X染色體印記效應(yīng)檢驗(yàn)及合并X染色體失活與印記效應(yīng)的關(guān)聯(lián)分析研究
發(fā)布時(shí)間：2018-08-25 12:22
【摘要】：背景:關(guān)聯(lián)分析(association analysis)是用來檢驗(yàn)等位基因頻率或基因型頻率在兩組個(gè)體(患病人群和正常人群)之間是否存在差異的方法。其主要目的是為了定位疾病位點(diǎn),利用疾病位點(diǎn)和標(biāo)記位點(diǎn)的關(guān)系來找到遺傳變異。如果標(biāo)記位點(diǎn)和疾病位點(diǎn)之間的距離很接近,它們可能存在連鎖不平衡(linkage disequilibrium),那么這兩個(gè)位點(diǎn)很有可能是共同遺傳給后代的。如果在患病的人群中這個(gè)標(biāo)記位點(diǎn)的頻率比正常人群的高,利用關(guān)聯(lián)分析方法就可能將該疾病位點(diǎn)進(jìn)行定位。遺傳印記效應(yīng)(genomic imprinting)是我們熟知的一種病因?qū)W因素。遺傳印記基因的表達(dá)取決于等位基因是來自父親還是來自母親,而這種現(xiàn)象可能會(huì)導(dǎo)致疾病和基因之間的關(guān)聯(lián)。遺傳印記現(xiàn)象會(huì)影響后代在子宮內(nèi)的發(fā)育以及出生后個(gè)體的成長(zhǎng)發(fā)育。與常染色體上變異的遺傳印記作用有關(guān)的疾病有:Beckwith-Wiedemann 綜合征、Prader-Will 綜合征、Angelman 綜合征、糖尿病和精神分裂癥等。另外,X染色體上的印記基因在復(fù)雜疾病和性狀的形成上也許起到了關(guān)鍵的作用,如Turner綜合征和孤獨(dú)癥等。目前已經(jīng)有很多方法可以用來檢驗(yàn)基于核心家庭和一般家系常染色體上的遺傳印記效應(yīng)。有關(guān)X染色體上印記效應(yīng)的檢驗(yàn),僅僅有最近新提出的基于核心家庭數(shù)據(jù)的X染色體質(zhì)量性狀位點(diǎn)上的親代不對(duì)稱檢驗(yàn)方法(parental-asymmetry test on X chromosome,XPAT)。然而該方法并不適用于一般的家系數(shù)據(jù)。X 染色體失活(X chromosome inactivation,XCI)是一種劑量補(bǔ)償(dose compensation)的機(jī)制,通常發(fā)生在胚胎發(fā)育早期,女性的兩條X染色體中的一條發(fā)生了失活現(xiàn)象,從而導(dǎo)致女性個(gè)體的每一個(gè)細(xì)胞中,只有一條來自父親或者母親的染色體表達(dá)。通常,這種X染色體失活的現(xiàn)象是隨機(jī)的,即女性的兩條X染色體失活的比例是50%:50%。但是,如果失活現(xiàn)象不是隨機(jī)的,那就稱之為偏倚失活(skewed X chromosome inactivation)。偏倚失活通常意味著有75%或以上的細(xì)胞失活同一條X染色體,而另外25%的細(xì)胞失活另一條X染色體。另外,跟常染色體一樣,X染色體還存在著一種特殊現(xiàn)象就是逃逸失活(escape from X chromosome inactivation)的情況,即兩條X染色體均表達(dá),沒有失活。在一些女性個(gè)體中的某一條X染色體上,大概有四分之三的基因是沉默了的,其余四分之一的基因?qū)儆谔右菔Щ顓^(qū)域。然而,現(xiàn)有的X染色體上的關(guān)聯(lián)分析方法中,僅考慮了 X染色體失活,并沒有合并遺傳印記的效應(yīng)。因此,本文的研究目的主要有以下兩點(diǎn):(1)基于家系數(shù)據(jù),提出X染色體質(zhì)量性狀位點(diǎn)上遺傳印記效應(yīng)檢驗(yàn)方法;(2)基于兩代人的病例對(duì)照數(shù)據(jù),提出同時(shí)合并X染色體失活和印記效應(yīng)的關(guān)聯(lián)分析方法。方法:(1)考慮X染色體上的位點(diǎn),參考常染色體上的PPAT方法,利用家系中所有有信息的核心家庭,當(dāng)感興趣的SNP位點(diǎn)與疾病之間存在關(guān)聯(lián)的情況下,提出基于家系數(shù)據(jù)的X染色體親代不對(duì)稱檢驗(yàn)方法(pedigree parental-asymmetry test on X chromosome,XPPAT)。當(dāng)某些家系中存在缺失基因型個(gè)體時(shí),我們根據(jù)觀察到的個(gè)體基因型,采用Monte Carlo重抽樣方法對(duì)缺失個(gè)體的基因型進(jìn)行反推,進(jìn)一步提出基于家系數(shù)據(jù)的X染色體Monte Carlo親代不對(duì)稱檢驗(yàn)方法(Monte Carlo pedigree parental-asymmetry test on X chromosome,XMCPPAT)。通過模擬得到所提出方法的第一類錯(cuò)誤率和檢驗(yàn)效能。最后,通過一個(gè)來自北美的類風(fēng)濕關(guān)節(jié)炎基因數(shù)據(jù)對(duì)新提出方法進(jìn)行實(shí)例驗(yàn)證。(2)參考Wang等人提出的最大化似然比的檢驗(yàn)方法,針對(duì)不同的X染色體失活模式(隨機(jī)失活、偏倚失活和逃逸失活),將一個(gè)個(gè)體來自父親和母親的等位基因分別進(jìn)行賦值。對(duì)女性的等位基因進(jìn)行賦值時(shí),用r∈[0,2]來衡量X染色體失活的偏倚程度,然后通過男性的等位基因賦值來體現(xiàn)X染色體是否失活。而這種賦值方式的效應(yīng)量可以體現(xiàn)印記效應(yīng)是否存在。這樣可以將X染色體失活和遺傳印記效應(yīng)的信息同時(shí)合并到Logistic回歸模型中。對(duì)不同的r值,得到不同的LR值,記為L(zhǎng)Rr。取LRr的最大值作為檢驗(yàn)統(tǒng)計(jì)量,注意到其在無關(guān)聯(lián)的原假設(shè)下的分布未知。所以,我們還采用了一種permutation的方法得到新提出方法的經(jīng)驗(yàn)P值進(jìn)行統(tǒng)計(jì)推斷。相應(yīng)的方法記為XCII方法(association test incorporating X chromosome inactivation and imprinting effects)。通過模擬得到所提出方法的第一類錯(cuò)誤率和檢驗(yàn)效能。結(jié)果:(1)在不同的模擬背景下,包括兩種不同的樣本量、兩組不同的等位基因頻率、三種不同的近交系數(shù)和五種不同的遺傳印記效應(yīng)模型,模擬結(jié)果表明所提出的方法可以很好地控制第一類錯(cuò)誤率。并且,新方法的檢驗(yàn)效能比現(xiàn)有的XPAT方法要高出很多。通過Monte Carlo重抽樣方法對(duì)缺失基因型進(jìn)行反推,XMCPPAT方法在存在缺失基因型個(gè)體時(shí)能控制第一類錯(cuò)誤率。再者,由于女性中近交系數(shù)的改變對(duì)XPPAT和XMCPPAT方法的結(jié)果幾乎不產(chǎn)生影響,因而新提出的XPPAT和XMCPPAT方法不受女性中Hardy-Weinberg平衡律(Hardy-Weinberg equilibrium,HWE)是否成立的影響。值得注意的是,對(duì)適用于缺失數(shù)據(jù)的XMCPPAT方法,我們采用了三種方式對(duì)等位基因頻率進(jìn)行處理,包括:真實(shí)的等位基因頻率、由女性奠基者估算出的等位基因頻率和由男性奠基者估算出的等位基因頻率,將統(tǒng)計(jì)量分別記為XMCPPATt、XMCPPATf和XMCPPATm。另外,基于完整數(shù)據(jù),用XPPATfull進(jìn)行檢驗(yàn),作為所有方法的金標(biāo)準(zhǔn)。從結(jié)果上看,應(yīng)用女性奠基者估算出的等位基因頻率的XMCPPATf方法與基于完整數(shù)據(jù)的XPPATfull方法以及基于真實(shí)的等位基因頻率的XMCPPATt方法檢驗(yàn)效能很接近。這意味著,XMCPPATt和XMCPPATf方法可以捕獲大部分缺失基因型個(gè)體的信息。然而,XMCPPATm不能很好地控制第一類錯(cuò)誤率。(2)模擬結(jié)果表明,XCII方法可以將第一類錯(cuò)誤率穩(wěn)定在設(shè)定的顯著性水平附近,說明了 XCII方法用以檢驗(yàn)合并X染色體失活與印記效應(yīng)信息的位點(diǎn)與疾病之間關(guān)聯(lián)的有效性。在檢驗(yàn)效能方面,當(dāng)X染色體失活和遺傳印記效應(yīng)同時(shí)存在時(shí),XCII方法的檢驗(yàn)效能整體上比Wang的方法高。當(dāng)僅有X染色體失活而印記效應(yīng)不存在時(shí),XCII方法的檢驗(yàn)效能仍比Wang的方法高。因此,考慮X染色體上的關(guān)聯(lián)分析研究時(shí),我們更推薦使用第三章新提出的XCII方法。結(jié)論:(1)新提出的XPPAT和XMCPPAT檢驗(yàn)統(tǒng)計(jì)量可以有效地檢驗(yàn)基于家系數(shù)據(jù)的X染色體質(zhì)量性狀位點(diǎn)上的印記效應(yīng),XMCPPAT方法比現(xiàn)有的方法檢驗(yàn)效能更高,更適用于對(duì)包含缺失基因型個(gè)體的數(shù)據(jù)進(jìn)行印記效應(yīng)的檢驗(yàn)。(2)考慮X染色體上的關(guān)聯(lián)分析研究時(shí),很多疾病同時(shí)跟X染色體失活和遺傳印記效應(yīng)相關(guān)聯(lián),相比只考慮X染色體失活的Wang的方法,XCII方法的表現(xiàn)更好。因此,我們推薦使用同時(shí)考慮X染色體失活和印記效應(yīng)的XCII方法。
[Abstract]:BACKGROUND: Association analysis is a method used to test whether allele frequencies or genotype frequencies differ between two groups of individuals (the sick and the normal). The main purpose of association analysis is to locate disease sites and use the relationship between disease sites and marker sites to find genetic variations. If the frequency of this marker is higher in the affected population than in the normal population, it is possible to locate the disease site by association analysis. Genetic imprinting is a well-known etiological factor. The expression of genetic imprinting genes depends on whether the allele is from the father or the mother, and this phenomenon may lead to disease and gene association. Genetic imprinting affects the development of offspring in the uterus and the development of individuals after birth. Diseases associated with genetic imprinting of autosomal variations include Beckwith-Wiedemann syndrome, Prader-Will syndrome, Angelman syndrome, diabetes and schizophrenia. In addition, imprinting genes on the X chromosome may play a key role in the formation of complex diseases and characteristics, such as Turner syndrome and schizophrenia. Autism and so on. At present, there are many methods which can be used to test the genetic imprinting effect on autosomal chromosomes of nuclear families and general families. X chromosome inactivation (XCI) is a dose compensation mechanism, usually occurring in the early embryonic development, in which one of the two X chromosomes of a woman is inactivated, leading to a female individual. In each cell, only one chromosome is expressed from the father or mother. Usually, this X-chromosome inactivation is random, i.e. the ratio of two X-chromosomes inactivation in women is 50%:50%. However, if the inactivation is not random, it is called skewed X-chromosome inactivation. Usually it means that 75% or more of the cells are inactivated on the same X chromosome, while 25% of the cells are inactivated on the other X chromosome. About three-quarters of the genes on an X chromosome are silent, and the remaining one-quarter belong to the escape-inactivation region. The following two points are pointed out: (1) Based on the family coefficient data, a method for testing the genetic imprinting effect on the quality trait loci of X chromosome is proposed; (2) Based on the case-control data of two generations, an association analysis method combining both X chromosome inactivation and imprinting effect is proposed. A pedigree parental-asymmetric test on X chromosome (XPPAT) based on family coefficient data is proposed for all informative nuclear families in a family. When there are deleted genotypes in some families, we use the observed ones. The genotypes of deleted individuals were retrieved by Monte Carlo resampling method, and the Monte Carlo parental asymmetry test on X chromosome (XMCPPAT) based on family coefficient data was proposed. The first class error rate and XMCPPAT of the proposed method were obtained by simulation. Finally, the proposed method was validated by a North American rheumatoid arthritis gene data set. (2) Referring to the maximum likelihood ratio test proposed by Wang et al., an individual was selected from his father and mother for different X chromosome inactivation patterns (random inactivation, bias inactivation and escape inactivation). When assigning female alleles, the bias of X-chromosome inactivation is measured by R < [0,2], and then the X-chromosome inactivation is reflected by the male allele assignment. The effect of this assignment can reflect the existence of imprinting effect. This can inactivate and lose X-chromosome. The information of biography effect is merged into the logistic regression model at the same time. Different values of R are obtained, which are recorded as LR R. The maximum of LR R is taken as the test statistic and the distribution of LR R is unknown under the original assumption of irrelevance. Therefore, we also use a permutation method to obtain the empirical P value of the new method. Statistical inference. The corresponding method is called the association test incorporating X chromosome inactivation and imprinting effects. Three different inbreeding coefficients and five different genetic imprinting effect models were used to simulate the results. The simulation results show that the proposed method can control the first kind of error rate very well. Moreover, the test efficiency of the new method is much higher than that of the existing XPAT method. Moreover, since the change of inbreeding coefficient in women has little effect on the results of XPPAT and XMCPPAT methods, the new XPPAT and XMCPPAT methods are not affected by the Hardy-Weinberg equilibrium (HWE) in women. Yes, for the XMCPPAT method applicable to missing data, we used three methods to process allele frequencies, including true allele frequencies, allele frequencies estimated by female founders, and allele frequencies estimated by male founders. The statistics were recorded as XMCPPATt, XMCPPATf, and XMCPPATm, respectively. The results showed that the XMCPPATf method based on the allele frequencies estimated by the female founders was very close to the XPPATful method based on the complete data and the XMCPPATt method based on the true allele frequencies. Tt and XMCPPATf methods can capture the information of most deleted genotypes. However, XMCPPATm can not control the first class error rate very well. (2) Simulation results show that XCII method can stabilize the first class error rate near the set significance level, indicating that XCII method is used to test the combined X chromosome inactivation and imprinting effect letter. When X chromosome inactivation and genetic imprinting effect coexist, the efficiency of XCII method is higher than that of Wang's method on the whole. When only X chromosome is inactivated and imprinting effect does not exist, the efficiency of XCII method is still higher than that of Wang's method. Conclusion: (1) The newly proposed XPPAT and XMCPPAT test statistic can effectively test the imprinting effect on X chromosome quality trait loci based on family coefficient data. The XMCPPAT method is more effective than the existing methods and is more suitable for detecting inclusion deficiencies. (2) Considering X-chromosome Association analysis, many diseases are associated with both X-chromosome inactivation and genetic imprinting. The XCII method performs better than Wang's method, which only considers X-chromosome inactivation. Therefore, we recommend that both X-chromosome inactivation and X-chromosome inactivation be considered. And the imprinting effect of XCII method.
【學(xué)位授予單位】：南方醫(yī)科大學(xué)
【學(xué)位級(jí)別】：碩士
【學(xué)位授予年份】：2017
【分類號(hào)】：R394
，
本文編號(hào)：2202875
[Abstract]:BACKGROUND: Association analysis is a method used to test whether allele frequencies or genotype frequencies differ between two groups of individuals (the sick and the normal). The main purpose of association analysis is to locate disease sites and use the relationship between disease sites and marker sites to find genetic variations. If the frequency of this marker is higher in the affected population than in the normal population, it is possible to locate the disease site by association analysis. Genetic imprinting is a well-known etiological factor. The expression of genetic imprinting genes depends on whether the allele is from the father or the mother, and this phenomenon may lead to disease and gene association. Genetic imprinting affects the development of offspring in the uterus and the development of individuals after birth. Diseases associated with genetic imprinting of autosomal variations include Beckwith-Wiedemann syndrome, Prader-Will syndrome, Angelman syndrome, diabetes and schizophrenia. In addition, imprinting genes on the X chromosome may play a key role in the formation of complex diseases and characteristics, such as Turner syndrome and schizophrenia. Autism and so on. At present, there are many methods which can be used to test the genetic imprinting effect on autosomal chromosomes of nuclear families and general families. X chromosome inactivation (XCI) is a dose compensation mechanism, usually occurring in the early embryonic development, in which one of the two X chromosomes of a woman is inactivated, leading to a female individual. In each cell, only one chromosome is expressed from the father or mother. Usually, this X-chromosome inactivation is random, i.e. the ratio of two X-chromosomes inactivation in women is 50%:50%. However, if the inactivation is not random, it is called skewed X-chromosome inactivation. Usually it means that 75% or more of the cells are inactivated on the same X chromosome, while 25% of the cells are inactivated on the other X chromosome. About three-quarters of the genes on an X chromosome are silent, and the remaining one-quarter belong to the escape-inactivation region. The following two points are pointed out: (1) Based on the family coefficient data, a method for testing the genetic imprinting effect on the quality trait loci of X chromosome is proposed; (2) Based on the case-control data of two generations, an association analysis method combining both X chromosome inactivation and imprinting effect is proposed. A pedigree parental-asymmetric test on X chromosome (XPPAT) based on family coefficient data is proposed for all informative nuclear families in a family. When there are deleted genotypes in some families, we use the observed ones. The genotypes of deleted individuals were retrieved by Monte Carlo resampling method, and the Monte Carlo parental asymmetry test on X chromosome (XMCPPAT) based on family coefficient data was proposed. The first class error rate and XMCPPAT of the proposed method were obtained by simulation. Finally, the proposed method was validated by a North American rheumatoid arthritis gene data set. (2) Referring to the maximum likelihood ratio test proposed by Wang et al., an individual was selected from his father and mother for different X chromosome inactivation patterns (random inactivation, bias inactivation and escape inactivation). When assigning female alleles, the bias of X-chromosome inactivation is measured by R < [0,2], and then the X-chromosome inactivation is reflected by the male allele assignment. The effect of this assignment can reflect the existence of imprinting effect. This can inactivate and lose X-chromosome. The information of biography effect is merged into the logistic regression model at the same time. Different values of R are obtained, which are recorded as LR R. The maximum of LR R is taken as the test statistic and the distribution of LR R is unknown under the original assumption of irrelevance. Therefore, we also use a permutation method to obtain the empirical P value of the new method. Statistical inference. The corresponding method is called the association test incorporating X chromosome inactivation and imprinting effects. Three different inbreeding coefficients and five different genetic imprinting effect models were used to simulate the results. The simulation results show that the proposed method can control the first kind of error rate very well. Moreover, the test efficiency of the new method is much higher than that of the existing XPAT method. Moreover, since the change of inbreeding coefficient in women has little effect on the results of XPPAT and XMCPPAT methods, the new XPPAT and XMCPPAT methods are not affected by the Hardy-Weinberg equilibrium (HWE) in women. Yes, for the XMCPPAT method applicable to missing data, we used three methods to process allele frequencies, including true allele frequencies, allele frequencies estimated by female founders, and allele frequencies estimated by male founders. The statistics were recorded as XMCPPATt, XMCPPATf, and XMCPPATm, respectively. The results showed that the XMCPPATf method based on the allele frequencies estimated by the female founders was very close to the XPPATful method based on the complete data and the XMCPPATt method based on the true allele frequencies. Tt and XMCPPATf methods can capture the information of most deleted genotypes. However, XMCPPATm can not control the first class error rate very well. (2) Simulation results show that XCII method can stabilize the first class error rate near the set significance level, indicating that XCII method is used to test the combined X chromosome inactivation and imprinting effect letter. When X chromosome inactivation and genetic imprinting effect coexist, the efficiency of XCII method is higher than that of Wang's method on the whole. When only X chromosome is inactivated and imprinting effect does not exist, the efficiency of XCII method is still higher than that of Wang's method. Conclusion: (1) The newly proposed XPPAT and XMCPPAT test statistic can effectively test the imprinting effect on X chromosome quality trait loci based on family coefficient data. The XMCPPAT method is more effective than the existing methods and is more suitable for detecting inclusion deficiencies. (2) Considering X-chromosome Association analysis, many diseases are associated with both X-chromosome inactivation and genetic imprinting. The XCII method performs better than Wang's method, which only considers X-chromosome inactivation. Therefore, we recommend that both X-chromosome inactivation and X-chromosome inactivation be considered. And the imprinting effect of XCII method.
【學(xué)位授予單位】：南方醫(yī)科大學(xué)
【學(xué)位級(jí)別】：碩士
【學(xué)位授予年份】：2017
【分類號(hào)】：R394
，
本文編號(hào)：2202875
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