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Lecture 12

BIOC15Fall2013 Lecture 12 and Lecture 13.docx

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University of Toronto Scarborough
Biological Sciences
Karen Williams

BIOC15Fall2013 Lecture 12 Notes: Chromosome mutations and Cancer and Lecture 13 Notes: Cancer and Deletion mapping: using chromosome mutations Chromosome mutations o Variations in chromosome structure or chromosome number o Variations in chromsomes number: o Aneuploidy  chromosome number is not a multiple of the haploid chromosome #, resulting from loss or gain of one or more chromosomes, ex: trisomy o Monoploidy (haploidy)  contains one copy of each homolog o Polyploidy  more than the normal diploid number of chromosome sets, ex: triploidy o Variation in chromosome structure: o Duplication  increase in the number of copies of a chromosomal region o Inversion  180 degree rotation of a chromosomal region o Translocation:  Non-reciprocal unequal exchanged between non homologous chromosomes  Reciprocal  parts of 2 non homologous chromosome trade places o Deletion  removal of a segment of DNA o Transposition  movement of short DNA segments from one position in the genome to another Cancer cells and karyotypic instability o These are changes that produce genomic and karyotypic instability o Defects in the DNA replication machinery  there are higher rates of mutation among cells with defective DNA repair machinery (mismatch repair and damage repair) because replication error persist o Increased rate of chromosomal aberrations  broken chromosomes, multiple copies of chromosomes, deletions of large chromosomal segments or a whole chromosome fidelity of chromosome reproduction is decreased in tumour cells Types of duplications o Tandem duplications  duplications arranged one after the other (same order or reversed order) o o Nontandem (dispersed duplications)  same order or reverse order o o chromosome breakage can produce duplications o according to one scenario, nontandem duplications could be produced by insertion of a fragment elsewhere on the homologous chromosome o Unequal crossing over can increase or decrease copy number o duplication of the X chromosome polytene region 16A causes Bar eyes o unequal pairins and corssing over during meiosis in females homozygous for this duplication produce chromosomes that have either one copy of region 16A (normal eyes) or 3 copies of 16A (causing the more abnormal double-bar eyes o 1 Deletions o the loss of a segment within one chromosome and the juxtaposition of the two segments on either side of the deleted segment o ex: cri du chat syndrome Inversions o chromosomal rearrangement in which the chromosome is broken 2x and flipped 180 degrees between being rejoined o creates loops in polytene chromosomes that reveal the breakpoint of the inversions o o in an inversion loop one chromosomal region rotates to conform to similar region in the other homolog o crossing over with an inversion loop produces aberrant recombinant chromatids Naming chromosomal aberrations o Duplication -> Dp(3L) = duplication in left arm of chromosome 3 o In(I) = inversion in chromosome 1 o T(3R) = translocation in the right arm of chromosome 3 o Df(3R) = deficiency in the right arm of chromosome 3 Translocation o the segment of one chromosome moved to another chromosome o translocated chromsomes are stained in red and green  reciprocal translocation o o Robertsonian translocations can reshape genomes  reciprocal translocation in acrocentric chromsomes such that the long chromosome becomes the small one and vice versa o Down syndrome and Robertsonian translocation o one way of getting 3 chromosomes 21 (trisomy 21 which is Down Syndrome) is through translocation between chromosomes 21 and 14 o so you end up with 2 ‘free’ 21 chromosomes, and the one attached to the 14, making 3 total 2 o Philadelphia chromosome (Ph) o associated with chronic myelogenous leukemia (CML) o used to be called leucocythaemia  many white blood cells o characterized by reciprocal translocation between chromosomes 9 and 22 o o this rearrangement makes an abnormal hybrid gene composed of part of the c-abl gene and part of the bcr gene o the hybrid gene encodes an abnormal fused protein that disrupts control of cell division o The protein encoded by c-abl is a protein tyrosine kinase, an enzyme that adds phosphate groups to tyrosine amino acids on other proteins. o This enzyme is an essential part of the set of signals that dictate cell growth and division  Normal cells closely regulate the activity of the c-abl protein, blocking its function most of the time but activating it in response to stimulation by growth factors in the environment. o By contrast, the fused protein encoded by bcr/c-abl in cells carrying the translocation is not amenable to regulation  It is always active, even in the absence of growth factor, and this leads to runaway cell division  cancer In a translocation homozygote, chromosomes, segregate normally during meiosis I o If the breakpoint of a reciprocal translocation do not affect the gene function, there are no genetic consequences in homozygotes o Chromosome pairing in a translocation heterozygote o in a translocation heterozygote, the two haploid sets of chromosomes carry different arrangements of DNA o chromosome pairing during prophase I of meiosis is maximized by formation of a cruciform structure  3 segreggation patterns are possible 3 o o balanced gametes are produced by alternate segregation and not by adjacent 1 or adjacent 2 segregation Reciprocal interchromosomal translocation o position effect: the expression of the gene changes because of its changed position in the genome o o When a chromosomal rearrangement such as an inversion of a segment of DNA places the gene next to highly compacted heterochromatin near the centromere, the gene's expression may cease  gene expression may be silenced in some cells and not in others Burkitt Lymphoma o Associated with reciprocal translocation between chromosomes 8 and 14 o Charachterized by change in neighbours for the MYC gene leading to cell growth and division that is not controlled (cancer) o Cancer o uncontrolled growth in a mass of cells may result in transformation such that the cell growth is no longer restrainged by contact inhibition  oncogenesis o cell cycle is controlled by the concentration of cyclin-dependent kinases at regular checkpoint  control activity of other proteins by phosphorylating them o we are going to consider: proto-onco genes, tumor suppressor genes, mutator genes o cancer producing mutations are of 2 general types 4 o o oncogene  a gene whose action stimulated unregulated cell proliferation o example 1: on the Ph chromosome, ABL gene within new location gives BCR-ABL oncogene that expresses a tyrosine kinase continuously  this causes growth of white blood cells o example 2: Burkitt lymphoma MYC oncogene in the translocation is overexpressed leading to uncontrolled growth o example 3: c-kit (cellular in this case canine kit) is a truncated protein tyrosine kinase involved in osteosarcoma in dogs (bone cancer) o tumour suppressor genes  suppress the normal cell growth if mutated they lead to uncontrolled cell growth o example retinoblastoma RBI Evidence from mouse models that cancer is caused by several mutations o transgenic mice with dominant mutations in the myc gene and in the ras gene = increased mutation rate when mutation found in both genes and earlier onset of cancer due to that o the myc oncogene produces tumours slowed than the ras oncogene but when put together, the rate is higher than either one on their own o o mice with recessive mutation in the p53 gene  heterozygous individual have a later onset i
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