Biology subjects

Brajer, P.

Publications and source records attributed to Brajer, P..

3 recordsLinked to original sources

bioRxiv2021

3D genomic capture of regulatory immuno-genetic profiles in COVID-19 patients for prognosis of severe COVID disease outcome

Human infection with the SARS-CoV-2 virus leads to coronavirus disease (COVID-19). A striking characteristic of COVID-19 infection in humans is the highly variable host response and the diverse clinical outcomes, ranging from clinically asymptomatic to severe immune reactions leading to hospitalization and death. Here we used a 3D genomic approach to analyse blood samples at the time of COVID diagnosis, from a global cohort of 80 COVID-19 patients, with different degrees of clinical disease outcomes. Using 3D whole genome EpiSwitch(R) arrays to generate over 1 million data points per patient, we identified a distinct and measurable set of differences in genomic organization at immune-related loci that demonstrated prognostic power at baseline to stratify patients with mild forms of illness and those with severe forms that required hospitalization and intensive care unit (ICU) support. Further analysis revealed both well established and new COVID-related dysregulated pathways and loci, including innate and adaptive immunity; ACE2; olfactory, G{beta}{psi}, Ca2+ and nitric oxide (NO) signalling; prostaglandin E2 (PGE2), the acute inflammatory cytokine CCL3, and the T-cell derived chemotactic cytokine CCL5. We identified potential therapeutic agents for mitigation of severe disease outcome, with several already being tested independently, including mTOR inhibitors (rapamycin and tacrolimus) and general immunosuppressants (dexamethasone and hydrocortisone). Machine learning algorithms based on established EpiSwitch(R) methodology further identified a subset of 3D genomic changes that could be used as prognostic molecular biomarker leads for the development of a COVID-19 disease severity test.

biochemistry↗

bioRxiv2019

Structural variation of the malaria-associated human glycophorin A-B-E region

Approximately 5% of the human genome consists of structural variants, which are enriched for genes involved in the immune response and cell-cell interactions. A well-established region of extensive structural variation is the glycophorin gene cluster, comprising three tandemly-repeated regions about 120kb in length, carrying the highly homologous genes GYPA, GYPB and GYPE. Glycophorin A and glycophorin B are glycoproteins present at high levels on the surface of erythrocytes, and they have been suggested to act as decoy receptors for viral pathogens. They act as receptors for invasion of a causative agent of malaria, Plasmodium falciparum. A particular complex structural variant (DUP4) that creates a GYPB/GYPA fusion gene is known to confer resistance to malaria. Many other structural variants exist, and remain poorly characterised. Here, we analyse sequences from 6466 genomes from across the world for structural variation at the glycophorin locus, confirming 15 variants in the 1000 Genomes project cohort, discovering 9 new variants, and characterising a selection using fibre-FISH and breakpoint mapping. We identify variants predicted to create novel fusion genes and a common inversion duplication variant at appreciable frequencies in West Africans. We show that almost all variants can be explained by unequal cross over events (non-allelic homologous recombination, NAHR) and. by comparing the structural variant breakpoints with recombination hotspot maps, show the importance of a particular meiotic recombination hotspot on structural variant formation in this region.

genetics↗

bioRxiv2018

The malaria-protective human glycophorin structural variant DUP4 shows somatic mosaicism and association with hemoglobin levels

Glycophorin A and glycophorin B are red blood cell surface proteins that are both receptors for the parasite Plasmodium falciparum, which is the principal cause of malaria in sub-Saharan Africa. DUP4 is a complex structural genomic variant that carries extra copies of a glycophorin A - glycophorin B fusion gene, and has a dramatic effect on malaria risk by reducing the risk of severe malaria by up to 40%. Using fiber-FISH and Illumina sequencing, we validate the structural arrangement of the glycophorin locus in the DUP4 variant, and reveal somatic variation in copy number of the glycophorin A-glycophorin B fusion gene. By developing a simple, specific, PCR-based assay for DUP4 we show the DUP4 variant reaches a frequency of 13% in a village in south-eastern Tanzania. We genotype a substantial proportion of that village and demonstrate an association of DUP4 genotype with hemoglobin levels, a phenotype related to malaria, using a family-based association test. Taken together, we show that DUP4 is a complex structural variant that may be susceptible to somatic variation, and show that it is associated with a malarial-related phenotype in a non-hospitalized population.\n\nSignificance statementPrevious work has identified a human complex genomic structural variant called DUP4, which includes two novel glycophorin A-glycophorin B fusion genes, is associated with a profound protection against severe malaria. In this study, we present data showing the molecular basis of this complex variant. We also show evidence of somatic variation in the copy number of the fusion genes. We develop a simple robust assay for this variant and demonstrate that DUP4 is at an appreciable population frequency in Tanzania and that it is associated with higher hemoglobin levels in a malaria-endemic village. We suggest that DUP4 is therefore protective against malarial anemia.

genetics↗