Biology subjects

Xenophontos, M.

Publications and source records attributed to Xenophontos, M..

3 recordsLinked to original sources

bioRxiv2026

Analyzing globin gene variation in gnomAD: implications for variant interpretation in hemoglobinopathies

Background Given the augmented sampling and ancestry stratification of the Genome Aggregation Database (gnomAD) v4.1 compared to v2.1.1, population evidence for globin gene variants was assessed for changes in the American College of Medical Genetics and Genomics and the Association for Molecular Pathology (ACMG/AMP) criteria fulfillment, which can alter downstream variant interpretation. Methods Variants and constraint metrics for -globin locus genes HBA1, HBA2, and HBZ, and {beta}-globin locus genes HBB, HBD, HBG1, HBG2, and HBE1, were extracted from gnomAD v2.1.1 and v4.1 callsets, harmonized, matched to ClinVar annotations, and evaluated against BA1, BS1, BS2, BS2_Supporting, and PM2_Supporting ACMG/AMP criteria using Clinical Genome Resource Hemoglobinopathy Variant Curation Expert Panel thresholds. Results Globin gene variants increased fourfold across gnomAD releases, with HBB contributing the largest share. In v4.1, 68.7% of quality-passing variants were ancestry-specific, 14.4% overlapped ClinVar and PM2_Supporting fulfillment rose from 81.5% to 93.5%. Among variants present in both releases, ACMG/AMP population-criterion assessments were largely concordant, with conflicting combinations in <1%. Conclusions Leveraging augmented sampling and improved ancestry representation, gnomAD v4.1 increased globin gene variant discovery, particularly for rare variants, enabling more precise allele frequency estimates and robust assessment of BA1, BS1, and PM2_Supporting, although criterion fulfillment remains release- and callset-specific.

genetics↗

bioRxiv2022

Evaluation of in silico predictors on short nucleotide variants in HBA1, HBA2 and HBB associated with haemoglobinopathies

IntroductionHaemoglobinopathies are the commonest monogenic diseases worldwide and are caused by variants in the globin gene clusters. With over 2400 variants detected to date, their interpretation using the ACMG/AMP guidelines is challenging, with computational evidence able to provide valuable input about their functional annotation. While many in silico predictors have already been developed, their performance varies for different genes and diseases. Materials and MethodsWe evaluate 31 in silico predictors using a dataset of 1627 variants in HBA1, HBA2, and HBB. Through varying the decision threshold for each tool, we analyse their performance (a) as binary classifiers of pathogenicity, and (b) using different nonoverlapping pathogenic and benign thresholds for their optimal use in the ACMG/AMP framework. ResultsCADD, Eigen-PC, and REVEL are the overall top performers, with the former reaching moderate strength level for pathogenic prediction. Eigen-PC and REVEL achieve the highest accuracies for missense variants, while CADD is also a reliable predictor of nonmissense variants. Moreover, SpliceAl is the top performing splicing predictor, reaching strong level of evidence, while GERP++ and phyloP are the most accurate conservation tools. DiscussionThis study provides evidence about the optimal use of computational evidence in globin gene clusters under the ACMG/AMP framework.

bioinformatics↗

bioRxiv2017

The Nucleosome Remodelling and Deacetylation complex restricts Mediator access to enhancers to control transcription

A number of different chromatin remodelling complexes in mammalian cells are implicated in the control of gene expression. The genetic requirements for many such complex components have been described, and the biochemical activities of complex components characterised in vitro, yet the molecular mechanisms by which these biochemical activities impact transcriptional regulation in vivo remain ill-defined. Using an inducible system with fine temporal resolution, we show that the Nucleosome Remodelling and Deacetylation (NuRD) complex directly regulates chromatin architecture at enhancer regions in ES cells, in turn influencing the activity of RNA polymerase II via Mediator. Through this mechanism NuRD restricts Mediator access to enhancer chromatin during lineage commitment, thereby enabling appropriate transcriptional regulation. In contrast, acetylation levels of histone H3 lysine 27 are not immediately impacted by NuRD activity, correlating with transcriptional response only after expression levels have changed. These findings provide a detailed, molecular picture of genome-wide modulation of lineage-specific transcription by an abundant chromatin remodelling complex.

molecular biology↗