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Translating Mouse Systems Genetics to Discovery in Human Disease
Get PDFThis dissertation is the culmination of my graduate studies in the laboratory of Jake Lusis at UCLA. The research presented here utilizes systems genetics studies performed in mice to aid in discovery in human disease in three separate studies. A significant portion of disease-oriented research is performed in mice, but a major criticism from the medical community is that laboratory mice are generally inbred and thus have no genetic variation among individuals. Almost 15 years ago, the Lusis lab developed a novel genetic resource for association analysis in the mouse called the Hybrid Mouse Diversity Panel (HMDP). The HMDP is a panel of inbred mouse strains that was developed for performing association studies with adequate statistical power and resolution for mapping of complex traits. Mouse genome wide association studies (GWAS) studies are a powerful tool and can be performed relatively easily, but translating the data obtained from these studies to human disease is still in its infancy. My dissertation work reveals three different novel approaches to the utilization of data from GWAS studies performed on the HMDP for translation into human disease processes, namely cardiovascular disease. The first study utilizes novel genetic signatures in murine macrophages to predict disease incidence and survival in humans. The second study utilizes a traditional GWAS to candidate gene discovery to elucidate the mechanisms underlying cardiac remodeling in humans. Lastly, the third study utilizes mouse GWAS data for novel heart failure biomarker discovery in humans. As an introduction to this dissertation, Chapter 1 briefly summarizes the history of GWAS in mice using the HMDP and GWAS in humans. Chapter 2 is a completed and accepted first-author manuscript entitled “Natural diversity reveals macrophage activation spectra predictive of inflammation and cancer survival.” Chapter 3 explores the role of CD200, a candidate gene obtained from a large heart failure GWAS study in mice, and it’s receptor, CD200R1 in cardiac homeostasis and injury. Chapter 4 describes a novel approach to biomarker discovery for human heart failure using data from a large heart failure GWAS study. Chapter 5 is a departure from mouse systems genetics. In this chapter, I describe the strengths and pitfalls of exome sequencing. In addition, I describe two cases of rare cardiovascular disease in which exome sequencing is utilized to find causal variants of disease. Ultimately, I’d like to use what I’ve learned in my studies of mouse genetics and translate this to discovery in human disease. In conclusion, this dissertation work contributes significant findings to the expanding knowledge of utilizing mouse GWAS for discovery in human disease
Green 14
No full textLong-time friends Harry and Ilona Skrastins, Mr. Putnins, Mrs. Lusis, and Mrs. Heinbergs in the home of Peter and Ilga Green in 1996
Green 14 copy
No full textLong-time friends Harry and Ilona Skrastins, Mr. Putnins, Mrs. Lusis, and Mrs. Heinbergs in the home of Peter and Ilga Green in 1996
Poruks 36
No full text1969 Confirmation of Edmonton area Latvian youth. Left to right front row: Cynthia Jones, VIcki Jones, Liesma Caks, Zaiga Endols. Second row left to right: Linda Lusis, Maija Poruks, Modris Endols, Uldis Bruzis. Back row left to right: Karlis Tigeris, Vilnis Caks, Karlis Poruks
Bruzis 27
No full textConfirmation ceremony for Edmonton area, Latvian youth, 1969. 
Front row left to right: Maija Poruks, Linda Lusis, Cynthia Jones, Reverend Avotins, Zaiga Endols, Liesma Caks, Vciky Jones.
Back row left to right: Vilnis Caks, Modros Endols, Uldis Bruzis, Karlis Poruks, Karlis Tigeris
‘Sandwich-men parade the streets’: Conceptualizing regionalism and the north-south divide in British lawn tennis
No full textThe bulk of tennis historiography has tended to project a Southern-centric image of the sport, through descriptions of its clubs and tournaments, its players, and associations. Both the Lawn Tennis Association and the Wimbledon Championships began and have remained bastions of Southern hegemony, but there existed (and continues to exist) a large and active ‘tennis culture’ in the North that has been overlooked. The aim of this paper is to critically explore the notion of a north-south divide in tennis, commencing from the late nineteenth century to the early post-war period. Comparing both northern and southern regions, including Scotland and Wales, it focuses on the emergence of clubs and tournaments, the attitudes, values and behaviours of players and spectators, and the formation of associations. Evidence suggests the existence of a north-south divide, but one that is qualitatively distinct from that experienced in popular team sports; less a reliance on the construction of Northern sporting heroes, with their concomitant representative personalities and characters, and more a focus on the construction of regional stereotypes of clubs, tournaments and players, and the focus on different values, all set in broader historical contexts of rising and waning fortunes of Northern regions in industry and commerce.Peer reviewedPublished
TCS in Action
No full text In the context of the respective needs of companies, universities and individual graduates in the partnership process, this paper describes a TCS Programme involving Welsh Water, a major UK utility provider, Lusis Business Solutions, an IT company, and the Department of Computer Science of the University of Wales, Swansea. The author presents a case study of a project to control coagulation in water treatment through a neural network, illustrating how the structure of the partnership was used to facilitate and produce a successful outcome. Finally he summarizes the key benefits of the Programme experienced by the various participants. </jats:p
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Get PDFPrevious studies had shown that the integration of genome wide expression profiles, in metabolic tissues, with genetic and phenotypic variance, provided valuable insight into the underlying molecular mechanisms. We used RNA-Seq to characterize hypothalamic transcriptome in 99 inbred strains of mice from the Hybrid Mouse Diversity Panel (HMDP), a reference resource population for cardiovascular and metabolic traits. We report numerous novel transcripts supported by proteomic analyses, as well as novel non coding RNAs. High resolution genetic mapping of transcript levels in HMDP, reveals both local and trans expression Quantitative Trait Loci (eQTLs) demonstrating 2 trans eQTL 'hotspots' associated with expression of hundreds of genes. We also report thousands of alternative splicing events regulated by genetic variants. Finally, comparison with about 150 metabolic and cardiovascular traits revealed many highly significant associations. Our data provide a rich resource for understanding the many physiologic functions mediated by the hypothalamus and their genetic regulation
