Lesson 2 Chromosome structure and abnormalities 22-23 full.pdf

Chromosomes: structure and abnormalities MD210 – GGE – Lesson 2 1 Essential Learning Outcomes By the end of this lesson you should be able to: • Understand the concept of ploidy • Describe the common numerical chromosome abnormalities and understand how they can arise • Demonstrate an understandi...

Chromosomes: structure and abnormalities MD210 – GGE – Lesson 2 1 Essential Learning Outcomes By the end of this lesson you should be able to: • Understand the concept of ploidy • Describe the common numerical chromosome abnormalities and understand how they can arise • Demonstrate an understanding of the inheritance patterns of structural chromosome abnormalities 2 Ploidy • The number of complete sets of chromosomes in a cell, and hence the number of possible alleles for autosomal/pseudoautosomal genes • Can be defined in terms of different types of genetic content (n) or chromosome number/amount of DNA (c) • N only changes when the types of genetic content changes, not with replication of chromatids • C changes when the chromosome number changes, for example following DNA replication (S phase) 3 Leonard and Penny Hofstadter 4 Genome of Leonard & Penny’s Baby Penny’s Oocyte (n=1, haploid) 22 Autosomes 1 sex chromosome (X) Many copies of Penny’s mtDNA + Leonard’s Sperm (n=1, haploid) 22 autosomes 1 sex chromosome (X or Y) = Fertilisation Fusion of 2 Haploid Gametes Zygote (n=2, diploid) Normal baby = 46, XX (female) or 46, XY (Male) 5 Meiosis in Baby Hofstadter 1. Oogonia Cell 100 In Daughter of Leonard and Penny Autosome No 1 - 2 Copies (2n, 2c) 1 Leonard Ch1 1 Penny Ch1 2n, 2c Interphase 2n, 4c 2. Round of DNA Replication (Interphase) Doubles Leonard Ch 1 (2 Leonard sister chromatids) Doubles Penny Ch1 (2 Penny sister chromatids) Autosome No 1 - 2 Copies (2n, 4c) Meiosis I 1n, 2c 3. Round of Cell Division (Meiosis I)-2 Cells Each with 2 homologous chromosomes of Autosome 1 (1n, 2c) 4. Round of Cell Division (Meiosis II)-4 Cells Each with 1 Copy (chromatid) of Autosome 1 (1n, 1c) Meiosis II 1n, 1c 6 Homologous recombination in Meiosis 1n, 1c Meiosis I: 2n, 4c Recombination occurs during Meiosis I Leonard and Penny Homologs Align Penny Ch 1 Leonard Ch 1 The Inner Chromatids CROSS OVER 1n, 2c 1n, 2c Separate the homologous chromosomes (Paired Chromatids stay together) Haploid (1n) after Meiosis I 1n, 1c 1n, 1c 1n, 1c Meiosis II The Chromatids Separate 4 Cells (haploid gametes) after Meiosis II 2 with mixture/composite 7 Meiois in People The Sex Chromosomes DOES CROSSING OVER OCCUR ? In females Crossing over occurs X Chromosome Pairing Is Similar To Autosomes In Males X and Y Chromosomes do Pair Crossing Over Occurs at a small section at Tip of Short Arm (pseudo-autosomal region) 8 The Purpose of Sex in Biology To generate genetic diversity How? Gametogenesis How many possible chromosome combinations? Go to www.menti.com 9 The Purpose of Sex in Biology To generate genetic diversity How? Gametogenesis How many possible chromosome combinations? Gametogenesis creates 223 or 2n (where n= the haploid number) possible combinations Homologous recombination (crossing over) How many possible combinations? 10 Numerical Chromosome Abnormalities • Change in chromosome number • Arise from errors in mitosis and meiosis • Clinically evident • Not inherited (de novo) 11 Ploidy - Terminology • Euploidy: A normal diploid chromosome complement (2n) of 46 chromosomes (46, XX or 46, XY) • Haploid: (n) normal chromosome number in the gametes of 23 chromosomes (23, X or 23, Y) • Aneuploidy: Chromosome number varies from normal diploid complement (e.g. 47, XY, +13 = Patau Syndrome) • Polyploidy: Multiples of the haploid chromosome complement of >2n A girl with Patau Syndrome By TRIsoMY Favorite Things Inspired By Natalia's Trisomy 13 LIFE Facebook, CC BY 4.0, https://en.wikipedia.org/w/index.ph p?curid=51999654 12 Terminology • Triploidy: Triple chromosome complement (3n) (e.g. 69, XXX) • Trisomy: Three copies of a chromosome (e.g. 47, XX, +18 = Edwards Syndrome) • Monosomy: One copy of a chromosome (e.g. 46, X, = Turner Syndrome, the only viable monosomy) Turner Syndrome (45, X) By Johannes Nielsen -, CC BY 2.0, https://commons.wikimedia.org/w/index.php?curi d=2502522 13 Interphase FISH • Analyses Nuclear DNA • Analyse amniocentesis directly • No need to grow cells • Partial info in <24h • Detects common trisomies e.g. Chr 18 (pictured) Sex Chrs 14 Sex chromosome abnormalities • Less deleterious than autosomes – why? • 45, X = Turner syndrome • 47, XXY = Klinefelter Syndrome • 47, XXX = Female, mostly normal • 47, XYY = Male, tall, mostly normal 15 Match the karyotype to the finding www.menti.com • 47, XY, +13 • 45, XX, rob(14;21)(q10;q10) • 46, XX, t(9,22)(q34.1;q11.2) • 47, XY, +21 • 46, XY, rob(14;21)(q10;q10), +21 Match the karyotype to the finding • 47, XY, +13 • 45, XX, rob(14;21)(q10;q10) • 46, XX, t(9,22)(q34.1;q11.2) • 47, XY, +21 • 46, XY, rob(14;21)(q10;q10), +21 • Patau Syndrome • Balanced robertsonian translocation • CML • Down Syndrome (trisomy 21) • Translocation Down Syndrome A Clinical Case - D K Male Child First Born to Parents (mother aged 38 father 51) floppy ( hypotonic) single crease across his palm large tongue atypical facial features suggestive of ? 19 Down syndrome – Trisomy 21 • +21 • Only autosomal trisomy compatible with survival into adulthood • Variable degree of intellectual disability • Increased risk of congenital defects of heart and digestive system • Decline in cognitive function is common after 50 and Alzheimer’s in 50% • https://ghr.nlm.nih.gov/condition/down-syndrome 20 How did it arise? Remember… Diploid Cell 23 Pairs of Chromosomes 22 pairs of autosomes 1 pair of sex chromosomes ( XX or XY) Normal After meiosis I = 2 Cells with 23 chromosomes (chromatid pairs) After Meiosis II = 4 Cells each with 23 chromatids (haploid gametes) 21 Trisomy and monosomy Chr 21 Meiosis I N-DJ Meiosis II N-DJ Fertilization Trisomy Trisomy Monosomy Trisomy Monosomy Euploidy (Diploid) 22 Chances of recurrence? • More likely in oogonia vs sperm (why might that be)? • Greater risk with older age of mother (why might that be)? 23 Suppose There Were a Normal Number of Chromosomes: 46 XY? How could you explain DK’s phenotype? 24 Another way that trisomy/monosomy can occur? • Robertsonian translocation – the break occurs at the short arm of the acrocentric chromosomes (13, 14, 15, 21, 22, Y) and results in a fusion chromosome and risk of trisomy/monosomy in children • 4% of Down Syndrome is translocation (familial) DS – rob(14;21) or rob(21;21) 25 Menti - Translocation Down Syndrome • A parent with this robertsonian translocation rob(14;21) can have a healthy child. True or false? 26 Translocation Down Syndrome • A parent with this robertsonian translocation rob(14;21) can have a healthy child. Possible Gametes after Meiosis II: DS 27 In Pairs - Translocation Down Syndrome • Can a parent with a robertsonian translocation resulting in an isochromosome 21 can have a healthy child? If so how? 28 Translocation Down Syndrome • Can a parent with a robertsonian translocation resulting in an isochromosome 21 can have a healthy child? If so how? Possible Gametes after Meiosis II: DS 29 Translocation Down Syndrome • Can a parent with a robertsonian translocation resulting in an isochromosome 21 can have a healthy child? If so how? Possible Zygotes after Fertilisation: DS 30 A Case 21 Year Old Female Presented with Extensive Bruising, Heavy Vaginal Bleeding Full Blood Count White Cell Count – Low Platelet Count - Low Bone Marrow – Great Excess of Promyelocytes Peripheral blood smear: Excess of promyelocytes with multiple Auer rods 31 Mentimeter 1. What does she have? 2. How can we confirm the diagnosis? APML -FISH • RAR gene (Retinoic Acid Receptor) controls differentiation of WBCs beyond promyelocyte – Chr 17 • PML – functions in haematopoiesis and late erythropoiesis, tumor suppressor gene – Chr 15 • PML-RARα protein function – WBC stuck at promyelocyte stage and proliferate abnormally • Probes normally Hybridise to Different Chromosomes • In APML – both probes hybridise to just one chromosome (PML-RAR fusion) Chr17. Courtesy: Hossein Mossafa 33 Acute ProMyelocytic Leukaemia -Treatment • ATRA (all Trans Retinoic Acid) • Vitamin A derivative • Interacts with RARα to Induce Cell differentiation and apoptosis • So Vitamin A derivatives can play a role in managing this type of leukaemia 34 Things to Remember 1. Cross over at meiosis means that homologous chromosome pairs become mixed up as they pass through generations 2. Down syndrome is usually but not always associated with three copies of chromosome 21 (trisomy 21) 3. Trisomy 21 is the most common form of aneuploidy in live-born infants 4. Parent with balanced reciprocal translocations can be phenotypically normal but will generate gametes with balanced and unbalanced chromosome complement 5. APML and CML are examples of genetic diseases that occur via translocation and are non-hereditary (somatic mutation) 35