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Chromosomes Dr Pupak Derakhshandeh, PhD Ass Prof Medical Science of Tehran University What are chromosomes? Chromosomes are the structures that hold our genes Genes are the individual instructions that tell our bodies how to develop and function They govern our physical and medical characteristics, such as hair color, blood type and susceptability to disease. Each chromosome has a p and q arm; p is the shorter arm and q is the longer arm. The arms are separated by a pinched region known as the centromere How many chromosomes do humans have? The typical number of chromosomes in a human cell is 46 - two pairs of 22 + XX/XY Holding an estimated 30,000 to 35,000 genes. One set of 23 chromosomes is inherited from the biological mother (from the egg), and the other set is inherited from the biological father (from the sperm). study of the chromosomes with a microscope , then Stainning The chromosomes look like strings with light and dark "bands" A picture, or chromosome map, of all 46 chromosomes is called a karyotype The karyotype : identify chromosome abnormalities: that are evident in either the structure or the number of chromosomes. study of the chromosomes The pairs have been numbered from 1 to 22, with the 23rd pair labeled "X" and "Y." In addition, each chromosome arm is defined further by numbering the bands that appear after staining The higher the number, the further that area is from the centromere. Study of the chromosomes The first 22 pairs of chromosomes are called "autosomes" Final pair is called the "sex chromosomes." The sex chromosomes an individual has determines that person's gender; females have two X chromosomes (XX), and males have an X and a Y chromosome (XY) Karyotype )46, Xy) How Chromosome Abnormalities Happen? Meiosis Mitosis Maternal Age Environment Meiosis Chromosome abnormalities : happen as a result of an error in cell division. “Meiosis” : the cell division that the egg and sperm go through when they are developing. Normally, meiosis causes a halving of chromosome material, so that each parent gives 23 chromosomes to a pregnancy Meiosis Meiosis Chromosome abnormalities Abnormality of chromosome number or structure: Numerical Abnormalities Structural Abnormalities Numerical Abnormalities When an individual is missing either a chromosome from a pair (monosomy) or has more than two chromosomes of a pair (trisomy). An example: Down Syndrome, also known as Trisomy 21 (an individual with Down Syndrome has three copies of chromosome 21, rather than two). Turner Syndrome is an example of monosomy the individual is born with only one sex chromosome, an X. Kleinfelter Syndrome is an example of trisomy the individual is born with three sex chromosome, XXY. Down Syndrome (Trisomy 21( Trisomy 2( Down Syndrome (Trisomy 21( Down syndrom )Trisomy 21, 46) critical region: A region on the long (q) arm of chromosome 21 Down syndrome causes mental retardation, a characteristic facial appearance, and multiple malformations Associated with a major risk for heart malformations a small but still significant risk of acute leukemia . 3 copies of chromosome number 21 incidence of 1 in 660 and is by far the most common chromosomal abnormality Slight flattening of the face A low bridge of the nose (lower than the usually flat nasal bridge of the normal newborn) An epicanthal fold (a fold of skin over top of the inner corner of the eye, which can also be seen less frequently in normal babies) A ring of tiny harmless white spots around the iris mental retardation Trisomy 18, 47 Ch. Trisomy 18, 47 Ch. incidence of about 1 in 3,000 There is a 3:1 preponderance of females to males Thirty percent of affected newborns die within the first month 50% by two months and 90% by one year. severe mental retardation microcephaly overlapping fingers, and rocker bottom feet Neurologically they are hypertonic Other common malformations include congenital heart, kidney, .... abnormalities. Trisomy 18, 47 Ch. Trisomy 13 (XX/XY, 47 Ch) has an incidence of 1 in 5,000 Forty-four percent of affected newborns succumb in the first month of life and 69% by six months Only 18% of the babies born with trisomy 13 survive the first year microcephaly microophthalmia (small eyes) cleft lip or cleft palate polydactyly (extra fingers) congenital heart defects urogenital defects brain malformations severe mental retardation. Turner Syndrome (45 , X) 45, X Turner Syndrome (45, X) Turner syndrome • Only females • One X chromosome • Or has two X chromosomes but one is damaged • Short stature • Delayed growth of the skeleton • Sometimes heart abnormalities • Usually infertile due to ovarian failure • Diagnosis is by blood test (karyotype) • 1 out of every 2,500 female live births worldwide • Short neck with a webbed appearance Kleinefelter XXY Kleinefelter47/XXY Klinefelter syndrome (47, XXY) In boys and men 47 chromosomes with XXY sex chromosomes XXY is one of the most common chromosomal abnormalities 1 in 500 male births the most common genetic cause of male infertility Often : undiagnosed : variation in clinical presentation Small testes , insufficient production of testosterone , and infertility Klinefelter syndrome (47, XXY) Breast enlargement, lack of facial and body hair, a rounded body type , to be overweight , and be taller than their fathers and brothers Learning and/or behavioral problems Testosterone replacement corrects the symptoms of androgen deficiency Sex chromosome and autosomal chromosome abnormalities is higher in spermatozoa from patients with Klinefelter syndrome than in those from normal men. Fragile X Syndrome 1 in 3,600 males and 1 in 4,000 to 6,000 females with the full mutation worldwide It is estimated that 1 in 250 females and 1 in 700 males are carriers of the premutation. It is second only to Down Syndrome as a cause of mental retardation Fragile X syndrome appears in children of all ethnic, racial and socio-economic backgrounds Fragile X Syndrome most common inherited form of familial mental retardation (CGG)n trinucleotide expansion in the FMR1 gene leading to the typical Martin-Bell phenotype Clinical features vary depending on age and seX Expansion of a (CCG)n repeat in the FMR2 gene corresponds to the FRAXE fragile site which lies distal to FRAXA and is also associated with mental retardation, but it is less frequent and lacks a consistent phenotype Fragile X Syndrome Fragile X Syndrome Chromosome abnormalities Abnormality of chromosome number or structure: Numerical Abnormalities Structural Abnormalities Structural Abnormalities Deletions: A portion of the chromosome is missing or deleted (>5 Mb). Paraderwilli Syndrome (Ch 15) Angleman Syndrome (Ch 15) Imprinting effect DELETIONS Deletion refers to the loss of a segment of a chromosome This can be terminal (close to the end of the chromosome on the long arm or the short arm) or it can be interstitial (within) eg.DGS II DELETIONS Structural Abnormalities • Duplications: A portion of the chromosome is duplicated, resulting in extra genetic material. • Oncogenes (c-onc, c-fos, c-myc) DUPLICATIONS refers to an extra chromosomal segment within the same homologous chromosome or an extra chromosomal segment on another nonhomologous chromosome. Again, the clinical findings are highly variable depending upon the chromosomal segments involved. Gene in expantion: Huntington Disease/ Fragile X, …. DUPLICATIONS Structural Abnormalities Translocations: When a portion of one chromosome is transferred to another chromosome. There are two main types of translocations. In a reciprocal translocation, segments from two different chromosomes have been exchanged. In a Robertsonian translocation, an entire chromosome has attached to another at the centromere. TRANSLOCATIONS Translocation involves two nonhomologous chromosomes (e.g., chromosome 2 and chromosome 6) Following a break in each of the chromosomes, and subsequent reunion a segment of chromosome 2 becomes attached to chromosome 6 TRANSLOCATIONS Balanced reciprocal translocation Balanced reciprocal translocation Robertsonian translocation The reciprocal transfer of the long arms of two of the acrocentric chromosomes: 13, 14, 15, 21 or 22 On rare occasions, other nonacrocentric chromosomes undergo Robertsonian translocation a reciprocal transfer of the whole long or short arms close to the centromere A relatively common Robertsonian translocation is between chromosome 14 and chromosome 21 In meiosis, a trivalent is formed. Robertsonian translocation Structural Abnormalities Inversions: A portion of the chromosome has broken off, turned upside down and reattached, therefore the genetic material is inverted. eg Ch9 inv in Iran Inversions involve only one chromosome the intervening segment is rejoined in an inverted or opposite manner. Since there is no loss nor gain of chromosomal material, inversion carriers are normal Paracentric: does not include the centromere pericentric:inverted segment contains the centromere In meiosis, the normal chromosome and the inverted chromosome will form a loop to allow pairing of specific DNA sequences that occur within the inversion loop result in gametes with both deletions and duplications inversion carriers have a relatively low risk of having abnormal offspring. Inversions Rings: A portion of a chromosome has broken off and formed a circle or ring. This can happen with or without loss of genetic material. Ring Oncology Chronic Myelogenous Leukemia (CML) a clonal expansion of transformed hematopoietic progenitor cells: Myeloid Monocytic Erythroid Megakaryocytic lymphoid lineages Molecular level CML: characterized by the bcr-abl fusion gene reciprocal translocation t(9;22)(q34;q11) creating the Philadelphia (Ph) chromosome survival time of patients : to 5 to 7 years Hematology Bone marrow Chronic myelogenous leukemia (CML) 15% to 20% of leukemias in adults incidence of 1 to 2 cases per 100,000 population myeloproliferative disorder: results from neoplastic transformation of hematopoietic progenitor cells affects myeloid, monocytic, erythroid, megakaryocytic, and lymphoid lineages Chronic myelogenous leukemia occurs more frequently in males than in females (ratio of 1.3 to 1) Incidence: increases with age the median age at presentation is between 45 and 55 years Up to 30% of patients with CML are 60 years or older which is an important consideration for the selection of therapeutic strategies stem-cell transplantation treatment with interferon-alfa (Intron A, Roferon-A) The Philadelphia Chromosome a reciprocal translocation between the long arms of chromosome 9 and chromosome 22 the large segment of the c-abl gene from chromosome 9q34 to the part of the bcr gene on chromosome 22q11 in a head-to-tail fashion creating a hybrid bcr-abl gene that is transcribed into a chimeric bcr-abl mRNA Role of the bcr-abl Fusion Gene in CML Pathogenesis Ch 9: c-abl gene :a proto-oncogene Encodes: a nonreceptor tyrosine kinase with a molecular mass of 145 kd (p145cabl) It is localized in both cytoplasm and nucleus It consists of 11 exons 230 kilobases (kb) Role of the bcr-abl Fusion Gene in CML Pathogenesis c-abl gene : Exon 1 has two alternative forms 1a and 1b In most cases the breakpoint in the abl gene occurs in the 5¢ part of abl exon a1/2 within the segment between exons 1a and 1b Abl exons a2 to a11:are transposed into a region of the bcr gene between exons 12 and 16 (also referred to as b1 to b5) on chromosome 22 creating a bcr-abl fusion mRNA of 8.5 kb The fusion mRNAs are translated into a 210-kd chimeric protein called p210bcr-abl Detection of bcr-abl Cytogenetic analysis Ph chromosome in 90% of patients with CML Such analysis is tedious and time-consuming allows the examination of only 20 to 25 metaphases per bone marrow sample misses the 5% of patients who are Ph-negative but bcr-abl-positive Despite these shortcomings, cytogenetic analysis is the gold standard in the diagnosis of CML. Molecular tools important for detecting the molecular abnormalities associated with Ph for monitoring the course of disease during treatment These include polymerase chain reaction (PCR) as well as Southern blot Western blot analyses RT-PCR Quantitative reverse transcriptase– polymerase chain reaction following patients with CML after stem-cell transplantation Its use for monitoring patients receiving interferon-alpha is not well-defined FISH Fluorescence in situ hybridization allows for the analysis of metaphase and nondividing interphase cells Results of FISH studies are easily quantifiable fluorescence in situ hybridization (FISH) fluorescence in situ hybridization (FISH) FISH Bcr Abl AblBcr Abl-Bcr