Autosomal reciprocal translocations: prenatal selection, segregation and assessment of empirical risks for reciprocal translocation carriers of having a liveborn child with chromosome imbalance

Chromosomal Rearrangements ◽

Accurate Estimate ◽

Meiotic Segregation ◽

Preferential Formation ◽

Increased Risk ◽

Chromosome Imbalance ◽

Liveborn Child ◽

Аутосомные реципрокные транслокации (АРТ), являются наиболее частой структурной хромосомной перестройкой. Носители АРТ имеют повышенный риск рождения детей с хромосомным дисбалансом, который может варьировать от низкого до высокого в зависимости от характеристик транслокации и типа патологической мейотической сегрегации. Целью исследования являлся анализ пренатальной селекции, мейотической сегрегации и оценка эмпирического риска рождения жизнеспособного ребенка с хромосомным дисбалансом у 49 носителей АРТ. Оценка пахитенной диаграммы проводилась для каждой транслокации на основании количественных характеристик мейотического квадривалента. Наблюдаемый и ожидаемый хромосомный дисбаланс при всех типах патологической сегрегации оценивался в процентах от гаплоидной длины аутосом. Оценка жизнеспособности плодов и потенциальных зигот с хромосомным дисбалансом проводилась с использованием модели, основанной на измерении хромосомных сегментов дистальнее точек разрывов и определении относительного размера хромосомного дисбаланса. Установлена тенденция к преимущественной пренатальной селекции зигот вследствие альтернативного типа сегрегации АРТ. Показано, что анализ количественных характеристик квадривалента и пахитенной диаграммы позволяет оценить тип патологической мейотической сегрегации, приводящей к наименьшему хромосомному дисбалансу, и риск формирования несбалансированных гамет. Определено, что оценка жизнеспособности зигот, основанная на сопоставлении относительного размера несбалансированных хромосомных сегментов, может быть дополнительным этапом при установлении повторного риска рождения ребенка с хромосомной патологией у носителей АРТ. В 80% случаев транслокаций риск рождения жизнеспособного ребенка с хромосомным дисбалансом расценивается как низкий. Мейотическая сегрегация хромосом у носителей АРТ происходит с преимущественным формированием и последующей пренатальной селекцией зигот вследствие альтернативного, непатологического типа сегрегации. Для каждой транслокации необходимо проводить оценку наиболее вероятного типа патологической сегрегации и жизнеспособности плодов или новорожденных. Эмпирический риск не может быть использован как единственный и решающий фактор при оценке повторного риска рождения жизнеспособного ребенка с хромосомным дисбалансом. Autosomal reciprocal translocations are among the most frequent chromosomal rearrangements in man. Though phenotypically normal, the carrier of reciprocal translocation may be at increased risk of having a chid with multiple malformations and mental retardation due to malsegregation at meiosis resulting in gametes with chromosome imbalance. An accurate estimate of the probability of this event is understandably desirable. Aim. The aim of this investigation was an analysis of prenatal selection, meiotic segregation and assessment of empirical risks for reciprocal translocation carriers of having a liveborn child with unbalanced karyotype on 49 reciprocal translocation carriers. Materials and Methods. The pachytene diagrams were analyzed for each translocation taking in account the exact lengths of the chromosomes involved. The observed and most probable unbalanced segments were evaluated using the Chromosome Imbalance Size-Viability Model and Surface of Viable Unbalances consisting of the measurement of chromosomal segments distal to the breakpoints expressed in percentage of haploid autosomal length - %HAL. Results. The tendency to preferential prenatal selection of zygotes is established due to the 2:2 alternate segregation. It is shown that the analysis of quantitative characteristics of quadrivalent and pachytene diagram allows to estimate the type of malsegregation producing the smallest imbalance and the risk of formation of unbalanced gametes. Evaluation of viability of zygotes may be an additional step in establishing of the recurrence risks. In 80% of cases the risk of a viable child with a chromosomal imbalance is regarded as low. Conclusions. Meiotic segregation of chromosomes in carriers of autosomal reciprocal translocations occurs with preferential formation and subsequent prenatal selection of zygotes due to alternate segregation. It is necessary to assess segregation giving the smallest imbalance and viability of the imbalance. Empirical risk was not found to be useful as a discriminating risk predictor in individual genetic counselling.

Analysis of chromosome segregation in reciprocal translocation carriers

Nauchno-prakticheskii zhurnal «Medicinskaia genetika» ◽

10.25557/2073-7998.2020.03.16-18 ◽

2020 ◽

pp. 16-18

Author(s):

З.Н. Тонян ◽

И.Л. Пуппо ◽

А.Ф. Сайфитдинова ◽

Ю.А. Логинова ◽

О. Г. Чиряева ◽

...

Keyword(s):

Genetic Counseling ◽

Chromosome Segregation ◽

Birth Defects ◽

Spontaneous Abortions ◽

Meiotic Segregation ◽

Cleavage Stage ◽

Recurrent Spontaneous Abortions ◽

Increased Risk

Аутосомные реципрокные транслокации (АРТ) приводят к повышенному риску образования несбалансированных гамет вследствие патологической сегрегации хромосом в мейозе у носителей. В настоящей статье приведены результаты анализа типов сегрегации для 26 АРТ, а также определены теоретически возможные варианты сегрегации хромосом. В 73% случаев у носителей АРТ в более, чем 50% бластомеров наблюдалось совпадение теоретического и детектируемого типов сегрегации. Полученные данные можно использовать для оптимизации персонализированного медико-генетического консультирования семей, где один из супругов является носителем АРТ, и имеющих репродуктивные проблемы, высокий риск неразвивающейся беременности и/или рождения ребенка с хромосомной патологией. Autosomal reciprocal translocations (ART) lead to an increased risk of imbalanced gametes formation due to pathological meiotic segregation. Segregation type was analyzed and theoretical segregation pattern was determined in 26 cleavage stage embryos in this article. A coincidence of theoretical and detectable segregation types was observed in more than 50 % of blastomeres in 73 % of cases. The data obtained may be used for personalized genetic counseling in families with high risks of recurrent spontaneous abortions, infertility or children with birth defects due to ART.

Mapping a Telomere Using the Translocation eT1(III;V) in Caenorhabditis elegans

Genetics ◽

10.1093/genetics/150.3.1059 ◽

1998 ◽

Vol 150 (3) ◽

pp. 1059-1066

Author(s):

K A Adames ◽

Jocelyn Gawne ◽

Chantal Wicky ◽

Fritz Müller ◽

Ann M Rose

Keyword(s):

Caenorhabditis Elegans ◽

Dark Spot ◽

Meiotic Segregation ◽

Wild Type ◽

C Elegans ◽

Embryonic Arrest ◽

Telomere Probe ◽

Left Portion

Abstract In Caenorhabditis elegans, individuals heterozygous for a reciprocal translocation produce reduced numbers of viable progeny. The proposed explanation is that the segregational pattern generates aneuploid progeny. In this article, we have examined the genotype of arrested embryonic classes. Using appropriate primers in PCR amplifications, we identified one class of arrested embryo, which could be readily recognized by its distinctive spot phenotype. The corresponding aneuploid genotype was expected to be lacking the left portion of chromosome V, from the eT1 breakpoint to the left (unc-60) end. The phenotype of the homozygotes lacking this DNA was a stage 2 embryonic arrest with a dark spot coinciding with the location in wild-type embryos of birefringent gut granules. Unlike induced events, this deletion results from meiotic segregation patterns, eliminating complexity associated with unknown material that may have been added to the end of a broken chromosome. We have used the arrested embryos, lacking chromosome V left sequences, to map a telomere probe. Unique sequences adjacent to the telomeric repeats in the clone cTel3 were missing in the arrested spot embryo. The result was confirmed by examining aneuploid segregants from a second translocation, hT1(I;V). Thus, we concluded that the telomere represented by clone cTel3 maps to the left end of chromosome V. In this analysis, we have shown that reciprocal translocations can be used to generate segregational aneuploids. These aneuploids are deleted for terminal sequences at the noncrossover ends of the C. elegans autosomes.

Balanced Chromosomal Rearrangements Associated with Hypoprolificacy in Australian Boars (Sus scrofa domesticus)

Cells ◽

10.3390/cells10082000 ◽

2021 ◽

Vol 10 (8) ◽

pp. 2000

Author(s):

Foyez Shams ◽

Darryl D’Souza ◽

Tariq Ezaz

Keyword(s):

Prevalence Rate ◽

De Novo ◽

Chromosomal Rearrangements ◽

Economic Losses ◽

Founder Population ◽

Routine Monitoring ◽

Cytogenetic Analyses ◽

Clinical Conditions

Balanced chromosomal rearrangements, mainly reciprocal translocations, are considered to be the causative agent of several clinical conditions in farmed pigs, resulting in hypoprolificacy and economic losses. Literature suggests that reciprocal translocations are heritable and can occur de novo. The prevalence rate of these balanced structural rearrangements of chromosomes differs from country to country and varies between 0.5% and 3.3%. The Australian pig population is descendent of a small founder population and has since been a closed genetic group since the 1980s. Hence, any incident of reciprocal translocation along with the pedigree of boars that contribute sperm for artificial insemination has the potential to have an economic consequence. To date, there has been no published account for screening of reciprocal translocation associated with hypoprolificacy in the Australian pig population. In this study, we performed standard and molecular cytogenetic analyses to identify evidence of chromosome rearrangements and their association with hypoprolificacy in a representative 94 boar samples from a commercial nucleus herd. We identified three novel rearrangements between chromosomes 5 and 14, between chromosomes 9 and 10, and between chromosomes 10 and 12. In addition, we also detected a reciprocal translocation between chromosomes 3 and 16 that has previously been detected in pig herds in France. The prevalence rate was 6.38% within the samples used in this study. All four rearrangements were found to have an association with hypoprolificacy. Further study and routine monitoring will be necessary to identify any further rearrangements that will allow breeders to prevent the propagation of reciprocal translocations from generation to generation within the Australian pig population.

B–A chromosome mediated 3:1 disjunction in heterozygous reciprocal translocations of maize

Genome ◽

10.1139/g92-110 ◽

1992 ◽

Vol 35 (5) ◽

pp. 714-718 ◽

Cited By ~ 1

Author(s):

B. Kindiger ◽

S. Hamann

Keyword(s):

Zea Mays ◽

Plant Breeding ◽

Zea Mays L ◽

Chromosome Mapping ◽

Root Tip ◽

Meiotic Segregation ◽

Basic Information ◽

Unusual Chromosome

In maize (Zea mays L.), meiotic segregation products of reciprocal translocations are well defined. The predictible meiotic behaviors and products generated by these interchanges allow them to be used as tools to gain basic information in cytogenetics, genetics, and plant breeding. In combining a classic reciprocal translocation with a single B–A chromosome from a tertiary trisomic B–A translocation stock, unique individuals with unusual chromosome karyotypes are generated. In cases where a B–A chromosome was present, the frequency of 3:1 disjunction within the ring of four was increased. In the case of T6–9(5454) + B–6Ld, cytological identification, via root-tip mitosis, was able to identify the specific tertiary trisomic products generated. These karyotypes are predictable and highly repeatable. Such karyotypes may have specific uses in chromosome mapping, chromosome dosage studies, or genetic or molecular investigations.Key words: reciprocal translocations, tertiary trisomes, interchange trisomes, B–A translocations, maize.

O-206 Meiotic segregation analysis for reciprocal translocation carriers: Assessment of factors influencing meiotic segregation patterns

Human Reproduction ◽

10.1093/humrep/deab128.017 ◽

2021 ◽

Vol 36 (Supplement_1) ◽

Author(s):

P Xie ◽

H Liang ◽

P Yangqin ◽

T Yueqiu ◽

L Ge

Keyword(s):

Risk Factors ◽

Protective Factor ◽

Snp Array ◽

Female Gender ◽

Meiotic Segregation ◽

Balanced Translocation ◽

Chromosome Arm ◽

Independent Risk Factors

Abstract Study question To analyze factors that could influence meiotic segregation patterns for reciprocal translocation carriers. Summary answer Involvement of an Acr-ch, female gender, and lower TAR1 (ratio of translocated segment 1 over the chromosome arm) were independent risk factors for alternate segregation. What is known already Reciprocal translocation is one of the more common structural rearrangements of chromosomes, which is associated with reproductive risks, such as infertility, spontaneous abortion and the delivery of babies with mental retardation or developmental delay. Extensive studies on meiotic segregation patterns of sperm, blastomere, and blastocysts have identified several factors that may influence the generation of unbalanced rearrangement of reciprocal translocations, including carrier’s gender and age, location of breakpoints, chromosome type, and the quadrivalent structure. However, some results are controversial. Study design, size, duration A retrospective study from October 2013 to December 2019, a total of 10846 blastocysts originating from 2871 oocyte retrieval cycles from 2253 couples with one of the partners carrying reciprocal were investigated. The mean maternal age was 29.97±4 years (20 –47years). Participants/materials, setting, methods Trophectoderm biopsy of blastocysts was performed on the 5th or 6th day of development. Whole genome amplification (WGA) was performed on all samples, and the WGA was analyzed with SNP array or NGS. Segregation patterns of quadrivalent in 10846 blastocysts were analyzed. Risk factors for segregation patterns were explored through analyzing carriers’ demographic and cytogenetic characteristics using multivariate generalized linear mixed models (GLMMs). Main results and the role of chance The percentage of normal/balanced blastocysts was 34.3%, and 2:2 segregation was observed in 90.0% of blastocysts. Increased TAR1 (the ratio of translocated segment 1 over the chromosome arm) was noted as an independent protective factor for the proportion of alternate segregation (P = 0.004). The female gender and involvement of an Acr-ch were found independent risk factors for alternate segregation (P < 0.001). A higher TAR1 reduced the risk of adjacent-1 segregation; longer translocated segment and female gender increased the risk of adjacent-2 segregation (P = 0.009 and P < 0.001, respectively). Female gender and involvement of an Acr-ch enhanced the risk of 3:1 segregation (P < 0.001 and P = 0.012, respectively). Limitations, reasons for caution About 1400 blastocysts were not diagnosed in the 2871 cycles, which might cause bias in the results. Secondly, the interchromosomal effect of reciprocal translocations was not analyzed in this study. Wider implications of the findings In conclusion, a carrier’s gender, involvement of an Acr-ch, and location of breakpoints may influence the segregation patterns. Besides, involvement of an Acr-ch, female gender, and lower TAR1 are independent risk factors for alternate segregation. These results may provide more appropriate genetic counseling for couples with balanced translocation. Trial registration number no

Genomic Analysis, Progress and Future Perspectives in Dairy Cattle Selection: A Review

Animals ◽

10.3390/ani11030599 ◽

2021 ◽

Vol 11 (3) ◽

pp. 599

Author(s):

Miguel A. Gutierrez-Reinoso ◽

Pedro M. Aponte ◽

Manuel Garcia-Herreros

Keyword(s):

Dairy Cattle ◽

Production Efficiency ◽

Association Studies ◽

Phenotypic Traits ◽

Progeny Testing ◽

Genome Wide Association Studies ◽

Genetic Progress ◽

Breeding Programs ◽

Increased Risk ◽

Genomics comprises a set of current and valuable technologies implemented as selection tools in dairy cattle commercial breeding programs. The intensive progeny testing for production and reproductive traits based on genomic breeding values (GEBVs) has been crucial to increasing dairy cattle productivity. The knowledge of key genes and haplotypes, including their regulation mechanisms, as markers for productivity traits, may improve the strategies on the present and future for dairy cattle selection. Genome-wide association studies (GWAS) such as quantitative trait loci (QTL), single nucleotide polymorphisms (SNPs), or single-step genomic best linear unbiased prediction (ssGBLUP) methods have already been included in global dairy programs for the estimation of marker-assisted selection-derived effects. The increase in genetic progress based on genomic predicting accuracy has also contributed to the understanding of genetic effects in dairy cattle offspring. However, the crossing within inbred-lines critically increased homozygosis with accumulated negative effects of inbreeding like a decline in reproductive performance. Thus, inaccurate-biased estimations based on empirical-conventional models of dairy production systems face an increased risk of providing suboptimal results derived from errors in the selection of candidates of high genetic merit-based just on low-heritability phenotypic traits. This extends the generation intervals and increases costs due to the significant reduction of genetic gains. The remarkable progress of genomic prediction increases the accurate selection of superior candidates. The scope of the present review is to summarize and discuss the advances and challenges of genomic tools for dairy cattle selection for optimizing breeding programs and controlling negative inbreeding depression effects on productivity and consequently, achieving economic-effective advances in food production efficiency. Particular attention is given to the potential genomic selection-derived results to facilitate precision management on modern dairy farms, including an overview of novel genome editing methodologies as perspectives toward the future.

The Neurobiology of Aggression

Neurobiology of Mental Illness ◽

10.1093/med/9780199934959.003.0085 ◽

2013 ◽

pp. 1103-1111

Author(s):

R. James ◽

R. Blair

Keyword(s):

Decision Making ◽

Motor Behavior ◽

Neural Systems ◽

Emotional Modulation ◽

Good Decision ◽

Norm Violations ◽

Instrumental Aggression ◽

Increased Risk ◽

The Individual ◽

This chapter considers the neurobiology of aggression both the neural systems mediating this behavior as well as how these systems can become perturbed such that the aggression is maladaptive to the individual. A distinction will be drawn between planned, goal directed instrumental aggression and threat/ frustration based reactive aggression. Instrumental aggression implicates the neural systems involved in instrumental motor behavior generally as well as emotional learning and decision making systems that allow the selection of one action over another. Conditions decreasing the responsiveness of neural systems allowing good decision making (amygdala, striatum, ventromedial prefrontal cortex) are associated with an increased risk for maladaptive instrumental aggression. Reactive aggression implicates sub cortical systems involved in the basic response to threat as well as cortical systems involved in emotional modulation and the response to norm violations.

Job control and risk of disability pension in the nationwide Danish Work Life Course Cohort

European Journal of Public Health ◽

10.1093/eurpub/ckz185.166 ◽

2019 ◽

Vol 29 (Supplement_4) ◽

Author(s):

A Svane-Petersen ◽

E Framke ◽

J K Sørensen ◽

R Rugulies ◽

I E H Madsen

Keyword(s):

Life Course ◽

Disability Pension ◽

Job Control ◽

Work Life ◽

Self Report ◽

Reporting Bias ◽

Job Exposure Matrix ◽

Transfer Payments ◽

Increased Risk ◽

Abstract Background A large number of studies have found job control to be consistently associated with an increased risk of disability pension. However, most previous studies have measured job control by self-report, introducing possible reporting bias inflating the risk estimates. Furthermore, previous studies have not accounted for the potential selection of individuals with pre-existing risk factors for disability pensioning into low control jobs. Methods We analyzed data from the nationwide register-based Danish Work Life Course Cohort (DAWCO; n = 960,562 with approx. 6 million person-years). We measured job control annually by a job exposure matrix, based on a scale of five self-reported items from The Danish Work Environment Cohort Study, and disability pension using registers on public transfer payments. To account for potential selection into occupations with lower levels of job control, we included numerous life course confounders, including parental socioeconomic position and psychiatric and somatic diagnoses. Results Employees in jobs with lower levels of job control had increased risk of disability pensioning. The association attenuated after adjustment for confounders but was not explained by selection into job groups with lower levels of job control (hazard ratio: 1.16 (95% CI: 1.03-1.31). Conclusions Our findings suggest that lower levels of job control are associated with an increased risk of disability pension, and that this association is explained by neither reporting bias nor a selection of individuals with an increased risk of disability pensioning into job groups with lower levels of job control. Key messages Lower levels of job control appear associated with an increased risk of disability pension independent of life course confounders. Further research is needed on preventive measures in occupations with low levels of job control.

PRODUCTION OF PLATELETS FOR TRANSFUSION - CURRENT METHODS AND PROBLEMS TO BE SOLVED

10.1055/s-0038-1643998 ◽

1987 ◽

Author(s):

M K Elias ◽

C Th Smit Sibinga

Keyword(s):

Whole Blood ◽

Platelet Rich Plasma ◽

Synthetic Medium ◽

Buffy Coat ◽

Cotton Wool ◽

Single Donor ◽

Increased Risk ◽

Multiple Donors ◽

And Storage ◽

Initially, whole blood or platelet rich plasma were used as sources of platelets. Nowadays the methods of platelet concentrates (pc) production adopted in Blood Banks include the traditional method of platelet preparation by differential centrifugation of units of whole blood, besides the much more sophisticated technique of extracorporeal collection of pc with improved immunological compatibility.Manually pc are produced by the platelet rich plasmamethod, the buffy coat method and multiple bag plateletapheresis. The machine collection of pc is done by plateletapheresis or platelet elutriation, with different degrees of automation.The standard manual method remains quantitatively the most important source of platelets.However, there are major concerns:-the need of multiple donors-The high contamination with white cells, predominantly lymphocytes-these pc are depleted from larger and more active platelets, as these are sedimented with the red cells-increased risk of bacterial contamination. To solve these problems there are some potention solutions:-use of single donor collectioon techniques-depletion of leucocytes by:a.elutriation of platelets from the buffy coatb.filtration of random pc through cotton wool columnc. prostacyclin inhibition of platelet aggregation followed by cellulose acetate filtrationd.filtration on elutriated platelets through cotton wool-use of a platelet synthetic medium void of glucose for resuspension and storage of pc to prevent lactate accumulation and pH fall-use of closed sterile harness systems to collect platelets by surge plateletapheresis, which allows extended storage of leucocyte depleted pc.Selection of the most appropriate platelet concentrate depends on the interrelationship of many factors:1) yield 2) function 3) viability after storage 4) afety 5) purity 6) potency 7) efficacy (recovery, survival and haemostatic capacity).

Whole genome paired-end sequencing elucidates functional and phenotypic consequences of balanced chromosomal rearrangement in patients with developmental disorders

Journal of Medical Genetics ◽

10.1136/jmedgenet-2018-105778 ◽

2019 ◽

Vol 56 (8) ◽

pp. 526-535 ◽

Cited By ~ 13

Author(s):

Caroline Schluth-Bolard ◽

Flavie Diguet ◽

Nicolas Chatron ◽

Pierre-Antoine Rollat-Farnier ◽

Claire Bardel ◽

...

Keyword(s):

Developmental Disorders ◽

Chromosomal Rearrangements ◽

Position Effect ◽

Data Interpretation ◽

Major Influence ◽

Whole Genome ◽

Dna Breaks ◽

Gene Expression Studies ◽

Non Homologous End Joining

BackgroundBalanced chromosomal rearrangements associated with abnormal phenotype are rare events, but may be challenging for genetic counselling, since molecular characterisation of breakpoints is not performed routinely. We used next-generation sequencing to characterise breakpoints of balanced chromosomal rearrangements at the molecular level in patients with intellectual disability and/or congenital anomalies.MethodsBreakpoints were characterised by a paired-end low depth whole genome sequencing (WGS) strategy and validated by Sanger sequencing. Expression study of disrupted and neighbouring genes was performed by RT-qPCR from blood or lymphoblastoid cell line RNA.ResultsAmong the 55 patients included (41 reciprocal translocations, 4 inversions, 2 insertions and 8 complex chromosomal rearrangements), we were able to detect 89% of chromosomal rearrangements (49/55). Molecular signatures at the breakpoints suggested that DNA breaks arose randomly and that there was no major influence of repeated elements. Non-homologous end-joining appeared as the main mechanism of repair (55% of rearrangements). A diagnosis could be established in 22/49 patients (44.8%), 15 by gene disruption (KANSL1, FOXP1, SPRED1, TLK2, MBD5, DMD, AUTS2, MEIS2, MEF2C, NRXN1, NFIX, SYNGAP1, GHR, ZMIZ1) and 7 by position effect (DLX5, MEF2C, BCL11B, SATB2, ZMIZ1). In addition, 16 new candidate genes were identified. Systematic gene expression studies further supported these results. We also showed the contribution of topologically associated domain maps to WGS data interpretation.ConclusionPaired-end WGS is a valid strategy and may be used for structural variation characterisation in a clinical setting.