Aneuploid Syndromes Research Articles

The genetic basis of aneuploidy tolerance in wild yeast.

Aneuploidy is highly detrimental during development yet common in cancers and pathogenic fungi - what gives rise to differences in aneuploidy tolerance remains unclear. We previously showed that wild isolates of Saccharomyces cerevisiae tolerate chromosome amplification while laboratory strains used as a model for aneuploid syndromes do not. Here, we mapped the genetic basis to Ssd1, an RNA-binding translational regulator that is functional in wild aneuploids but defective in laboratory strain W303. Loss of SSD1 recapitulates myriad aneuploidy signatures previously taken as eukaryotic responses. We show that aneuploidy tolerance is enabled via a role for Ssd1 in mitochondrial physiology, including binding and regulating nuclear-encoded mitochondrial mRNAs, coupled with a role in mitigating proteostasis stress. Recapitulating ssd1Δ defects with combinatorial drug treatment selectively blocked proliferation of wild-type aneuploids compared to euploids. Our work adds to elegant studies in the sensitized laboratory strain to present a mechanistic understanding of eukaryotic aneuploidy tolerance.

Generation of a novel isogenic trisomy panel in human embryonic stem cells via microcell-mediated chromosome transfer

Aneuploidy is the gain or loss of a chromosome. Down syndrome or trisomy (Ts) 21 is the most frequent live-born aneuploidy syndrome in humans and extensively studied using model mice. However, there is no available model mouse for other congenital Ts syndromes, possibly because of the lethality of Ts in vivo, resulting in the lack of studies to identify the responsible gene(s) for aneuploid syndromes. Although induced pluripotent stem cells derived from patients are useful to analyse aneuploidy syndromes, there are concerns about differences in the genetic background for comparative studies and clonal variations. Therefore, a model cell line panel with the same genetic background has been strongly desired for sophisticated comparative analyses. In this study, we established isogenic human embryonic stem (hES) cells of Ts8, Ts13, and Ts18 in addition to previously established Ts21 by transferring each single chromosome into parental hES cells via microcell-mediated chromosome transfer. Genes on each trisomic chromosome were globally overexpressed in each established cell line, and all Ts cell lines differentiated into all three embryonic germ layers. This cell line panel is expected to be a useful resource to elucidate molecular and epigenetic mechanisms of genetic imbalance and determine how aneuploidy is involved in various abnormal phenotypes including tumourigenesis and impaired neurogenesis.

From sperm to offspring: Assessing the heritable genetic consequences of paternal smoking and potential public health impacts.

Individuals who smoke generally do so with the knowledge of potential consequences to their own health. What is rarely considered are the effects of smoking on their future children. The objective of this work was to review the scientific literature on the effects of paternal smoking on sperm and assess the consequences to offspring. A literature search identified over 200 studies with relevant data in humans and animal models. The available data were reviewed to assess the weight of evidence that tobacco smoke is a human germ cell mutagen and estimate effect sizes. These results were used to model the potential increase in genetic disease burden in offspring caused by paternal smoking, with specific focus on aneuploid syndromes and intellectual disability, and the socioeconomic impacts of such an effect. The review revealed strong evidence that tobacco smoking is associated with impaired male fertility, and increases in DNA damage, aneuploidies, and mutations in sperm. Studies support that these effects are heritable and adversely impact the offspring. Our model estimates that, with even a modest 25% increase in sperm mutation frequency caused by smoke-exposure, for each generation across the global population there will be millions of smoking-induced de novo mutations transmitted from fathers to offspring. Furthermore, paternal smoking is estimated to contribute to 1.3 million extra cases of aneuploid pregnancies per generation. Thus, the available evidence makes a compelling case that tobacco smoke is a human germ cell mutagen with serious public health and socio-economic implications. Increased public education should be encouraged to promote abstinence from smoking, well in advance of reproduction, to minimize the transmission of harmful mutations to the next-generation.

Muscular and Skeletal Anomalies in Human Trisomy in an Evo‐Devo Context Using 3‐D Imaging and Anatomical Dissections, with Notes on Down Syndrome, Cyclopia and Medical Implications

We report the muscular and skeletal abnormalities observed in a very rare and precious 28-week human Trisomy 18 cyclopic fetus, and compare this individual with other humans with Trisomy 18 (Edwards syndrome) as well as with Trisomy 13 (Patau syndrome) and Trisomy 21 (Down syndrome), in the first detailed systematic musculoskeletal comparison of these three important syndromes. Our observations, comparisons, and literature review allow us to examine and discuss similarities and differences from the individual to the syndrome level; to delineate the muscle anomalies caused by aneuploid syndromes; to identify those muscular traits which are diagnostic for each one of the common aneuploid syndromes; to help chart the morphogenetic pathways of these diagnostic anomalies; and to assess the variability (descriptive and quantitative) shown by the diagnostic muscular defects in the different aneuploid syndromes. Importantly, this work comes at a time when there is a rising need for comparisons between vertebrate model organisms and humans in the relatively new and increasingly important field of evolutionary developmental biology, so the novel data presented and discussed here will contribute to a better and transformative understanding of both “normal” and abnormal development, evolution, birth defects, cyclopia and trisomies, and anatomical variations, and will thus have crucial medical implications.

The effects of varying chromosome arm dosage on maize plant morphogenesis.

Maize is an especially well-suited species for studying the effects of aneuploidy on plant development. We used B-A translocations and testers that were crossed seven times into inbred W22 to generate a dosage series for 14 chromosome arms. This is the first report of dosage effects on maize morphogenesis using inbred B-A stocks and inbred tester stocks. We compared plants containing one dose or three doses of each of the 14 chromosome arms with plants containing two doses for seven measured traits. These were leaf width, leaf length, plant height, ear height, internode length, ear node circumference, and tassel branch number. We observed the typical maize aneuploid syndrome wherein one dose was more widespread and more severe in its effects than three doses. All but two of the one-dose effects were negative, and all of the three-dose effects were negative. The occurrence of positive responses by hyperploid plants in our earlier B-A-A study and the absence of any positive responses among the hyperploids reported for the 14 simple B-A translocations tested for dosage effects in the present study and previously may reflect gene dosage interaction between the two chromosome arm segments present in the B-A-A translocations. The overall congruence of our results with those of previous studies suggests that the traits measured are quantitative traits controlled by multiple genes whose activities provide a balanced regulation that transcends individual inbred lines or diverse genetic backgrounds and that such genes may be especially abundant in chromosome arm 1L.

Gene expression analysis of induced pluripotent stem cells from aneuploid chromosomal syndromes

Gene expression analysis of induced pluripotent stem cells from aneuploid chromosomal syndromes

Gene balance hypothesis: Connecting issues of dosage sensitivity across biological disciplines

We summarize, in this review, the evidence that genomic balance influences gene expression, quantitative traits, dosage compensation, aneuploid syndromes, population dynamics of copy number variants and differential evolutionary fate of genes after partial or whole-genome duplication. Gene balance effects are hypothesized to result from stoichiometric differences among members of macromolecular complexes, the interactome, and signaling pathways. The implications of gene balance are discussed.

Modeling abnormal early development with induced pluripotent stem cells from aneuploid syndromes

Many human diseases share a developmental origin that manifests during childhood or maturity. Aneuploid syndromes are caused by supernumerary or reduced number of chromosomes and represent an extreme example of developmental disease, as they have devastating consequences before and after birth. Investigating how alterations in gene dosage drive these conditions is relevant because it might help treat some clinical aspects. It may also provide explanations as to how quantitative differences in gene expression determine phenotypic diversity and disease susceptibility among natural populations. Here, we aimed to produce induced pluripotent stem cell (iPSC) lines that can be used to improve our understanding of aneuploid syndromes. We have generated iPSCs from monosomy X [Turner syndrome (TS)], trisomy 8 (Warkany syndrome 2), trisomy 13 (Patau syndrome) and partial trisomy 11;22 (Emanuel syndrome), using either skin fibroblasts from affected individuals or amniocytes from antenatal diagnostic tests. These cell lines stably maintain the karyotype of the donors and behave like embryonic stem cells in all tested assays. TS iPSCs were used for further studies including global gene expression analysis and tissue-specific directed differentiation. Multiple clones displayed lower levels of the pseudoautosomal genes ASMTL and PPP2R3B than the controls. Moreover, they could be transformed into neural-like, hepatocyte-like and heart-like cells, but displayed insufficient up-regulation of the pseudoautosomal placental gene CSF2RA during embryoid body formation. These data support that abnormal organogenesis and early lethality in TS are not caused by a tissue-specific differentiation blockade, but rather involves other abnormalities including impaired placentation.

Phenotypic Consequences of Aneuploidy inArabidopsis thaliana

Aneuploid cells are characterized by incomplete chromosome sets. The resulting imbalance in gene dosage has phenotypic consequences that are specific to each karyotype. Even in the case of Down syndrome, the most viable and studied form of human aneuploidy, the mechanisms underlying the connected phenotypes remain mostly unclear. Because of their tolerance to aneuploidy, plants provide a powerful system for a genome-wide investigation of aneuploid syndromes, an approach that is not feasible in animal systems. Indeed, in many plant species, populations of aneuploid individuals can be easily obtained from triploid individuals. We phenotyped a population of Arabidopsis thaliana aneuploid individuals containing 25 different karyotypes. Even in this highly heterogeneous population, we demonstrate that certain traits are strongly associated with the dosage of specific chromosome types and that chromosomal effects can be additive. Further, we identified subtle developmental phenotypes expressed in the diploid progeny of aneuploid parent(s) but not in euploid controls from diploid lineages. These results indicate long-term phenotypic consequences of aneuploidy that can persist after chromosomal balance has been restored. We verified the diploid nature of these individuals by whole-genome sequencing and discuss the possibility that trans-generational phenotypic effects stem from epigenetic modifications passed from aneuploid parents to their diploid progeny.

JAK2 V617F-positive essential thrombocythemia in a patient with Klinefelter syndrome: a case report

Klinefelter syndrome (KS) is the most commonly diagnosed X chromosome aneuploid syndrome among males. The association between hematologic malignancies such as non-Hodgkin lymphoma and leukemia and KS has been established recently on the basis of numerous case reports and a large cohort study. The risk of chronic myeloproliferative disease (MPD) as a hematologic malignancy in KS, however, has not been evaluated to date. Moreover, to our knowledge, there is only one case report that observed MPD in a patient with KS. Even though the Janus kinase 2 (JAK2) mutation was considered the primary cause in the pathogenesis of MPD, the mutation status was not described in that report. We found JAK2 V617F mutation–positive essential thromobocythemia (ET) in a patient with KS. To the best of our knowledge, this case represents the first case report of JAK2 V617F mutation in a patient with KS. Furthermore, we also suggest the hypothesis that X chromosome aneuploidy as a “pre-JAK2” cytogenetic change may be associated with the development of clonal hematopoiesis and carcinogenesis, because of the finding of higher oncogenic potential of extra X chromosome. In this study, we present the first report of JAK2 V617F-positive ET in a patient with KS, as well as a review of the relevant literature.

The gene balance hypothesis: implications for gene regulation, quantitative traits and evolution

The gene balance hypothesis states that the stoichiometry of members of multisubunit complexes affects the function of the whole because of the kinetics and mode of assembly. Gene regulatory mechanisms also would be governed by these principles. Here, we review the impact of this concept with regard to the effects on the genetics of quantitative traits, the fate of duplication of genes following polyploidization events or segmental duplication, the basis of aneuploid syndromes, the constraints on cis and trans variation in gene regulation and the potential involvement in hybrid incompatibilities.

Reflections on studies of gene expression in aneuploids

Aneuploidy involves changes in chromosomal copy number compared with normal euploid genotypes. Studies of gene expression in aneuploids in a variety of species have claimed many different types of responses. Studies of individual genes suggest that there are both structural gene dosage effects and compensation in aneuploids, and that subtle trans-acting effects across the genome are quite prevalent. A discussion is presented concerning the normalization procedures for studying gene expression in aneuploids. A careful documentation of the modulations of gene expression in aneuploids should provide insight into the nature of cancerous cells and the basis of aneuploid syndromes.

Dominance and gene dosage balance in health and disease: why levels matter!

The classical concept of genetic dominance is a simplification of a more quantitative reality. This is clearly exemplified by aneuploid syndromes, of which the best known case is trisomy 21. Moreover, there is an increasing number of clinical conditions due to reduced dosage (haploinsufficiency) of genes encoding transcription factors and other proteins involved in signal transduction and macromolecular complexes. In such genetic diseases, a high degree of phenotypic variability is observed, which calls for an explanation. The sources of dominance are heterogeneous and difficult to cover in a brief review. Here, we will focus on the molecular bases of dosage-sensitive syndromes from the perspective of the gene dosage balance hypothesis, which postulates that stoichiometric alterations of macromolecular complexes or cellular networks are responsible for dominant phenotypes, because of the existing non-linear relationships between the genotypic and phenotypic values with which they are associated.

Effects of aneuploidy on genome structure, expression, and interphase organization in Arabidopsis thaliana.

Aneuploidy refers to losses and/or gains of individual chromosomes from the normal chromosome set. The resulting gene dosage imbalance has a noticeable affect on the phenotype, as illustrated by aneuploid syndromes, including Down syndrome in humans, and by human solid tumor cells, which are highly aneuploid. Although the phenotypic manifestations of aneuploidy are usually apparent, information about the underlying alterations in structure, expression, and interphase organization of unbalanced chromosome sets is still sparse. Plants generally tolerate aneuploidy better than animals, and, through colchicine treatment and breeding strategies, it is possible to obtain inbred sibling plants with different numbers of chromosomes. This possibility, combined with the genetic and genomics tools available for Arabidopsis thaliana, provides a powerful means to assess systematically the molecular and cytological consequences of aberrant numbers of specific chromosomes. Here, we report on the generation of Arabidopsis plants in which chromosome 5 is present in triplicate. We compare the global transcript profiles of normal diploids and chromosome 5 trisomics, and assess genome integrity using array comparative genome hybridization. We use live cell imaging to determine the interphase 3D arrangement of transgene-encoded fluorescent tags on chromosome 5 in trisomic and triploid plants. The results indicate that trisomy 5 disrupts gene expression throughout the genome and supports the production and/or retention of truncated copies of chromosome 5. Although trisomy 5 does not grossly distort the interphase arrangement of fluorescent-tagged sites on chromosome 5, it may somewhat enhance associations between transgene alleles. Our analysis reveals the complex genomic changes that can occur in aneuploids and underscores the importance of using multiple experimental approaches to investigate how chromosome numerical changes condition abnormal phenotypes and progressive genome instability.

Comprehensive molecular cytogenetic analysis of the human blastocyst stage

The high frequency of chromosomal abnormalities observed in human gametes and embryos is unlike that seen in other mammalian species and is of great clinical significance, leading to high rates of pregnancy loss, and live-born children with aneuploid syndromes. Although much is known concerning the aneuploidy rates of oocytes, cleavage stage embryos and fetuses during pregnancy, the chromosomal status of blastocysts has been relatively little investigated. A total of 158 good quality blastocysts were examined using micromanipulation, whole genome amplification and comparative genomic hybridization. From the obtained data, it was evident that the aneuploidy rate (38.8%) is significantly lower for blastocysts than for embryos at earlier stages (51%). However, in many cases, chromosome errors, including monosomy, imbalance affecting the larger chromosomes and complex aneuploidy persisted to this final stage of preimplantation development. This study represents the first attempt to gain a detailed insight into the extent and type of chromosome errors seen at the blastocyst stage, using a comprehensive molecular cytogenetic method. Our data suggest that the blastocyst stage does not represent an absolute selective barrier, and that the majority of aneuploid embryos are lost at the time of implantation or shortly thereafter.

Genetic basis for dosage sensitivity in Arabidopsis thaliana.

Aneuploidy, the relative excess or deficiency of specific chromosome types, results in gene dosage imbalance. Plants can produce viable and fertile aneuploid individuals, while most animal aneuploids are inviable or developmentally abnormal. The swarms of aneuploid progeny produced by Arabidopsis triploids constitute an excellent model to investigate the mechanisms governing dosage sensitivity and aneuploid syndromes. Indeed, genotype alters the frequency of aneuploid types within these swarms. Recombinant inbred lines that were derived from a triploid hybrid segregated into diploid and tetraploid individuals. In these recombinant inbred lines, a single locus, which we call SENSITIVE TO DOSAGE IMBALANCE (SDI), exhibited segregation distortion in the tetraploid subpopulation only. Recent progress in quantitative genotyping now allows molecular karyotyping and genetic analysis of aneuploid populations. In this study, we investigated the causes of the ploidy-specific distortion at SDI. Allele frequency was distorted in the aneuploid swarms produced by the triploid hybrid. We developed a simple quantitative measure for aneuploidy lethality and using this measure demonstrated that distortion was greatest in the aneuploids facing the strongest viability selection. When triploids were crossed to euploids, the progeny, which lack severe aneuploids, exhibited no distortion at SDI. Genetic characterization of SDI in the aneuploid swarm identified a mechanism governing aneuploid survival, perhaps by buffering the effects of dosage imbalance. As such, SDI could increase the likelihood of retaining genomic rearrangements such as segmental duplications. Additionally, in species where triploids are fertile, aneuploid survival would facilitate gene flow between diploid and tetraploid populations via a triploid bridge and prevent polyploid speciation. Our results demonstrate that positional cloning of loci affecting traits in populations containing ploidy and chromosome number variants is now feasible using quantitative genotyping approaches.

Role of Cytogenetics and Molecular Cytogenetics in the Diagnosis of Genetic Imbalances

Five decades ago, Tijo and Levan (1956) first recognized the correct chromosome number in man to be 46. Shortly thereafter, several chromosome aneuploid syndromes were identified. In the early 1970s, various chromosomal-banding techniques were developed that allowed the recognition of individual chromosomes and deletions and duplications as etiologies for numerous chromosome syndromes. Slightly more than 10 years ago, fluorescence in situ hybridization (FISH) procedures, using fluorescent-labeled DNA sequences were developed and clinical use of this technique allowed for the identification of cryptic chromosome abnormalities associated with microdeletions and microduplications. The use of subtelomere region-specific FISH probes further led to the identification of deletions and other unbalanced rearrangements in individuals with mental retardation with an apparently normal karyotype. More recently, microarray comparative genomic hybridization was developed, and the technique has recently become incorporated into the clinical cytogenetics laboratory for the identification of submicrosopic deletions and duplications that are associated with developmental delay. The intent of this article is to review the cytogenetic and molecular cytogenetic techniques currently available for the diagnosis of individuals with neurologic disease and genetic imbalances that result in neurologic disturbances and to summarize the most efficient and appropriate use of these techniques in clinical practice.

Genetic Basis for Dosage Sensitivity in A. thaliana

Aneuploidy, the relative excess or deficiency of specific chromosome types, results in gene dosage imbalance. Plants can produce viable and fertile aneuploid individuals, while most animal aneuploids are inviable or developmentally abnormal. The swarms of aneuploid progeny produced by Arabidopsis triploids constitute an excellent model to investigate the mechanisms governing dosage sensitivity and aneuploid syndromes. Indeed, genotype alters the frequency of aneuploid types within these swarms. Recombinant inbred lines that were derived from a triploid hybrid segregated into diploid and tetraploid individuals. In these recombinant inbred lines, a single locus, which we call SENSITIVE TO DOSAGE IMBALANCE (SDI), exhibited segregation distortion in the tetraploid subpopulation only. Recent progress in quantitative genotyping now allows molecular karyotyping and genetic analysis of aneuploid populations. In this study, we investigated the causes of the ploidy-specific distortion at SDI. Allele frequency was distorted in the aneuploid swarms produced by the triploid hybrid. We developed a simple quantitative measure for aneuploidy lethality and using this measure demonstrated that distortion was greatest in the aneuploids facing the strongest viability selection. When triploids were crossed to euploids, the progeny, which lack severe aneuploids, exhibited no distortion at SDI. Genetic characterization of SDI in the aneuploid swarm identified a mechanism governing aneuploid survival, perhaps by buffering the effects of dosage imbalance. As such, SDI could increase the likelihood of retaining genomic rearrangements such as segmental duplications. Additionally, in species where triploids are fertile, aneuploid survival would facilitate gene flow between diploid and tetraploid populations via a triploid bridge and prevent polyploid speciation. Our results demonstrate that positional cloning of loci affecting traits in populations containing ploidy and chromosome number variants is now feasible using quantitative genotyping approaches.

Developmental impact on trans-acting dosage effects in maize aneuploids.

The reduction in vigor or viability caused by aneuploidy may be the result of trans-acting dosage effects that reduce gene expression. To investigate the molecular and developmental parameters of aneuploid syndromes, the expression of sucrose synthase1 (sus1) and shrunken1 (sh1) was studied in 2-week-old plants. Expression of sus1 and sh1 was first investigated in euploids, where it was found that both transcripts varied in a diurnal fashion. Chromosome arm number can be varied in a series from one to three doses in maize. In the 14 aneuploid dosage series examined, most caused changes in sus1 and sh1 RNA levels that were both gene and tissue specific. Results were compared to previous data from embryo and endosperm tissue. More dosage effects were detected and the magnitude of RNA level modulation was greater in 2-week-old plant tissue. These findings suggest that the molecular consequences of aneuploidy might become more severe as development progresses.

New genes? Possibly, MABy...

Congenital malformations account for a very substantial proportion of pediatric morbidity in the human population. Cytogenetic deletions have a live birth incidence of approximately 1 in 7000, and such deletions have often been utilized in human genetics for the mapping of genes involved in rare mendelian traits. To date, however, a relatively small proportion of the genetic defects responsible for congenital malformations have been identified. Somewhat surprisingly, no systematic approach has yet been taken to correlate cytogenetic deletions with phenotype in humans. Here, Brewer et al.1 Brewer C. et al. A chromosomal deletion map of human malformations. Am. J. Hum. Genet. 1998; 63: 1153-1159 Abstract Full Text Full Text PDF PubMed Scopus (132) Google Scholar report the first attempt to do so. They have analyzed the distribution of 289 whole or partial deletion bands in 47 common congenital malformations covering a wide spectrum of developmental processes, and thereby identified 199 statistically significant malformation-associated bands (MABs). The average number of significant MABs detected per malformation was 4.3. Only 6% of the MABs identified contain previously identified mendelian loci associated with the malformation, and a further 6% overlap with known aneuploid syndrome regions. Thus, assuming that haploinsufficiency for one or more genes in the deleted regions plays a causative role in the associated malformations (already proven in the cases of several well known deletion syndromes), this analysis should provide rich hunting grounds for the identification of human developmental genes.