Biology subjects

Jensen, A.

Publications and source records attributed to Jensen, A..

5 recordsLinked to original sources

bioRxiv2021

Neutrophils impose strong selective pressure against PfEMP1 variants implicated in cerebral malaria

Plasmodium falciparum, the deadliest form of human malaria, remains one of the major threats to human health in endemic regions. Its virulence is attributed to its ability to modify infected red blood cells (iRBC) to adhere to endothelial receptors by placing variable antigens known as PfEMP1 on the surface of the red cell. PfEMP1 expression on the red cell surface determines the cytoadhesive properties of the iRBCs and is implicated in severe manifestations of malaria. To evade antibody mediated responses the parasite undergoes continuous switches of expression between different PfEMP1 variants. Recently it became clear that in addition to antibody mediated responses, PfEMP1 triggers an innate immune response, however, the role of neutrophils, the most abundant white blood cells in the human circulation, in malaria remains elusive. Here we show that neutrophils recognize and kill blood stages of several P. falciparum isolates, and we identify neutrophil ICAM-1 and specific PfEMP1s implicated in cerebral malaria as the key molecules involved in this killing. Our data provide mechanistic insight into the interactions between neutrophils and iRBCs and demonstrate the important influence of PfEMP1 on the selective innate response to cerebral malaria.

microbiology↗

bioRxiv2021

G-quadruplex RNA motifs influence gene expression in the malaria parasite Plasmodium falciparum

G-quadruplexes are non-helical secondary structures that can fold in vivo in both DNA and RNA. In human cells, they can influence replication, transcription and telomere maintenance in DNA, or translation, transcript processing and stability of RNA. We have previously showed that G-quadruplexes are detectable in the DNA of the malaria parasite Plasmodium falciparum, despite a very highly A/T-biased genome with unusually few guanine-rich sequences. Here, we show that RNA G-quadruplexes can also form in P. falciparum RNA, using rG4-seq for transcriptome-wide structure-specific RNA probing. Many of the motifs, detected here via the rG4seeker pipeline, have non-canonical forms and would not be predicted by standard in silico algorithms. However, in vitro biophysical assays verified the formation of non-canonical motifs. The G-quadruplexes in the P. falciparum transcriptome are frequently clustered in certain genes and associated with regions encoding low-complexity peptide repeats. They are overrepresented in particular classes of genes, notably those that encode PfEMP1 virulence factors, stress response genes and DNA binding proteins. In vitro translation experiments and in vivo measures of translation efficiency showed that G-quadruplexes can influence the translation of P. falciparum mRNAs. Thus, the G-quadruplex is a novel player in post-transcriptional regulation of gene expression in this major human pathogen.

microbiology↗

bioRxiv2020

Combining genome-wide studies of breast, prostate, ovarian and endometrial cancers maps cross-cancer susceptibility loci and identifies new genetic associations

We report a meta-analysis of breast, prostate, ovarian, and endometrial cancer genome-wide association data (effective sample size: 237,483 cases/317,006 controls). This identified 465 independent lead variants (P<5x10-8) across 192 genomic regions. Four lead variants were >1Mb from previously identified risk loci for the four cancers and an additional 23 lead variant-cancer associations were novel for one of the cancers. Bayesian models supported pleiotropic effects involving at least two cancers at 222/465 lead variants in 118/192 regions. Gene-level association analysis identified 13 shared susceptibility genes (P<2.6x10-6) in 13 regions not previously implicated in any of the four cancers and not uncovered by our variant-level meta-analysis. Several lead variants had opposite effects across cancers, including a cluster of such variants in the TP53 pathway. Fifty-four lead variants were associated with blood cell traits and suggested genetic overlaps with clonal hematopoiesis. Our study highlights the remarkable pervasiveness of pleiotropy across hormone-related cancers, further illuminating their shared genetic and mechanistic origins at variant- and gene-level resolution.

genetics↗

bioRxiv2020

Pleiotropy-guided transcriptome imputation from normal and tumor tissues identifies new candidate susceptibility genes for breast and ovarian cancer

Familial, genome-wide association (GWAS), and sequencing studies and genetic correlation analyses have progressively unraveled the shared or pleiotropic germline genetics of breast and ovarian cancer. In this study, we aimed to leverage this shared germline genetics to improve the power of transcriptome-wide association studies (TWAS) to identify candidate breast cancer and ovarian cancer susceptibility genes. We built gene expression prediction models using the PrediXcan method in 681 breast and 295 ovarian tumors from The Cancer Genome Atlas and 211 breast and 99 ovarian normal tissue samples from the Genotype-Tissue Expression project and integrated these with GWAS meta-analysis data from the Breast Cancer Association Consortium (122,977 cases/105,974 controls) and the Ovarian Cancer Association Consortium (22,406 cases/40,941 controls). The integration was achieved through novel application of a pleiotropy-guided conditional/conjunction false discovery rate approach for the first time in the setting of a TWAS. This identified 14 new candidate breast cancer susceptibility genes spanning 11 genomic regions and 8 new candidate ovarian cancer susceptibility genes spanning 5 genomic regions at conjunction FDR < 0.05 that were > 1 Mb away from known breast and/or ovarian cancer susceptibility loci. We also identified 38 candidate breast cancer susceptibility genes and 17 candidate ovarian cancer susceptibility genes at conjunction FDR < 0.05 at known breast and/or ovarian susceptibility loci. Overlaying candidate causal risk variants identified by GWAS fine mapping onto expression prediction models for genes at known loci suggested that the association for 55% of these genes was driven by the underlying GWAS signal. SignificanceThe 22 new genes identified by our cross-cancer analysis represent promising candidates that further elucidate the role of the transcriptome in mediating germline breast and ovarian cancer risk.

genetics↗

bioRxiv2019

Restoration, dispersal and settlement of native European oyster (Ostrea edulis) in energetic tidal areas

We modelled the pelagic larval phase of native European oyster (Ostrea edulis) in the Solent. The Solent is a complex and tidally energetic environment on the south coast of the UK. Until recently it was the largest self-sustaining fishery of the native oyster in Europe. We developed a new larval settlement behavioural model that is the simplest plausible model which remains consistent with all available data and evidence on larval behaviour. We used a hydrodynamic sub-model, a Lagrangian advection sub-model, and an individual agent based model. The results demonstrate how isolated oyster assemblages can re-populate larger areas of historical inhabitance. We predict the most likely patterns of redistribution from refugia or from fisheries seeding. We show that settlement swimming behaviour is as equally important as passive hydrodynamic transport for larval survival and adult distribution and that settlement swimming behaviour has a profound impact on settlement patterns. The models show that managed broodstock refugia have the potential to seed much larger oyster beds in contrast to broad-scale seeding. Such refugia have the advantage of maintaining a locally high and mature population with potential for reef features and their associated biodiversity. We show that such refugia may be best placed in the tidally dynamic and exposed areas rather than on sheltered coastal sites as they have been in the past. Our model is insensitive to parameter variation and could be an effective and practical management tool in the face of a paucity of field data on larval distribution and behaviour.

zoology↗