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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 -
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 -
Trends in Genetics : TIG Dec 2023Chromosome copy number imbalances, otherwise known as aneuploidies, are a common but poorly understood feature of cancer. Here, we describe recent advances in both... (Review)
Review
Chromosome copy number imbalances, otherwise known as aneuploidies, are a common but poorly understood feature of cancer. Here, we describe recent advances in both detecting and manipulating aneuploidies that have greatly advanced our ability to study their role in tumorigenesis. In particular, new clustered regularly interspaced short palindromic repeats (CRISPR)-based techniques have been developed that allow the creation of isogenic cell lines with specific chromosomal changes, thereby facilitating experiments in genetically controlled backgrounds to uncover the consequences of aneuploidy. These approaches provide increasing evidence that aneuploidy is a key driver of cancer development and enable the identification of multiple dosage-sensitive genes encoded on aneuploid chromosomes. Consequently, measuring aneuploidy may inform clinical prognosis, while treatment strategies that target aneuploidy could represent a novel method to counter malignant growth.
Topics: Humans; Aneuploidy; Neoplasms
PubMed: 37778926
DOI: 10.1016/j.tig.2023.09.002 -
Developmental Cell Feb 2024A balanced gene complement is crucial for proper cell function. Aneuploidy, the condition of having an imbalanced chromosome set, alters the stoichiometry of gene copy... (Review)
Review
A balanced gene complement is crucial for proper cell function. Aneuploidy, the condition of having an imbalanced chromosome set, alters the stoichiometry of gene copy numbers and protein complexes and has dramatic consequences at the cellular and organismal levels. In humans, aneuploidy is associated with different pathological conditions including cancer, microcephaly, mental retardation, miscarriages, and aging. Over the last century, Drosophila has provided a valuable system for studying the consequences of systemic aneuploidies. More recently, it has contributed to the identification and molecular dissection of aneuploidy-induced cellular behaviors and their impact at the tissue and organismal levels. In this perspective, we review this active field of research, first by comparing knowledge from yeast, mouse, and human cells, then by highlighting the contributions of Drosophila. The aim of these discussions was to further our understanding of the functional interplay between aneuploidy, cell physiology, and tissue homeostasis in human development and disease.
Topics: Humans; Animals; Mice; Drosophila; Aneuploidy; Gene Dosage; Cell Physiological Phenomena; Saccharomyces cerevisiae
PubMed: 38320484
DOI: 10.1016/j.devcel.2023.12.009 -
Mammalian Genome : Official Journal of... Mar 2022An organism or cell carrying a number of chromosomes that is not a multiple of the haploid count is in a state of aneuploidy. This condition results in significant... (Review)
Review
An organism or cell carrying a number of chromosomes that is not a multiple of the haploid count is in a state of aneuploidy. This condition results in significant changes in the level of expression of genes that are gained or lost from the aneuploid chromosome(s) and most cases in humans are not compatible with life. However, a few aneuploidies can lead to live births, typically associated with deleterious phenotypes. We do not understand why phenotypes arise from aneuploid syndromes in humans. Animal models have the potential to provide great insight, but less than a handful of mouse models of aneuploidy have been made, and no ideal system exists in which to study the effects of aneuploidy per se versus those of raised gene dosage. Here, we give an overview of human aneuploid syndromes, the effects on physiology of having an altered number of chromosomes and we present the currently available mouse models of aneuploidy, focusing on models of trisomy 21 (which causes Down syndrome) because this is the most common, and therefore, the most studied autosomal aneuploidy. Finally, we discuss the potential role of carrying an extra chromosome on aneuploid phenotypes, independent of changes in gene dosage, and methods by which this could be investigated further.
Topics: Aneuploidy; Animals; Chromosome Disorders; Chromosomes; Disease Models, Animal; Down Syndrome; Mice; Trisomy
PubMed: 34719726
DOI: 10.1007/s00335-021-09930-z -
Obstetrics and Gynecology Jul 2016Prenatal aneuploidy screening has changed dramatically in recent years with increases in the types of chromosomal abnormalities reliably identified and in the proportion... (Review)
Review
Prenatal aneuploidy screening has changed dramatically in recent years with increases in the types of chromosomal abnormalities reliably identified and in the proportion of aneuploid fetuses detected. Initially, screening was available only for trisomies 21 and 18 and was offered only to low-risk pregnancies. Improved detection with the quadruple- and first-trimester multiple marker screens led to the option of aneuploidy screening for women 35 years of age and older. Cell-free DNA tests now screen for common autosomal trisomies and sex chromosome aneuploidies. Cell-free DNA screening is particularly effective in older women because of higher positive predictive values and lower false-positive rates. Integrated first- and second-trimester multiple marker tests provide specific risks for trisomies 21, 18, and possibly 13, and may detect an even wider range of aneuploidies. Given current precision in risk assessment, based on maternal age and preferences for screening or diagnostic tests, counseling has become more complex. This review addresses the benefits and limitations of available aneuploidy screening methods along with counseling considerations when offering them.
Topics: Aneuploidy; Chromosome Disorders; Female; Humans; Pregnancy; Prenatal Diagnosis; Risk Assessment; Risk Factors
PubMed: 27275786
DOI: 10.1097/AOG.0000000000001385 -
Environmental Health : a Global Access... Oct 2016Aneuploidy, defined as structural and numerical aberrations of chromosomes, continues to draw attention as an informative effect biomarker for carcinogens and male... (Review)
Review
Aneuploidy, defined as structural and numerical aberrations of chromosomes, continues to draw attention as an informative effect biomarker for carcinogens and male reproductive toxicants. It has been well documented that aneuploidy is a hallmark of cancer. Aneuploidies in oocytes and spermatozoa contribute to infertility, pregnancy loss and a number of congenital abnormalities, and sperm aneuploidy is associated with testicular cancer. It is striking that several carcinogens induce aneuploidy in somatic cells, and also adversely affect the chromosome compliment of germ cells. In this paper we review 1) the contributions of aneuploidy to cancer, infertility, and developmental abnormalities; 2) techniques for assessing aneuploidy in precancerous and malignant lesions and in sperm; and 3) the utility of aneuploidy as a biomarker for integrated chemical assessments of carcinogenicity, and reproductive and developmental toxicity.
Topics: Aneuploidy; Animals; Biomarkers; Carcinogens; Humans; Male; Neoplasms; Reproduction; Spermatozoa
PubMed: 27729050
DOI: 10.1186/s12940-016-0180-6 -
Genes Oct 2019Aneuploidy, a deviation from a balanced genome by either gain or loss of chromosomes, is generally associated with impaired fitness and developmental defects in... (Review)
Review
Aneuploidy, a deviation from a balanced genome by either gain or loss of chromosomes, is generally associated with impaired fitness and developmental defects in eukaryotic organisms. While the general physiological impact of aneuploidy remains largely elusive, many phenotypes associated with aneuploidy link to a common theme of stress adaptation. Here, we review previously identified mechanisms and observations related to aneuploidy, focusing on the highly diverse eukaryotes, fungi. Fungi, which have conquered virtually all environments, including several hostile ecological niches, exhibit widespread aneuploidy and employ it as an adaptive strategy under severe stress. Gambling with the balance between genome plasticity and stability has its cost and in fact, most aneuploidies have fitness defects. How can this fitness defect be reconciled with the prevalence of aneuploidy in fungi? It is likely that the fitness cost of the extra chromosomes is outweighed by the advantage they confer under life-threatening stresses. In fact, once the selective pressures are withdrawn, aneuploidy is often lost and replaced by less drastic mutations that possibly incur a lower fitness cost. We discuss representative examples across hostile environments, including medically and industrially relevant cases, to highlight potential adaptive mechanisms in aneuploid yeast.
Topics: Adaptation, Physiological; Aneuploidy; Ecosystem; Fungi; Genome, Fungal; Polymorphism, Genetic
PubMed: 31658789
DOI: 10.3390/genes10100787 -
Proceedings of the National Academy of... May 2023Aneuploidy syndromes impact multiple organ systems but understanding of tissue-specific aneuploidy effects remains limited-especially for the comparison between...
Aneuploidy syndromes impact multiple organ systems but understanding of tissue-specific aneuploidy effects remains limited-especially for the comparison between peripheral tissues and relatively inaccessible tissues like brain. Here, we address this gap in knowledge by studying the transcriptomic effects of chromosome X, Y, and 21 aneuploidies in lymphoblastoid cell lines, fibroblasts and iPSC-derived neuronal cells (LCLs, FCL, and iNs, respectively). We root our analyses in sex chromosome aneuploidies, which offer a uniquely wide karyotype range for dosage effect analysis. We first harness a large LCL RNA-seq dataset from 197 individuals with one of 6 sex chromosome dosages (SCDs: XX, XXX, XY, XXY, XYY, and XXYY) to i) validate theoretical models of SCD sensitivity and ii) define an expanded set of 41 genes that show obligate dosage sensitivity to SCD and are all in (i.e., reside on the X or Y chromosome). We then use multiple complementary analyses to show that effects of SCD in LCLs are preserved in both FCLs (n = 32) and iNs (n = 24), whereas effects (i.e., those on autosomal gene expression) are mostly not preserved. Analysis of additional datasets confirms that the greater cross-cell type reproducibility of vs. effects is also seen in trisomy 21 cell lines. These findings i) expand our understanding of X, Y, and 21 chromosome dosage effects on human gene expression and ii) suggest that LCLs may provide a good model system for understanding effects of aneuploidy in harder-to-access cell types.
Topics: Humans; Reproducibility of Results; Aneuploidy; Down Syndrome; Sex Chromosomes; Gene Expression
PubMed: 37192167
DOI: 10.1073/pnas.2218478120 -
F&S Science May 2023Segmental aneuploidies (SAs) are structural imbalances, namely, gains or losses, involving a chromosomal segment. Most preimplantation genetic testing platforms can... (Review)
Review
Segmental aneuploidies (SAs) are structural imbalances, namely, gains or losses, involving a chromosomal segment. Most preimplantation genetic testing platforms can detect segmental imbalances greater than 5-10 Mb, either full or mosaic; however, questions remain about clinical significance. An in-depth review was performed to determine the accuracy, frequency, and types of SAs detected in preimplantation embryos. A comprehensive search of the literature revealed an incidence of approximately 8.15% in preimplantation embryos, compared with a prevalence of 3.55% in prenatal diagnosis samples. Several studies have used rebiopsy analysis to validate the accuracy and reproducibility of such findings in blastocyst-stage embryos. A comparison of these studies yielded a mean confirmation rate of SAs slightly higher than 30%. This result could be attributed to their mitotic origin as well as to the technical limitations of preimplantation genetic testing. In addition, the few available studies in which embryos with a segmental finding were transferred in utero are analyzed to discuss the reproductive competence of such embryos. Except for 1 study, all outcomes were described for segmental embryos in a mosaic state. As a result, there is still insufficient evidence to provide accurate information about the effect of segmental imbalances on embryonic reproductive competence and to determine gestational and newborn risks.
Topics: Female; Humans; Infant, Newborn; Pregnancy; Aneuploidy; Blastocyst; Genetic Testing; Preimplantation Diagnosis; Reproducibility of Results
PubMed: 36948460
DOI: 10.1016/j.xfss.2023.03.004