Our understanding of genetic predisposition to inflammatory and autoimmune diseases has been enhanced by large scale quantitative trait loci (QTL) linkage mapping and genome-wide association studies (GWAS). However, the resolution and interpretation of QTL linkage mapping or GWAS findings are limited. In this work, we complement genetic predictions for several human diseases including multiple sclerosis (MS) and systemic capillary leakage syndrome (SCLS) with genetic and functional data in model organisms to associate genes with phenotypes and diseases. Focusing on MS, an autoimmune inflammatory disease of the central nervous system (CNS), we experimentally tested the effect of three of the GWAS candidate genes (SLAMF1, SLAMF2 and SLAMF7) in the experimental autoimmune encephalomyelitis (EAE) mouse model and found a male-specific locus distal to these loci regulating CNS autoimmune disease. Functional data in mouse suggests this male-specific locus modulates the frequency of immune cells including CD11b+, TCRαβ+CD4+Foxp3+, and TCRαβ+CD8+IL-17+ cells during EAE disease. Orchiectomy experiments demonstrate that this male specific phenotype is dependent on testis but not testosterone (T) or 5α-dihydrotestosterone (DHT). Using a bioinformatic approach, we identified SLAMF8 and SLAMF9 along with other differentially expressed genes in linkage with MS-GWAS predictions whose expression is testis-dependent, but not directly regulated by T or DHT, as potential positional candidates regulating CNS autoimmune disease. Further refinement of this locus is required to identify the causal gene(s) that may be targeted for prevention and/or treatment of MS in men. Using SCLS, an extremely rare disorder of unknown etiology characterized by recurrent episodes of vascular leakage, we identified and modeled this disease in an inbred mouse strain, SJL, using susceptibility to histamine- and infection-triggered vascular leak as the major phenotypic readout. This trait “Histamine hypersensitivity” (Histh/Histh) was mapped to a region on Chr 6. Remarkably, Histh is syntenic to the genomic locus most strongly associated with SCLS in humans (3p25.3). Subsequent studies found that the Histh locus is not unique to SJL but additional mouse strains also exhibit Histh phenotype. Considering GWAS studies in SCLS are limited by the small number of patients, we utilized interval-specific SNP-based association testing among Histh phenotyped mouse strains to predict Histh candidates. Furthermore, to dissect the complexity of Histh QTL, we developed network-based functional prediction methods to rank genes in this locus by predicting functional association with multiple Histh-related processes. The top-ranked genes include Cxcl12, Ret, Cacna1c, and Cntn3, all of which have strong functional associations and are proximal to SNPs segregating with Histh. Lastly, we utilized the power of integrating genetic and functional approaches to understand susceptibility to Bordetella pertussis and pertussis toxin (PTX) induced histamine sensitization (Bphs/Bphs), a sub-phenotype with an established role in autoimmunity. Congenic mapping in mice had earlier linked Bphs to histamine H1 receptor gene (Hrh1/H1R) and demonstrated that H1R differs at three amino acid residues in Bphs-susceptible and -resistant mice. Our subsequent studies identified eight inbred mouse strains that were susceptible to Bphs despite carrying a resistant H1R allele. Genetic analyses mapped the locus complementing Bphs to mouse Chr 6, in linkage disequilibrium with Hrh1; we have designated this Bphs-enhancer (Bphse). Similar to the approaches used for Histh, we utilized interval-specific SNP based association testing and network-based functional enrichment to predict nine candidate loci for Bphse including Atp2b2, Atg7, Pparg, Syn2, Ift122, Raf1, Mkrn2, Timp4 and Gt(ROSA)26Sor. Overall, these studies demonstrate the power of integrating genetic and functional methods in humans and animal models to predict highly plausible loci underlying QTL/GWAS data.

京都大学 / 新制・課程博士 / 博士(農学) / 甲第24680号 / 農博第2563号 / 新制||農||1100(附属図書館) / 学位論文||R5||N5461(農学部図書室) / 京都大学大学院農学研究科応用生物科学専攻 / (主査)教授 寺内 良平, 教授 髙野 義孝, 教授 吉田 健太郎 / 学位規則第4条第1項該当 / Doctor of Agricultural Science / Kyoto University / DFAM

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京都大学 / 新制・論文博士 / 博士(農学) / 乙第13412号 / 論農博第2895号 / 新制||農||1085(附属図書館) / 学位論文||R3||N5322(農学部図書室) / 京都大学大学院農学研究科農学専攻 / (主査)教授 冨永 達, 教授 土井 元章, 教授 那須田 周平 / 学位規則第4条第2項該当 / Doctor of Agricultural Science / Kyoto University / DFAM

Peanut (Arachis hypogaea L.) is second major legume crop grown after soybean in the United States, and its productivity is often limited by drought stress. Drought negatively impacts the yield and quality of peanut. Drought stress in peanut causes an annual loss of approximately $520 million in the United States. Improving peanut yield under water deficit conditions is crucial for peanut growers to maintain their profitability in the market. To achieve this, it is essential to either breed or adopt already available drought tolerant cultivars that can produce higher yield under water deficit conditions. Therefore, the objectives of this research were to (1) evaluate five commercially available virginia and runner type peanut cultivars for pod yield stability using multilocation trials by studying G x E interaction across 13 environments including year, location, and irrigation regime. Linn and Binns, AMMI, Shukla, Wricke's, Finlay and Wilkinson stability models were used to determine pod yield stability. Bailey and Sullivan showed higher stability and adaptability across all stability indices whereas Wynne and TUFRunner presented high mean productivity with lesser stability across environments reflecting specific adaptation to just a few environments. Bailey and Sullivan are recommended for sustainable production across the growing region of Virginia and Carolinas. The second objective (2) was identification of drought tolerance related quantitative trait loci (QTL) and genetic markers to facilitate the development of drought tolerant cultivars. Three diverse recombinant inbred line (RIL) populations, derived from crossing lines N05006 x N04074FCT (Pop-1), line N05006 x Phillips, an old virginia-type cultivar (Pop-2), and lines N08086olJCT x PI 585005 (Pop-3) were phenotyped for the Normalized Difference Vegetation Index (NDVI), Canopy Temperature Depression (CTD), SPAD-meter relative chlorophyll content of the leaves (SPAD) and wilting for QTL mapping. Mapping identified 27 minor QTL on eight chromosomes for all physiological characteristics, i.e NDVI, CTD, SPAD and wilting, with logarithmic of odds values ranging from 2.5 to 38.5 and the phenotypic variance explained by these traits from 1.04 to 11.46 %. There were 4 loci on chromosome 2 associated with NDVI in Pop-1 and Pop-3, explaining 1.8 to 10.38% of the phenotypic variation. These genomic regions may be important resources in peanut breeding programs to improve drought tolerance. Further research is needed to increase the marker density in order to fine map the identified QTL and validate markers linked with these regions. / Doctor of Philosophy / Peanut is a multi million-dollar industry in the United States, but water limitations have a detrimental impact on yield, quality, and grower income. Drought along with aflatoxin contamination are two major challenges faced by U.S peanut industry. Annual losses to peanut caused by drought are around $520 million in the United States. Irrigation can alleviate water shortage in drought prone regions, but around 65% of peanut production in U.S is under rainfed condition, meaning that only rainfall can satisfy peanut crop water requirements. The most feasible and economical solution to peanut growers under these circumstances is to adopt drought tolerant varieties. In this research, our goal was to facilitate breeding drought tolerant cultivars through identification of molecular markers associated with drought tolerance and to identify already available drought tolerant peanut cultivars that could be a game changer for the producers. Therefore, the objectives of my research were to (1) evaluate in multiple environments five commercially available virginia and runner type peanut cultivars for pod yield stability and grade factors. In this study, we considered 13 environments, including 4 years, 4 locations, and 2 water regime. Statistical tools including Linn and Binns, AMMI, Shukla, Wricke's, and Finlay and Wilkinson were used to determine pod yield stability. These stability indices showed that Bailey and Sullivan are more stable and adaptable across different locations in terms of yield, whereas Wynne and TUFRunner presented high mean yield with lesser stability showing specific adaptation to only few environments. Based on stability analysis, Bailey and Sullivan are recommended for sustainable production across different growing region of Virginia and Carolinas. The second objective (2) was to identify drought tolerance related genomic regions using three mapping populations. Phenotyping and genotyping of three diverse recombinant inbred line (RIL) populations, derived from crossing lines N05006 x N04074FCT (Pop-1), lines N05006 x Phillips, an old virginia-type cultivar (Pop-2), and lines N08086olJCT x PI 585005 (Pop-3) were done to find quantitative trait loci (QTL) for drought related traits. These population were phenotyped for the Normalized Difference Vegetation Index (NDVI), Canopy Temperature Depression (CTD), SPAD-meter relative chlorophyll content of the leaves (SPAD) and wilting for QTL mapping. These surrogate traits are related to trait of interest for drought tolerance. NDVI is effective in predicting biomass and yield. Similarly, CTD is associated with transpiration efficiency and carbon dioxide assimilation. Mapping identified 27 minor QTL on eight chromosomes for all physiological characteristics, i.e NDVI, CTD, SPAD and wilting with logarithmic of odds values range from 2.5 to 38.5 and the phenotypic variance explained by these traits ranging from 1.04 to 11.46 %. There were 4 loci on chromosome 2 associated with NDVI in Pop-1 and Pop-3, explaining 1.8 to 10.38% of the phenotypic variation. These genomic regions may be important resources in peanut breeding programs to improve drought tolerance. Further research is needed to increase the marker density in order to fine map the identified QTL and validate markers linked with these regions.