大Y染色体临床效应及其形成机理初步研究
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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(P>0.05),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(P<0.05),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(P<0.007),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(P<0.001),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(P<0.001),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。
Chromosome polymorphism is the minor differences in the chromosome morphology between human groups. In traditional genetic view, chromosome polymorphism usually does not have obvious phenotypic or pathological significance. But a growing number of studies have shown that chromosome polymorphism could produce clinical effects, and was related to reproductive abnormalities, such as early recurrent spontaneous abortion, early embryo growth arrest, fetal malformations and so on.
Big Y chromosome is a common chromosome polymorphism. While according to previous statistics, the percentage of big Y chromosome in the male patients of reproductive abnormalities is up to 2.18%-21.73%. With the increasing development of assisted reproductive technology, many infertile patients resort to in vitro fertilization-embryo transfer technology, including many patients of big Y chromosome.
There were few studies on the formation mechanism of big Y chromosome. The prenatal and postnatal diagnosis of the fetal Yassmine made a study of were Yqh+/Yqh- chimera, which meant there were two cell populations involving Y chromosome heterochromatin of differing lengths in the same individual. It was explained that a postzygotic simple deletion or unequal crossover event between sister chromatids in the DYZ region has occured. The results suggested the formation of big Y chromosome may be closely associated with DYZ region.
DYZ stands for human Y-chromosome specific repeated DNA family, including DYZ1, DYZ2 and DYZ3 so far. DYZ1 is the major tandem repeat sequence of Y chromosome distal heterochromatin, accounting for almost 40% of total length of Y chromosome. DYZ1 is made up of 3.6 kb, and 2000-4000 repetitions in normal male. Comparing DYZ1 genomic instability of men exposed to radiation with that of male patients of recurrent spontaneous abortion (RSA), Deepali found the latter was more common, suggesting DYZ1 may play a key role in the Y chromosome folding and structural integrity.
Based on the above concept, at first, we studied the effect of big Y chromosome on in vitro fertilization-embryo transfer outcome by a retrospective clinical study. Then, DYZ1 integrity and copy number variation in patients of Y chromosome polymorphism and recurrent spontaneous abortion were studied to detect whether DYZ1 may play a key role in Y chromosome polymorphism and early recurrent spontaneous abortion.
Section 1 Effect of big Y chromosome on in vitro fertilization-embryo transfer outcome
OBJECTIVES The effect of big Y chromosome on in vitro fertilization embryo transfer outcome was studied by a retrospective clinical study.
METHODS In vitro fertilization-fresh embryo transfer cycles completed at Reproductive Medical Center of Provincial Hospital Affiliated to Shandong University from January 2006 to December 2008 were selected. In big Y group (33 patients and 47 treatment cycles total), the male chromosome of the patients were big Y by G-banding and their wives were excluded of known diseases which may influence the outcome of in vitro fertilization-embryo transfer; while in the control group, all other 6620 treatment cycles of the same period were involved.
RESULTS There was no significant difference between the big Y group and the control group in fertilization rate, cleavage rate, good-quality embryo rate, embryo imbed rate, pregnancy rate and early abortion rate(P＞0.05), but the ratios of deformed babies and female at birth were higher in the big Y group(P＜0.05).
CONCLUSIONS In conventional in vitro fertilization and embryo transfer cycles, there is no significant difference in embryonic development and recent pregnancy outcome between patients with the big Y chromosome and normal patients. Women whose husbands have big Y chromosome undergoing conventional in vitro fertilization embryo transfer cycles are more likely to give birth to girls.
Section 2 DYZ1 stability, Y chromosome polymorphism and early recurrent spontaneous abortion
OBJECTIVES DYZ1 integrity and copy number variation in patients of Y chromosome polymorphism and recurrent spontaneous abortion were studied to detect whether DYZ1 play a key role in Y chromosome polymorphism and early recurrent spontaneous abortion.
METHODS DYZ1 of the male patients resorted to our center at the same period was selected to study. Among them, unexplained early RSA male patients were 106 cases; patients of Y chromosome polymorphism were 86 cases, including big Y patients (Y≥chromosome 18) 79 cases and small Y patients (Y≤chromosome 21) 7 cases; men at the same period who had at least one normal birth and were excluded of chromosome abnormalities were 100 cases.
RESULTS After PCR and electrophoresis, of RSA patients,1 case showed deletion of 266 bp from 25 to 290 bp and 2 cases showed deletion of 773bp from 1347 to 2119 bp; of small Y patients,2 cases showed deletion of 266 bp from 25 to 290 bp, 4 cases showed deletion of 773bp from 1347 to 2119 bp and 275 bp from 3128 to 3420 bp; while big Y patients and normal fertile men were found no part missing of DYZ1. By real-time fluorescent quantitative PCR, in normal fertile men, the mean of DYZ1 copies was 3900; big Y patients for 5571, significantly different (P＜0.007) when compared with normal fertile men which means DYZ1 copy number in patients of big Y chromosome was more than that of the normal fertile men; RSA patients for 2655, significantly different (P＜0.001) when compared with normal fertile men which means DYZl copy number in unexplained early RSA patients was less than that of the normal fertile men; small Y patients for 1059, significantly different (P＜0.001) when compared with normal fertile men which means DYZ1 copy number in small Y patients was less than that of the normal fertile men.
CONCLUSIONS More DYZ1 copy number may increase the visible length of Y-chromosome under the microscope, and there is a close relation between reduced length of Y chromosome under the microscope and DYZl part deletion, while the decrease of DYZ1 copy number within normal range may be a cause of early recurrent spontaneous abortion.
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(P>0.05),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(P<0.05),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(P<0.007),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(P<0.001),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(P<0.001),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。
Chromosome polymorphism is the minor differences in the chromosome morphology between human groups. In traditional genetic view, chromosome polymorphism usually does not have obvious phenotypic or pathological significance. But a growing number of studies have shown that chromosome polymorphism could produce clinical effects, and was related to reproductive abnormalities, such as early recurrent spontaneous abortion, early embryo growth arrest, fetal malformations and so on.
Big Y chromosome is a common chromosome polymorphism. While according to previous statistics, the percentage of big Y chromosome in the male patients of reproductive abnormalities is up to 2.18%-21.73%. With the increasing development of assisted reproductive technology, many infertile patients resort to in vitro fertilization-embryo transfer technology, including many patients of big Y chromosome.
There were few studies on the formation mechanism of big Y chromosome. The prenatal and postnatal diagnosis of the fetal Yassmine made a study of were Yqh+/Yqh- chimera, which meant there were two cell populations involving Y chromosome heterochromatin of differing lengths in the same individual. It was explained that a postzygotic simple deletion or unequal crossover event between sister chromatids in the DYZ region has occured. The results suggested the formation of big Y chromosome may be closely associated with DYZ region.
DYZ stands for human Y-chromosome specific repeated DNA family, including DYZ1, DYZ2 and DYZ3 so far. DYZ1 is the major tandem repeat sequence of Y chromosome distal heterochromatin, accounting for almost 40% of total length of Y chromosome. DYZ1 is made up of 3.6 kb, and 2000-4000 repetitions in normal male. Comparing DYZ1 genomic instability of men exposed to radiation with that of male patients of recurrent spontaneous abortion (RSA), Deepali found the latter was more common, suggesting DYZ1 may play a key role in the Y chromosome folding and structural integrity.
Based on the above concept, at first, we studied the effect of big Y chromosome on in vitro fertilization-embryo transfer outcome by a retrospective clinical study. Then, DYZ1 integrity and copy number variation in patients of Y chromosome polymorphism and recurrent spontaneous abortion were studied to detect whether DYZ1 may play a key role in Y chromosome polymorphism and early recurrent spontaneous abortion.
Section 1 Effect of big Y chromosome on in vitro fertilization-embryo transfer outcome
OBJECTIVES The effect of big Y chromosome on in vitro fertilization embryo transfer outcome was studied by a retrospective clinical study.
METHODS In vitro fertilization-fresh embryo transfer cycles completed at Reproductive Medical Center of Provincial Hospital Affiliated to Shandong University from January 2006 to December 2008 were selected. In big Y group (33 patients and 47 treatment cycles total), the male chromosome of the patients were big Y by G-banding and their wives were excluded of known diseases which may influence the outcome of in vitro fertilization-embryo transfer; while in the control group, all other 6620 treatment cycles of the same period were involved.
RESULTS There was no significant difference between the big Y group and the control group in fertilization rate, cleavage rate, good-quality embryo rate, embryo imbed rate, pregnancy rate and early abortion rate(P＞0.05), but the ratios of deformed babies and female at birth were higher in the big Y group(P＜0.05).
CONCLUSIONS In conventional in vitro fertilization and embryo transfer cycles, there is no significant difference in embryonic development and recent pregnancy outcome between patients with the big Y chromosome and normal patients. Women whose husbands have big Y chromosome undergoing conventional in vitro fertilization embryo transfer cycles are more likely to give birth to girls.
Section 2 DYZ1 stability, Y chromosome polymorphism and early recurrent spontaneous abortion
OBJECTIVES DYZ1 integrity and copy number variation in patients of Y chromosome polymorphism and recurrent spontaneous abortion were studied to detect whether DYZ1 play a key role in Y chromosome polymorphism and early recurrent spontaneous abortion.
METHODS DYZ1 of the male patients resorted to our center at the same period was selected to study. Among them, unexplained early RSA male patients were 106 cases; patients of Y chromosome polymorphism were 86 cases, including big Y patients (Y≥chromosome 18) 79 cases and small Y patients (Y≤chromosome 21) 7 cases; men at the same period who had at least one normal birth and were excluded of chromosome abnormalities were 100 cases.
RESULTS After PCR and electrophoresis, of RSA patients,1 case showed deletion of 266 bp from 25 to 290 bp and 2 cases showed deletion of 773bp from 1347 to 2119 bp; of small Y patients,2 cases showed deletion of 266 bp from 25 to 290 bp, 4 cases showed deletion of 773bp from 1347 to 2119 bp and 275 bp from 3128 to 3420 bp; while big Y patients and normal fertile men were found no part missing of DYZ1. By real-time fluorescent quantitative PCR, in normal fertile men, the mean of DYZ1 copies was 3900; big Y patients for 5571, significantly different (P＜0.007) when compared with normal fertile men which means DYZ1 copy number in patients of big Y chromosome was more than that of the normal fertile men; RSA patients for 2655, significantly different (P＜0.001) when compared with normal fertile men which means DYZl copy number in unexplained early RSA patients was less than that of the normal fertile men; small Y patients for 1059, significantly different (P＜0.001) when compared with normal fertile men which means DYZ1 copy number in small Y patients was less than that of the normal fertile men.
CONCLUSIONS More DYZ1 copy number may increase the visible length of Y-chromosome under the microscope, and there is a close relation between reduced length of Y chromosome under the microscope and DYZl part deletion, while the decrease of DYZ1 copy number within normal range may be a cause of early recurrent spontaneous abortion.
引文
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20. Iwamoto T, Nakahori Y, Nakagome Y, et al. Pericentric inversion with a minute deletion of the Y chromosome in a severely oligozoospermic man[J]. Clin Genet,1995,48:272-274.
21. Blanco P, ShlumukovaM, Sargent CA, et al. Divergent outcomes of intrachromosomal recombination on the human Y chromosome:male infertility and recurrent polymorphism[J]. J Med Genet,2000,37(10):752-758.
22. Yassmine Akkari, Helen Lawce, Stephen Kelson, et al. Y chromosome heterochromatin of differing lengths in two cell populations of the same individual[J]. Prenat Diagn,2005,25:304-306.
23.陈咏健,刘平,廉颖,等.大Y携带者不良孕产史与胚胎非整倍率增高的关系[J].中国优生与遗传杂志,2006,4(3)：39-41.
24.胡晓东,曾勇,莫美兰,等.大Y染色体对体外受精与胚胎移植的影响[J].实用医学杂志,2007,23(2)：178.
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28.程涌江,叶竟妍.Y染色体长度变异与疾病的关系[J].中国优生与遗传杂志,2006,13(6)：34-35.
29. Li Z, Haines CJ, Han Y. Micro-deletions of the human Y chromosome and their relationship with male infertility [J]. J Genet Genomics,2008,35(4):193-199.
30. Kent-FirstM, Muallem A, Shultz J, et al. Defining regions of the Y-chromosome responsible formale infertility and identification of a fourth AZF region (AZFd) by Y-chromosome microdeletion detection[J]. Mol Rep rod Dev,1999,53(1):27-41.
31. Vogt PH, Falcao CL, Hanstein R, et al. The AZF proteins[J]. Int J Androl,2008,31(4):383-394.
32. Sheri Dewan M.S., Elizabeth E. Puscheck M.D. Y-chromosome microdeletions and recurrent pregnancy loss[J]. Fertility and Sterility,2006,85(2):441-445.
33. Karaer A, Karaer K, Ozaksit G, et al. Y chromosome azoospermia factor region microdeletions and recurrent pregnancy loss[J]. Am J Obstet Gynecol,2008,24.[Epub ahead of print]
34. Feride Iffet Sahin, Zerrin Yilmaz, Ozge Ozalp Yuregir, etc. Chromosome heteromorphisms:an impact on infertility [J].2008,25(5):191-195.
35. Minocherhomji S, Athalye AS, Madon PF, etc. A case-control study identifying chromosomal polymorphic variations as forms of epigenetic alterations associated with the infertility phenotype. [J]Fertil Steril.2009,92(1):88-95.
36. De la Fuente-Cortes BE, Cerda-Flores RM, Davila-Rodriguez MI, et al. Chromosomal abnormalities and polymorphic variants in couples with repeated miscarriage in Mexico [J]. Reprod Biomed Online,2009,18(4):543-548.
37. Celep F, Karaguzel A, Ozeren M,et al. The frequency of chromosomal abnormalities in patients with reproductive failure[J]. Eur J Obstet Gynecol Reprod Biol,2006,127(1):106-109.
38. Madon PF, Athalye AS, Parikh FR. Polymorphic variants on chromosomes
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39. Chatzimeletiou K, Taylor J, Marks K, et al. Paternal inheritance of a 16qh-polymorphism in a patient with repeated IVF failure [J]. Reprod Biomed Online,2006,13(6):864-867.
40.王丽,许立红,张浩波,等.通过辅助生殖技术出生的后代性别比例分析[J].山东医药,2005,45(24)：57-58.
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43. Blaschke RJ, Rappold G. The pseudoautosomal regions, SHOX and disease[J]. Curr Opin Genet Dev 2006,16:233-239.
44. Noordam MJ, Repping S.The human Y chromosome:a masculine chromosome[J]. Curr Opin Genet Dev,2006,16(3):225-232.
45.李铮,陈向锋,沙艳伟.人类Y染色体进化突变与男性不育[J].中华男科学杂志,2009,04(15)：291-296。
46. Li Z, Haines CJ, Han Y. Micro-deletions of the human Y chromosome and their relationship with male infertility[J]. J Genet Genomics,2008,35(4):193-199.
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50. Fourtounas C, Spyridonidis A, Dousdampanis P, et al. Microchimerism in peripheral blood and urine in renal transplant recipients:preliminary results[J]. Transplant Proc,2008,40(10):3434-3436.
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20. Iwamoto T, Nakahori Y, Nakagome Y, et al. Pericentric inversion with a minute deletion of the Y chromosome in a severely oligozoospermic man[J]. Clin Genet,1995,48:272-274.
21. Blanco P, ShlumukovaM, Sargent CA, et al. Divergent outcomes of intrachromosomal recombination on the human Y chromosome:male infertility and recurrent polymorphism[J]. J Med Genet,2000,37(10):752-758.
22. Yassmine Akkari, Helen Lawce, Stephen Kelson, et al. Y chromosome heterochromatin of differing lengths in two cell populations of the same individual[J]. Prenat Diagn,2005,25:304-306.
23.陈咏健,刘平,廉颖,等.大Y携带者不良孕产史与胚胎非整倍率增高的关系[J].中国优生与遗传杂志,2006,4(3)：39-41.
24.胡晓东,曾勇,莫美兰,等.大Y染色体对体外受精与胚胎移植的影响[J].实用医学杂志,2007,23(2)：178.
25.肖翰,符生苗.142例反复流产夫妇的染色体研究[J].中国优生与遗传杂志,1996,4(1)：49-51.
26.陈竺主编.中国遗传学.第1版.北京：人民卫生出版社,2002,26.
27.程烽,张宝珍,朱忠勇.507例男性不育症患者细胞遗传学分析[J].中国优生与遗传杂志,2001,9(3)：38.
28.程涌江,叶竟妍.Y染色体长度变异与疾病的关系[J].中国优生与遗传杂志,2006,13(6)：34-35.
29. Li Z, Haines CJ, Han Y. Micro-deletions of the human Y chromosome and their relationship with male infertility [J]. J Genet Genomics,2008,35(4):193-199.
30. Kent-FirstM, Muallem A, Shultz J, et al. Defining regions of the Y-chromosome responsible formale infertility and identification of a fourth AZF region (AZFd) by Y-chromosome microdeletion detection[J]. Mol Rep rod Dev,1999,53(1):27-41.
31. Vogt PH, Falcao CL, Hanstein R, et al. The AZF proteins[J]. Int J Androl,2008,31(4):383-394.
32. Sheri Dewan M.S., Elizabeth E. Puscheck M.D. Y-chromosome microdeletions and recurrent pregnancy loss[J]. Fertility and Sterility,2006,85(2):441-445.
33. Karaer A, Karaer K, Ozaksit G, et al. Y chromosome azoospermia factor region microdeletions and recurrent pregnancy loss[J]. Am J Obstet Gynecol,2008,24.[Epub ahead of print]
34. Feride Iffet Sahin, Zerrin Yilmaz, Ozge Ozalp Yuregir, etc. Chromosome heteromorphisms:an impact on infertility [J].2008,25(5):191-195.
35. Minocherhomji S, Athalye AS, Madon PF, etc. A case-control study identifying chromosomal polymorphic variations as forms of epigenetic alterations associated with the infertility phenotype. [J]Fertil Steril.2009,92(1):88-95.
36. De la Fuente-Cortes BE, Cerda-Flores RM, Davila-Rodriguez MI, et al. Chromosomal abnormalities and polymorphic variants in couples with repeated miscarriage in Mexico [J]. Reprod Biomed Online,2009,18(4):543-548.
37. Celep F, Karaguzel A, Ozeren M,et al. The frequency of chromosomal abnormalities in patients with reproductive failure[J]. Eur J Obstet Gynecol Reprod Biol,2006,127(1):106-109.
38. Madon PF, Athalye AS, Parikh FR. Polymorphic variants on chromosomes
probably play a significant role in infertility [J].Reprod Biomed Online,2005, 11(6):726-732.
39. Chatzimeletiou K, Taylor J, Marks K, et al. Paternal inheritance of a 16qh-polymorphism in a patient with repeated IVF failure [J]. Reprod Biomed Online,2006,13(6):864-867.
40.王丽,许立红,张浩波,等.通过辅助生殖技术出生的后代性别比例分析[J].山东医药,2005,45(24)：57-58.
41. Practice Committee of the American Society for Reproductive Medicine. Definitions of infertility and recurrent pregnancy loss[J]. Fertil Steril.2008,90(5 Suppl):S60.
42. STERN C. The problem of complete Y-linkage in man[J]. Am J Hum Genet.1957,9(3):147-166.
43. Blaschke RJ, Rappold G. The pseudoautosomal regions, SHOX and disease[J]. Curr Opin Genet Dev 2006,16:233-239.
44. Noordam MJ, Repping S.The human Y chromosome:a masculine chromosome[J]. Curr Opin Genet Dev,2006,16(3):225-232.
45.李铮,陈向锋,沙艳伟.人类Y染色体进化突变与男性不育[J].中华男科学杂志,2009,04(15)：291-296。
46. Li Z, Haines CJ, Han Y. Micro-deletions of the human Y chromosome and their relationship with male infertility[J]. J Genet Genomics,2008,35(4):193-199.
47. Cooke,H.J. (1976) Nature 262,182-186.
48. Nakahori Y, Mitani K, Yamada M, et al. A human Y-chromosome specific repeated DNA family (DYZ1) consists of a tandem array of pentanucleotides[J]. Nucleic Acids Res.1986,14(19):7569-7580.
49. Araujo C, Galera MF, Galera BB, et al. Molecular identification of chromosome Y sequences in Brazilian patients with Turner syndrome[J]. Gynecol Endocrinol.2008; 24(12):713-717.
50. Fourtounas C, Spyridonidis A, Dousdampanis P, et al. Microchimerism in peripheral blood and urine in renal transplant recipients:preliminary results[J]. Transplant Proc,2008,40(10):3434-3436.