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Chromosomal mutations 1 Content • Chromosomes • Chromosome mutations – Chromosome number changes – Chromosome structure changes • Examples – Trisomies – Alterations in sex chromosomes 2 Karyotype – a complete set of chromosomes • The number and appearance of chromosomes in the nucleus of a eukaryotic cell – Each organism have a specific karyotype • • • • In humans: female 46, XX, male 46, XY Somatic cell: diploid 2N Gamete: haploid 1N Some polyploid cells exist in humans – megakaryocyte, hepatocytes, muscle and heart cells – several nuclei • 0.6% of the live-born have chromosomal anomaly • • Numerical abnormalities • Structural abnormalities 0.2 % of newborns have a chromosomal anomaly with symptoms • 0.2% symptoms during childhood or teenage 3 • 0.2% symptomless changes Chromosomal abnormalities • Chromosomes contain a person’s genes alteration usually causes a disease – Not necessarily inherited – Due to excess or loss of genetic material • Chromosome abnormalities are due to an error in during meiosis (gametes) – If it occurs later transmitted to progeny → mosaicism • 50% to 80% of abortions during first trimester show chromosomal abnormalities aneuploidy fetal wastage • Female meiosis is long prone to chromosomal abnormalities 4 Normal set of metaphase chromosomes Diploid (2N) Aneuploidy Nullisomic (2N-2) • Aneuploidy= abnormal number of chromosomes Monosomic (2N-1) – extra or missing chromosome(s) numerical abnormality Doubly monosomic (2N-1-1) Trisomic (2N+1) Tetrasomic (2N+2) 5 Variations in number of complete chromosome sets Normal chromosomes Diplod (2N) Monoploid only one set of chromosomes (haploid) Monoploid (N) Polyploid tree or more sets of chromosomes Triploid (3N)) Tetraploid (4N) 6 Structural abnormalities of chromosomes • A break occuring during DNA replication or recombination event may remain unrepaired – Balances and unbalanced translocations, inversions → unbalanced gamete in meiosis → disease to progeny • Can be inherited, 60-70 % p q – Requires intact telomere and centromere regions to be transmitted • 30% are new alterations 7 Balanced translocations https://www.youtube.com/watch?v=MLDCJ2gUC84 • Translocations involve the breakage and rejoining of two or several chromosomes • In balanced translocation there is an equal exchange of chromosomal material Reciprocal translocation: the location of a gene changes, but the amount of genetic material is • Most often either normal or unaltered translocation carrier chromosomes are inherited • Doesn’t usually cause problems for • Other distributions lead to a carrier, but a progeny may be non-balanced chromosomes affected miscarriage 8 t(9;22) Philadelphia chromosome BCR-ABL fusion gene, uncontrollable division of cells, leukemia 9 Fused genes/proteins Second Translocation Associated diseases t(8;14)(q24;q32) Burkitt's lymphoma c-myc on chromosome 8, IGH (immunoglobulin heavy locus) on chromosome gives the fusion protein lymphocyte- 14, proliferative ability induces massive transcription of fusion protein t(11;14)(q13;q32) Mantle cell lymphoma cyclin D1 on chromosome 11, gives fusion protein cellproliferative ability t(14;18)(q32;q21) Follicular lymphoma (~90% of cases) IGH (immunoglobulin heavy locus) on chromosome 14, Bcl-2 on chromosome 18, induces massive transcription of gives fusion protein anti-apoptotic abilities fusion protein t(10;(various))(q11;(various)) Papillary thyroid cancer RET proto-oncogene on chromosome 10 PTC (Papillary Thyroid Cancer) - Placeholder for any of several other genes/proteins t(2;3)(q13;p25) Follicular thyroid cancer PAX8 - paired box gene 8 on chromosome 2 PPARγ1 (peroxisome proliferator-activated receptor γ 1) on chromosome 3 t(8;21)(q22;q22) Acute myeloblastic leukemia with maturation ETO on chromosome 8 AML1 on chromosome 21 found in ~7% of new cases of AML, carries a favorable prognosis and predicts good response to cytosine arabinoside therapy t(9;22)(q34;q11) Philadelphia chromosome Chronic myelogenous leukemia (CML), acute lymphoblastic leukemia (ALL) Abl1 gene on chromosome 9[15] BCR ("breakpoint cluster region" on chromosome 22 t(15;17)(q22;q21) Acute promyelocytic leukemia PML protein on chromosome 15 RAR-α on chromosome 17 persistent laboratory detection of the PML-RARA transcript is strong predictor of relapse t(12;15)(p13;q25) Acute myeloid leukemia, congenital fibrosarcoma, secretory breast carcinoma, mammary analogue TEL on chromosome 12 secretory carcinoma of salivary glands t(9;12)(p24;p13) t(12;21)(p12;q22) t(11;18)(q21;q21) t(1;11)(q42.1;q14.3) t(2;5)(p23;q35) t(11;22)(q24;q11.2-12) CML, ALL ALL MALT lymphoma Schizophrenia Anaplastic large cell lymphoma Ewing's sarcoma JAK on chromosome 9 TEL on chromosome 12 API-2 TEL on chromosome 12 AML1 on chromosome 21 MLT ALK FLI1 NPM1 EWS t(17;22) dermatofibrosarcoma protuberans Collagen I on chromosome 17 Platelet derived growth factor B on chromosome 22 First IGH (immunoglobulin heavy locus) on chromosome 14, induces massive transcription of fusion protein TrkC receptor on chromosome 15 10 t(4;11)(q21;p13): meiosis • Translocation chromosomes have aligned with homologous chromosome segments in the division plane and a tetravalent is formed. • What kind of segregation possibilities there are in the I division? Normal situation 11 Jukka Moilanen (http://www.oppiportti.fi/op/ltg01005/do) Robertsonian centric translocation • Fusion of 2 acrocentric chromosomes very close to the centromeres rearranged chromosome includes the long arms • Balanced centric translocation between chr. 13, 14, 15, 21 and 22 • Short arm is lost (no phenotypic effect) 45 chr. • t(13;14)(p10;q10) – carriers 1:1500 – Predisposes to trisomy 13 ja miscarriage, mild infertility • t(14q;21q), most frequent – In carrier pregnancies 20% risk for extra copy of chr. 21 (Down syndrome) 12 Meiosis in the carrier of Robertsonian transloction t(14;21) • Trivalent aligning • (A) half of the gametes will have normal and half translocation • (B,C) unbalanced chromosomes – (B) monosomia or trisomy 14: miscarriage – 3:0 : miscarriage – (C) trisomy 21 normal T carrier extra 14 14 deficiency extra 21 21 deficiency 13 Unbalanced translocation Loss of genetic material or too much of it deletions and duplications • Extra gene material (>4%) or missing material (>2%): miscarriage • Small alteration (microdeletion/ duplication): chromosome disease • Usually sproradic, with mild phenotype, inheritable changes –Deletions of short arm of chr. 4 and 5: intellectual disability –Prader-Will: 15q11-13 paternal deletion • intellectual disability, over-weight, special features –Angelman syndrome: 15q11-13, maternal deletion • severe intellectual disability, epilepsy, anxiety, special features 14 Inversions • If two breaks occur in one chromosome the region between the breaks may rotate 180 degrees before rejoining with the two end fragments the overall amount of the genetic material is not changed • inv9(p11;q13), most common in general population, 1 -3% – Often detected in infertility studies 15 Inversions • Recombination doesn’t happen in short inversions • In long inversions, inversion chromosome aligns with homologous chromosome inversion loop crossing-over deletions or duplications 16 Chromosome deletions and duplications • Due non-disjunction during meiosis • Defect in I meiotic division: – Chromosome pair in same pool diploid ja nullisome gametes – Most common cytological cause for trisomies – The age of mother correlates with defects in meiosis I gamete trisomic monosomic Chromosome deletions and duplications Defect in meiosis II: • One extra chromosome/one chromosome lost • Rarely cause aneuploidy gamete trisomic monosomic normal Chromosome deletions and duplications • trisomy, 2N+1 – chr.21, 13, 18, (8), (9) contain less genes • Almost all chr. 16 trisomies are due to defect in maternal meiosis I • 90% chr. 13 ja 21 trisomies: maternal, generally defects in meiosis I • 90% chr.18 trisomies maternal 2/3 defects in meiosis II • monosomy, 2N-1 • 2q31q33 –syndrome (partial) • Turneri syndrome (X-chr.) 19 21-trisomy, Down syndrome • incidence 1:600 • often defect in I division of meiosis, in 80% cases maternal – The age of mother correlates with the risk of trisomy-21 20 • Critical genes for the syndrome locate in region 21q22 – 21q22.1-q22.3: 289 genes • DSCR1 (Down Syndrome Critical Region gene1): causes intellectual disability and heart defects – Overexpressed in brains of Down fetuses • DSCR4: affects development of morphologic features, hypotonia and intellectual disability – Expressed mainly in placenta • Severity of symptoms vary, life time about 40 years (~ 50%) – Intellectual disability, fastened aging – Infections, heart problems (not all), dysfunction of intestinal tract – Females are fertile, men not 21 http://www.answers.com/topic/down-syndrome Function of DSCR1 • Protein affects the transcription of genes by inhibiting the calsineurin dependent signaling pathway and thus possibly disturbs the development of central nervous system Normal Nature 441, 582-583(1 June 2006) Down syndrome 22 DSCR1 and also DYRK1A Trisomy 18/ Edwards syndrome • • • • • • • • • More common that trisomy 13, 1: 5000 ~ 95 % clear trisomies and 5 % mosaic cases Partial trisomy 18 due to translocation (~2%) Smallest extra region of chr.18 that causes the syndrome is q21-22 Brain anomalies , Microcephaly severe developmental disbility Heart defects (~90%) clenched hands “rocker bottom feet” lifetime1-2 months, death latest at 1year of age 23 Sex chromosome alterations SRY • Sex chromosomes, X and Y, determine the genetic characteristics of sex-linked traits • X and Y share sequence homology segments, pseudoautosomal regions (PAR1, 2, 3) – inherited in the same manner as autosomes – in males, pairing and recombination are restricted to the PARs – Reduced recombination in PAR1 can lead to aneuploid sperm, which can cause X-chromosome monosomy (Turner European Journal of Human Genetics syndrome) or XXY (Kleinfelter syndrome) in the offspring (2008) 16, 771–779 • recombination is necessary in males • SRY-part (pter-q11.2) of Y contains genes that direct the development of the masculine features without femine phenotype • Deletion or duplication of X/Y chr. is less harmful than changes in the number of other chromosomes 24 Turner syndrome • 45, X, mosaicism – mosaicism allow the survival in utero: placental rescue cell line 46, XX – loss of genes in PAR1 affect development of placenta lethality • Incidence 1: 2500 newborn girls, more common in miscarriages (8.6% vs 0.04%) • Poorly developed fibrotic gonads lack of germ cells and ovarian follicles no oocytes – Activity of two active X chrs are needed to maintain the germ cells and later ovaries • No estrogen synthesis lack of female features – No puberty without hormone therapy (estrogen and progesterone) • Somatic abnormalities due to abnormal dosage of PAR genes – Short stature (<150 cm) SHOX important for bone development and growth – Lymphedema of the hands and feet – Heart defect 25 Klinefelter syndrome • Most common sex chromosome alteration in males • 47, XXY 1: 500-1000 newborn males – 48, XXXY, or 49, XXXXY: variant formsmore severe signs and symptoms – Extra copies of X chromosome are inactivated • Extra copies of genes on the X chr. interfere with male sexual development often prevent testes to function normally reduce the levels of testosterone • Affects male physical and cognitive development – – – – – Infertile, small testes Slightly feminized physique (breast development, wide hip) Poor muscle tone Tall stature Some have learning and psychological problems • Testosterone treatment to improve musculine phenotype, concentration and strenght 26 • Not inherited 47, XYY • 1:1000 newborn males • Affected usually very tall • Fertility and sexual development are normal normal physical appearance • May include learning disabilities and behavioral problems such as impulsivity • Not inherited 27