introduction to cytogenetics
play

Introduction to Cytogenetics Part 2 Erica Andersen, PhD Section - PowerPoint PPT Presentation

Dec 24, 2022 •259 likes •1.08k views

Introduction to Cytogenetics Part 2 Erica Andersen, PhD Section Chief, Cytogenetics and Genomic Microarray, ARUP Laboratories Associate Professor, Department of Pathology University of Utah Introduction to Cytogenetics II Structural

  1. Introduction to Cytogenetics Part 2 Erica Andersen, PhD Section Chief, Cytogenetics and Genomic Microarray, ARUP Laboratories Associate Professor, Department of Pathology University of Utah

  2. Introduction to Cytogenetics II • Structural Chromosome Abnormalities – Underlying Mechanisms – Nomenclature – Deletions and Duplications – Translocations and Segregation Mechanisms – X-chromosome Abnormalities – Inversions and Recombinant Chromosomes • Cytogenetics in Cancer – Hematologic malignancies overview – Cytogenetic abnormalities and nomenclature – Genetic basis of cancer: oncogenes, tumor suppressors

  3. Structural Abnormalities • Definition: Breakage and rejoining of chromosomes or chromosome segments • May be either balanced or unbalanced • Breakpoints can disrupt gene expression (within a gene or regulatory element) • Can create gene fusions or affect gene expression (↑↓) by position effect – Common in cancer

  4. Mechanisms Underlying Structural Rearrangements- Errors in… • Recombination: exchanges between homologous, non-allelic sequences via non-allelic homologous recombination (NAHR) • Repair: double-stranded breaks that are repaired incorrectly by non-homologous end-joining (NHEJ) • Replication: discontinuous replication of the lagging strand leads to invasion into other replication forks: fork stalling and template switching (FoSTes)

  5. Structural abnormalities (Abnormal is on the right) Deletions Duplications Insertions Terminal Interstitial Robertsonian Translocations Reciprocal Translocations Balanced Unbalanced Balanced Unbalanced

  6. Structural abnormalities (Abnormal is on the right) Inversions Ring chromosomes Paracentric Pericentric inversion inversion Isochromosomes Recombinant chromosomes

  7. Normal variable chromosomal features/ Heteromorphisms (NOTE: generally, these are not included in the karyotype) Normal 9’s Variation in length (+ or -) • 1qh+ • Yqh+ • 13ps+ • 9qh- • 21pstk- • 16qh+ Variation in position 9qh- inv(9)(p12q13) • inv(2)(p11.2q13) • inv(9)(p12q13) • Yqs

  8. Designation of Regions, Bands, Sub-bands Idiogram Sub-band 400 550 700 Region Band Example: 4p15.3 Telomere 6 (pter) p arm 5.3 5 5.2 1 4 3 5.1 2 1 Centromere 0 12 1 3 1 2 3 4 5 2 q arm 6 7 8 1.1 1 1.2 3 2 1.3 3 4 5 Telomere (qter) Chr. 4

  9. Differences in level of resolution by sample type 350 400-425 550-700 BM AF POC PB

  10. Standard Nomenclature for Karyotype Designation General designation includes: • Chromosome number (count)-based on #centromeres – Expressed relative to the ploidy level • Sex chromosome constitution – Use +/- for acquired sex chromosome aneuploidy only • List of abnormalities present – Ordered by chromosome number (sex chromosomes, then autosomes 1-22) and abnormality type (numerical abnormalities/aneuploidies, then structural abnormalities, listed alphabetically and by arm/band, low to high) • Multiple cell lines – Mosaicism: List abnormal clone(s) first, list multiple abnormal clones from largest to smallest in size – Chimerism: List recipient (individual’s karyotype) first

  11. Common symbols and abbreviated terms (constitutional studies) • + additional normal or abnormal chromosome (trisomy) • - loss of a chromosome (monosomy) • add added material of unknown origin, typically resulting in a loss of material distal to breakpoint • del deletion • der derivative chromosome, due to structural rearrangement(s) • dic dicentric chromosome • dup duplication • dn de novo (not inherited) • i isochromosome (composed of two identical chromosome arms) • idic isodicentric chromosome (isochromosome w/ two centromeres) • ins insertion • inv inversion • mar marker chromosome, unknown origin • mat maternal origin • mos mosaic (multiple cell lines/clones present) • pat paternal origin • r ring chromosome • rob Robertsonian translocation, a whole arm translocation between acrocentric chromosomes • t translocation • / separates clones (for mosaic karyotypes) • // separates clones (for chimeric karyotypes) • [ ] indicate number of cells (for mosaic or chimeric karyotypes)

  12. Structural Abnormalities Description (Illustrated by Examples) • Terminal vs interstitial – add(11)(q23) – del(4)(p16.3) – dup(17)(p11.2p13) • Interchromosomal vs intrachromosomal – t(9;22)(q34;q11.2) – inv(3)(q21q26.2) – ins(2)(q13p11.2p14) • Whole chromosome arm rearrangements – i(12)(p10) – der(1;7)(q10;p10) – rob(13;14)(q10;q10) • Combination of abnormalities – 47,XY,+8,t(8;14)(q24;q32) – der(7)del(7)(p11.2)del(7)(q22) – mos 45,X[12]/46,X,idic(X)(p11.22)[8]

  13. Nomenclature Practice: Structural Abnormalities

  14. Abnormal, constitutional Female p13 p11.2

  15. Abnormal, constitutional 46,XX,del(11)(p11.2p13) Female p13 p11.2

  16. Abnormal, constitutional Male with Klinefelter syndrome q22 q24.1 q32

  17. Abnormal, constitutional 47,XXY,ins(13;12)(q32;q22q24.1) Male with Klinefelter syndrome q22 q24.1 q32

  18. Abnormal, constitutional

  19. Abnormal, constitutional 45,XX,rob(14;15)(q10;q10)

  20. Abnormal, constitutional Female q11.2 q23.3

  21. Abnormal, constitutional 47,XX,+der(22)t(11;22)(q23.3;q11.2) Female q11.2 q23.3

  22. Structural abnormalities Deletions Duplications Insertions Terminal Interstitial Robertsonian Translocations Reciprocal Translocations Balanced Unbalanced Balanced Unbalanced

  23. Some recurrent deletions and duplications 1p36 del * Cri du chat Wolf- Tetrasomy 5p15 del Hirschhorn 4p16.3 del 2q37 del BDMR BWS/RSS 11p15 dup pat/mat Pallister- * Potocki- Killian WAGR Shaffer 7q11.23 del 11p11.2 11p13 del (WBS)/dup del Langer- Jacobsen Giedion 11q24 del 8q24 del Inv dup 15 * Miller-Dieker 17p13.3 RB1 del PWS/AS Rubenstein Smith-Magenis/ 13q14 15q11-13 -Taybi Potocki-Lupski del HNPP/CMT1A del pat/mat 16p13.3 del 17p11.2 17p11.2 del/dup & dup mat del/dup Alagille Xp22.31 STS/KAL del 20p12 del 18p- 22q11 del * Cat-eye (VCFS)/dup Phelan- 18q- McDermid 22q13 del Image modified from Gardner, Sutherland and Shaffer Chromosome Abnormalities and Genetic Counseling 4 th ed (2011)

  24. Incidence of Recurrent Deletion and Duplication Syndromes Syndrome Incidence Cause 1p36 deletion 1:7500 Terminal deletion 1q21.1 deletion (distal) 1:500 Interstitial deletion (SD) 4p-/Wolf-Hirschhorn 1:50,000 Terminal deletion 5p-/Cri du chat 1:50,000 Terminal deletion 7q11.23/Williams 1:7500 Interstitial deletion (SD) 15q11q13/Prader willi 1:20,000 Interstitial deletion (pat)/mUPD/Me defect/mutation 22q11.2/DiGeorge/VCFS 1:5000 Interstitial deletion (SD)

  25. Low copy repeats (LCRs) mediate many recurrent genomic rearrangements via NAHR Key NAHR-prone regions Deletion disorders Del/dup disorders Liu et al, 2012

  26. Segmental duplication (low-copy repeat, LCR) architecture mediates recurrent CNVs/rearrangements Emanuel and Saitta, Nat Rev Genet 2007

  27. NAHR: misalignment and exchange occurs between non-allelic homologous sequences (LCRs) DxD=allelic HR Balanced recombinants DxA=non-allelic HR Unbalanced Duplicated recombinants Deleted Emanuel and Saitta, Nat Rev Genet 2007

  28. NAHR underlies many recurrent genomic rearrangements Liu et al., 2012

  29. Multiple techniques are employed for the detection of different cytogenetic abnormalities Balanced Sensitivity Culturing Unbalanced abs? Technique Resolution Global? required? abs? Structural (mosaicism) info? G-banded 3-5 Mb 10-15% Yes Yes Yes Yes chromosomes (550 bands) Metaphase FISH 100’s kb n/a Yes No Yes Yes Interphase FISH 100’s kb 1-5% No No Yes Yes GMA 10- 100’s kb 10-20% No Yes Yes No  Sizes: kb=1x10 3 , Mb=1x10 6

  30. Structural abnormalities Deletions Duplications Insertions Terminal Interstitial Robertsonian Translocations Reciprocal Translocations Balanced Unbalanced Balanced Unbalanced

  31. Incidence of chromosome abnormalities detected in newborns Abnormality Rate/1000 Rate (1/n) Autosomal Trisomy 1.62 617 Sex Chromosome Aneuploidies (All) 2.70 375 Balanced Structural Rearrangements 2.04 490 Translocations, insertions 0.97 1,028 Inversions 0.16 6,331 Robertsonians 0.91 1,099 Unbalanced Structural Rearrangements 0.63 1,587 Translocations, insertions, inversions 0.09 10,935 Robertsonians 0.07 13,366 Deletions, rings 0.06 17,184 +Markers (e.g. isochromosomes) 0.41 2,455 Data from: Milunsky and Milunsky, Genetic Disorders of the Fetus, 6 th Ed. (2010). Benn, Chp. 6  ~1/500 is a carrier of a balanced rearrangement

  32. Effects of Translocations • Constitutional carriers are at risk for infertility, recurrent miscarriage and/or birth of a child with a congenital anomaly syndrome – Most risk figures fall into the range of 0-30% for a liveborn child with an abnormality (higher end if previous child) • May disrupt gene expression (breakpoint within a gene or regulatory element by position effect) – In prenatal setting and de novo, risk ~6% (Warburton ‘91) • Create gene fusions and affect gene expression by position effect – Esp. in cancer ex. t(9;22) BCR-ABL1 chimeric transcript or t(11;14) CCND1 upregulation by translocation near the IGH locus regulatory region

Recommend

INTRODUCTION TO CYTOGENETICS AND MOLECULAR TESTING IN MDS Saturday, September 29, 2018 Cyrus C.

INTRODUCTION TO CYTOGENETICS AND MOLECULAR TESTING IN MDS Saturday, September 29, 2018 Cyrus C.

INTRODUCTION TO CYTOGENETICS AND MOLECULAR TESTING IN MDS Saturday, September 29, 2018 Cyrus C. Hsia, HBSc, MD, FRCPC Associate Professor of Medicine, Schulich School of Medicine and Dentistry, Western University Associate Medical Director,

850 views • 30 slides
noted to have cytogenetics aconsistent chromosomal abnormality Spectacular success Era

noted to have cytogenetics aconsistent chromosomal abnormality Spectacular success Era

First human cancer Mother of noted to have cytogenetics aconsistent chromosomal abnormality Spectacular success Era of targeted of Glivec therapy Year Total Dead 1.0 Imatinib 276 14 1990-2000 960 357 0.8 1982-1989

814 views • 52 slides
Cytogenetics Update Lynda J Campbell lynda.campbell@svhm.org.au Ph Nowell and Hungerford,

Cytogenetics Update Lynda J Campbell lynda.campbell@svhm.org.au Ph Nowell and Hungerford,

Cytogenetics Update Lynda J Campbell lynda.campbell@svhm.org.au Ph Nowell and Hungerford, 1960 Janet Rowley showed the Ph chromosome to be a balanced rearrangement: t(9;22) 9 22 Acute lymphoblastic leukaemia Moorman et al, Blood, 2007

719 views • 55 slides
Cytogenetics Lucienne Michaux Centrum voor Menselijke Erfelijkheid, UZLeuven 18/11/2017

Cytogenetics Lucienne Michaux Centrum voor Menselijke Erfelijkheid, UZLeuven 18/11/2017

BHS training course Laboratory Hematology Cytogenetics Lucienne Michaux Centrum voor Menselijke Erfelijkheid, UZLeuven 18/11/2017 Organization of the Lecture Definition and principles Tools Applications of cytogenetic

571 views • 35 slides
Telomeres and Telomerase: The Means to the End Elizabeth H. Blackburn Nobel Lecture 2009

Telomeres and Telomerase: The Means to the End Elizabeth H. Blackburn Nobel Lecture 2009

Telomeres and Telomerase: The Means to the End Elizabeth H. Blackburn Nobel Lecture 2009 Karolinska Institutet Maize breeding Ancient. Mayan corn god . modern - cytogenetics - chromosome discoveries Barbara McClintock Cold Spring

875 views • 72 slides
Shape of the dose-response for Cancer Christophe Badie Cancer Genetics and Cytogenetics group

Shape of the dose-response for Cancer Christophe Badie Cancer Genetics and Cytogenetics group

INTEGRATED SYSTEMS LEVEL ANALYSIS OF MYELOID LEUKAEMOGENESIS AND EVALUATION OF THE MOLECULAR ALTERATIONS OF ANTIGENIC T-CELL RECEPTOR REPERTOIRE FOLLOWING X-IRRADIATION WP5 Shape of the dose-response for Cancer Christophe Badie Cancer Genetics

329 views • 29 slides
Prognostic factors in MDS Esther N Oliva Grande Ospedale Metropolitano BMM Reggio Calabria,

Prognostic factors in MDS Esther N Oliva Grande Ospedale Metropolitano BMM Reggio Calabria,

Myelodysplastic syndromes: chaos and order Prognostic factors in MDS Esther N Oliva Grande Ospedale Metropolitano BMM Reggio Calabria, Italy Prognosis linked to treatment 4 Age, comorbidites, cytogenetics (genetics) and blasts, as well as the

364 views • 35 slides
INTRODUCTION INTRODUCTION INTRODUCTION INTRODUCTION INTRODUCTION INTRODUCTION INTRODUCTION

INTRODUCTION INTRODUCTION INTRODUCTION INTRODUCTION INTRODUCTION INTRODUCTION INTRODUCTION

TRAINING COURSE ON SOCIAL PROTECTION & FORMALIZATION TRINIDAD AND TOBAGO MARCH 15, 2017 INTRODUCTION INTRODUCTION INTRODUCTION INTRODUCTION INTRODUCTION INTRODUCTION INTRODUCTION INTRODUCTION Design of the NIS Assistance from the

547 views • 23 slides
INTRODUCTION Introduction 2/42 INTRODUCTION Alternations I am giving bread to the

INTRODUCTION Introduction 2/42 INTRODUCTION Alternations I am giving bread to the

Patterns of variation in the expression of case and agreement Andrs Brny Leiden University Centre for Linguistics 9 November 2019, BaSIS Workshop a.barany@hum.leidenuniv.nl INTRODUCTION Introduction 2/42 INTRODUCTION

1.37k views • 42 slides
Introduction Introduction Introduction Introduction Outline Motivation Failures

Introduction Introduction Introduction Introduction Outline Motivation Failures

Introduction Introduction Introduction Introduction Outline Motivation Failures Definition and concepts Process and product properties Principles SE Approaches Motivation Software and the economy The economies of

1.03k views • 49 slides
Introduction Introduction Introduction Nationwide Cause for Concern 1

Introduction Introduction Introduction Nationwide Cause for Concern 1

Introduction Introduction Introduction Nationwide Cause for Concern 1 https://www.cdc.gov/std/stats17/infographic.htm Introduction Epidemiology in Western Colorado CPHE Surveillance Data Report, May 2018 Chlamydia Epidemiology in Western

977 views • 39 slides
DAQ introduction Purpose of this talk : (1) Introduction for those who have not been in every

DAQ introduction Purpose of this talk : (1) Introduction for those who have not been in every

DAQ introduction Purpose of this talk : (1) Introduction for those who have not been in every meeting (2) Some ideas of diagrams for section 7.1 (Introduction) of TP. Giles Barr 25 Jan 2018, Pembroke College On DUNE, the reality is there is a

474 views • 10 slides
INTRODUCTION cf. Schneider, Chapter 1 INTRODUCTION THEY ARE OUT TO GET YOU INTRODUCTION WHAT

INTRODUCTION cf. Schneider, Chapter 1 INTRODUCTION THEY ARE OUT TO GET YOU INTRODUCTION WHAT

ADVANCED COMPUTER SECURITY INTRODUCTION cf. Schneider, Chapter 1 INTRODUCTION THEY ARE OUT TO GET YOU INTRODUCTION WHAT IS SECURITY? A systems security policies describe What the system is supposed to do Store and provide access

479 views • 16 slides
Overview Introduction to SMIL Introduction to W3C and XML Introduction to SMIL

Overview Introduction to SMIL Introduction to W3C and XML Introduction to SMIL

Overview Introduction to SMIL Introduction to W3C and XML Introduction to SMIL Writing a SMIL file Adding Media Objects Martin Halvey Clipping media files January 2008 Timing and Synchronising Layout World Wide

387 views • 14 slides
14 Introduction Introduction Bad guys can put malware into Example: hosts

14 Introduction Introduction Bad guys can put malware into Example: hosts

Introduction Introduction source Encapsulation ISO/OSI reference model message M application segment H t H t M transport network datagram H n H n H t M presentation: allow applications to frame link H l H n H t M interpret

583 views • 4 slides
Previous Lecture Introduction to SMIL 2 Introduction to W3C and XML Introduction to SMIL

Previous Lecture Introduction to SMIL 2 Introduction to W3C and XML Introduction to SMIL

Previous Lecture Introduction to SMIL 2 Introduction to W3C and XML Introduction to SMIL Writing a SMIL file Adding Media Objects Martin Halvey Clipping media files January 2008 Timing and Synchronising Layout

322 views • 8 slides
Lecture 1 Andreas Habegger Introduction Zynq Introduction Zynq Introduction Zynq PS vs. PL

Lecture 1 Andreas Habegger Introduction Zynq Introduction Zynq Introduction Zynq PS vs. PL

Introduction Zynq Lecture 1 Andreas Habegger Introduction Zynq Introduction Zynq Introduction Zynq PS vs. PL Processing System Processor Peripherals Data Buses AXI Bus Conclusion BTE5380 - Embedded Systems Octobre 2014 Andreas Habegger

1.81k views • 30 slides
2018.06 01 SMILE5 Introduction S E 5 02 Alpha Cloud M I L 03 Company Introduction 04

2018.06 01 SMILE5 Introduction S E 5 02 Alpha Cloud M I L 03 Company Introduction 04

2018.06 01 SMILE5 Introduction S E 5 02 Alpha Cloud M I L 03 Company Introduction 04 Project References S E 5 PART.1 SMILE5 Introduction M I L Introduction STORION-SMILE5 Residential Energy Storage System Inverter 5kW Output Input

1.06k views • 25 slides
Introduction to CICS Course introduction Course introduction What is CICS? What is an

Introduction to CICS Course introduction Course introduction What is CICS? What is an

Introduction to CICS Course introduction Course introduction What is CICS? What is an application server? Why use an application server? Course introduction Services provided by CICS How CICS applications are defined Scaling CICS to meet

1.84k views • 146 slides
Network Visualization Introduction Presented by Shahed Introduction Introduction Basic

Network Visualization Introduction Presented by Shahed Introduction Introduction Basic

Network Visualization Introduction Presented by Shahed Introduction Introduction Basic building blocks Node Links (relationship between nodes) Spatial information Network data

584 views • 9 slides
Introduction Introduction (1) Main argument of the paper: universities are not only

Introduction Introduction (1) Main argument of the paper: universities are not only

Le jugement des pairs comme outil de management des universits Peer-review as a management tool Christine Musselin (CSO, Sciences Po et CNRS) Avril 2013, Lirrsistible ascension du capitalisme acadmique Introduction Introduction (1)

590 views • 28 slides
JABLOTRON JA-100 introduction November 2011 Introduction Todays goals First introduction of

JABLOTRON JA-100 introduction November 2011 Introduction Todays goals First introduction of

JABLOTRON JA-100 introduction November 2011 Introduction Todays goals First introduction of the brand new JA-100 alarm system Visions Basic architecture System components Setting Help us with final validations You are the FIRST ones

1.69k views • 111 slides
Introduction Introduction to storage and to storage and filesystems filesystems Introduction

Introduction Introduction to storage and to storage and filesystems filesystems Introduction

Moreno Baricevic Gilberto Daz Axel Kohlmeyer Stefano Cozzini ULA ICTP CNR-IOM DEMOCRITOS Merida, VENEZUELA Trieste, ITALY Trieste, ITALY Introduction Introduction to storage and to storage and filesystems filesystems Introduction

1.19k views • 51 slides
1 Introduction Introduction Communication System Baseband an adjective that describes

1 Introduction Introduction Communication System Baseband an adjective that describes

Introduction Introduction Physical Layer Mobile network Global ISP Provides the means to transmit bits Basic Concepts of from sender to receiver, Data Transmission Defines the mechanical, electrical, and Home network timing

463 views • 7 slides

More recommend