DOCSLIB.ORG

Dicentric X Isochromosomes in Man R

Total Page：16

File Type：pdf, Size：1020Kb

Download full-text PDF Read full-text
Dicentric X Isochromosomes in Man R J Med Genet: first published as 10.1136/jmg.13.6.496 on 1 December 1976. Downloaded from Journal of Medical Genetics (1976). 13, 496-500. Dicentric X isochromosomes in man R. T. HOWELL, S. H. ROBERTS, and R. J. BEARD From the Child Health Laboratories, Department of Child Health, University Hospital of Wales, Heath Park, Cardiff Summary. Four cases of Turner's syndrome are presented in which an appa- rent X isochromosome i(Xq) has been found to possess two regions of centromeric heterochromatin. It is suggested that these chromosomes were isodicentric struc- tures capable offunctioning as monocentric elements as a result ofthe inactivation of one centromere. The prevalence of mosaicism is believed to be a consequence of the dicentric nature ofthese chromosomes, and it is considered possible that a high proportion of X isochromosomes are structurally dicentric. Banding patterns showed that the exchange site involved in the formation ofthe dicentric chromosome was different in at least three ofthe cases. The possibility that certain X isochromosomes Methods were dicentric was first postulated by de la Chapelle Chromosome preparations were made from peripheral et al (1966). In 2 of 5 cases investigated they noted blood lymphocyte cultures ofall 4 patients using standard that the isochromosome had an apparently elon- procedures. Preparations from skin fibroblast cultures an gated centromeric region. In 3 cases they found (Cases 1 and 2) and ovarian tissue culture (Case 3)copyright. abnormal anaphase configurations such as bridges, were also investigated. Slides were either stained with pseudochiasmata, and lagging chromosomes, indica- aceto-orcein in order to examine chromosome morpho- tive of the presence of a dicentric chromosome. logy and to obtain counts, Giemsa-banded using a tryp- When de la Chapelle and Stenstrand (1974) re- sin digestion technique modified from Seabright (1971), 2 or C-banded by a modification of the barium hydroxide investigated the isochromosomes in which the method described by Sumner et al (1971). elongated centromeric region had been found, they showed, by C-banding, the presence of 2 regions of centromeric heterochromatin, while in 2 other cases Clinical features http://jmg.bmj.com/ they showed the isochromosomes to be monocentric. The 4 patients all presented certain features typical of Yanagisawa and Yokoyama (1975) and Cohen et al Turner's syndrome, which are summarized in Table I. (1975) have reported apparently dicentric X iso- chromosomes with 2 C-bands, while Disteche et al (1972), Therman et al (1974), and de la Chapelle Cytogenetic studies and Stenstrand (1974) have described very long (a) Chromosome counts chromosomes consisting of 2 almost complete X Chromosome counts from orcein stained preparations chromosomes including 2 regions of centromeric of the 4 cases are shown in Table II. Mosaicism for the on September 25, 2021 by guest. Protected heterochromatin. abnormal chromosome was found in Cases 2, 3, and 4. In 4 to for In Case 2, the majority of cells in the blood cultures had females referred us chromosome studies a 45,X constitution, while the skin cultures consisted because they possessed features of Turner's syn- mostly of 46,X,dic(X)(pl 1) cells. In Case 3, roughly drome, an abnormal large metacentric chromosome equal proportions of 45,X and 46,X,dic(X)(pl 1) cells was found. In all of these cases, C-banding were observed in the blood cultures, but only 46,X,dic showed 2 distinct regions of centromeric hetero- (X)(pl 1) cells were found in the ovarian cultures. In chromatin, and trypsin-Giemsa banding suggested Case 4, complements of 47,X,dic(X)(pl1),dic(X)(p11) that the abnormal chromosome was structurally were found, in addition to 45,X and 46,X,dic(X)(pl 1). isodicentric, dic(X)(qter-*pll::p1 1->qter). (b) Structure of abnormal chromosomes Orcein-stained preparations. In all 4 cases, the Received 29 January 1976. presence of an X isochromosome was indicated in meta- 496 J Med Genet: first published as 10.1136/jmg.13.6.496 on 1 December 1976. Downloaded from Dicentric X isochromosomes in man 497 TABLE I SOME RELEVANT CLINICAL FEATURES OF THE FOUR CASES Age at Secondary Serum LH Case Reason for Investi- Height Weight Intelli- Webbing Sexual Amenor- and FSH Other No. Investigation gation (cm) (kg) gence of Neck Characters rhoea Gonads Levels Features (y) 1 Hypogonadism 17 140 60 Normnal Absent Absent Primary Not LH 30IU/1 Polydac- investi- FSH 80IU/1 tyly; gated horse- shoe kidney 2 Short stature; 12 132 35 Normal Present (Pre- (Pre- Not FSH 19.4 Pigmented increased pubertal) pubertal) investi- IU/1 naevi; carrying angle gated emotional 3 Short stature; 17 131 41 Normal Absent Absent Primary Streak LH 50IU/1 lack of ovaries FSH 801U/1 secondary vestigial sexual uterus characters 4 Primary 18 142 58 Normal Absent Slight Primary Streak Not investi- amenorrhoea breast ovaries gated develop- vestigial ment uterus after oestrogen therapy TABLE II CHROMOSOME COUNTS FROM THE 4 CASES Number of Mitoses Case No. Tissue < 45, random 45,X 46,X,dic(X)(pl 1) 47,X,dic(X)(pl 1), Total loss dic(X)(pll) copyright. [Blood 4 0 76 0 80} 92 Skin 2 0 10 0 12 Blood 3 66 11 0 801 2 ~112 lSkin 3 4 25 0 32) Blood 3 40 57 0 100) 3 ~~~~~~~~~~~~~~~~~~~128 tOvary 2 0 26 0 28) Blood 11 17 72 5 105 http://jmg.bmj.com/ phases having 46 chromosomes, because there appeared G-banded preparations. Examples of the abnor- to be 7 A group and 15 C group chromosomes. In mal X chromosome from the 4 cases after trypsin- Cases 1, 2, and 3, the abnormal X did not have the ap- Giemsa treatment are shown in Fig. 2, and diagrams of pearance of a dicentric chromosome. In Case 4, how- their banding pattems in Fig. 3. In Cases 1 and 2, the ever, it was recognizable in 36 out of 72 cells by its banding pattem was found to be asymmetrical about the dicentric morphology (Fig. 1A), or the presence of a centromeric constriction, thus showing that the abnormal secondary constriction (Fig. 1B). chromosomes were not classical isochromosomes. The shorter of the two arms was a normal long arm (Xq), on September 25, 2021 by guest. Protected C-banded preparations. Three C-banded abnor- while the longer consisted of a normal Xq with addi- mal X chromosomes from each of the cases are shown in tional material proximal to the centromere. This Fig. 2. Two regions of centromeric heterochromatin material included a prominent darkly staining band are clearly indicated in all of the examples. In Cases 1, which was interpreted as representing an interstitial 2, and 3, one C-band was at the centromeric constriction centromeric region because it corresponded in position and one was interstitial. The interstitial C-band was to the interstitial C-band, and was the same distance often separated into a pair of darkly staining spots, one from the landmark band Xq21 (Paris Conference, 1971; on each chromatid. In Case 4, the abnormal chromo- Fig. 3b) on the abnormal arm as was the normal centro- some sometimes had 2 centromeric constrictions, each mere from the landmark band Xq21 on the normal arm. with a C-band (Fig. 2 s and t). Fig. 2u shows 2 abnor- In Case 2, a narrow dark band was sometimes visible mal X chromosomes from a cell with 47 chromosomes. midway between the two centromeric bands (Fig. 2 j and The distance between the C-bands was consistent k). This band is believed to be equivalent to the fine within a case, but varied between cases. sub-band occasionally shown by our banding technique J Med Genet: first published as 10.1136/jmg.13.6.496 on 1 December 1976. Downloaded from 498 Howell, Roberts, and Beard arm of an X chromosome. Chromosomes of this kind may be referred to as isodicentric (Darlington and Wylie, 1953), and their most probable mode of origin is by an isochromatid break of the short arm of an X chromosome close to the centromere, with sister union of the chromatids proximal to the centromere. Their formation in other ways such 'W as translocation between two X chromosomes, or meiotic crossover within a paracentric inversion loop cannot, however, be discounted. It is prob- able that the other abnormal X chromosomes with 2 C-bands already reported (Disttche et al, 1972; 'z de la Chapelle and Stenstrand, 1974; Therman et al, 1974; Yanagisawa and Yokoyama, 1975; Cohen et al, 1975) were similarly isodicentric, but formed by breakage and sister union at different sites. A In the present cases, banding showed that dif- ferent break points were involved in the formation of the abnormal chromosomes. These are shown ~ ~~~~~~~~~~~~~~~~.@ in Fig. 3. In G-banded preparations of Case 2, the ,'; '... narrow dark band sometimes visible midway be- .. *...::::i .. tween the 2 centromeric bands (Fig. 2j and k; Fig. 3) indicated that the break point was further from the |~~~~~~~~~~~~~~~~~~~~~~~...., .'.... centromere than in the other cases where this band was absent. In Case 3, C-banding showed that the & break point was closer to the centromere than in the other cases. The length of the intercentric region .ww copyright. in Cases 1 and 4 was similar, indicating that, in these t 2 cases, the break points were in a similar position. B,M It is generally accepted that most dicentric chro- mosomes are unstable for two reasons. Firstly, the ,~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~ rearrangement of chromosome material and subse- quent loss of the acentric fragment results in an imbalance which must be compatible with survival chromosome to (In the 4 FIG.
Load more

Recommended publications
  • Pathogenetics. an Introductory Review
    The Egyptian Journal of Medical Human Genetics (2016) 17, 1–23 HOSTED BY Ain Shams University The Egyptian Journal of Medical Human Genetics www.ejmhg.eg.net www.sciencedirect.com REVIEW Pathogenetics. An introductory review Mohammad Saad Zaghloul Salem 1 Faculty of Medicine, Ain-Shams University, Cairo, Egypt Received 1 July 2015; accepted 7 July 2015 Available online 27 July 2015 KEYWORDS Abstract Pathogenetics refers to studying the different aspects of initiation/development/progres Pathogenetics; sion and pathogenesis of genetic defects. It comprises the study of mutagens or factors capable Mutagens; of affecting the structural integrity of the genetic material leading to mutational changes that, in Mutation; the majority of cases, result in harmful effects due to the resulting disturbances of functions of Pathogenetic mechanisms; mutated components of the genome. The study of mutagens depicts different types of mutagenic Anti-mutation mechanisms factors, their nature, their classification according to their effects on the genetic material and their different modes of action. The study of mutation involves different types of mutations classified according to various parameters, e.g. magnitude, severity, target of mutational event as well as its nature, which can be classified, in turn, according to whether it is spontaneous or induced, static or dynamic, somatic or germinal mutation etc. Finally, pathogenetics comprises studying and delin- eating the different and innumerable pathophysiological alterations and pathogenetic mechanisms that are directly and indirectly involved in, and leading to, the development of genetic disorders, coupled with a parallel study of various anti-mutation mechanisms that play critical roles in minimizing the drastic effects of mutational events on the genetic material and in effective protection against the development of these diseases.
    [Show full text]
  • But Broke Down More Frequently Than Those Stabilised by Natural Degree
    HYBRIDITY SELECTION IN CAMPANULA C. D. DARLINGTON and L. F. LA COUR John Innes Horticultural Institution, Bayfordbury, Hert ford, Herts. Received25.Viii.49 CONTENTS I. Introduction . .217 2. Building Newlypes . .218 3. Ring-Formation and the Hybridity Optimum . .219 4. Analytic Crosses . .222 5. Unbalanced Types . .224 6. Fertility and the Breeding System . .226 7. New Interchanges . .227 8. The Stable Telocentric . .228 9. Telocentrics and Interchanges . 230 10. A Monosomic Plant . 231 II. New Telocentrics and Isochromosomes . .233 12. The Origin of lsochromosomes . .237 13. Pollen-Grain Inheritance . .239 14. The Future of lsochromosomes . .240 IS. The Evolution of Chromosome Numbers . 241 16. Conclusions . .242 17. Summary . 243 18. References . .246 Appendix: Compound Constrictions by L. F. La Cour 243 I. INTRODUCTION INour first account of ring formation in Campanula persicfo1ia (Gairdner and Darlington, 1931)weshowed how mechanical rules could be applied for the construction of plants with large rings at meiosis by the combination of interchanged chromosomes found in wild races. In our second account (Darlington and Gairdner, 1937)weshowed how large rings were maintained by the elimination of homozygotes but broke down more frequently than those stabilised by natural selection in Oenothera, owing to the occurrence of crossing-over between interstitial segments in opposite complexes. We also showed the high degree of structural hybridity in regard to inversions which was correlated with interchange hybridity in a cross-fertilising species. Our present object is to make use of the interchanges and other break- ages as markers in determining how hybridity is maintained by selection in the species, in other words how the breeding system works.
    [Show full text]
  • Epigenetic Control of Mammalian Centromere Protein Binding: Does DNA Methylation Have a Role?
    Journal of Cell Science 109, 2199-2206 (1996) 2199 Printed in Great Britain © The Company of Biologists Limited 1996 JCS3386 Epigenetic control of mammalian centromere protein binding: does DNA methylation have a role? Arthur R. Mitchell*, Peter Jeppesen, Linda Nicol†, Harris Morrison and David Kipling MRC Human Genetics Unit, Western General Hospital, Crewe Road, Edinburgh EH4 2XU, UK *Author for correspondence (internet [email protected]) †Present address: MRC Reproductive Biology Unit, Edinburgh, UK SUMMARY Chromosome 1 of the inbred mouse strain DBA/2 has a block of minor satellite DNA sequences on chromosome 1. polymorphism associated with the minor satellite DNA at The binding of the CENP-E protein does not appear to be its centromere. The more terminal block of satellite DNA affected by demethylation of the minor satellite sequences. sequences on this chromosome acts as the centromere as We present a model to explain these observations. This shown by the binding of CREST ACA serum, anti-CENP- model may also indicate the mechanism by which the B and anti-CENP-E polyclonal sera. Demethylation of the CENP-B protein recognises specific sites within the arrays minor satellite DNA sequences accomplished by growing of minor satellite DNA on mouse chromosomes. cells in the presence of the drug 5-aza-2′-deoxycytidine results in a redistribution of the CENP-B protein. This protein now binds to an enlarged area on the more terminal Key words: Centromere satellite DNA, Demethylation, Centromere block and in addition it now binds to the more internal antibody INTRODUCTION A common feature of many mammalian pericentromeric domains is that they contain families of repetitive DNA The centromere of mammalian chromosomes is recognised at sequences (Singer, 1982).
    [Show full text]
  • Chromosome 18
    Chromosome 18 Description Humans normally have 46 chromosomes in each cell, divided into 23 pairs. Two copies of chromosome 18, one copy inherited from each parent, form one of the pairs. Chromosome 18 spans about 78 million DNA building blocks (base pairs) and represents approximately 2.5 percent of the total DNA in cells. Identifying genes on each chromosome is an active area of genetic research. Because researchers use different approaches to predict the number of genes on each chromosome, the estimated number of genes varies. Chromosome 18 likely contains 200 to 300 genes that provide instructions for making proteins. These proteins perform a variety of different roles in the body. Health Conditions Related to Chromosomal Changes The following chromosomal conditions are associated with changes in the structure or number of copies of chromosome 18. Distal 18q deletion syndrome Distal 18q deletion syndrome occurs when a piece of the long (q) arm of chromosome 18 is missing. The term "distal" means that the missing piece (deletion) occurs near one end of the chromosome arm. The signs and symptoms of distal 18q deletion syndrome include delayed development and learning disabilities, short stature, weak muscle tone ( hypotonia), foot abnormalities, and a wide variety of other features. The deletion that causes distal 18q deletion syndrome can occur anywhere between a region called 18q21 and the end of the chromosome. The size of the deletion varies among affected individuals. The signs and symptoms of distal 18q deletion syndrome are thought to be related to the loss of multiple genes from this part of the long arm of chromosome 18.
    [Show full text]
  • Chromosomal Rearrangements Genetic Variation Alterationsalterations Inin Chromosomechromosome Structurestructure
    chromosomal rearrangements Genetic variation AlterationsAlterations inin ChromosomeChromosome StructureStructure ! There are two primary ways in which the structure of chromosomes can be altered – 1. The total amount of genetic information in the chromosome can change " Decrease: Deficiencies/Deletions " Increase: Duplications & Insertions – 2. The genetic material may remain the same, but is rearranged " Inversions " Translocations PeCtoerp Jy.r Riguhsts e©llT, ihGee nMetciGcsr: aCwop-Hyriilgl hCt o©m Ppeaanriseosn, IEndcu.c Pateiromn,i sInsico.,n p ruebqliusihriendg faosr B reenpjarmodinu cCtuiomnm oirn gdsisplay 3 Chromosomal aberations/ rearrangements Chromosomal abberations/ rearrangements deletion Duplication Inversion translocation. Chromosomal abberations/ rearrangements • For chromosomal rearrangement to occur, there has to be two or more double-stranded breaks in the chromosomes of a cell. • DSBs are potentially lethal, unless they are repaired by repair enzymes. Chromosomal rearrangements • If the two ends of the same break are rejoined, the original DNA order is restored. • If the ends of two different breaks are joined together, results in a chromosomal rearrangement. • The only chromosomal rearrangements that survive meiosis are those that produce DNA molecules that have one centromere and two telomeres. • acentric chromosome: Without a centromere • Do not get dragged to either pole at anaphase of mitosis or meiosis Chromosomal • Are not incorporated into either progeny nucleus. rearrangements Therefore acentric chromosomes are not inherited. Chromosomal Re-arragements • Dicentric chromosome: With two centromere • pulled simultaneously to opposite poles at anaphase, forming an anaphase bridge. • Generally do not get incorporated into either progeny cell. • A chromosome lacking a telomere, cannot replicate properly Chromosomal • The larger the segment Re-arragements that is lost or duplicated, the more chance, that it will cause phenotypic abnormalities.
    [Show full text]
  • Abstracts from the 51St European Society of Human Genetics Conference: Electronic Posters
    European Journal of Human Genetics (2019) 27:870–1041 https://doi.org/10.1038/s41431-019-0408-3 MEETING ABSTRACTS Abstracts from the 51st European Society of Human Genetics Conference: Electronic Posters © European Society of Human Genetics 2019 June 16–19, 2018, Fiera Milano Congressi, Milan Italy Sponsorship: Publication of this supplement was sponsored by the European Society of Human Genetics. All content was reviewed and approved by the ESHG Scientific Programme Committee, which held full responsibility for the abstract selections. Disclosure Information: In order to help readers form their own judgments of potential bias in published abstracts, authors are asked to declare any competing financial interests. Contributions of up to EUR 10 000.- (Ten thousand Euros, or equivalent value in kind) per year per company are considered "Modest". Contributions above EUR 10 000.- per year are considered "Significant". 1234567890();,: 1234567890();,: E-P01 Reproductive Genetics/Prenatal Genetics then compared this data to de novo cases where research based PO studies were completed (N=57) in NY. E-P01.01 Results: MFSIQ (66.4) for familial deletions was Parent of origin in familial 22q11.2 deletions impacts full statistically lower (p = .01) than for de novo deletions scale intelligence quotient scores (N=399, MFSIQ=76.2). MFSIQ for children with mater- nally inherited deletions (63.7) was statistically lower D. E. McGinn1,2, M. Unolt3,4, T. B. Crowley1, B. S. Emanuel1,5, (p = .03) than for paternally inherited deletions (72.0). As E. H. Zackai1,5, E. Moss1, B. Morrow6, B. Nowakowska7,J. compared with the NY cohort where the MFSIQ for Vermeesch8, A.
    [Show full text]
  • The Cytogenetics of Hematologic Neoplasms 1 5
    The Cytogenetics of Hematologic Neoplasms 1 5 Aurelia Meloni-Ehrig that errors during cell division were the basis for neoplastic Introduction growth was most likely the determining factor that inspired early researchers to take a better look at the genetics of the The knowledge that cancer is a malignant form of uncon- cell itself. Thus, the need to have cell preparations good trolled growth has existed for over a century. Several biologi- enough to be able to understand the mechanism of cell cal, chemical, and physical agents have been implicated in division became of critical importance. cancer causation. However, the mechanisms responsible for About 50 years after Boveri’s chromosome theory, the this uninhibited proliferation, following the initial insult(s), fi rst manuscripts on the chromosome makeup in normal are still object of intense investigation. human cells and in genetic disorders started to appear, fol- The fi rst documented studies of cancer were performed lowed by those describing chromosome changes in neoplas- over a century ago on domestic animals. At that time, the tic cells. A milestone of this investigation occurred in 1960 lack of both theoretical and technological knowledge with the publication of the fi rst article by Nowell and impaired the formulations of conclusions about cancer, other Hungerford on the association of chronic myelogenous leu- than the visible presence of new growth, thus the term neo- kemia with a small size chromosome, known today as the plasm (from the Greek neo = new and plasma = growth). In Philadelphia (Ph) chromosome, to honor the city where it the early 1900s, the fundamental role of chromosomes in was discovered (see also Chap.
    [Show full text]
  • Nonrandom Distribution of Interhomolog Recombination Events Induced by Breakage of a Dicentric Chromosome in Saccharomyces Cerevisiae
    INVESTIGATION Nonrandom Distribution of Interhomolog Recombination Events Induced by Breakage of a Dicentric Chromosome in Saccharomyces cerevisiae Wei Song,* Malgorzata Gawel,* Margaret Dominska,* Patricia W. Greenwell,* Einat Hazkani-Covo,* Kerry Bloom,† and Thomas D. Petes*,1 *Department of Molecular Genetics and Microbiology, Duke University Medical Center, Durham, North Carolina 27710, and †Department of Biology, University of North Carolina, Chapel Hill, North Carolina 27599 ABSTRACT Dicentric chromosomes undergo breakage in mitosis, resulting in chromosome deletions, duplications, and translocations. In this study, we map chromosome break sites of dicentrics in Saccharomyces cerevisiae by a mitotic recombination assay. The assay uses a diploid strain in which one homolog has a conditional centromere in addition to a wild-type centromere, and the other homolog has only the wild-type centromere; the conditional centromere is inactive when cells are grown in galactose and is activated when the cells are switched to glucose. In addition, the two homologs are distinguishable by multiple single-nucleotide polymorphisms (SNPs). Under conditions in which the conditional centromere is activated, the functionally dicentric chromosome undergoes double-stranded DNA breaks (DSBs) that can be repaired by mitotic recombination with the homolog. Such recombination events often lead to loss of heterozygosity (LOH) of SNPs that are centromere distal to the crossover. Using a PCR-based assay, we determined the position of LOH in multiple independent recombination events to a resolution of 4 kb. This analysis shows that dicentric chromosomes have re- combination breakpoints that are broadly distributed between the two centromeres, although there is a clustering of breakpoints within 10 kb of the conditional centromere.
    [Show full text]
  • Molecular‑Cytogenetic Study of De Novo Mosaic Karyotype 45,X/46,X,I(Yq)/46,X,Idic(Yq) in an Azoospermic Male: Case Report and Literature Review
    MOLECULAR MEDICINE REPORTS 16: 3433-3438, 2017 Molecular‑cytogenetic study of de novo mosaic karyotype 45,X/46,X,i(Yq)/46,X,idic(Yq) in an azoospermic male: Case report and literature review YUTING JIANG1, RUIXUE WANG1, LINLIN LI1, LINTAO XUE2, SHU DENG1 and RUIZHI LIU1 1Center for Reproductive Medicine, Center for Prenatal Diagnosis First Hospital, Jilin University, Changchun, Jilin 130021; 2Reproductive Medical and Genetic Center, People's Hospital of Guangxi Zhuang Autonomous Region, Nanning, Guangxi 520021, P.R. China Received August 11, 2016; Accepted May 9, 2017 DOI: 10.3892/mmr.2017.6981 Abstract. The present study describes a 36-year-old male carries one centromere and duplication of the short or long with the 45,X/46,X,i(Yq)/46,X,idic(Yq) karyotype, who arm, and the idic(Y) consists of two identical arms that are suffered from azoospermia attributed to maturation arrest of positioned as mirror images to one another, with an axis of the primary spermatocyte. To the best of our knowledge, this symmetry lying between two centromeres (3). The two types rare karyotype has not yet been reported in the literature. The of chromosome are often unstable during cell division. results of detailed molecular-cytogenetic studies of isodicen- Patients with iso(Y) or idic(Y) may develop mosaic tric (idic)Y chromosomes and isochromosome (iso)Y, which karyotypes with variable phenotypes, such as spermatogenic are identified in patient with complex mosaic karyotypes, are failure, sexual infantilism, hypospadias, ambiguous genitalia, presented. The presence of mosaicism of the three cell lines and a normal male phenotype (4).
    [Show full text]
  • Expandable and Reversible Copy Number Amplification Drives Rapid Adaptation to Antifungal Drugs Robert T Todd, Anna Selmecki*
    RESEARCH ADVANCE Expandable and reversible copy number amplification drives rapid adaptation to antifungal drugs Robert T Todd, Anna Selmecki* Department of Microbiology and Immunology, University of Minnesota Medical School, Minneapolis, Minnesota, United States Abstract Previously, we identified long repeat sequences that are frequently associated with genome rearrangements, including copy number variation (CNV), in many diverse isolates of the human fungal pathogen Candida albicans (Todd et al., 2019). Here, we describe the rapid acquisition of novel, high copy number CNVs during adaptation to azole antifungal drugs. Single- cell karyotype analysis indicates that these CNVs appear to arise via a dicentric chromosome intermediate and breakage-fusion-bridge cycles that are repaired using multiple distinct long inverted repeat sequences. Subsequent removal of the antifungal drug can lead to a dramatic loss of the CNV and reversion to the progenitor genotype and drug susceptibility phenotype. These findings support a novel mechanism for the rapid acquisition of antifungal drug resistance and provide genomic evidence for the heterogeneity frequently observed in clinical settings. Introduction The evolution of antifungal drug resistance is an urgent threat to human health worldwide, particu- larly for hospitalized and immune-compromised individuals (Perea and Patterson, 2002; Pfal- ler, 2012; Vandeputte et al., 2012). Only three classes of antifungal drugs are currently available *For correspondence: [email protected] and resistance to all three classes occurred for the first time in the emerging fungal pathogen Can- dida auris (Chen and Sorrell, 2007; Ghannoum and Rice, 1999; Lockhart et al., 2017). Importantly, Competing interests: The the mechanisms and dynamics of acquired antifungal drug resistance, in vitro or in a patient under- authors declare that no going antifungal drug therapy, are not fully understood.
    [Show full text]
  • Cytokinesis Breaks Dicentric Chromosomes Preferentially at Pericentromeric Regions and Telomere Fusions
    Downloaded from genesdev.cshlp.org on October 2, 2021 - Published by Cold Spring Harbor Laboratory Press Cytokinesis breaks dicentric chromosomes preferentially at pericentromeric regions and telomere fusions Virginia Lopez,1,2,5 Natalja Barinova,1,2,5 Masayuki Onishi,3 Sabrina Pobiega,1,2 John R. Pringle,3 Karine Dubrana,2,4 and Stephane Marcand1,2 1Laboratoire Telom eres et Reparation du Chromosome, Service InstabiliteG en etique Reparation et Recombinaison, Institut de Radiobiologie Moleculaire et Cellulaire, Commissariat a l’Energie Atomique et aux Energies Alternatives, 92265 Fontenay-aux- Roses, France; 2UMR967, Institut National de la Sante et de la Recherche Medicale, 92265 Fontenay-aux-Roses, France; 3Department of Genetics, Stanford University School of Medicine, Stanford, California 94305, USA; 4Laboratoire Instabilite Gen etique et Organisation Nucleaire, Service InstabiliteG en etique Reparation et Recombinaison, Institut de Radiobiologie Moleculaire et Cellulaire, Commissariat a l’Energie Atomique et aux Energies Alternatives, 92265 Fontenay-aux-Roses, France Dicentric chromosomes are unstable products of erroneous DNA repair events that can lead to further genome rearrangements and extended gene copy number variations. During mitosis, they form anaphase bridges, resulting in chromosome breakage by an unknown mechanism. In budding yeast, dicentrics generated by telomere fusion break at the fusion, a process that restores the parental karyotype and protects cells from rare accidental telomere fusion. Here, we observed that dicentrics lacking telomere fusion preferentially break within a 25- to 30-kb-long region next to the centromeres. In all cases, dicentric breakage requires anaphase exit, ruling out stretching by the elongated mitotic spindle as the cause of breakage. Instead, breakage requires cytokinesis.
    [Show full text]
  • Diatom Centromeres Suggest a Mechanism for Nuclear DNA Acquisition
    Diatom centromeres suggest a mechanism for nuclear PNAS PLUS DNA acquisition Rachel E. Dinera,b, Chari M. Noddingsc, Nathan C. Lianc, Anthony K. Kangc, Jeffrey B. McQuaida,b, Jelena Jablanovicb, Josh L. Espinozab, Ngocquynh A. Nguyenc, Miguel A. Anzelmatti Jr.b, Jakob Janssonc, Vincent A. Bielinskic, Bogumil J. Karasc,1, Christopher L. Dupontb, Andrew E. Allena,b, and Philip D. Weymanc,2 aIntegrative Oceanography Division, Scripps Institution of Oceanography, University of California, San Diego, La Jolla, CA 92037; bMicrobial and Environmental Genomics Group, J. Craig Venter Institute, La Jolla, CA 92037; and cSynthetic Biology and Bioenergy Group, J. Craig Venter Institute, La Jolla, CA 92037 Edited by James A. Birchler, Division of Biological Sciences, University of Missouri, Columbia, MO, and approved June 13, 2017 (received for review January 17, 2017) Centromeres are essential for cell division and growth in all eukary- transposons, which can vary substantially in copy number and otes, and knowledge of their sequence and structure guides the organization (16). A common feature of centromeric DNA in many development of artificial chromosomes for functional cellular biol- eukaryotes is low-GC content. Centromeres of Schizosaccharomyces ogy studies. Centromeric proteins are conserved among eukaryotes; pombe and other yeast species feature an unconserved core of AT- however, centromeric DNA sequences are highly variable. We rich DNA sequence often surrounded by inverted repeats (17–20). combined forward and reverse genetic approaches with chromatin The centromeres of the protist Plasmodium have no apparent se- immunoprecipitation to identify centromeres of the model diatom quence similarity besides being 2–4-kb regions of extremely low-GC Phaeodactylum tricornutum .
    [Show full text]