Rodent malaria parasites (RMPs) serve as tractable models for experimental genetics, and as valuable tools to study malaria parasite biology and host-parasitevector interactions. Plasmodium vinckei, one of four RMPs adapted to laboratory mice, is the most geographically widespread species and displays considerable phenotypic and genotypic diversity amongst its subspecies and strains. The phenotypes and genotypes of P. vinckei isolates have been relatively less characterized compared to other RMPs, hampering its use as an experimental model for malaria. Here, we have studied the phenotypes and sequenced the genomes and transcriptomes of ten P. vinckei isolates including representatives of all five subspecies, all of which were collected from wild thicket rats (Thamnomys rutilans) in sub-Saharan Central Africa between the late 1940s and mid 1960s. We have generated a comprehensive resource for P. vinckei comprising of five high-quality reference genomes, growth profiles and genotypes of P. vinckei isolates, and expression profiles of genes across the intra-erythrocytic developmental stages of the parasite. We observe significant phenotypic and genotypic diversity among P. vinckei isolates, making them particularly suitable for classical genetics and genomics-driven studies on malaria parasite biology. As part of a proof of concept study, we have shown that experimental genetic crosses can be performed between P. vinckei parasites to potentially identify genotype-phenotype relationships. We have also shown that they are amenable to genetic manipulation in the laboratory.

A Thesis submitted to The University of Arizona College of Medicine - Phoenix in partial fulfillment of the requirements for the Degree of Doctor of Medicine. / Genetic association studies simplify genotype‐phenotype relationship investigation by considering only the presence of a given polymorphism and the presence or absence of a given downstream phenotype. Although such associations do not indicate causation, collections of phenotypes sharing association with a single genetic polymorphism may provide valuable mechanistic insights. In this thesis we explore such genetic pleiotropy with Deep Phenotype Association Studies (DeePAS) using data from the Age‐Related Eye Study 2 (AREDS2). We also employ a novel text mining approach to extract pleiotropic associations from the published literature as a hypothesis generation mechanism. Is it possible to identify pleiotropic genetic associations across multiple published abstracts and validate these in data from AREDS2? Data from the AREDS2 trial includes 123 phenotypes including AMD features, other ocular conditions, cognitive function and cardiovascular, neurological, gastrointestinal and endocrine disease. A previously validated relationship extraction algorithm was used to isolate descriptions of genetic associations with these phenotypes in MEDLINE abstracts. Results were filtered to exclude negated findings and normalize variant mentions. Genotype data was available for 1826 AREDS2 participants. A DeePAS was performed by evaluating the association between selected SNPs and all available phenotypes. Associations that remained significant after Bonferroni‐correction were replicated in AREDS. LitWAS analysis identified 9372 SNPs with literature support for at least two distinct phenotypes, with an average of 3.1 phenotypes/SNP. PheWAS analyses revealed that two variants of the ARMS2‐HTRA1 locus at 10q26, rs10490924 and rs3750846, were significantly associated with sub‐retinal hemorrhage in AMD (rs3750846 OR 1.79 (1.41‐2.27), p=1.17*10‐7). This associated remained significant even in populations of participants with neovascular AMD. Furthermore, odds ratios for the development of sub‐retinal hemorrhage in the presence of the rs3750846 SNP were similar between incident and prevalent AREDS2 sub‐populations (OR: 1.94 vs 1.75). This association was also replicated in data from the AREDS trial. No literature‐defined pleiotropic associations tested remained significant after multiple‐testing correction. The rs3750846 variant of the ARMS2‐HTRA1 locus is associated with sub‐retinal hemorrhage. Automatic literature mining, when paired with clinical data, is a promising method for exploring genotype‐phenotype relationships.

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Denna självobservationsstudie undersöker hur övande av instrument påverkar det psy- kiska måendet samt hur det psykiska måendet påverkar övningen. Syftet med arbetet är att undersöka hur mycket övning som ska planeras i för väg så att det gynnar mitt mående samtidigt som övningen är effektiv. Under tre veckors tid användes tre olika sätt att pla- nera övning för att senare kunna hitta mönster i mående och övningskvalitet. En vecka planerades övningen i för väg, en vecka planerades ingen övning utan all övning var spon- tan och baserad på motivation och lust, och en vecka kombinerades dessa sätt genom att planera en del övning i för väg men även lämna utrymme för spontan övning. Studien ut- går från det fenomenologiska perspektivet och frågeställningarna lyder Upplever jag att övningens kvalitet påverkar mitt psykiska mående, och i sådana fall på vilka sätt? Upplever jag att det finns psykiska aspekter som påverkar min övning, och i sådana fall på vilka sätt? och I vilka situationer upplever jag att jag har en bra balans mellan planerad respektive spontan övning som gynnar både min övning och mitt psykiska mående? I undersökningen dokumenterades tankar kring övningen i en ljudloggbok i samband med övningstillfällena och mitt psykiska mående dokumenterades i en applikation, i form av en digital dagbok. Detta dokumenterade material bearbetades med hjälp av tematisk analys. Det framkom- mer i resultatet att mitt mående ofta speglar hur övningen har gått och har jag mått dåligt innan övningen så har det ofta varit svårt att fokusera, vilket påverkade övningens kvali- tet. Det framkommer också att det fanns väldigt lite motivation till övning under veckan där jag planerade all övning i för väg samt veckan där ingen övning planerades i för väg. Under veckan där en del övning planerades i förväg och en del övning skedde spontant visade sig att spontan övning ofta skedde till följd av planerad uppvärmning/övning tidi- gare samma dag. / This self-observation study examines how practicing an instrument affects the mental state and how the mental state affects the practice. The purpose of the study is to investi- gate how much exercise should be planned in advance so that it benefits my well-being while the exercise is effective. During three weeks, three different ways of planning exer- cise were used in order to later find patterns in mood and exercise quality. One week the exercise was planned in advance, one week no exercise was planned but all exercise was spontaneous and based on motivation and desire, and one week these ways were com- bined by planning some exercise in advance but also leaving room for spontaneous exer- cise. The study is based on the phenomenological perspective and the questions are: Do I feel that the quality of the exercise affects my psychological well-being, and if so, in what ways? Do I feel that there are psychological aspects that affect my practice? If so, in what ways? and In which situations do I feel that I have a good balance between planned and spontaneous practice that benefits both my practice and my mental well-being? Thoughts about the exercise were documented in an audio log book in connection with the exercise sessions and my mental state was documented in an application, in the form of a digital diary. This documented material was processed using thematic analysis. It appears in the results that my mood often reflects how the exercise went and if I felt bad before the ex- ercise, it was often difficult to focus, which affected the quality of the exercise. It also ap- pears that there was very little motivation for exercise during the week where I planned all exercise in advance and the week where no exercise was planned in advance. During the week where some exercise was planned in advance and some exercise happened spontaneously, it turned out that spontaneous exercise often happened as a result of planned warm-up/exercise earlier the same day.