Interchromosomal Effect Research Articles

Meiotic Heterogeneity of Trivalent Structure and Interchromosomal Effect in Blastocysts With Robertsonian Translocations.

BackgroundRobertsonian translocations are common structural rearrangements and confer an increased genetic reproductive risk due to the formation of trivalent structure during meiosis. Studies on trivalent structure show meiotic heterogeneity between different translocation carriers, although the factors causing heterogeneity have not been well elaborated in blastocysts. It is also not yet known whether interchromosomal effect (ICE) phenomenon occurs in comparison with suitable non-translocation control patients. Herein, we aimed to evaluate the factors that cause meiotic heterogeneity of trivalent structure and the ICE phenomenon.MethodsWe designed a retrospective study, comprising 217 Robertsonian translocation carriers and 134 patients with the risk of transmitting monogenic inherited disorders (RTMIDs) that underwent preimplantation genetic testing (PGT). Data was collected between March 2014 and December 2019. The segregation products of trivalent structure were analyzed based on the carrier’s gender, age and translocation type. In addition, to analyze ICE phenomenon, aneuploidy abnormalities of non-translocation chromosomes from Robertsonian translocation carriers were compared with those from patients with RTMIDs.ResultsWe found that the percentage of male carriers with alternate segregation pattern was significantly higher [P < 0.001, odds ratio (OR) = 2.95] than that in female carriers, while the percentage of adjacent segregation pattern was lower (P < 0.001, OR = 0.33). By contrast, no difference was observed between young and older carriers when performing stratified analysis by age. Furthermore, segregation pattern was associated with the D;G chromosomes involved in Robertsonian translocation: the rate of alternate segregation pattern in Rob(13;14) carriers was significantly higher (P = 0.010, OR = 1.74) than that in Rob(14;21) carriers, whereas the rate of adjacent segregation pattern was lower (P = 0.032, OR = 0.63). Moreover, the results revealed that the trivalent structure could significantly increase the frequencies of chromosome aneuploidies 1.30 times in Robertsonian translocation carriers compared with patients with RTMIDs (P = 0.026), especially for the male and young subgroups (P = 0.030, OR = 1.35 and P = 0.012, OR = 1.40), while the mosaic aneuploidy abnormalities presented no statistical difference.ConclusionsOur study demonstrated that meiotic segregation heterogeneity of trivalent structure is associated with the carrier’s gender and translocation type, and it is independent of carrier’s age. ICE phenomenon exists during meiosis and then increases the frequencies of additional chromosome abnormalities.

The impact of patient, embryo, and translocation characteristics on the ploidy status of young couples undergoing preimplantation genetic testing for structural rearrangements (PGT-SR) by next generation sequencing (NGS).

To evaluate the factors that affect the incidence of euploid balanced embryos and interchromosomal effect (ICE) in carriers of different structural rearrangements. This retrospective study includes 95 couples with reciprocal translocations (RecT) and 36 couples with Robertsonian translocations (RobT) undergoing Preimplantation Genetic Testing for Structural Rearrangements (PGT-SR) between March 2016 and July 2019. Next-generation sequencing (NGS) was the technique used coupled with trophectoderm (TE) biopsy. Only cases with females under 38 years were included. A total of 532 blastocysts were evaluated. The euploidy rate was similar in RobT when compared with RecT carriers [57/156 (36.5%) vs. 112/376 (29.8%), p = 0.127]. The pure ICE rate was significantly higher in RobT carriers [48/156 (30.8%) vs. 53/376 (14.1%), p < 0.001] than it was in RecT carriers. Female age was the independent factor for the probability of obtaining a euploid embryo in RecT and RobT carriers, and increasing female age decreases the probability of obtaining a euploid embryo. In RecT carriers, no significant differences were observed in euploidy rates, pure ICE, or combined ICE according to the length of the translocated fragment and the chromosome group. However, total ICE was significantly lower when there was a breakpoint in the short chromosome arm together with a breakpoint in the long arm [(44/158 (27.8%) for pq or qp, 51/155 (32.9%) for pp and 30/63 (47.6%) for qq; p = 0.02]. The incidence of euploid/balanced blastocysts was similar in both types of translocations. However, there was a significant increase in pure ICE in RobT compared to RecT carriers. In RecT carriers, the presence of the breakpoints in the long arm of the chromosomes involved in the rearrangement resulted in a higher total ICE.

Analysis of sperm chromosomes in six carriers of rare and common Robertsonian translocations*

Summary Introduction Robertsonian translocation (RobT) is the central fusion of the long arms of two acrocentric chromosomes, leading to 45 chromosomes in humans. The most common ones are rob(13;14) and rob(14;21) (91%). Other types of RobT are so-called rare cases. In the general population RobTs occur with a frequency of approximately 0.123%, but among men with reproductive failure this value rises 9-fold. Infertility in RobT carriers is associated with the formation of unbalanced spermatozoa resulting from segregation of the chromosomes involved in trivalent during the meiotic prophase. In spermatozoa of many RobT carriers an increased level of chromosomal aneuploidy is observed. Materials and Methods We examined the hyperhaploidy level of chromosomes 7, 9, 18, 21, 22, X and Y in spermatozoa of 6 RobT unrelated carriers: two carriers with rare rob(13;15), one with rare rob(13;22), and three of the common rob(13;14). Results were compared with the control data from a group of 7 fertile men with a normal karyotype. Fluorescent in situ hybridization (FISH) was applied. Results We found an increased level of sperm aneuploidy regarding at least one of the analyzed chromosomes in each of the carriers, while in rare RobTs interchromosomal effect (ICE) was observed. Meiotic segregation pattern of a rare rob(13;15) carrier revealed the 76% of normal /balanced spermatozoa. Disucussion Due to the relatively high population frequency of RobTs, their influence on reproductive failure, hight risk of imbalancement in prenatal diagnosis (7%), and small amount of data for rare RobTs, each newly characterized case is valuable in genetic counseling.

The Interchromosomal Effect: Different Meanings for Different Organisms.

The term interchromosomal effect was originally used to describe a change in the distribution of exchange in the presence of an inversion. First characterized in the 1920s by early Drosophila researchers, it has been observed in multiple organisms. Nearly half a century later, the term began to appear in the human genetics literature to describe the hypothesis that parental chromosome differences, such as translocations or inversions, may increase the frequency of meiotic chromosome nondisjunction. Although it remains unclear if chromosome aberrations truly affect the segregation of structurally normal chromosomes in humans, the use of the term interchromosomal effect in this context persists. This article explores the history of the use of the term interchromosomal effect and discusses how chromosomes with structural aberrations are segregated during meiosis.

Interchromosomal effect: Report of a father and son, bearing different translocations of the same chromosome, and a review of the current literature.

Interchromosomal effect is a controversial phenomenon postulating that during gametogenesis of translocation carriers, aside from the unbalanced segregation of chromosomes involved in the translocation, other, structurally normal chromosomes might also be affected and segregated abnormally. Here, we present a balanced reciprocal translocation carrier t(15;20)(q11;p13), and his son, bearing a different translocation of chromosome 15, t(15;Y)(q11;q12). To further elucidate the so-far-controversial interchromosomal effect phenomenon, published original articles and case reports about interchromosomal effect were reviewed. The father was a carrier of t(15;20)(q11;p13). His wife's karyotype was normal. During a pregnancy occurred without any preceding procedure, amniocentesis was recommended to the family and performed. Result of the amniocentesis revealed a different translocation of chromosome 15; t(15;Y)(q11;q12). To our knowledge, this is the first report of two generations within a family, bearing different translocations of a chromosome. On top of all previous studies investigating ICE, our case adds an important finding, showing not only the rate of aneuploidies of structurally normal chromosomes, but also the rate of this 'alternating translocations' might be increased in translocation carriers, and this could be an important clue about interchromosomal effects.

Investigation of the interchromosomal effects in male carriers with structural chromosomal abnormalities using FISH.

The interchromosomal effect (ICE) refers to the uncertainty during meiosis where the rearrangement of the chromosomes affects the segregation of the chromosomes that are not involved in the structural chromosomal abnormalities. The aim of this study is to investigate the existence of ICE in the sperm nuclei of the males who have structural chromosomal abnormalities. Nine male individuals who are the carriers of the structural chromosomal abnormalities (patient group) and 14 male individuals who did not have any chromosomal abnormalities (control group) were diagnosed by the classical cytogenetic analysis. The aneuploidy of chromosomes 2, 3, 12, 13, 17, 18, 21, X, and Y in the sperm nuclei was investigated using the fluorescence in situ hybridization (FISH) method in these individuals. The patient group included 5 Robertsonian translocation (ROB) carriers, 3 reciprocal translocation (RCP) carriers, and 1 inversion carrier. A total of 51921 sperm nuclei were analyzed (19484 from the patient group and 32437 from the control group). While ICE was determined in 4 of 5 patients who were the carriers of ROB and an inversion carrier patient, it was not determined in the patient carrier of RCP. Our results suggest that there is ICE in the male carriers with a structural chromosomal abnormality, which appears to be translocation, breakpoint, chromosome, and patient dependent.

Мейотическая коориентация негомологичных хромосом у человека

Концепция мейотической коориентаци негомологичных хромосом (МКНХ) как модели мейоза, экспериментально подтвержденная на Drosophila, была предложена в 1971 г. для объяснения интерхромосомного эффекта у человека, но с тех пор не получила достаточных доказательств. Представленные в настоящей статье данные «неканонического» поведения половых хромосом в определенных ситуациях являются основанием для признания существования этого явления в сперматогенезе человека. The concept of meiotic co-orientation of non-homologous chromosomes as a model of meiosis, experimentally confirmed in Drosophila, was proposed in 1971 to explain the interchromosomal effect in humans, but has not received sufficient evidence since. The data of the “non-canonical” behavior of sex chromosomes presented in this article are the basis for recognizing the existence of this phenomenon in human spermatogenesis.

Chromosomal segregation in sperm of the Robertsonian translocation (21;22) carrier and its impact on IVF outcome.

To assess the variability of meiotic segregation patterns in sperm of Robertsonian translocation (RobT) carrier t(21;22) and present effect on reproductive outcome. Infertile couple enrolled in IVF/ICSI program. Sperm chromosomal segregation analysis was done using FISH; preimplantation genetic testing for aneuploids (PGT-A) was performed by NGS. Patients had a low fertilization rate and a negative outcome after the first IVF/ICSI cycle, so they were advised to do chromosomal aberration analysis before their next attempt. The second IVF/ICSI procedure resulted in pregnancy, and two blastocysts were cryopreserved. The NIFTY test has shown low risk for all tested trisomies, sex chromosomes aneuploidis, and deletion syndromes, so a healthy female child was born. During pregnancy, karyotypisation results revealed that the male partner is a RobT carrier t(21;22). Sperm segregation analysis of chromosomes 21 and 22 has shown six types of sperm chromosome sets. The majority of sperm cells had a normal/balanced RobT form of a haploid set of chromosomes (68.5-76%) called an "alternate." Sperm cells that had additional chromosome 21 or 22, or lack of chromosome 21 or 22, were present in 4-12%. PGT-A performed on two cryopreserved blastocysts revealed one embryo euploid and the other with the mosaic aneuploidy of chromosome 7 present in 50% of the cells. Infertile couples with a RobT male carrier who have semen comprising of normal/alternate form in the majority have a good prognosis of IVF/ICSI outcome. PGT is recommended because of the possible occurrence of viable trisomic embryos and potential interchromosomal effect.

Interchromosomal effect in carriers of translocations and inversions assessed by preimplantation genetic testing for structural rearrangements (PGT-SR).

Balanced carriers of structural rearrangements have an increased risk of unbalanced embryos mainly due to the production of unbalanced gametes during meiosis. Aneuploidy for other chromosomes not involved in the rearrangements has also been described. The purpose of this work is to know if the incidence of unbalanced embryos, interchromosomal effect (ICE) and clinical outcomes differ in carriers of different structural rearrangements. Cohort retrospective study including 359 preimplantation genetic testing cycles for structural rearrangements from 304 couples was performed. Comparative genomic hybridisation arrays were used for chromosomal analysis. The results were stratified and compared according to female age and carrier sex. The impact of different cytogenetic features of chromosomal rearrangements was evaluated. In carriers of translocations, we observed a higher percentage of abnormal embryos from day 3 biopsies compared with day 5/6 biopsies and for reciprocal translocations compared with other rearrangements. We observed a high percentage of embryos with aneuploidies for chromosomes not involved in the rearrangement that could be attributed to total ICE (aneuploid balanced and unbalanced embryos). No significant differences were observed in these percentages between types of rearrangements. Pure ICE (aneuploid balanced embyos) was independent of female age only for Robertsonian translocations, and significantly increased in day 3 biopsies for all types of abnormalities. Furthermore, total ICE for carriers of Robertsonian translocations and biopsy on day 3 was independent of female age too. High ongoing pregnancy rates were observed for all studied groups, with higher pregnancy rate for male carriers. We observed a higher percentage of abnormal embryos for reciprocal translocations. No significant differences for total ICE was found among the different types of rearrangements, with higher pure ICE only for Robertsonian translocations. There was a sex effect for clinical outcome for carriers of translocations, with higher pregnancy rate for male carriers. The higher incidence of unbalanced and aneuploid embryos should be considered for reproductive counselling in carriers of structural rearrangements.

Recombination suppression in heterozygotes for a pericentric inversion induces the interchromosomal effect on crossovers in Arabidopsis.

SummaryDuring meiosis, recombination ensures allelic exchanges through crossovers (COs) between the homologous chromosomes. Advances in our understanding of the rules of COs have come from studies of mutations including structural chromosomal rearrangements that, when heterozygous, are known to impair COs in various organisms. In this work, we investigate the effect of a large heterozygous pericentric inversion on male and female recombination in Arabidopsis. The inversion was discovered in the Atmcc1 mutant background and was characterized through genetic and next‐generation sequencing analysis. Reciprocal backcross populations, each consisting of over 400 individuals, obtained from the mutant and the wild type, both crossed with Landsberg erecta, were analyzed genome‐wide by 143 single‐nucleotide polymorphisms. The negative impact of inversion became evident in terms of CO loss in the rearranged chromosome in both male and female meiosis. No single‐CO event was detected within the inversion, consistent with a post‐meiotic selection operating against unbalanced gametes. Cytological analysis of chiasmata in F1 plants confirmed that COs were reduced in male meiosis in the chromosome with inversion. Crossover suppression on the rearranged chromosome is associated with a significant increase of COs in the other chromosomes, thereby maintaining unchanged the number of COs per cell. The CO pattern observed in our study is consistent with the interchromosomal (IC) effect as first described in Drosophila. In contrast to male meiosis, in female meiosis no IC effect is visible. This may be related to the greater strength of interference that constrains the CO number in excess of the minimum value imposed by CO assurance in Arabidopsis female meiosis.

57. ADDITIONAL DATA FOR CONTROVERSIAL INTER-CHROMOSOMAL EFFECT SUSCEPTIBILITY IN PGT-SR PATIENTS

Introduction NGS based translocation testing has been widely used as the possibility of detecting other chromosomal aneuploidies. Some studies claimed that balanced translocation carriers may have an increased risk for aneuploidies unrelated to translocation due to inter-chromosomal effect (ICE). Translocation causes unusual segregation of chromosomes involved in translocation. Furthermore this rearrangement may have an effect on the segregation of other structurally normal chromosomes during meiosis. Here we present a report of aneuploidy and complex aneuploidy rates among the embryos derived from patients carrying balanced chromosomal rearrangements (reciprocal or robertsonian translocations). Materials and Methods Whole Genome Amplification (WGA) was performed using SurePlex DNA Amplification System (Illumina, USA) and DOPlify (PerkinElmer Health Sciences - Australia). on biopsied cells. Veriseq PGS kit was used for further processing of WGA samples. BlueFuse Multi Software was used to analyse the data obtained from Miseq System. Results In this study, we collected 705 embryos from 168 patients with an average age of 31. At least one of the couples was previously reported to be a translocation carrier. According to our findings, 25.6% of these embryos was euploid and 69,4% was aneuploid/complex aneuploid (mosaic embryo results were excluded). 29.33% aneuploidy was detected in translocation of interest only. The rest (39.43%) was due to aneuploidy of other chromosomes . According to our in house PGT-A data (7200 embryos collected from 2177 patients) sum of aneuploidy and complex aneuploidy rates was 45.8. Overall these results fail to provide any support for the presence of an ICE. Conclusion In balanced chromosomal rearrangement carriers PGD by NGS array not only detects unbalanced chromosomal rearrangements due to chromosomes involved in translocation but also detects the possibility of other chromosomal aneuploidies. According to our findings, aneuploidy and complex aneuploidy rates do not increase in the embryos obtained from PGT-SR group of patients. Moreover, in addition to translocation chromosomes, we observed an additional aneuploidy risk related to other chromosomes in these embryos. Our data supports previous studies suggesting that ICE in embryos derived from balanced chromosomal rearrangement carriers is elusive. On the other hand average maternal age of PGT-A patients is significantly higher than PGT-SR group (35.1 vs 31.2 respectively). Although it is thought that increased maternal age may cause aneuploidy in some of the cases, some embryos have an increased aneuploidy rate regardless of maternal age. Nevertheless euploid embryo ratio in PGT-SR group is compared to PGT-A is relatively lower (25.6 vs 36.7) thus our results emphasize the importance of 24 chromosome scan in embryos derived from balanced translocation carriers NGS based translocation testing has been widely used as the possibility of detecting other chromosomal aneuploidies. Some studies claimed that balanced translocation carriers may have an increased risk for aneuploidies unrelated to translocation due to inter-chromosomal effect (ICE). Translocation causes unusual segregation of chromosomes involved in translocation. Furthermore this rearrangement may have an effect on the segregation of other structurally normal chromosomes during meiosis. Here we present a report of aneuploidy and complex aneuploidy rates among the embryos derived from patients carrying balanced chromosomal rearrangements (reciprocal or robertsonian translocations). Whole Genome Amplification (WGA) was performed using SurePlex DNA Amplification System (Illumina, USA) and DOPlify (PerkinElmer Health Sciences - Australia). on biopsied cells. Veriseq PGS kit was used for further processing of WGA samples. BlueFuse Multi Software was used to analyse the data obtained from Miseq System. In this study, we collected 705 embryos from 168 patients with an average age of 31. At least one of the couples was previously reported to be a translocation carrier. According to our findings, 25.6% of these embryos was euploid and 69,4% was aneuploid/complex aneuploid (mosaic embryo results were excluded). 29.33% aneuploidy was detected in translocation of interest only. The rest (39.43%) was due to aneuploidy of other chromosomes . According to our in house PGT-A data (7200 embryos collected from 2177 patients) sum of aneuploidy and complex aneuploidy rates was 45.8. Overall these results fail to provide any support for the presence of an ICE. In balanced chromosomal rearrangement carriers PGD by NGS array not only detects unbalanced chromosomal rearrangements due to chromosomes involved in translocation but also detects the possibility of other chromosomal aneuploidies.

70. PREIMPLANTATION GENETIC TESTING FOR YQH-AUTOSOME TRANSLOCATION CARRIERS: ANALYSIS OF GAMETE SEGREGATION

Introduction Y-autosome translocations occur in approximately 1:2000 in population and represent special group of reciprocal exchanges. Due to a balanced nature they do not influence on phenotype in general. However, Y-autosome translocation can dislocate sex bivalent formation and chromosome synapsis in the first meiotic division prophase that led to gamete aneuploidy or pachytene arrest. More often Y-derived DNA, predominantly Yq12 band, is translocated onto the short arm of acrocentric chromosomes, mainly chromosomes 15 and 22 due to a strong correlation in their satellite DNA sequences. In women inheritance of such derivative acrocentric chromosomes could be associated with the risk of ovarian malignancy, but the particular mechanism of this pathological effect is not entirely clear since the Yq12 band consists of tandemly organized satellite DNA sequences. It can be associated with the transcription of satellite DNAwhich occurs during carcinogenesis. Material & methods Two families with Yq12/15p and one – with Yq12/22p translocations were analyzed during IVF cycle with PGT in International Centre for Reproductive Medicine. The mean age of men and women was 36±2.8 and 34.25±1.4 years respectively. Karyotyping analysis was performed using GTG banding technique on metaphase chromosomes from peripheral blood lymphocytes. Fluorescence in situ hybridization (FISH) was used to clarify the breakpoint on chromosomes and confirm the chromosomes-specificity of the probes. Additionally, seven chromosomes (13, 14, 15 or 22, 16, 18, 21, X), which are not involved in rearrangement, were analyzed. Results FISH with chromosome specific probes was performed on blastomere from cleavage-stage embryo. A total of 42 blastomeres were analyzed. In 43% of the blastomeres «adjacent-1» segregationwith derivate autosome and X or Y chromosomes was revealed. Segregation 3:1 was observed in 10% of the cells, with no predominant inheritance of the derivative autosome. In 21% of cells the type of chromosome segregation could not be determined due to mosaicismor polyploidy. 45% of the cells were aneuploid for autosomes, which are not involved in the translocation, which may be connected with interchromosomal effect. Conclusions Carriers of Yq12/15p or Yq12/22p translocations have a predominant inheritance of the derivative autosome, which can be associated with the disruption ofsex bivalent segregation. This research was supported by Russian Foundation for Basic Research (grant # 18-34-00279 ).

Retrospective analysis of meiotic segregation pattern and interchromosomal effects in blastocysts from inversion preimplantation genetic testing cycles

To determine factors affecting unbalanced chromosomal rearrangement originating from parental inversion and interchromosomal effect occurrence in blastocysts from inversion carriers. Retrospective study. University-affiliated center. Couples with one partner carrying inversion underwent preimplantation genetic testing for chromosomal structural rearrangement cycles. Not applicable. Unbalanced rearrangement embryo rate, normal embryo rate, interchromosomal effect. Preimplantation genetic testing was performed for 576 blastocysts from 57 paracentric (PAI) and 94 pericentric (PEI) inversion carriers. The percentage of normal/balanced blastocysts was significantly higher in PAI than PEI carriers (70.4% vs. 57.5%). Logistic regression indicated the inverted segment size ratio was a statistically significant risk factor for abnormality from parental inversion in both PEI and PAI. The optimal cutoff values to predict unbalanced rearrangement risk were 35.7% and 57%. In PAI, rates of abnormality from parental inversion were 0% and 12.1% in the <35.7% and ≥35.7% groups, respectively, with no gender difference. For PEI, the rates of abnormality from parental inversion were 7.9% and 33.1% in the <57% and ≥57% groups, respectively. In the ≥57% group, the rate of unbalanced rearrangement was significantly higher from paternal than maternal inversion (43.3% vs. 23.6%). In inversion carriers, 21,208 chromosomes were examined, and 187 (0.88%) malsegregations were identified from structurally normal chromosomes. In controls, 56,488 chromosomes were assessed, and 497 (0.88%) aneuploidies were identified, indicating no significant difference. The risk of unbalanced rearrangement is affected by the ratio of inverted segment size in both PAI and PEI carriers and is associated with gender.

Possible impact of interchromosomal effect at the blastocyst stage in cases undergoing PGT-A for translocations

Introduction PGT-A for translocations has been a valid approach in order to detect chromosomally normal/balanced embryos. While earlier studies utilized PGT-A for only rearranged chromosomes, comprehensive chromosomal analysis by array comparative genomic hybridization (aCGH) is nowadays the gold standard in PGT-A for translocation cases, allowing detection of a wide range of chromosomal abnormalities other than the ones involved in rearrangement -known as interchromosomal effect. Estimating the impact of interchromosomal effect based on the type of rearrangement can therefore greatly help the clinical management and may lead to the development of individual clinical strategies to maximize the outcome involving PGT-A approach at the blastocyst stage. This study is performed in order to analyze the presence as well as possible impact of interchromosomal effect in embryos of reciprocal and Robertsonian translocation carriers undergoing PGT-A for translocations. Material & Methods This retrospective study was conducted in Bahceci Fulya IVF Centre, between January 2014 and December 2017. It included a total of 128 PGT-A for translocations cycles performed for female and male reciprocal (n=87) and Robertsonian (n=41) translocation carriers. For all suitable embryos, a trophectoderm (TE) biopsy was performed on either on day 5 or day 6 and aCGH was used for comprehensive chromosomal screening (CCS) analysis. Patients and their embryos were grouped according to the nature of translocation as Group I (Reciprocal translocation carriers) and Group II (Robertsonian translocation carriers). Major laboratory as well as clinical parameters were compared between groups. Results Main patient & cycle parameters such as mean female age, number of previous ART trials, number of oocytes retrieved, fertilized, biopsied etc. were found to be similar in both groups (p>0.05). Results regarding embryo analysis and clinical outcome are shown in Table 1. Percent of embryos containing chromosomal abnormalities not involving rearranged chromosomes was significantly lover in embryos of reciprocal translocation carriers (Group I) whereas in the same group, the contribution of translocated chromosomes in overall aneuploidy was found to be significantly higher. Table 1: Embryo analysis and clinical outcome between groups. Group I Group II p Num. of cycles (n) 87 41 Embryos biopsied (n) 315 145 Embryos processed for analysis (n) 307 137 Embryos diagnosed (n, %) 304 (99.0) 135 (98.5) NS Normal embryos (n, %) 77 (25.3) 50 (37.0) NS Abnormal embryos (n, %) 227(74.7) 85 (63.0) NS Aneuploid/balanced embryos (n, %) 73 (24.0) 58 (43.0) p=0.0061 Euploid/unbalanced embryos (n, %) 100 (32.9) 14 (10.4) P Num. of cycles cancelled prior to ET (n) 39 (44.8) 13 (31.7) NS Num. of ET cycles (n) 40 31 Pregnancy rate (b-hCG+, n, %) 31 (77.5) 20 (64.5) NS Clinical pregnancy rate (Sac+, n, %) 29 (72.5) 17 (54.8) NS Live birth/Ongoing (%) 22 (55.0) 13 (41.9) NS Missed abortus (%) 6 (15.0) 4 (12.9) NS Conclusions Our data and results have shown that, although they generate acceptable clinical pregnancies, embryos of Robertsonian translocation carriers have increased aneuploidies for chromosomes not involved in the translocation. This result indicates that besides cleavage stage, interchromosomal effect can significantly contribute the genetic status of human embryos at the blastocyst stage, leading to poorer clinical outcome.

Interaction of acrocentric chromosome involved in translocation and sex of the carrier influences the proportion of alternate segregation in autosomal reciprocal translocations.

Are meiotic segregation patterns of reciprocal translocations affected by the combined effect of chromosome type and carrier's sex? Interaction of an acrocentric chromosome (Acr-ch) involved in the translocation and sex of the carrier influences the proportion of alternate segregation for normal or balanced chromosome contents during meiotic segregation in autosomal reciprocal translocations. Carriers of reciprocal translocations are at a significantly increased risk of fertility problems due to the generation of unbalanced gametes in meiotic segregation of a quadrivalent. Previous studies have reported that meiotic segregation patterns of a quadrivalent can be affected by factors such as a carrier's sex and age and the chromosome type. However, the reported proportion of alternate segregation does not differ significantly, except in one study, and whether combined effects between these factors exist is unclear. A retrospective study of array comparative genomic hybridization (aCGH) outcome data from patients with autosomal reciprocal translocations was conducted to analyse meiotic segregation patterns and blastocyst euploidy rates. We enroled 473 couples whose embryos were tested between January 2013 and September 2016. Meiotic segregation patterns of 2101 blastocysts from 243 female carriers, including 76 cases with translocations involving Acr-ch, and 230 male carriers, including 88 cases with translocations involving Acr-ch, were analysed according to chromosome type, carrier's sex and age. In cases with translocations involving the Acr-ch subgroup, the proportion of alternate segregation (53.9 vs 33.4%, P < 0.0001) was significantly higher in male carriers than in female carriers, with the proportion of 3:1 segregation (6.8 vs 16.3%, P < 0.0001) being significantly lower. The proportions of alternate segregation were similar between sexes in cases with translocations not involving the Acr-ch subgroup. Meanwhile, in the female carrier subgroup, the proportion of alternate segregation (33.4 vs 45.2%, P < 0.001) was significantly lower and the proportion of 3:1 segregation (16.3 vs 8.2%, P < 0.001) was significantly higher in cases with translocations involving Acr-ch than in those not. In the male carrier subgroup, the proportion of alternate segregation (53.9 vs 46.9%, P = 0.031) was higher and the proportion of adjacent-1 segregation (27.1 vs 37.3%, P < 0.001) was significantly lower in cases with translocations involving Acr-ch than in those not. Carrier's age did not affect the meiotic segregation patterns. However the euploidy rates were significantly lower in couples with advanced compared to young maternal age respectively. Mosaic embryos were not identified using aCGH in this study. Patients with complex chromosome rearrangements and translocations involving sex chromosomes were excluded. Interchromosomal effect was not analysed. The findings of this study provide detailed information for genetic counselling of couples with autosomal reciprocal translocations on their chances of producing euploid gametes. This research was supported by the National Key Research and Development Program of China (2016YFC1000202); the National Natural Science Foundation of China (81671522); the Natural Science Foundation of Shandong Province in China (ZR2016HP09); and the Innovative Foundation of Reproductive Hospital Affiliated to Shandong University (20171114, 20171111). No competing interests are declared. N/A.

Infertility patients with chromosome inversions are not susceptible to an inter-chromosomal effect.

The aim of this study was to evaluate the incidence of an inter-chromosomal effect (ICE) in blastocyst-stage embryos from carriers of balanced chromosome inversions. Infertility patients (n = 52) with balanced inversions (n = 66cycles), and maternal age-matched controls that concurrently cycled (n = 66), consented to an IVF cycle with preimplantation genetic testing for aneuploidy (PGT-A). Blastocyst-stage embryos underwent trophectoderm biopsy for PGT-A with only euploid blastocysts transferred in a subsequent frozen embryo transfer. Subtypes of inversions were included in aggregate: paracentric/pericentric, polymorphic/non-polymorphic, male/female carriers, and varying inversion sizes. The incidence of aneuploidy was not significantly higher for the inversion patients compared to the controls (inversion = 48.8% vs. control = 47.2% ns). Following euploid blastocyst transfer, there were excellent live birth outcomes. Carriers of balanced chromosome inversions did not exhibit higher aneuploidy rates for chromosomes that were not involved in the inversion compared to maternal age-matched controls, signifying the absence of an inter-chromosomal effect for this data set. These results provide the largest investigation of blastocyst embryos regarding the debated existence of an ICE resulting from the presence of an inversion during meiosis. However, further studies are warranted to investigate an ICE among inversions subtypes that were outside the scope of this study.

Analysis of chromosomes of embryos derived from translocation carriers during preimplantation genetic diagnosis cycles

To explore the effect of chromosomal translocations on the composition of embryonic chromosomes and its mechanism. For 52 couples with one partner carrying a chromosomal translocation, results of next generation sequencing of all embryos derived from 61 cycles were divided into different groups based on the type of translocations, gender of the carrier, and maternal age. Effect of parental chromosomal translocations on the composition of embryonic chromosomes of each group was analyzed. A significant difference was found between carriers of reciprocal and Robertsonian translocations in terms of proportion of abnormal embryos and structurally normal chromosomes (63.3% vs. 27.5%, and 1.1% vs. 0.3%, respectively). Compared with male carriers, there was an increase in the rate of abnormalities for female carriers (67.2% vs. 58.3% for reciprocal translocations, and 45.5% vs. 13.8% for Robertsonian translocations). The risk for chromosomal abnormality also increased with the maternal age. No significant difference was found in the proportion of abnormal embryos between carriers divided by involvement of acrocentric chromosomes or terminal chromosomal breakpoints. The types of parental translocation, gender of carrier, maternal age, and interchromosomal effect have certain effect on the composition of embryonic chromosomes.

Analysis of Meiotic Segregation Pattern and Interchromosomal Effects in a Bull Heterozygous for a 3/16 Robertsonian Translocation

Robertsonian translocations are the most frequent chromosomal rearrangements detected in cattle. Here, we report on the detection of a new Robertsonian translocation between chromosomes BTA3 and BTA16. This rob(3;16) was dicentric, suggesting that its occurrence was recent. FISH analysis of decondensed sperm nuclei revealed a relatively low rate of unbalanced gametes produced by adjacent segregation (5.87%). In addition, and for the first time in bovines, a significant interchromosomal effect (ICE) was detected for 2 different autosomes: BTA17 (global disomy + nullisomy rate of 9%) and BTA20 (1.8%). These results suggest that ICE should be taken into consideration when assessing the putative effect of Robertsonian translocations on reproduction.

Local Inversion Heterozygosity Alters Recombination throughout the Genome

Crossovers (COs) are formed during meiosis by the repair of programmed DNA double-strand breaks (DSBs) and are required for the proper segregation of chromosomes. More DSBs are made than COs, and the remaining DSBs are repaired as noncrossovers (NCOs). The distribution of recombination events along a chromosome occurs in a stereotyped pattern that is shaped by CO-promoting and CO-suppressing forces, collectively referred to as crossover patterning mechanisms. Chromosome inversions are structural aberrations that, when heterozygous, disrupt the recombination landscape by suppressing crossing over. In Drosophila species, the local suppression of COs by heterozygous inversions triggers an increase in crossing over on freely recombining chromosomes termed the interchromosomal (IC) effect [1, 2]. The molecular mechanism(s) by which heterozygous inversions suppress COs, whether noncrossover gene conversions (NCOGCs) are similarly affected, and what mediates the increase in COs in the rest of the genome remain open questions. By sequencing whole genomes ofindividual offspring from mothers containing heterozygous inversions, we show that, although COs are suppressed by inversions, NCOGCs occur throughout inversions at higher than wild-type frequencies. We confirm that CO frequency increases on the freely recombining chromosomes, yet CO interference remains intact. Intriguingly, NCOGCs do not increase in frequency on the freely recombining chromosomes and the total number of DSBs is approximately the same per genome. Together, our data show that heterozygous inversions change the recombination landscape by altering the relative proportions of COs and NCOGCs and suggest that DSB fate may be plastic until a CO assurance checkpoint has been satisfied.

Preimplantation genetic diagnosis for translocations and interchromosomal effect assessed by array CGH

Preimplantation genetic diagnosis for translocations and interchromosomal effect assessed by array CGH