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Seminars in Cell & Developmental Biology Sep 2015Meiosis is one of the defining events in gametogenesis. Male and female germ cells both undergo one round of meiotic cell division during their development in order to... (Review)
Review
Meiosis is one of the defining events in gametogenesis. Male and female germ cells both undergo one round of meiotic cell division during their development in order to reduce the ploidy of the gametes, and thereby maintain the ploidy of the species after fertilisation. However, there are some aspects of meiosis in the female germline, such as the prolonged arrest in dictyate, that appear to predispose oocytes to missegregate their chromosomes and transmit aneuploidies to the next generation. These maternally-derived aneuploidies are particularly problematic in humans where they are major contributors to miscarriage, age-related infertility, and the high incidence of Down's syndrome in human conceptions. This review will discuss how events that occur in foetal oocyte development and during the oocytes' prolonged dictyate arrest can influence meiotic chromosome segregation and the incidence of aneuploidy in adult oocytes.
Topics: Animals; Chromosome Segregation; Crossing Over, Genetic; Female; Humans; Meiosis; Oocytes; Oogenesis; Recombination, Genetic; Trisomy
PubMed: 26454098
DOI: 10.1016/j.semcdb.2015.10.005 -
Fertility and Sterility Mar 2014To determine the relationship between the age of the female partner and the prevalence and nature of human embryonic aneuploidy. (Review)
Review
The nature of aneuploidy with increasing age of the female partner: a review of 15,169 consecutive trophectoderm biopsies evaluated with comprehensive chromosomal screening.
OBJECTIVE
To determine the relationship between the age of the female partner and the prevalence and nature of human embryonic aneuploidy.
DESIGN
Retrospective.
SETTING
Academic.
PATIENT(S)
Trophectoderm biopsies.
INTERVENTION(S)
Comprehensive chromosomal screening performed on patients with blastocysts available for biopsy.
MAIN OUTCOME MEASURE(S)
Evaluation of the impact of maternal age on the prevalence of aneuploidy, the probability of having no euploid embryos within a cohort, the complexity of aneuploidy as gauged by the number of aneuploid chromosomes, and the trisomy/monosomy ratio.
RESULT(S)
Aneuploidy increased predictably after 26 years of age. A slightly increased prevalence was noted at younger ages, with >40% aneuploidy in women 23 years and under. The no euploid embryo rate was lowest (2% to 6%) in women aged 26 to 37, was 33% at age 42, and was 53% at age 44. Among the biopsies with aneuploidy, 64% involved a single chromosome, 20% two chromosomes, and 16% three chromosomes, with the proportion of more complex aneuploidy increasing with age. Finally, the trisomy/monosomy ratio approximated 1 and increased minimally with age.
CONCLUSION(S)
The lowest risk for embryonic aneuploidy was between ages 26 and 30. Both younger and older age groups had higher rates of aneuploidy and an increased risk for more complex aneuploidies. The overall risk did not measurably change after age 43. Trisomies and monosomies are equally prevalent.
Topics: Adult; Aneuploidy; Biopsy; Blastocyst; Cohort Studies; Ectoderm; Female; Genetic Testing; Humans; Maternal Age; Middle Aged; Retrospective Studies; Young Adult
PubMed: 24355045
DOI: 10.1016/j.fertnstert.2013.11.004 -
Science (New York, N.Y.) Aug 2023Most cancers exhibit aneuploidy, but its functional significance in tumor development is controversial. Here, we describe ReDACT (Restoring Disomy in Aneuploid cells...
Most cancers exhibit aneuploidy, but its functional significance in tumor development is controversial. Here, we describe ReDACT (Restoring Disomy in Aneuploid cells using CRISPR Targeting), a set of chromosome engineering tools that allow us to eliminate specific aneuploidies from cancer genomes. Using ReDACT, we created a panel of isogenic cells that have or lack common aneuploidies, and we demonstrate that trisomy of chromosome 1q is required for malignant growth in cancers harboring this alteration. Mechanistically, gaining chromosome 1q increases the expression of and suppresses p53 signaling, and we show that mutations are mutually exclusive with 1q aneuploidy in human cancers. Thus, tumor cells can be dependent on specific aneuploidies, raising the possibility that these "aneuploidy addictions" could be targeted as a therapeutic strategy.
Topics: Humans; Cell Cycle Proteins; Mutation; Neoplasms; Oncogenes; Proto-Oncogene Proteins; Trisomy; Gene Editing; Tumor Suppressor Protein p53; Carcinogenesis
PubMed: 37410869
DOI: 10.1126/science.adg4521 -
Cell Apr 2023Aneuploidy, the presence of chromosome gains or losses, is a hallmark of cancer. Here, we describe KaryoCreate (karyotype CRISPR-engineered aneuploidy technology), a...
Aneuploidy, the presence of chromosome gains or losses, is a hallmark of cancer. Here, we describe KaryoCreate (karyotype CRISPR-engineered aneuploidy technology), a system that enables the generation of chromosome-specific aneuploidies by co-expression of an sgRNA targeting chromosome-specific CENPA-binding ɑ-satellite repeats together with dCas9 fused to mutant KNL1. We design unique and highly specific sgRNAs for 19 of the 24 chromosomes. Expression of these constructs leads to missegregation and induction of gains or losses of the targeted chromosome in cellular progeny, with an average efficiency of 8% for gains and 12% for losses (up to 20%) validated across 10 chromosomes. Using KaryoCreate in colon epithelial cells, we show that chromosome 18q loss, frequent in gastrointestinal cancers, promotes resistance to TGF-β, likely due to synergistic hemizygous deletion of multiple genes. Altogether, we describe an innovative technology to create and study chromosome missegregation and aneuploidy in the context of cancer and beyond.
Topics: Humans; Aneuploidy; Centromere; Chromosome Deletion; Neoplasms; Clustered Regularly Interspaced Short Palindromic Repeats; Genetic Techniques
PubMed: 37075754
DOI: 10.1016/j.cell.2023.03.029 -
Genes Jan 2021Advances in embryo and reproductive genetics have influenced clinical approaches to overcome infertility. Since the 1990s, many attempts have been made to decipher the...
Advances in embryo and reproductive genetics have influenced clinical approaches to overcome infertility. Since the 1990s, many attempts have been made to decipher the genetic causes of infertility and to understand the role of chromosome aneuploidies in embryo potential. At the embryo stage, preimplantation genetic testing for chromosomal abnormalities and genetic disorders has offered many couples the opportunity to have healthy offspring. Recently, the application of new technologies has resulted in more comprehensive and accurate diagnoses of chromosomal abnormalities and genetic conditions to improve clinical outcome. In this Special Issue, we include a collection of reviews and original articles covering many aspects of embryo diagnosis, genome editing, and maternal-embryo cross-communication during the implantation process.
Topics: Aneuploidy; Animals; Disease Models, Animal; Embryo Implantation; Embryo, Mammalian; Embryonic Development; Genetic Testing; Humans; Infertility; Mice; Preimplantation Diagnosis
PubMed: 33477974
DOI: 10.3390/genes12010118 -
International Journal of Molecular... Mar 2022Human female fertility and reproductive lifespan decrease significantly with age, resulting in an extended post-reproductive period. The central dogma in human female... (Review)
Review
Human female fertility and reproductive lifespan decrease significantly with age, resulting in an extended post-reproductive period. The central dogma in human female reproduction contains two important aspects. One is the pool of oocytes in the human ovary (the ovarian reserve; approximately 10 at birth), which diminishes throughout life until menopause around the age of 50 (approximately 10 oocytes) in women. The second is the quality of oocytes, including the correctness of meiotic divisions, among other factors. Notably, the increased rate of sub- and infertility, aneuploidy, miscarriages, and birth defects are associated with advanced maternal age, especially in women above 35 years of age. This postponement is also relevant for human evolution; decades ago, the female aging-related fertility drop was not as important as it is today because women were having their children at a younger age. Spindle assembly is crucial for chromosome segregation during each cell division and oocyte maturation, making it an important event for euploidy. Consequently, aberrations in this segregation process, especially during the first meiotic division in human eggs, can lead to implantation failure or spontaneous abortion. Today, human reproductive medicine is also facing a high prevalence of aneuploidy, even in young females. However, the shift in the reproductive phase of humans and the strong increase in errors make the problem much more dramatic at later stages of the female reproductive phase. Aneuploidy in human eggs could be the result of the non-disjunction of entire chromosomes or sister chromatids during oocyte meiosis, but partial or segmental aneuploidies are also relevant. In this review, we intend to describe the relevance of the spindle apparatus during oocyte maturation for proper chromosome segregation in the context of maternal aging and the female reproductive lifespan.
Topics: Aging; Aneuploidy; Chromosome Segregation; Female; Humans; Meiosis; Oocytes; Pregnancy; Spindle Apparatus
PubMed: 35270022
DOI: 10.3390/ijms23052880 -
F1000Research 2019Prenatal testing in recent years has been moving toward non-invasive methods to determine the fetal risk for genetic disorders without incurring the risk of miscarriage.... (Review)
Review
Prenatal testing in recent years has been moving toward non-invasive methods to determine the fetal risk for genetic disorders without incurring the risk of miscarriage. Rapid progress of modern high-throughput molecular technologies along with the discovery of cell-free fetal DNA in maternal plasma led to novel screening methods for fetal chromosomal aneuploidies. Such tests are referred to as non-invasive prenatal tests (NIPTs), non-invasive prenatal screening, or prenatal cell-free DNA screening. Owing to many advantages, the adoption of NIPT in routine clinical practice was very rapid and global. As an example, NIPT has recently become a standard screening procedure for all pregnant women in the Netherlands. On the other hand, invasive sampling procedures remain important, especially for their diagnostic value in the confirmation of NIPT-positive findings and the detection of Mendelian disorders. In this review, we focus on current trends in the field of NIPT and discuss their benefits, drawbacks, and consequences in regard to routine diagnostics.
Topics: Aneuploidy; Cell-Free Nucleic Acids; Female; Fetus; Genetic Testing; Humans; Pregnancy; Prenatal Diagnosis
PubMed: 31214330
DOI: 10.12688/f1000research.16837.1 -
Cell Aug 2022Human cleavage-stage embryos frequently acquire chromosomal aneuploidies during mitosis due to unknown mechanisms. Here, we show that S phase at the 1-cell stage shows...
Human cleavage-stage embryos frequently acquire chromosomal aneuploidies during mitosis due to unknown mechanisms. Here, we show that S phase at the 1-cell stage shows replication fork stalling, low fork speed, and DNA synthesis extending into G2 phase. DNA damage foci consistent with collapsed replication forks, DSBs, and incomplete replication form in G2 in an ATR- and MRE11-dependent manner, followed by spontaneous chromosome breakage and segmental aneuploidies. Entry into mitosis with incomplete replication results in chromosome breakage, whole and segmental chromosome errors, micronucleation, chromosome fragmentation, and poor embryo quality. Sites of spontaneous chromosome breakage are concordant with sites of DNA synthesis in G2 phase, locating to gene-poor regions with long neural genes, which are transcriptionally silent at this stage of development. Thus, DNA replication stress in mammalian preimplantation embryos predisposes gene-poor regions to fragility, and in particular in the human embryo, to the formation of aneuploidies, impairing developmental potential.
Topics: Aneuploidy; Animals; Chromosome Breakage; Chromosome Segregation; DNA; DNA Replication; Embryonic Development; Humans; Mammals
PubMed: 35858625
DOI: 10.1016/j.cell.2022.06.028 -
Developmental Cell Sep 2021Aneuploidy is a ubiquitous feature of human tumors, but the acquisition of aneuploidy typically antagonizes cellular fitness. To investigate how aneuploidy could...
Aneuploidy is a ubiquitous feature of human tumors, but the acquisition of aneuploidy typically antagonizes cellular fitness. To investigate how aneuploidy could contribute to tumor growth, we triggered periods of chromosomal instability (CIN) in human cells and then exposed them to different culture environments. We discovered that transient CIN reproducibly accelerates the acquisition of resistance to anti-cancer therapies. Single-cell sequencing revealed that these resistant populations develop recurrent aneuploidies, and independently deriving one chromosome-loss event that was frequently observed in paclitaxel-resistant cells was sufficient to decrease paclitaxel sensitivity. Finally, we demonstrated that intrinsic levels of CIN correlate with poor responses to numerous therapies in human tumors. Our results show that, although CIN generally decreases cancer cell fitness, it also provides phenotypic plasticity to cancer cells that can allow them to adapt to diverse stressful environments. Moreover, our findings suggest that aneuploidy may function as an under-explored cause of therapy failure.
Topics: Aneuploidy; Cell Line, Tumor; Chromosomal Instability; Drug Resistance; Environment; Humans; Neoplasms; Treatment Outcome
PubMed: 34352222
DOI: 10.1016/j.devcel.2021.07.009 -
Ultrasound in Obstetrics & Gynecology :... Sep 2017To review clinical validation or implementation studies of maternal blood cell-free (cf) DNA analysis and define the performance of screening for fetal trisomies 21, 18... (Meta-Analysis)
Meta-Analysis Review
OBJECTIVES
To review clinical validation or implementation studies of maternal blood cell-free (cf) DNA analysis and define the performance of screening for fetal trisomies 21, 18 and 13 and sex chromosome aneuploidies (SCA).
METHODS
Searches of PubMed, EMBASE and The Cochrane Library were performed to identify all peer-reviewed articles on cfDNA testing in screening for aneuploidies between January 2011, when the first such study was published, and 31 December 2016. The inclusion criteria were peer-reviewed study reporting on clinical validation or implementation of maternal cfDNA testing in screening for aneuploidies, in which data on pregnancy outcome were provided for more than 85% of the study population. We excluded case-control studies, proof-of-principle articles and studies in which the laboratory scientists carrying out the tests were aware of fetal karyotype or pregnancy outcome. Pooled detection rates (DRs) and false-positive rates (FPRs) were calculated using bivariate random-effects regression models.
RESULTS
In total, 35 relevant studies were identified and these were used for the meta-analysis on the performance of cfDNA testing in screening for aneuploidies. These studies reported cfDNA results in relation to fetal karyotype from invasive testing or clinical outcome. In the combined total of 1963 cases of trisomy 21 and 223 932 non-trisomy 21 singleton pregnancies, the weighted pooled DR and FPR were 99.7% (95% CI, 99.1-99.9%) and 0.04% (95% CI, 0.02-0.07%), respectively. In a total of 563 cases of trisomy 18 and 222 013 non-trisomy 18 singleton pregnancies, the weighted pooled DR and FPR were 97.9% (95% CI, 94.9-99.1%) and 0.04% (95% CI, 0.03-0.07%), respectively. In a total of 119 cases of trisomy 13 and 212 883 non-trisomy 13 singleton pregnancies, the weighted pooled DR and FPR were 99.0% (95% CI, 65.8-100%) and 0.04% (95% CI, 0.02-0.07%), respectively. In a total of 36 cases of monosomy X and 7676 unaffected singleton pregnancies, the weighted pooled DR and FPR were 95.8% (95% CI, 70.3-99.5%) and 0.14% (95% CI, 0.05-0.38%), respectively. In a combined total of 17 cases of SCA other than monosomy X and 5400 unaffected singleton pregnancies, the weighted pooled DR and FPR were 100% (95% CI, 83.6-100%) and 0.004% (95% CI, 0.0-0.08%), respectively. For twin pregnancies, in a total of 24 cases of trisomy 21 and 1111 non-trisomy 21 cases, the DR was 100% (95% CI, 95.2-100%) and FPR was 0.0% (95% CI, 0.0-0.003%), respectively.
CONCLUSIONS
Screening by analysis of cfDNA in maternal blood in singleton pregnancies could detect > 99% of fetuses with trisomy 21, 98% of trisomy 18 and 99% of trisomy 13 at a combined FPR of 0.13%. The number of reported cases of SCA is too small for accurate assessment of performance of screening. In twin pregnancies, performance of screening for trisomy 21 is encouraging but the number of cases reported is small. Copyright © 2017 ISUOG. Published by John Wiley & Sons Ltd.
Topics: Aneuploidy; Cell-Free Nucleic Acids; Down Syndrome; Female; Humans; Maternal Serum Screening Tests; Pregnancy
PubMed: 28397325
DOI: 10.1002/uog.17484