Browsing by Subject "Genetic Predisposition to Disease"
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Item Analysis of Coding Region SNP's and Its Propensity to Cause Disease(2007-12-17) Kulkarni, Vinayak Vaman; Garner, Harold "Skip"Single Nucleotide Polymorphisms or (SNPs) are the most abundant form of variation present in the human genome. These variations in individuals are considered to be the cause of diseases, difference in response to treatment, susceptibility to diseases or may have no impact. Association studies aim at correlating an observed disease or a phenotype with these sequence variations. However very few of these SNPs are actually characterized according to the disease or phenotype they are implicated in. Currently, it is not possible to test and validate each and every SNP in the coding region of the human genome. Hence, the real challenge in association studies lies in carefully selecting reliable marker alleles which are most likely responsible for the observed phenotype or disease. This thesis addresses this problem by providing for each and every nucleotide in the human genome with a probabilistic value of it being involved in a disease or an important phenotype. Our hypothesis hinges on the fact that evolutionary conserved nucleotides are most important for gene function and hence would cause a disease if altered than non conserved nucleotides. By calculating the conservation of each base in all human Refseq exons and correlating the results with all SNPs in the Human Gene Mutation Database, a database of known disease causing SNPs and Database of Single Nucleotide Polymorphisms, we have exhaustively confirmed that the most conserved bases are indeed most sensitive to variation. Other factors known to be responsible for causing disease like alleles were also investigated. All the factors that were found to be responsible for disease alleles were chosen for the design of a classifier, which subsequently assigned a disease probability score to each coding base, based on these factors. This probability score represented the potential sensitivity to variation of each base. This will aid researchers rank SNPs and select candidate SNPs from a cohort for SNP-disease association studies. Identification of SNPs with disease-like signatures in SNP databases could provide researchers and clinicians with valuable information to aid them in the design and interpretation of epidemiological and genetic studies especially for those databases devoid of such annotation.Item A Mutation in Alk6b Causes Impaired Germ Cell Differentation and Testicular Germ Cell Tumors in Zebrafish(2010-11-02T18:19:23Z) Neumann, Joanie; Amatruda, James F.Germ cell tumors (GCTs) affect infants, children and young adults and are increasing in incidence worldwide. GCTs arise from pluripotent germ cells and can exhibit differentiated and undifferentiated histologies, which vary in their malignant potential and response to treatment. The pathways that determine tumor cell differentiation are not known, impeding the development of new therapies. Thus, the treatment of GCTs has remained static since the introduction 30 years ago of cisplatin which, while effective, causes severe side effects including hearing loss, infertility and kidney damage. We identified a zebrafish mutant line with a high incidence of GCT during a forward genetic screen to identify cancer susceptibility loci. Homozygous adult males develop tumors consisting of undifferentiated spermatogonia by 4 months of age while heterozygous males develop tumors around 7 to 9 months of age. We used interval haplotype analysis and high-resolution recombinational mapping to localize the mutation to a 0.82 cM interval on zebrafish chromosome 10. We identified a premature termination codon in Alk6b (Activin Receptor-like Kinase 6b) in the mutant animals. Alk6b is a member of the TGF-beta/BMP superfamily of receptors. BMP signaling has diverse roles including regulation of cell proliferation, differentiation, embryonic development, germ cell specification and gonadogenesis. Misregulation of the BMP signaling pathway has been implicated in various human cancers. In agreement with a critical role for Alk6b in controlling germ cell differentiation, we find evidence of impaired BMP signal transduction in the zebrafish GCTs, as well as evidence of alterations in the expression level of BMP target genes. We have also examined BMP signaling in a series of 40 clinically-annotated human GCTs of diverse histologic subtypes. In agreement with the predictions made from our zebrafish model, we find that undifferentiated GCTs such as dysgerminomas lack BMP signaling activity, whereas signaling is maintained in the differentiated subtype of Yolk Sac Tumors. These results confirm the relevance of the zebrafish model for understanding germ cell tumorigenesis, and will foster the development of improved, targeted therapy of human GCTs.