本文選題：外顯子測序 + 單核苷酸多態(tài)性��； 參考：《東南大學(xué)》2016年碩士論文

【摘要】：噪聲性聽力損失(Noise-induced Hearing Loss, NIHL)是長期接觸有害噪聲引起的進(jìn)行性感音神經(jīng)性聽力損傷。NIHL是由環(huán)境因素和遺傳因素交互作用發(fā)生的。以往研究關(guān)注較長時(shí)間噪聲暴露的遺傳易感性,但我們先期的研究發(fā)現(xiàn),新入職的青年工人,排除其他聽力損失的原因,在職業(yè)噪聲暴露三年內(nèi)存在聽力損失的風(fēng)險(xiǎn),為職業(yè)性噪聲暴露的敏感人群。本研究主要探討該NIHL敏感人群的遺傳易感性。首先采用全外顯子組測序法對5例短期內(nèi)接觸噪聲發(fā)生NIHL的青年工人進(jìn)行外顯子測序,對比SNP(亞洲人群頻率篩選)數(shù)據(jù)庫,篩選候選的易感SNP位點(diǎn)；進(jìn)而對候選SNP位點(diǎn)與青年工人較短時(shí)間發(fā)生NIHL的相關(guān)性進(jìn)行驗(yàn)證,并進(jìn)一步探討候選SNP位點(diǎn)與一般噪聲暴露人群NIHL的相關(guān)性；最后通過構(gòu)建NIHL動(dòng)物模型,檢測候選SNP的基因在噪聲暴露后mRNA的相對表達(dá)水平,以確定靶基因是否在轉(zhuǎn)錄水平上對噪聲暴露進(jìn)行應(yīng)答,在機(jī)制上驗(yàn)證易感性關(guān)聯(lián)的可能性。1.噪聲敏感人群的全外顯子組測序及候選SNP篩選對5例噪聲暴露三年內(nèi)就發(fā)生NEHL的新入職青年工人進(jìn)行全外顯子組測序,測序過程包括DNA提取、DNA質(zhì)檢、文庫構(gòu)建、外顯子區(qū)域捕獲、高通量測序、生物信息學(xué)分析。通過比對SNP(亞洲人群頻率篩選)數(shù)據(jù)庫,根據(jù)SNP位點(diǎn)位于外顯子區(qū)域、突變?yōu)榉峭x突變、4個(gè)以上測序樣本都發(fā)生突變,而正常漢族人群中等位基因頻率突小于0.2等標(biāo)準(zhǔn)納入目的靶基因。一共篩選出27個(gè)SNP位點(diǎn),其中5個(gè)測序樣本都突變的SNP位點(diǎn)有6個(gè),包括TTLL4 rs3731877、STK36rs1344642、BSPH1 rs60213124. HGC6.3 rs76543658、COL28A1 rs6952195、COL28A1 rs55745506。其中TTLL4基因編碼的蛋白是一種催化微管蛋白絡(luò)氨酸殘基磷酸化的蛋白,在細(xì)胞的生長、繁殖、分化過程中具有重要的作用；STK36基因編碼的蛋白屬于絲氨酸/蘇氨酸激酶家族；STK36基因的缺陷可能導(dǎo)致運(yùn)動(dòng)纖毛功能性缺失：BSPH1基因編碼粘附相關(guān)蛋白,參與機(jī)體能量代謝；基因庫中對于HGC6.3基因尚無明確定義：COL28A1基因編碼的蛋白質(zhì)屬于膠原蛋白家族,是一種生物性高分子化合物,在人體細(xì)胞中扮演結(jié)合組織的角色。2.候選SNP與噪聲性聽力損失遺傳易感性的研究2.1外顯子測序目的靶基因位點(diǎn)多態(tài)性與NIHL的相關(guān)性分析本研究著重對TTLL4 rs3731877、STK36 rs 1344642、BSPH1 rs60213124等三個(gè)SNP位點(diǎn)進(jìn)行驗(yàn)證。采用1：1配對病例對照方法,首先以19對接噪工齡小于3年的發(fā)生NIHL的工人和對照為研究對象,應(yīng)用聚合酶鏈反應(yīng)和直接測序法,分析候選SNP與NIHL易感性的相關(guān)關(guān)系；進(jìn)而以177對發(fā)生NIHL的工人和對照為研究對象,對目的靶基因的多態(tài)性與NIHL易感性進(jìn)行分析,并對靶基因多態(tài)性與NIHL的相關(guān)性進(jìn)行了年齡、工齡分層分析。研究結(jié)果顯示在短期內(nèi)接觸噪聲發(fā)生NIHL的青年工人中,BSPH1rs60213124位點(diǎn)的G、A等位基因頻率分布在組間存在統(tǒng)計(jì)學(xué)差異(x2=6.33,P0.05)：顯性模型(AA/AG VS.GG)分析結(jié)果顯示攜帶AA/AG基因型的個(gè)體患NIHL的危險(xiǎn)度是攜帶GG基因型個(gè)體的7.65倍(OR=7.65,95%CI=1.37-42.71).未發(fā)現(xiàn)BSPH1 rs60213124、TTLL4 rs3731877、STK36 re1344642位點(diǎn)多態(tài)性與其他工齡和年齡組發(fā)生NIHL的相關(guān)性。研究結(jié)果提示,BSPH1 rs60213124位點(diǎn)可能是短期內(nèi)接觸噪聲青年工人發(fā)生NIHL的易感基因位點(diǎn),但結(jié)果需要加大樣本量進(jìn)一步研究。2.2GJB2、NCL、CDH23、PCDH15基因多態(tài)性與NIHL的相關(guān)性分析本研究旨在探討GJB2基因rs2274083、rs2284084、rs72474224、NCL基因rs7598759、CDH23基因rs 10999947、PCDH15基因rs4935502、re108252693等位點(diǎn)的多態(tài)性與NIHL的相關(guān)性。研究結(jié)果表明,GJB2基因rs2274084的基因型分布在兩組組間存在統(tǒng)計(jì)學(xué)差異(x2=8.51,P=0.014),等位基因分布在兩組間也存在統(tǒng)計(jì)學(xué)差異(x2=8.06,P=0.005),攜帶CC基因型的個(gè)體患NIHL的危險(xiǎn)度是攜帶TT基因型個(gè)體的2.17倍(OR=2.17,95%CI=1.04-4.53).對該位點(diǎn)進(jìn)行工齡分層分析,在小于5年工齡組和大于15年工齡組,該位點(diǎn)基因型分布和等位基因頻率分布在病例組和對照組之間均存在統(tǒng)計(jì)學(xué)差異,并且大于15年工齡組的攜帶CC基因型個(gè)體罹患NIHL的危險(xiǎn)度要高于小于5年工齡組攜帶CC基因型的個(gè)體。CDH23rs10999947位點(diǎn)基因型分布在病例組和對照組之間存在統(tǒng)計(jì)學(xué)差異(X2=8.82,P=0.01),攜帶GG基因型的個(gè)體患NIHL的危險(xiǎn)度是AA基因型個(gè)體的4.03倍(OR=4.03,95%CI=1.44-11.3)。該位點(diǎn)隱形模型分析結(jié)果顯示,攜帶GG/AG基因型的個(gè)體患NIHL的危險(xiǎn)度是AA基因型個(gè)體的4.14倍(OR=4.14,95%CI=1.51-11.34)。對該SNP位點(diǎn)進(jìn)行人群年齡與工齡分層分析,結(jié)果顯示在年齡35-45歲段,該位點(diǎn)多態(tài)性與NIHL存在統(tǒng)計(jì)學(xué)相關(guān)(x2=6.3,P=0.04)。研究結(jié)果提示,GJB2基因rs2274084和CDH23基因rS10999947位點(diǎn)可能是NIHL的易感基因位點(diǎn)。3. NIHL動(dòng)物模型的構(gòu)建及耳蝸靶基因mRNA表達(dá)的檢測采用白噪聲暴露小鼠的方式構(gòu)建NIHL的動(dòng)物模型,對小鼠耳蝸內(nèi)靶基因在噪聲暴露后mRNA相對表達(dá)進(jìn)行檢測,以判斷目的靶基因是否在轉(zhuǎn)錄水平上在參與了NIHL的發(fā)生過程。ABR檢測結(jié)果顯示,噪聲暴露后兩組小鼠聽閾值組間存在統(tǒng)計(jì)學(xué)差異(P0.05),并且隨著電測聽頻率的升高,聽閾差值存在增大的趨勢�；啄や伷梢娫肼暯M小鼠耳蝸毛細(xì)胞出現(xiàn)缺損、倒伏嚴(yán)重。應(yīng)用熒光定量PCR對目的靶基因的表達(dá)進(jìn)行檢測,發(fā)現(xiàn)GJB2基因、CDH23基因、PCDH 15基因mRNA的相對表達(dá)量組間差異存在統(tǒng)計(jì)學(xué)差異(P0.05)。而對于其他靶基因,本研究未發(fā)現(xiàn)mRNA表達(dá)的差異。結(jié)果提示本研究構(gòu)建NIHL動(dòng)物模型成功,GJB2基因、CDH23基因、PCDH15基因可能參與了NIHL的發(fā)生過程。4.總結(jié)經(jīng)外顯子測序和比對SNP(亞洲人群頻率篩選)數(shù)據(jù)庫,初步獲得6個(gè)可能的青年工人短期內(nèi)噪聲暴露發(fā)生NIHL的候選SNP位點(diǎn),經(jīng)以接噪工齡小于3年發(fā)生NIHL的工人和對照為研究對象,分析候選SNP與NIHL易感性的相關(guān)關(guān)系,發(fā)現(xiàn)BSPH1rs60213124位點(diǎn)可能是短期內(nèi)接觸噪聲青年工人發(fā)生NIHL的易感基因位點(diǎn)。對GJB2、NCL、CDH23、PCDH15基因多態(tài)性與NIHL的相關(guān)性分析發(fā)現(xiàn)GJB2基因rs2274084和CDH23基因rs10999947位點(diǎn)與NIHL存在著相關(guān)性,GJB2基因rs2274084位點(diǎn)的CC基因型和CDH23基因rs10999947位點(diǎn)的GG基因型可能是噪聲性聽力損失的易感基因型。采用白噪聲暴露小鼠的方式成功構(gòu)建NIHL的動(dòng)物模型,對靶基因mRNA的表達(dá)檢測,發(fā)現(xiàn)GJB2基因、CDH23基因、PCDH 15基因mRNA的相對表達(dá)量在噪聲暴露組和對照組之間存在差異,GJB2基因、CDH23基因、PCDH15基因可能在轉(zhuǎn)錄水平上參與了NIHL的發(fā)生過程。
[Abstract]:Noise induced hearing loss (Noise-induced Hearing Loss, NIHL) is a long-term exposure to noxious noise caused by sexy sound neurogenic hearing impairment..NIHL is caused by the interaction of environmental factors and genetic factors. Previous studies focused on the genetic susceptibility to prolonged exposure to noise, but our previous study found that new recruits were recruited. Workers, excluding other hearing loss, have the risk of hearing loss within three years of occupational noise exposure. This is a sensitive group of occupational noise exposure. This study mainly discusses the genetic susceptibility to the NIHL sensitive population. First, 5 young workers with short term exposure to noise are revealed by the exon sequencing method. Subsequencing and comparing the SNP (Asian population frequency screening) database to screen candidate susceptible SNP loci, and then verify the correlation between the candidate SNP loci and the young workers in the short time of NIHL, and further explore the correlation between the candidate SNP loci and the NIHL in the general noise exposed population. Finally, the NIHL animal model is constructed and the detection weather is detected. The relative expression level of the SNP gene after noise exposure was selected to determine whether the target gene responds to the noise exposure at the transcriptional level, and the possibility of the susceptibility association is verified by the mechanism. The exon sequencing and candidate SNP screening of the.1. noise sensitive population in 5 cases of NEHL in the three year of noise exposure are the new recruits. The whole exon group was sequenced, and the sequencing process included DNA extraction, DNA quality inspection, library construction, exon capture, high throughput sequencing, bioinformatics analysis. By comparing the SNP (Asian population frequency screening) database, the SNP loci in exons were mutated into non synonymous mutations, and more than 4 sequencing samples were mutated, and positive The target gene of secondary gene frequency was less than 0.2 in the Han population. 27 SNP loci were screened out, of which 5 of the sequencing samples had 6 SNP loci, including TTLL4 rs3731877, STK36rs1344642, BSPH1 rs60213124. HGC6.3 rs76543658, COL28A1 rs6952195, and COL28A1 genes encoded eggs White is a protein that catalyzes the phosphorylation of the microtubulin complexate residue, which plays an important role in the growth, reproduction and differentiation of the cells; the protein encoded by the STK36 gene belongs to the serine / threonine kinase family; the defects of the STK36 gene may lead to the functional deletion of the sports cilium: the BSPH1 gene encodes the adhesion related protein and participates in the protein gene The energy metabolism of the body; there is no clear definition of HGC6.3 gene in the gene pool: the protein encoded by the COL28A1 gene belongs to the collagen family, is a biological polymer compound, plays the role of the binding tissue in human cells,.2. candidate SNP and the susceptibility of noise induced hearing loss, 2.1 exon sequencing target Analysis of the correlation between polymorphism of gene locus and NIHL, this study focuses on three SNP loci, such as TTLL4 rs3731877, STK36 RS 1344642, BSPH1 rs60213124 and other SNP loci. In order to analyze the correlation between candidate SNP and NIHL susceptibility, the polymorphism of target gene and NIHL susceptibility were analyzed with 177 pairs of NIHL workers and controls, and the correlation between target gene polymorphism and NIHL was analyzed. Among young workers who were born with NIHL, the frequency distribution of G and A alleles at the BSPH1rs60213124 locus was statistically different (x2=6.33, P0.05). The dominant model (AA/AG VS.GG) analysis showed that the risk of NIHL with AA/AG genotype was 7.65 times as large as that of the GG genotype (OR=7.65,95%CI=1.37-42.71). 13124, TTLL4 rs3731877, STK36 re1344642 locus polymorphism is associated with the occurrence of NIHL in other working age groups and age groups. The results suggest that BSPH1 rs60213124 loci may be a susceptible gene locus for NIHL in young workers exposed to noise in the short term, but the results need to be increased to further study.2.2GJB2, NCL, CDH23, PCDH15 gene polymorphism. The correlation analysis between sex and NIHL was aimed at exploring the correlation between the polymorphism of the GJB2 gene rs2274083, rs2284084, rs72474224, NCL gene rs7598759, CDH23 gene RS 10999947, PCDH15 gene rs4935502, re108252693 and other loci. X2=8.51, P=0.014), the distribution of alleles in the two groups was also statistically different (x2=8.06, P=0.005), and the risk of NIHL with the CC genotype was 2.17 times that of the TT genotype (OR=2.17,95%CI=1.04-4.53). The distribution and allele frequency distribution were statistically different between the case group and the control group, and the risk degree of NIHL in the CC genotype individuals with the 15 year old group was higher than that of the individuals carrying the CC genotype in the group less than 5 years old. The genotype distribution of the.CDH23rs10999947 loci of the individuals carrying the CC genotype was statistically significant between the case group and the control group. X2=8.82 (P=0.01), the risk degree of NIHL in individuals carrying GG genotype was 4.03 times (OR=4.03,95%CI=1.44-11.3) of AA genotype individuals. The stealth model analysis showed that the risk of NIHL in individuals carrying the GG/AG genotype was 4.14 times (OR=4.14,95%CI=1.51-11.34) for AA genotype individuals. Age and age stratification analysis showed that the polymorphism of the site was statistically related to NIHL (x2=6.3, P=0.04) at age 35-45 years. The results suggest that the rS10999947 locus of the GJB2 gene rs2274084 and CDH23 gene may be the construction of the.3. NIHL animal model of the susceptible gene locus of NIHL and the detection of the mRNA expression of the cochlear target gene. The animal model of NIHL was constructed by noise exposed mice, and the relative expression of mRNA in the mouse cochlea target gene was detected after noise exposure to determine whether the target gene was involved in the transcription of NIHL at the transcriptional level and.ABR detection results showed that there was a statistical difference between the two groups of hearing threshold groups after the noise exposure (P0.05). And with the increase of the frequency of electrical audiometry, the difference of hearing threshold increased. The cochlear hair cells in the group of basal membrane were visible and the lodging was serious. The expression of target gene was detected by fluorescence quantitative PCR. The difference of the relative expression of the relative expression of the GJB2 gene, CDH23 gene and PCDH 15 gene mRNA was found to be statistically significant. P0.05. But for other target genes, there is no difference in the expression of mRNA in this study. The results suggest that the NIHL animal model is successful in this study. The GJB2 gene, CDH23 gene, and PCDH15 gene may be involved in the occurrence of NIHL,.4. summarizes the exon sequencing and compares SNP (Asian population frequency screening) database, initially obtaining 6 possible In the short term, young workers exposed to the candidate SNP loci of NIHL, the workers and controls who were less than 3 years older than 3 years, analyzed the correlation between the candidate SNP and the NIHL susceptibility, and found that the BSPH1rs60213124 locus may be the susceptible gene locus of NIHL in young workers exposed to noise in the short term. For GJB2, NCL, CDH23. The correlation analysis between PCDH15 gene polymorphism and NIHL found that there was a correlation between the rs10999947 locus of the GJB2 gene rs2274084 and CDH23 gene and NIHL. The CC genotypes of the rs2274084 locus of the GJB2 gene and the CDH23 gene rs10999947 loci may be the susceptible genotypes of noise induced hearing loss. The animal model of NIHL was constructed and the expression of the target gene mRNA was detected. The relative expression of the GJB2, CDH23 and PCDH 15 gene mRNA was found to be different between the noise exposed group and the control group. The GJB2, CDH23, and PCDH15 genes may be involved in the occurrence of NIHL at the transcription level.
【學(xué)位授予單位】：東南大學(xué)
【學(xué)位級別】：碩士
【學(xué)位授予年份】：2016
【分類號】：R135.8

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本文編號：1911896