Biology subjects

van der Lee, R.

Publications and source records attributed to van der Lee, R..

3 recordsLinked to original sources

bioRxiv2017

Probabilistic data integration identifies reliable gametocyte-specific proteins and transcripts in malaria parasites

Plasmodium gametocytes are the sexual forms of the malaria parasite essential for transmission to mosquitoes. To better understand how gametocytes differ from asexual blood-stage parasites, we performed a systematic analysis of available omics data for P. falciparum and other Plasmodium species. 18 transcriptomic and proteomic data sets were evaluated for the presence of curated \"gold standards\" of 41 gametocyte-specific versus 46 non-gametocyte genes and integrated using Bayesian probabilities, resulting in gametocyte-specificity scores for all P. falciparum genes.\n\nTo illustrate the utility of the gametocyte score, we explored newly predicted gametocyte-specific genes as potential biomarkers of gametocyte carriage and exposure. We analyzed the humoral immune response in field samples against 30 novel gametocyte-specific antigens and found five antigens to be differentially recognized by gametocyte carriers as compared to malaria-infected individuals without detectable gametocytes. We also validated the gametocyte-specificity of 15 identified gametocyte transcripts on culture material and samples from naturally infected individuals, resulting in eight transcripts that were >1000-fold higher expressed in gametocytes compared to asexual parasites and whose transcript abundance allowed gametocyte detection in naturally infected individuals. Our integrated genome-wide gametocyte-specificity scores provide a comprehensive resource to identify targets and monitor P. falciparum gametocytemia.

microbiology↗

bioRxiv2017

Genome-scale detection of positive selection in 9 primates predicts human-virus evolutionary conflicts

Hotspots of rapid genome evolution hold clues about human adaptation. Here, we present a comparative analysis of nine whole-genome sequenced primates to identify high-confidence targets of positive selection. We find strong statistical evidence for positive selection acting on 331 protein-coding genes (3%), pinpointing 934 adaptively evolving codons (0.014%). Our stringent procedure and quality control of alignments and evolutionary inferences reveal substantial artefacts (20% of initial predictions) that have inflated previous estimates of positive selection, the large majority relating to transcript definitions (61%) or gene models (38%). Our final set of 331 positively selected genes (PSG) are strongly enriched for innate and adaptive immune functions, secreted and cell membrane proteins (e.g. pattern recognition, complement, cytokine pathways, defensins, immune receptors, MHC, Siglecs). We also find evidence for positive selection in reproduction, chromosome segregation and meiosis (e.g. centromere-associated CENPO, CENPT), apolipoproteins, smell/taste receptors, and proteins interacting with mitochondrial-encoded molecules. Focusing on the virus-host interaction, we retrieve most evolutionary conflicts known to influence antiviral activity (e.g. TRIM5, MAVS, SAMHD1, tetherin) and predict 70 novel cases through integration with virus-host interaction data (virus-human PPIs, immune cell expression, infection screens). Protein structure analysis identifies positive selection in the interaction interfaces between viruses and their human cellular receptors (CD4 - HIV; CD46 [MCP] - measles, adenoviruses; CD55 [DAF] - picornaviruses). Finally, the primate PSG consistently show high sequence variation in human exomes, suggesting ongoing evolution. Our curated dataset of positively selected genes and positions, available at http://www.cmbi.umcn.nl/[~]rvdlee/positive_selection/, is a rich source for studying the genetics underlying human (antiviral) phenotypes.

evolutionary biology↗

bioRxiv2017

CiliaCarta: An Integrated And Validated Compendium Of Ciliary Genes

The cilium is an essential organelle at the surface of most mammalian cells whose dysfunction causes a wide range of genetic diseases collectively called ciliopathies. The current rate at which new ciliopathy genes are identified suggests that many ciliary components remain undiscovered. We generated and rigorously analyzed genomic, proteomic, transcriptomic and evolutionary data and systematically integrated these using Bayesian statistics into a predictive score for ciliary function. This resulted in 285 candidate ciliary genes. We found experimental evidence of ciliary associations for 24 out of 36 analyzed candidate proteins. In addition, we show that OSCP1, which has previously been implicated in two distinct non-ciliary functions, causes a cilium dysfunction phenotype when depleted in zebrafish. The candidate list forms the basis of CiliaCarta, a comprehensive ciliary compendium covering 836 genes. The resource can be used to objectively prioritize candidate genes in whole exome or genome sequencing of ciliopathy patients and can be accessed at http://bioinformatics.bio.uu.nl/john/syscilia/ciliacarta/.

bioinformatics↗