Medical Genetics. T2. L2. 46th. 2024_81ae512a26f7baaf2d1fe4e65cf4f006.pdf

“Genetic variations” Medical Genetics Lecture 5 (via zoom) UMS – 42nd batch 28. 07. 2020 1 Genetic variations 2 Genetic Variations at DNA/Gene Level Polymorphism >1% Mutation...

“Genetic variations” Medical Genetics Lecture 5 (via zoom) UMS – 42nd batch 28. 07. 2020 1 Genetic variations 2 Genetic Variations at DNA/Gene Level Polymorphism >1% Mutation affected with sickle cell anaemia (a severe haemolytic anaemia) -> in certain parts of Africa 1/25 of the population are affected 6  Genetic Variations Mutations “Heritable alteration or change in genetic material” - Usually harmful and arise following exposure to mutagenic agents (e.g. as radiation, UV and chemicals) - Mutation that provide genetic variation help in evolution - beneficial - Mutations arising in somatic cells can not be transmitted - Majority occurs spontaneously through errors in DNA replication & repair 7  Genetic Variations Mutation (contd..) * Sickle cell disease – all mutant genes have a single base substitution (6th codon of betaglobin gene from GAG to GTG -> Glutamic acid to Valine) ** Cystic fibrosis – over 700 mutations have been described but one particular mutation ΔF508 accounts for ≈ 70% of all cases in northern Europeans *** Duchenne Muscular dystrophy (DMD) mutation include deletion, duplication & point mutation 8  Genetic Variations Mutations (contd..) - Mutations in the CODING sequence (or in the sequences which regulate gene expression) -> altered DNA may produces a changed m-RNA -> change in aa sequence of the protein encoded by the gene * in some cases protein function will be maintained * in other cases: will change or cease -> may leads to a clinical disorder - Sometimes advantageous e.g., heterozygous sickle cell carriers resistant to falciparum malaria - Either chromosomal alteration or point mutation 9  Genetic Variations Mutations (contd..) Fixed and stable - Insertions - Deletions - Duplications - Single base pair substitution dynamic or unstable 10 Reading Frame 11  Genetic Variations Insertion - Addition of one or more nucleotides into a gene - In coding sequence -> it can interrupt the reading frame Haemophilia A caused by insertion of LINE 1 repetitive sequences into the F8C gene 12  Genetic Variations Deletion - Loss of one or more nucleotides -> and may disrupt the reading frame 13  Genetic Variations Deletion (contd.) 14  Genetic Variations Deletion (contd..) - Large gene mutations are the causal mutations in several disorders -> Alpha-thalassaemia (entire gene deleted) Duchenne muscular dystrophy (partial deletion of the gene) 15  Genetic Variations Duplications -> doubling of the same nucleotides * DMD – 5-10% of mutations are -> due to duplication of exons with in the dystrophin gene * Charcot – Marie – Tooth disease – type 1a – 70% of mutation involve duplication of entire PMP22 gene 16  Genetic Variations Substitutions 1. Synonymous or silent mutation Single base pair substitution - > result in another triplet that codes for same amino acid 17  Genetic Variations Substitutions (contd..) 2. Non-synonymous mutations - alteration in the encoded protein -> abnormal function* - occurs less frequency * Mis-sense mutation * Nonsense mutation 18  Genetic Variations * Mis-sense Mutations - Involves single base pair substitutions - Replacement of one amino acid with another in the protein product -> structure of the protein altered eg. many of abnormal Hb 19  Genetic Variations * Nonsense Mutations - A substitution generate one of the stop codons - Result in premature termination of translation of peptide chain In most cases , - The produced shortened peptide chain is not likely to retain normal biological activity * particularly if the substitution resulted in the loss of an important functional region of the protein 20 * Dynamic or unstable mutations Triplet Repeats Normal feature in a Genome ………. CAG CAG CAG CAG ………. ………. CAG CAG CAG CAG CAG CAG CAG CAG CAG ………. Triplet Repeat Expansion 21  Genetic Variations Trinucleotide repeat expansion - Identified as mutational basis for a number of different single gene neurological disorders * Fragile X syndrome * Huntington’s disease * Myotonic dystrophy * Spinocerebellar ataxia * Friedreich ataxia etc., 22  Genetic Variations Trinucleotide repeat expansion (contd..) Classification -> Polyglutamine (or PolyQ) diseases repeated codon is CAG, which in a coding region, codes for glutamine (Q) resulting in a polyglutamine tract -> Non-polyglutamine diseases repeated codons do not code for glutamine * Trinucleotide repeat numbers in the normal range -> stably inherited & no phenotypic effect * Adverse phenotypic effects occur when -> the size of the expansion exceeds a critical length 23  Fragile X syndrome - most common single cause of inherited mental retardation - long arm of X chromosome – “CGG” – in the FMR1 gene Repeat number Phenotype effect ≤ 45 unaffected individuals 50 to 199 No adverse effect on phenotype Pre-mutation Over 200 fragile X syndrome Full mutation (silence gene expression & cause the clinical syndrome) - affect ≈1 in 4000 males with many more gene carriers - both mutations are unstable & tend to increase in size when transmit to the offspring - All the boys and about half the girls who inherit the full mutation are clinically affected. 24  Fragile X syndrome  Phenotypic features - Mental retardation of varying degree - developmental problems * learning disabilities * cognitive impairment - Macro-orchidism in post-pubertal males - a characteristic facial appearance * prominent forehead * large jaw * large ears * joint laxity * behavioral problems 25  Fragile X syndrome Transmission Fragile X pedigree shows transmission of the mutation through an unaffected male 26  Epigenetic effects These are inherited molecular changes that do not alter DNA sequence Can affect the expression of genes or function of the protein product Effects include - DNA methylation (e.g. Fragile X syndrome) - Alteration of chromatin configuration - Alteration of protein conformation 27  This teaching / learning material has been prepared for the 42nd batch of undergraduate medical students of the University of Jaffna. Students are advised to read the text books to enrich their knowledge on the subject as the contents may not cover the syllabus fully. The students are instructed to use this material for their own learning and should not publish in any form or site as reference since the contents have been obtained from standard text books and other educational resources - may not with the permission for publication. If students require any further clarifications they are requested to communicate with the respective teacher. 28 29