Portal de Periódicos da CAPES

Why are we still talking about chromosomal heteromorphisms?

2017; Elsevier BV; Volume: 35; Issue: 1 Linguagem: Inglês

10.1016/j.rbmo.2017.05.006

1472-6491

Helen G. Tempest, Joe Leigh Simpson,

Chromosomal and Genetic Variations

Chromosomal heteromorphisms have been with us since long before we could detect them through karyotyping. A paper by Cheng and colleagues in the current issue of RBM Online sheds further light on the association between heteromorphisms, infertility and reproductive outcomes following assisted reproductive technology (ART) (Cheng et al, 2017Cheng R. Ma Y. Nie Y. Qiao X. Yang Z. Zheng R. Xu L. Chromosomal polymorphisms are associated with female infertility and adverse reproductive outcomes after infertility treatment: a 4-year retrospective study.Reprod. Biomed. Online. 2017; 35: 72-80Google Scholar). Cytogenetic studies in the general population have revealed that 2–5% of individuals possess morphological variations in chromosomes 1, 9, 16, Y or in the acrocentric chromosomes (Bhasin, 2005Bhasin M.K. Human population cytogenetics: a review.Int. J. Hum. Genet. 2005; 5: 83-152Google Scholar, Hsu et al, 1987Hsu L.Y. Benn P.A. Tannenbaum H.L. Perlis T.E. Carlson A.D. Chromosomal polymorphisms of 1, 9, 16, and y in 4 major ethnic groups: a large prenatal study.Am. J. Med. Genet. 1987; 26: 95-101Crossref PubMed Scopus (93) Google Scholar). These heteromorphic variants are frequently inherited and consist of heterochromatic blocks of varying size and prominent acrocentric short arms, satellites, stalks and so forth. These regions consist of highly repetitive DNA not considered to contain protein-coding sequences. Thus, these heteromorphisms are thought to be benign with no associated clinical phenotype. However, the question of whether they are truly of no clinical significance is being increasingly evaluated, in particular with respect to infertility and recurrent spontaneous abortions. Assessments of the incidence of heteromorphisms in different ethnic infertile populations and in couples with recurrent spontaneous abortions have been published by multiple groups (Akbas et al, 2012Akbas H. Isi H. Oral D. Turkyilmaz A. Kalkanli-Tas S. Simsek S. Balkan M. Sakar M.N. Fidanboy M. Alp M.N. Budak T. Chromosome heteromorphisms are more frequent in couples with recurrent abortions.Genet. Mol. Res. 2012; 11: 3847-3851Crossref PubMed Scopus (19) Google Scholar, Caglayan et al, 2010Caglayan A.O. Ozyazgan I. Demiryilmaz F. Ozgun M.T. Are heterochromatin polymorphisms associated with recurrent miscarriage?.J. Obstet. Gynaecol. Res. 2010; 36: 774-776Crossref PubMed Scopus (25) Google Scholar, Duzcan et al, 2003Duzcan F. Atmaca M. Cetin G.O. Bagci H. Cytogenetic studies in patients with reproductive failure.Acta Obstet. Gynecol. Scand. 2003; 82: 53-56Crossref PubMed Google Scholar, Guo et al, 2012Guo T. Qin Y. Gao X. Chen H. Li G. Ma J. Chen Z.J. The role of male chromosomal polymorphism played in spermatogenesis and the outcome of ivf/icsi-et treatment.Int. J. Androl. 2012; 35: 802-809Crossref PubMed Scopus (33) Google Scholar, Hong et al, 2011Hong Y. Zhou Y.W. Tao J. Wang S.X. Zhao X.M. Do polymorphic variants of chromosomes affect the outcome of in vitro fertilization and embryo transfer treatment?.Hum. Reprod. 2011; 26: 933-940Crossref PubMed Scopus (44) Google Scholar, Liang et al, 2014Liang J. Zhang Y.S. Yu Y. Sun W.T. Jing J.L. Liu R.Z. Effect of chromosomal polymorphisms of different genders on fertilization rate of fresh ivf-icsi embryo transfer cycles.Reprod. Biomed. Online. 2014; 29: 436-444Abstract Full Text Full Text PDF PubMed Scopus (26) Google Scholar, Mierla, Stoian, 2012Mierla D. Stoian V. Chromosomal polymorphisms involved in reproductive failure in the romanian population.Balkan J. Med. Genet. 2012; 15: 23-28PubMed Google Scholar, Mierla et al, 2015Mierla D. Malageanu M. Tulin R. Albu D. Prevalence of chromosomal abnormalities in infertile couples in romania.Balkan J. Med. Genet. 2015; 18: 23-29PubMed Google Scholar, Sahin et al, 2008Sahin F.I. Yilmaz Z. Yuregir O.O. Bulakbasi T. Ozer O. Zeyneloglu H.B. Chromosome heteromorphisms: an impact on infertility.J. Assist. Reprod. Genet. 2008; 25: 191-195Crossref PubMed Scopus (62) Google Scholar, Sipek et al, 2014Sipek A. Mihalova R. Panczak A. Hrckova L. Janashia M. Kasprikova N. Kohoutova M. Heterochromatin variants in human karyotypes: a possible association with reproductive failure.Reprod. Biomed. Online. 2014; 29: 245-250Abstract Full Text Full Text PDF PubMed Scopus (21) Google Scholar, Sipek et al, 2015Sipek A. Panczak A. Mihalova R. Hrckova L. Suttrova E. Sobotka V. Lonsky P. Kasprikova N. Gregor V. Pericentric inversion of human chromosome 9 epidemiology study in czech males and females.Folia Biol. (Praha). 2015; 61: 140-146PubMed Google Scholar, Xiao et al, 2012Xiao Z.N. Zhou X. Xu W.M. Yang J. A preliminary study of the relationship between the long arm of the y chromosome (yqh plus) and reproductive outcomes in ivf/icsi-et.Eur. J. Obstet. Gynecol. Reprod. Biol. 2012; 165: 57-60Abstract Full Text Full Text PDF PubMed Scopus (12) Google Scholar, Xu et al, 2016Xu X.J. Zhang R. Wang W. Liu H.F. Liu L. Mao B. Zeng X.W. Zhang X.H. The effect of chromosomal polymorphisms on the outcomes of fresh ivf/icsi-et cycles in a chinese population.J. Assist. Reprod. Genet. 2016; 33: 1481-1486Crossref PubMed Scopus (16) Google Scholar). Most studies have reported that the incidence of heteromorphisms is three- to five-fold higher in the infertile population compared with fertile individuals (Hong et al, 2011Hong Y. Zhou Y.W. Tao J. Wang S.X. Zhao X.M. Do polymorphic variants of chromosomes affect the outcome of in vitro fertilization and embryo transfer treatment?.Hum. Reprod. 2011; 26: 933-940Crossref PubMed Scopus (44) Google Scholar, Minocherhomji et al, 2009Minocherhomji S. Athalye A.S. Madon P.F. Kulkarni D. Uttamchandani S.A. Parikh F.R. A case-control study identifying chromosomal polymorphic variations as forms of epigenetic alterations associated with the infertility phenotype.Fertil. Steril. 2009; 92: 88-95Abstract Full Text Full Text PDF PubMed Scopus (70) Google Scholar, Sahin et al, 2008Sahin F.I. Yilmaz Z. Yuregir O.O. Bulakbasi T. Ozer O. Zeyneloglu H.B. Chromosome heteromorphisms: an impact on infertility.J. Assist. Reprod. Genet. 2008; 25: 191-195Crossref PubMed Scopus (62) Google Scholar, Sipek et al, 2014Sipek A. Mihalova R. Panczak A. Hrckova L. Janashia M. Kasprikova N. Kohoutova M. Heterochromatin variants in human karyotypes: a possible association with reproductive failure.Reprod. Biomed. Online. 2014; 29: 245-250Abstract Full Text Full Text PDF PubMed Scopus (21) Google Scholar, Xu et al, 2016Xu X.J. Zhang R. Wang W. Liu H.F. Liu L. Mao B. Zeng X.W. Zhang X.H. The effect of chromosomal polymorphisms on the outcomes of fresh ivf/icsi-et cycles in a chinese population.J. Assist. Reprod. Genet. 2016; 33: 1481-1486Crossref PubMed Scopus (16) Google Scholar). Those studies that have investigated both sexes report that infertile men have the highest incidence of heteromorphisms, which predominantly involve the Y chromosome and often lead to impaired spermatogenesis. The majority of published studies focused solely on the male and rarely have they assessed whether heteromorphic variants are associated with specific underlying causes of infertility. Several major gaps in our current understanding of the impact of heteromorphisms on fertility exist for female carriers: can associations with specific infertility pathologies be identified? And are there adverse reproductive outcomes in carriers following ART? The study by Cheng et al, 2017Cheng R. Ma Y. Nie Y. Qiao X. Yang Z. Zheng R. Xu L. Chromosomal polymorphisms are associated with female infertility and adverse reproductive outcomes after infertility treatment: a 4-year retrospective study.Reprod. Biomed. Online. 2017; 35: 72-80Google Scholar is the largest published study to date (n = 19,950) investigating the association between female carriers of heteromorphisms, infertility and reproductive outcome. This study has also stratified patients based on the attributed cause of the female infertility (cervical/uterine abnormalities, endometriosis, ovulatory dysfunction, tubal infertility, unexplained infertility, and total infertility) with over 2,000 patients in each category. The incidence of heteromorphisms was significantly higher than in the fertile cohort for all investigated groups except patients with endometriosis. Furthermore, the unexplained infertility group was found to have the highest incidence compared to fertile controls (8.51% versus 3.74%, respectively). When examining the pregnancy outcomes in 18,963 women within the stratified groups, the incidence of spontaneous abortion was significantly higher in carrier women compared with non-carriers in the fertile group (4.95% versus 0.96%) and the tubal infertility group (6.17% versus 1.08%). Significant increases in preterm birth were also observed in women with variants when compared with those without variants for the following groups: fertile (2.97% versus 0.92%), tubal infertility (7.41% versus 1.36%), ovulatory dysfunction (6.13% versus 1.28%), and cervical and uterine abnormalities (8.89% versus 2.50%). The finding of an association between carriers of heteromorphic variants and adverse reproductive outcomes, including decreased rates of fertilization, poor embryo quality, lower rates of clinical and ongoing pregnancies and spontaneous abortions, has been previously reported in smaller studies. Surprisingly, the association of heteromorphic variants and adverse reproductive outcomes has predominantly only been observed previously in male carriers; either because females were excluded from the study or because no association was identified in female carriers (Guo et al, 2012Guo T. Qin Y. Gao X. Chen H. Li G. Ma J. Chen Z.J. The role of male chromosomal polymorphism played in spermatogenesis and the outcome of ivf/icsi-et treatment.Int. J. Androl. 2012; 35: 802-809Crossref PubMed Scopus (33) Google Scholar, Hong et al, 2011Hong Y. Zhou Y.W. Tao J. Wang S.X. Zhao X.M. Do polymorphic variants of chromosomes affect the outcome of in vitro fertilization and embryo transfer treatment?.Hum. Reprod. 2011; 26: 933-940Crossref PubMed Scopus (44) Google Scholar, Liang et al, 2014Liang J. Zhang Y.S. Yu Y. Sun W.T. Jing J.L. Liu R.Z. Effect of chromosomal polymorphisms of different genders on fertilization rate of fresh ivf-icsi embryo transfer cycles.Reprod. Biomed. Online. 2014; 29: 436-444Abstract Full Text Full Text PDF PubMed Scopus (26) Google Scholar, Xu et al, 2016Xu X.J. Zhang R. Wang W. Liu H.F. Liu L. Mao B. Zeng X.W. Zhang X.H. The effect of chromosomal polymorphisms on the outcomes of fresh ivf/icsi-et cycles in a chinese population.J. Assist. Reprod. Genet. 2016; 33: 1481-1486Crossref PubMed Scopus (16) Google Scholar). One study reported a lower embryo cleavage rate in female carriers, however no other associations for the other investigated reproductive outcomes were identified (Xu et al, 2016Xu X.J. Zhang R. Wang W. Liu H.F. Liu L. Mao B. Zeng X.W. Zhang X.H. The effect of chromosomal polymorphisms on the outcomes of fresh ivf/icsi-et cycles in a chinese population.J. Assist. Reprod. Genet. 2016; 33: 1481-1486Crossref PubMed Scopus (16) Google Scholar). In light of increasing evidence to suggest an association between heteromorphic regions, infertility and adverse reproductive outcomes, it is perhaps time to rethink heteromorphic variants as being ‘harmless’ chromosome aberrations. Current prevailing hypotheses of how these variants could impact fertility include altered regulation of the genome and aberrations in chromosome pairing and cell division. We now know that non-coding regions of the genome previously considered to be ‘junk’ DNA function to regulate and modulate the activity and gene expression of the protein-coding regions of the genome. Reproduction is an extremely complicated process (from gamete formation, through to fertilization and embryonic development), which requires genome regulation and expression at unprecedented levels compared with most somatic processes. Thus, it is plausible that heteromorphic variants may play a more crucial role in genome regulation and modulation during reproduction. This could, in part, explain why some carriers of heteromorphic variants ostensibly have no clinical phenotype except that related to reproductive outcome. Additionally the heterochromatic regions around the centromeres of the acrocentric chromosomes have been postulated to play a role in spindle attachment, chromosome pairing, and cell division. Thus perturbations in these heterochromatic regions may in fact have dire consequences for gene expression affecting gamete formation, fertilization, and embryogenesis, and could lead to errors in chromosome and chromatid cohesion potentially leading to an increased risk of chromosome aneuploidy. A recent study has in fact demonstrated a significant increase in chromosome aneuploidy in both sperm and embryos from male carriers of heteromorphic variants (Morales et al, 2016Morales R. Lledo B. Ortiz J.A. Ten J. Llacer J. Bernabeu R. Chromosomal polymorphic variants increase aneuploidies in male gametes and embryos.Syst. Biol. Reprod. Med. 2016; 62: 317-324Crossref PubMed Scopus (21) Google Scholar). Despite the increasing body of evidence to suggest heteromorphisms are associated with infertility and potentially poorer reproductive outcomes, the question remains: Can this information be utilized clinically? Unsurprisingly, further studies are needed to determine the mechanisms through which these variants in both males and females may impact fertility and pregnancy outcomes, and whether specific variants can be correlated with distinct infertility pathologies and adverse reproductive outcomes. Studies are also required to delineate the mechanisms through which heteromorphisms may impact human reproduction, with a focus on patients with unexplained infertility, poor embryonic development, preterm birth outcomes and spontaneous abortions. Perhaps most critically, follow-up studies are distinctly lacking. Studies of the progeny (or products of conception) of carriers of heteromorphic variants are sorely needed to better delineate the heritability and consequences of these variants. What is clear is that conventional cytogenetics still has an important role in the work-up, management and counseling of couples presenting with infertility and recurrent spontaneous abortion to detect not only structural and numerical chromosome aberrations but also the possible presence of heteromorphisms.