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Effect of AluYb8MUTYH Polymorphism on Human Mitochondrial DNA(mtDNA)

Author: ZhengBiXia
Tutor: WangYaPing
School: Nanjing University
Course: Immunology
Keywords: Base excision repair AluYb8MUTYH MtDNA D-LOOPregionBase excision repair T2DM MtDNAcontent qRT-PCR
CLC: R394
Type: Master's thesis
Year: 2012
Downloads: 30
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Abstract


Part Ⅰ Assoeiation between AluYb8MUTYH Polymorphism and Mutation Spectrum of MtDNA D-LOOP regionBackground and Objective:Base excision repair (BER) is the most common repair mechanism in mtDNA. As in human, the MUTYH gene which encode the A/G-specific adenine DNA glycosylase belongs to base excision repair glycosylase group, and prevents G:C to A:T transversion by cleaving adenine opposite8-OhdG. The human cells express two major MUTYH proteins, called type1and type2, have different subcellular sites. Type1contains a mitochondrial targeting signal (MTS) at N-terminal, colocatizes with mitochondria. Type2lacks MTS of the N-terminal14amino acids, targets to nuclei. This work aims to investigate the relationship between AluYb8MUTYH polymorphism and mutation spectrum of mtDNA D-LOOP region.Materials and Methods:AluYb8MUTYH genotypes were analyzed and identified by agarose gels electrophoresis in60health samples. The AluYb8MUTYH genotypes were classified as homozygous absence of this variation (absence/absence, A/A), homozygous presence of this variation (presence/presence, P/P), and heterozygote (absence/presence, A/P). The D-LOOP region of the samples were amplified by PCR. The PCR product were gel-purified and transferred to plasmid by T carriers. The plasmids with the aim segment were extracted from the bacteria. At last ten cloned plasmids of each study object were seqenced and mutations between different plasmids were detected.Results:350variable sites were detected in these samples. The mutation forms were consisted largely of base base substitution (67%). Deletion/insertion and short tandem repeats variation were also detected, with the mutation rate of4%and29%. The average mutation rate was6.02in objects with the wild-type genotypes,7.18in heterozygotes, and5.66in homozygotes with the variation. However, There is no significant difference between different genotypes.Conclusion:There was no significant relationship between AluYb8MUTYH polymorphism and mutation spectrum of mtDNA D-LOOP region. Part Ⅱ Association analysis between AluYb8MUTYH polymorphism and peripheral blood mitochondrial DNA content in type2diabetic patientsBackground and Objective:Type2diabetes mellitus is one of the major diseases that threaten human health, and its occurrence and development are closely related to oxidative stress. Hyperglycemia can cause free radical production, thus lead to the accumulation of DNA damage products. In type2diabetic patients,8-OHdG is the most common product of oxidative DNA damage. This8-OhdG specific DNA damage is mainly repaired by base excision repair mechanism(BER). Studies have identified the relationship between genetic variations of BER system genes (hOGG1, MUTYH) and the incidence of T2DM. AluYb8MUTYH is a MYH polymorphism caused by AluYb8insertion in intron15of the MYH gene and is polymorphic distributed in Chinese. Case-control study have revealed that AluYb8MUTYH polymorphism could be a novel genetic risk factor for T2DM. This study aims to explore underlying mitochondrial mechanism of AluYb8MUTYH P/P genotype and high risk of T2DM. Materials and Methods:There were125type2diabetic patients and146healthy controls recruited to identify genotypes for AluYb8MUTYH polymorphism. The mtDNA content was determined in PBLs-derived genomic DNAs of all participants by qRT-PCR. Relative mtDNA content (mtDNA/nDNA) of different genotype categories were compared.Results:In younger type2diabetes group(<60year), the relative mtDNA content of patients carried P/P genotype was significantly higher than those with A/P genotype and A/A genotype. This change was not found in older group (>60year). Compared with health control group, the relative mtDNA content of patients carried P/P genotype was significantly higher.There was no difference between T2DM group and health controls carried A/P genotype and A/A genotype.Conclusion:AluYb8MUTYH P/P genotype as a type2diabetes risk factor, could increase peripheral blood mtDNA content in type2diabetic patients.

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