcriptome maps of the GRG isolate and the lab-attenuated BA71V strain that highlighted GRG virulent-specific transcripts belonging to multigene families, including two predicted MGF 100 genes I7L and I8L. In parallel, we monitored transcriptome changes in the infected host macrophage cells. Of the 9,384 macrophage genes studied, transcripts for 652 host genes were differentially regulated between 5 and 16 hours-post-infection compared with only 25 between uninfected cells and 5 hours post-infection. NF-kB activated genes and lysosome components like S100 were upregulated, and chemokines such as CCL24, CXCL2, CXCL5 and CXCL8 downregulated. ImportanceAfrican swine fever virus (ASFV) causes haemorrhagic fever in domestic pigs with case fatality rates approaching 100%, and no approved vaccines or antivirals. The highly-virulent ASFV Georgia 2007/1 strain (GRG) was the first isolated when ASFV spread from Africa to the Caucasus region in 2007. Then spreading through Eastern Europe, and more recently across Asia. We used an RNA-based next generation sequencing technique called CAGE-seq to map the starts of viral genes across the GRG DNA genome. This has allowed us to investigate which viral genes are expressed during early or late stages of infection and how this is controlled, comparing their expression to the non-virulent ASFV-BA71V strain to identify key genes that play a role in virulence. In parallel we investigated how host cells respond to infection, which revealed how the ASFV suppresses components of the host immune response to ultimately win the arms race against its porcine host.

microbiology↗

bioRxiv2020

Promoter-proximal elongation regulates transcription in archaea

Recruitment of RNA polymerase and initiation factors to the promoter is the only known mechanisms for transcription activation and repression in archaea. Whether any of the subsequent steps towards productive transcription elongation is involved in regulation is not known. We characterised how the basal transcription machinery is distributed along genes in the archaeon Sulfolobus solfataricus. We discovered a distinct early elongation phase where RNA polymerases sequentially recruit the elongation factors Spt4/5 and Elf1 to form the transcription elongation complex (TEC) before the TEC escapes into productive transcription. TEC escape is rate-limiting for transcription output during exponential growth. Oxidative stress causes changes in TEC escape that correlate with changes in the transcriptome. Our results thus establish that TEC escape contributes to the basal promoter strength and facilitates transcription regulation. Impaired TEC escape coincides with the accumulation of initiation factors at the promoter and recruitment of termination factor aCPSF1 to the early TEC. This suggests two possible mechanisms for how TEC escape limits transcription, physically blocking upstream RNA polymerases during transcription initiation and premature termination of early TECs.

molecular biology↗

bioRxiv2019

Temporal Transcriptome and Promoter Architecture ofthe African Swine Fever Virus

The African Swine Fever Virus causes haemorrhagic fever in domestic pigs and presents the biggest global threat to animal farming in recorded history. Despite its importance, very little is known the mechanisms and temporal regulation of transcription in ASFV. Here we report the first detailed viral transcriptome analysis of ASFV during early and late infection of Vero cells. In addition to total RNA sequencing, we have characterised the transcription start sites and transcription termination sites at nucleotide-resolution, revealing the distinct DNA consensus motifs of early and late promoters, as well as the sequence determinants for transcription termination. ASFV can utilise alternative promoters to generate distinct proteins from the same transcription unit that differ with respect to the polypeptide N-terminus. Finally, our results reveal that the ASFV-RNAP undergoes transcript slippage at the 5 end of transcription units that in a promoter sequence-specific manner results in the addition of 5-AT and 5-ATAT tails to mRNAs.

genomics↗