Chromosomes and Chromosomal Aberrations PDF

Chromosomes and chromosomal aberrations  chromosomes Anatomical structure of chromosomes Classification of chromosomal abnormalities Description of chromosomal abnormalities Examples of chromosomal abnormalities Explanation of normal and abn...

Chromosomes and chromosomal aberrations  chromosomes Anatomical structure of chromosomes Classification of chromosomal abnormalities Description of chromosomal abnormalities Examples of chromosomal abnormalities Explanation of normal and abnormal karyotype  chromosomes Cystic fibrosis gene (chromosome 7) Chromosomes are made up of DNA. Each contains genes in a linear order. The cells of the human body contain 46 chromosomes in 23 pairs - one pair is inherited from the mother and the other from the father Chromosome pairs 1 - 22 are called autosomal. The 23rd pair is called sex or sex Sickle cell anemia gene (chromosome 11) chromosomes: XX is a woman, XY is a man chromosomes p CENTROMERE q chromosome 5  Comparison of karyotype of woman and man karyotype-woman karyotype-man  Chromosomes are visible during metaphase during cell division telomers DNA and the protein cap light bands enable binding to the are replicated at an early stage nuclear membrane contain slightly condensed chromatin transcriptionally active genes and rich in GC short arm p (petit) centromere binds to sister chromatids Important for chromosomal segregation in cell division 100 kilobases of repetitive DNA: some nonspecific; some chromosomally specific long arm q dark (G) bands are replicated later containing condensed telomers chromatin rich in AT Human chromosomes; appearance of colored chromosomes viewed under a light microscope chromosome 1 Different chromosome band resolutions reveal different parts of chromosomes A pair of homologous chromosomes (number 1) viewed during metaphase Locus (site of a gene or so-called DNA marker) Alleles (alternative form of the gene / marker)  Chromosomal theory of inheritance Both parts of a pair of homologous chromosomes carry alleles for the same gene All genes on the chromosome: 20 genes are shown in the region marked in red FZD2 AKAP10 ITGB4 KRTHA8 WD1 Genes are arranged in a linear order on a SOST chromosome MPP3 MLLT6 STAT3 BRCA1 breast cancer 1, GFAP NRXN4 NSF NGFR CACNB1 HOXB9 HTLVR ABCA5 CDC6 ITGB3 хромозом 17  Chromosome staining G - banding Q - banding C - banding R - banding T - banding NOR - banding high resolution banding Staining with restrictive endonucleases G- banding (a), Q-banding (b), R-banding (c) and C-banding (d).  Etiology of genetic diseases Mutations in nuclear DNA DNA mutations, which lead to the creation of an abnormal genetic product DNA mutations that affect post-translational modifications of proteins Mutations that affect transcription DNA mutations that lead to defects in mRNA maturation DNA mutations that affect translation Synthesis of an abnormal genetic product Missence mutations (point mutations) Merged fusion genes (hybrid genes) Insertions Deletions Elongated products Mutations in the termination codon (stop codon) Mutations when changing the reading frame (frameshift) Defective post-translational modification Reduced or absent synthesis of a normal genetic product Reduced transcription or absence Insertions Deletion or partial deletion Mutations in the promoter area of the gene Mutations in other regulatory sequences Reduced mRNA or their absence Mutations that lead to the loss or creation of new splices Mutations in the poly – A end Reduced transcription or its complete absence Mutations in the codon of initiation, elongation or termination ​​ Some diseases caused by the presence of mutant genes, which are the reason for the change in the structure of genetic product (protein) ✓Modifications of allosteric properties Haemoglobin variants with increased or decreased affinity lead to polycythaemia or methemoglobinemia ✓ reduced stability Unstable hemoglobin variants = haemolytic anemia Mutant forms of spectrin = haemolytic anemia Mutant forms of collagen = skeletal deformities ✓Reduced polymerization Mutant forms of hybrinogen = abnormal bleeding ✓Decreased secretion deficiency of α1 antitrypsin (PI-Z) degraded liver function ✓ reduced affinity for the substrate mutant forms of antithrombin III = thrombosis Some diseases caused by the presence of mutant genes, which are the reason for the change in the structure of genetic product (protein) ✓Defective receptor function Synthesis, transport, inability to bind to the LDL receptor = hypercholesterolaemia ✓ inability to signaling Insulin receptor = diabetes Christmas disease (factor IX deficiency) = bleeding ✓Defective photoreceptor function rhodopsin = retinitis pigmentosa ✓Modification of the active site of the enzyme mutations in the active site of lysosomal hydrolase = accumulation diseases Examples of DNA mutations that cause defective synthesis of a genetic product ✓Mutations that affect transcription Deletions α and β thalassemia; Duchenne type muscular dystrophy; hemophilia A and B; mucoviscidosis; Lesch-Nyhan syndrome; hypercholesterolemia; AT III deficit; growth hormone deficiency; osteogenesis imperfecta Insertions hemoglobin variants; hemophilia; lipoprotein lipase deficiency; Marfan syndrome; hypercholesterolemia Inversions δ and β thalassemia; Aro A-I deficiency; hemophilia Fusion, fusion (hybrid) genes δ and β thalassemia; color blindness Point mutations in 5` - promoter elements β thalassemia Duplications hypercholesterolaemia Examples of DNA mutations that cause defective synthesis of a genetic product ✓Mutations that affect mRNA maturation Mutations in splice sites; (invariant dinucleotides) α and β thalassemia; phenylketonuria; porphyria (acute) ✓Mutations in hidden splices in exons β thalassemia; ✓Mutations in the poly - A signal site α и β thalassemia; Examples of DNA mutations that cause defective synthesis of a genetic product ✓Mutations that affect translation ✓Mutations in the initiating codon α and β thalassemia; pseudohypoparathyroidism; retinal degeneration ✓Nonsense mutations β thalassemia; ✓Mutations in the poly - A signal site β thalassemia; hemophilia A and B; Lesch-Nyhan syndrome; hypercholesterolemia; 21- hydroxylase deficiency; protein C deficiency; acute porphyria; methylmalone acidemia, etc.. ✓Frameshift mutations β thalassemia; hemophilia; abnormal forms of fibrinogen; muscular dystrophy type Duchenne and many more. ✓Mutations in the terminal codon α thalassemia ✓Nonsense Mutations, that lead to the formation of an unstable protein ✓α and β thalassemia; elliptocidosis, etc.. Mutations in mitochondrial DNA The mitochondria contain the protein system for oxidative phosphorylation. This is where the oxidation of carbohydrates, fats and amino acids to CO2 and H2O occurs, releasing energy in the form of ATP. Mitochondria in humans have 37 genes encoding 13 proteins, 22 mRNA molecules and 2 mRNA molecules. ✓Point mutations MERRF (patients suffering from uncontrolled myoclonic epilepsy) MELAS (point mutation in tRNA leading to stop codon inactivation) ✓Deletions / insertions Kearns-Sayre syndrome; chronic ophthalmoplegia; Pearson syndrome ✓Mutations and neurodegenerative diseases Mitochondrial DNA mutations have been found in patients with Alzheimer’s, Parkinson’s, and Huntington’s chorea. ✓Mitochondrial mutations and aging With age, point mutations accumulate in the Mitochondrial DNA, reducing oxidative phosphorylation.  Chromosomal mutations Numerical Chromosomal Aberrations - Aneuploidy - Mosaicism - Polyploidy Structural chromosomal aberrations - Intrachromosomal aberrations - Interchromosomal aberrations - Marker chromosomes Chromosomal fragility and instability Factors that induce mutations  Classifications of chromosomal abnormalities Numerical (usually due to de novo error in meiosis aneuploidy - monosomy - trisomy polyploidy - triploidy Structurally (may be de novo defect in meiosis or inherited) translocations - reciprocal - Robertson (central fusion) deletions duplications inversions Different cell lines (occur post-zygote) mosaicism aneploidy polyploidy Deletions duplication Ring chromosome  Anomalies in the structure of chromosomes translocations Robertson reciprocal deletions duplications ring chromosomes  karyotype normal karyotype Male: 46,XY. 46 = number of chromosomes XY = sex chromosomes (XY = male, XX = woman). karyotype: international explanation final number of chromosomes, sex chromosomes, abnormalities / variants. 46,XY 47,XX,+21 47,XXX 69,XXY 45,XX,der(13;14)(q10;q10) 46,XY,t(2;4)(p12;q12) 46,XX,del(5)(p25) 46,XX,dup(2)(p13p22) 46,XY,inv(11)(p15q14) 46,XY,fra(X)(q27.3) 46,XY/47,XXY karyotype: international explanation final number of chromosomes, sex chromosomes, abnormalities / variants 46,XY 47,XX,+21 trisomy 21 (Down syndrome) 47,XXX Triple X syndrome 69,XXY Triploidy 45,XX,der(13;14)(p11;q11) Robertson translocation 46,XY,t(2;4)(p12;q12) reciprocal translocation 46,XX,del(5)(p25) chromosome 5 deletion 46,XX,dup(2)(p13p22) duplications of part of the short arm of ch 2 46,XY,inv(11)(p15q14) pericentric inversion of chromosome 11 46,XY,fra(X)(q27.3) fragile X syndrome 46,XY/47,XXY mosaicism: normal / Klinefelter syndrome  Chromosomal changes in early miscarriages 40% normal 60% abnormal: Trisomy (47 chromosomes - one extra) 30% 45, X (45 chromosomes - one missing) 10% Triploidy (69 chromosomes - three sets) 10% Tetraploidy (92 chromosomes - 4 sets) 5% Other chromosomal abnormalities chromosome 5% (Structural anomalies)