大Y染色体临床效应及其形成机理初步研究
发布时间：2018-07-21 10:16
【摘要】： 染色体多态性是指人类群体中染色体形态存在的微小差异。传统的遗传学认为,染色体多态性通常不具有明显的表型或病理学意义。但越来越多的研究表明,染色体多态性可产生临床效应,与生殖异常有关,包括早期复发性自然流产、早期胚胎停止发育、胎儿畸形等。 大Y染色体是常见的染色体多态性。据统计,大Y染色体在生殖异常的男性患者中的比例达2.18%-21.73%。随着生殖辅助技术的日益发展,许多不孕不育的患者求助于体外受精-胚胎移植技术,其中不乏有大Y患者。 关于大Y的形成机理的研究较少。Yassmine对一例胎儿的产前诊断及出生后诊断均为Yqh+／Yqh-嵌合体,推测这种情况可能是来源于合子形成后DYZ区的缺失或者姐妹染色单体的不平等交换。由此推测大Y的形成可能与DYZ区相关。 DYZ(human Y-chromosome specific repeated DNA family)是指人类Y染色体上特异性的重复序列,现在已经确定的包括DYZ1、DYZ2和DYZ3。其中DYZ1是Y染色体长臂远端的异染色质中主要串联重复序列,占Y染色体总长度的约40%。DYZ1长度为3.6kb,2000-4000次为其在正常男性人类的重复次数。 Deepali等将暴露于射线的男性与复发性自然流产(Recurrent spontaneousabortion, RSA)患者丈夫的DYZ1稳定性进行比较,发现后者的不稳定性更加常见,推测DYZ1在Y染色体的折叠和结构完整性方面有关键作用。 基于以上研究背景,本研究首先通过回顾性临床研究来探讨大Y染色体对体外受精-胚胎移植结局的影响。然后,通过对Y染色体上DYZ1完整性及拷贝数检测研究其在Y染色体多态性患者和早期复发性流产患者丈夫中的变化,以期探讨DYZ1在Y染色体多态性和早期复发性流产所起的作用。 第一部分：大Y染色体对体外受精-胚胎移植结局的影响 【目的】通过回顾性研究探讨大Y染色体对体外受精-胚胎移植结局的影响。 【方法】选取2006年1月至2008年12月在山东大学附属省立医院生殖医学中心完成的体外受精.新鲜胚胎移植周期。其中,男方染色体G显带为大Y(Y≥18号染色体)且其妻排除已知的影响体外受精.胚胎移植结果的疾病的治疗周期为大Y组(33例患者,47个治疗周期),同期在本中心进行体外受精-鲜胚移植治疗的其他治疗周期为群体对照组(共6620个治疗周期)。 【结果】大Y组与群体对照组比较,其受精率、卵裂率、优质胚胎率、种植率、妊娠率、早期流产率等各项指标的差异无统计学意义(P0.05),但在畸形率、出生性别比例方面,两组比较差异具有统计学意义(P0.05),即大Y组畸形儿出生与出生女孩所占比例有明显升高。 【结论】大Y染色体对体外受精-胚胎移植的胚胎发育及近期妊娠结果均无显著性影响,但在大Y染色体患者的妻子行体外受精-胚胎移植时,女孩更易出生。 第二部分：DYZ1稳定性在Y染色体多态性和早期复发性流产中的研究 【目的】通过对DYZ1完整性及拷贝数检测,探讨DYZ1在Y染色体多态性和早期复发性流产中所起的作用。 【方法】对同期就诊于本中心的男性的DYZ1进行研究。其中,不明原因早期RSA患者丈夫106例；Y染色体多态性患者86例,包括大Y患者(Y≥18号染色体)79例和小Y患者(Y≤21号染色体)7例,同期就诊的已正常生育并排除染色体异常的男性100例。 【结果】通过PCR电泳,在RSA患者丈夫中1例存在DYZ1头部的266个碱基(第25-290个碱基)缺失,2例存在DYZ1中部的773个碱基缺失(第1347-2119碱基)；在小Y患者中2例存在DYZ1头部的266个碱基(第25-290个碱基)缺失,4例存在中部的773个碱基缺失(第1347-2119碱基)和尾部的275个基因缺失(第3128-3420碱基)；在大Y患者和正常生育者中未发现DYZ1部分缺失。通过实时荧光定量PCR,正常生育男性的DYZ1拷贝数平均为3900；大Y患者的平均值为5571,与正常生育者比较差异有统计学意义(P0.007),即大Y患者DYZ1拷贝数比正常生育男性多；小Y患者的平均值为1059,与正常生育者比较差异有统计学意义(P0.001),即小Y患者DYZ1拷贝数比正常生育男性少；RSA患者丈夫的平均值为2655,与正常生育者比较差异有统计学意义(P0.001),即RSA患者丈夫DYZ1拷贝数比正常生育男性少。 【结论】DYZ1拷贝数增多可使显微镜下可视的Y染色体长度增加；DYZ1部分缺失和拷贝数减少可使显微镜下可视的Y染色体长度减少；DYZ1拷贝数正常范围内显著减少可能是早期复发性自然流产的病因之一。
[Abstract]:Chromosome polymorphism is a small difference in the form of chromosomes in a human population. Traditional genetics believes that chromosome polymorphism does not usually have obvious phenotypic or pathological significance. However, more and more studies have shown that chromosome polymorphisms can produce clinical effects, related to reproductive abnormalities, including early recurrent spontaneous abortion, early recurrent spontaneous abortion. The embryonic development, fetal malformation, and so on.
The large Y chromosome is a common chromosome polymorphism. According to statistics, the proportion of large Y chromosomes in male patients with reproductive abnormalities is 2.18%-21.73%., with the growing development of reproductive technology, many infertile patients have turned to in vitro fertilization and embryo transfer technology, among which there are no lack of large Y patients.
The study of the formation mechanism of large Y is less than.Yassmine for prenatal diagnosis and postnatal diagnosis of a fetus with Yqh+ / Yqh- chimerism. It is presumed that this situation may be derived from the deletion of the DYZ region after the formation of the zygote or the unequal exchange of sister chromatid. Therefore, the formation of large Y may be related to the DYZ region.
DYZ (human Y-chromosome specific repeated DNA family) refers to the specific repeat sequence on the human Y chromosome, which is now identified as DYZ1, DYZ2, and DYZ3.. DYZ1 is the main tandem repeats in the heterochromatin on the distal end of the long arm of the chromosome, accounting for the length of the total length of the chromosomes, and the 2000-4000 time it is in the positive. The number of repetitions of men.
Deepali and other radiographic men were compared with the DYZ1 stability of the Recurrent spontaneousabortion (RSA) patients. It was found that the instability of the latter was more common. It was suggested that DYZ1 had a key role in the folding and structural integrity of the Y chromosome.
Based on the above research background, this study first explored the effect of the large Y chromosome on the outcome of in vitro fertilization and embryo transfer through a retrospective clinical study. Then, the changes in the DYZ1 integrity and copy number of the Y chromosomes in the Y chromosome polymorphisms and the early recurrent flow patients were examined in order to explore the DYZ1 in Y. The role of chromosomal polymorphism and early recurrent spontaneous abortion.
Part I: the effect of large Y chromosome on the outcome of IVF embryo transfer
[Objective] to investigate the effect of large Y chromosome on the outcome of IVF embryo transfer in a retrospective study.
[Methods] in vitro fertilization and fresh embryo transfer period from January 2006 to December 2008 at the reproductive medical center of the Provincial Hospital Affiliated to Shandong University. In which the male chromosome G showed a large Y (Y > 18) and the wife excluded the known effect of in vitro fertilization. The treatment cycle of the result of embryo transfer was a large group of Y (33 cases). Patients, 47 treatment cycles), and other treatment cycles in the same period in the center for in vitro fertilization and fresh embryo transfer were group control (a total of 6620 treatment cycles).
[results] there was no significant difference in fertilization rate, cleavage rate, high quality embryo rate, implant rate, pregnancy rate and early abortion rate, but there was no significant difference between the two groups (P0.05), but the difference between the two groups was statistically significant (P0.05) in the deformity rate and the birth sex ratio (P0.05), that is, the large Y group was born and the girl was born There was a significant increase in the proportion.
[Conclusion] there is no significant effect of the large Y chromosome on the embryo development and the recent pregnancy results of in vitro fertilization and embryo transfer, but the girl is more likely to be born when the wife of the large Y chromosome patient is in vitro fertilization and embryo transfer.
The second part: DYZ1 stability in Y chromosome polymorphism and early recurrent spontaneous abortion.
[Objective] to explore the role of DYZ1 in Y chromosome polymorphism and early recurrent spontaneous abortion by detecting the integrity and copy number of DYZ1.
[Methods] a study was conducted on the male DYZ1 in the center for the same period. Among them, 106 cases of unexplained early RSA were husbands and 86 cases of Y chromosome polymorphisms, including 79 cases of large Y (Y > 18 chromosome) and 7 cases of small Y patients (Y < 21 chromosome), and 100 men who had normal birth and excluded abnormal chromosomes during the same period.
[results] by PCR electrophoresis, 266 bases (25-290 base) of DYZ1 head were absent in 1 cases of RSA's husbands, 2 cases had 773 base deletion (1347-2119 base) in central DYZ1; 2 cases in small Y patients had 266 bases (25-290 base) deletion in the head and 4 cases of deletion of Central RSA base (1347-). 2119 base and 275 gene deletion (3128-3420 base) in the tail; no partial deletion of DYZ1 was found in patients with large Y and normal fertility. By real-time fluorescence quantitative PCR, the average DYZ1 copy number of normal fertile men was 3900; the average value of the large Y patients was 5571, and the difference was statistically significant (P0.007), that is, large Y patients (P0.007). The number of copies of DYZ1 was more than that of the normal male, and the average value of the small Y patients was 1059, and the difference was statistically significant (P0.001), that is, the DYZ1 copies of the small Y patients were less than those of the normal ones; the mean value of the husbands of the RSA patients was 2655, and the difference was statistically significant (P0.001), that is, the husband DYZ1 of the RSA patient. The number of copies is less than that of normal fertile men.
[Conclusion] the increase of DYZ1 copy number can increase the length of Y chromosome visible under the microscope, and the deletion of DYZ1 and the decrease of copy number can reduce the length of the visible Y chromosome under the microscope, and the significant decrease in the normal range of DYZ1 copy number may be one of the causes of the early recurrent spontaneous abortion.
【学位授予单位】：山东大学
【学位级别】：硕士
【学位授予年份】：2010
【分类号】：R394
本文编号：2135201
[Abstract]:Chromosome polymorphism is a small difference in the form of chromosomes in a human population. Traditional genetics believes that chromosome polymorphism does not usually have obvious phenotypic or pathological significance. However, more and more studies have shown that chromosome polymorphisms can produce clinical effects, related to reproductive abnormalities, including early recurrent spontaneous abortion, early recurrent spontaneous abortion. The embryonic development, fetal malformation, and so on.
The large Y chromosome is a common chromosome polymorphism. According to statistics, the proportion of large Y chromosomes in male patients with reproductive abnormalities is 2.18%-21.73%., with the growing development of reproductive technology, many infertile patients have turned to in vitro fertilization and embryo transfer technology, among which there are no lack of large Y patients.
The study of the formation mechanism of large Y is less than.Yassmine for prenatal diagnosis and postnatal diagnosis of a fetus with Yqh+ / Yqh- chimerism. It is presumed that this situation may be derived from the deletion of the DYZ region after the formation of the zygote or the unequal exchange of sister chromatid. Therefore, the formation of large Y may be related to the DYZ region.
DYZ (human Y-chromosome specific repeated DNA family) refers to the specific repeat sequence on the human Y chromosome, which is now identified as DYZ1, DYZ2, and DYZ3.. DYZ1 is the main tandem repeats in the heterochromatin on the distal end of the long arm of the chromosome, accounting for the length of the total length of the chromosomes, and the 2000-4000 time it is in the positive. The number of repetitions of men.
Deepali and other radiographic men were compared with the DYZ1 stability of the Recurrent spontaneousabortion (RSA) patients. It was found that the instability of the latter was more common. It was suggested that DYZ1 had a key role in the folding and structural integrity of the Y chromosome.
Based on the above research background, this study first explored the effect of the large Y chromosome on the outcome of in vitro fertilization and embryo transfer through a retrospective clinical study. Then, the changes in the DYZ1 integrity and copy number of the Y chromosomes in the Y chromosome polymorphisms and the early recurrent flow patients were examined in order to explore the DYZ1 in Y. The role of chromosomal polymorphism and early recurrent spontaneous abortion.
Part I: the effect of large Y chromosome on the outcome of IVF embryo transfer
[Objective] to investigate the effect of large Y chromosome on the outcome of IVF embryo transfer in a retrospective study.
[Methods] in vitro fertilization and fresh embryo transfer period from January 2006 to December 2008 at the reproductive medical center of the Provincial Hospital Affiliated to Shandong University. In which the male chromosome G showed a large Y (Y > 18) and the wife excluded the known effect of in vitro fertilization. The treatment cycle of the result of embryo transfer was a large group of Y (33 cases). Patients, 47 treatment cycles), and other treatment cycles in the same period in the center for in vitro fertilization and fresh embryo transfer were group control (a total of 6620 treatment cycles).
[results] there was no significant difference in fertilization rate, cleavage rate, high quality embryo rate, implant rate, pregnancy rate and early abortion rate, but there was no significant difference between the two groups (P0.05), but the difference between the two groups was statistically significant (P0.05) in the deformity rate and the birth sex ratio (P0.05), that is, the large Y group was born and the girl was born There was a significant increase in the proportion.
[Conclusion] there is no significant effect of the large Y chromosome on the embryo development and the recent pregnancy results of in vitro fertilization and embryo transfer, but the girl is more likely to be born when the wife of the large Y chromosome patient is in vitro fertilization and embryo transfer.
The second part: DYZ1 stability in Y chromosome polymorphism and early recurrent spontaneous abortion.
[Objective] to explore the role of DYZ1 in Y chromosome polymorphism and early recurrent spontaneous abortion by detecting the integrity and copy number of DYZ1.
[Methods] a study was conducted on the male DYZ1 in the center for the same period. Among them, 106 cases of unexplained early RSA were husbands and 86 cases of Y chromosome polymorphisms, including 79 cases of large Y (Y > 18 chromosome) and 7 cases of small Y patients (Y < 21 chromosome), and 100 men who had normal birth and excluded abnormal chromosomes during the same period.
[results] by PCR electrophoresis, 266 bases (25-290 base) of DYZ1 head were absent in 1 cases of RSA's husbands, 2 cases had 773 base deletion (1347-2119 base) in central DYZ1; 2 cases in small Y patients had 266 bases (25-290 base) deletion in the head and 4 cases of deletion of Central RSA base (1347-). 2119 base and 275 gene deletion (3128-3420 base) in the tail; no partial deletion of DYZ1 was found in patients with large Y and normal fertility. By real-time fluorescence quantitative PCR, the average DYZ1 copy number of normal fertile men was 3900; the average value of the large Y patients was 5571, and the difference was statistically significant (P0.007), that is, large Y patients (P0.007). The number of copies of DYZ1 was more than that of the normal male, and the average value of the small Y patients was 1059, and the difference was statistically significant (P0.001), that is, the DYZ1 copies of the small Y patients were less than those of the normal ones; the mean value of the husbands of the RSA patients was 2655, and the difference was statistically significant (P0.001), that is, the husband DYZ1 of the RSA patient. The number of copies is less than that of normal fertile men.
[Conclusion] the increase of DYZ1 copy number can increase the length of Y chromosome visible under the microscope, and the deletion of DYZ1 and the decrease of copy number can reduce the length of the visible Y chromosome under the microscope, and the significant decrease in the normal range of DYZ1 copy number may be one of the causes of the early recurrent spontaneous abortion.
【学位授予单位】：山东大学
【学位级别】：硕士
【学位授予年份】：2010
【分类号】：R394
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