Chapter 6 Genetic Variability in Humans PDF

Chapter 6 Genetic variability in humans Dra Verónica Veses Jiménez Chapter overview Definition of genetic variation Effects of genetic variations Types of genetic variations – Mutations – Polymorphisms 2 Genetic variation: definition Genetic va...

Chapter 6 Genetic variability in humans Dra Verónica Veses Jiménez Chapter overview Definition of genetic variation Effects of genetic variations Types of genetic variations – Mutations – Polymorphisms 2 Genetic variation: definition Genetic variation is the variation in alleles and genes, both within and among populations In humans, 99.9% of the DNA sequence are the same The remaining 0.1% makes every person unique 3 Effects of genetic variation These variations can be: – Harmless (change in phenotype) – Harmful (genetic disease) – Latent (variations found in coding and regulatory regions, which are not harmful in themselves, however, under certain conditions, they might cause a problem, for example, susceptibility to heart attack) 4 Harmless genetic variations explain phenotypic differences 5  Harmful genetic variations cause inherited diseases whereas latent genetic variations predispose to other diseases Genetic diseases Complex diseases Infectious diseases - Cystic fibrosis - Alzheimer´s disease - Influenza - Down´s syndrom - Cardiovascular disease - Hepatitis - Turner´s syndrom - Diabetes (type 2) - Rubella - Parkinson Environment Genes 6 Types of Genetic variations Mutation: variations in the DNA sequence that are present at a frequency lower than 1% in a population. They can produce a gain of function and loss of function. They are recent in evolution and rare in population. Polymorphism: variations in the DNA sequence that are present at a frequency greater than 1 to 3% in a population. They have a weak effect or no effect. Old in evolutionary terms and common in population. 7 MUTATIONS 8 Origin of mutations Mutations can result from – DNA copying mistakes made during cell division – exposure to ionizing radiation – exposure to chemicals called mutagens – or infection by viruses 9 Classification of mutations – Genomic mutations: alterations in the number of intact chromosomes. alterations of the structure of individual chromosomes. – Genetic / molecular mutations (individual genes) 10 Genomic mutations: changes in the number of cromosomes Also known as aneuploidy They are due to errors in chromosome segregation during meiosis or mitosis They are the most common mutation in humans (1/25-50 cell divisions) They causes spontaneous miscarriages They are common in cancer cells 11 Example: trisomy 21 causes Down syndrome 12 Genomic mutations: changes in cromosomal structure There is an alteration in the structure of individual chromosomes The mutation involves only part of a chromosome, which may be spontaneous or due to abnormal segregation of chromosomes Their frequency is 1/1700 cell divisions They are generally incompatible with life or normal reproduction. They are common in cancer cells 13 Genetic mutations Alter individual genes Substitutions, deletions and insertions in a small scale Two basic mechanisms – Errors in DNA replication – Mutations in the DNA mismatch repair system 14 Classification Substitutions: – They can be transitions (change of one purine for another purine) or transversions (change of one purine by one pyrimidine or the opposite) – accordingly to the effect caused in the protein can be: Missense Nonsense Synonymous Silent (occurs in a non-coding region) 15 Missense mutation there is a change in a base that causes a change in the the amino acid sequence 16 Nonsense mutation There is a change in a base that inserts an artificial STOP codon, finishing translation prematurely 17 Synonymous mutation there is a change in a base but it does not change the amino acid encoded due to the degeneration of the genetic code 18 Insertion 19 Deletion 20 Both insertions and deletions can cause frameshift mutations 21 Summary Not all mutations have clinical consequences: – If the change does not alter the sequence of amino acids (silent) – If the amino acid change does not alter the properties of the polypeptide (synonymous) If the mutation occurs in a germline cell the change will be inheritable If the mutation occurs in a somatic cell the offspring will not receive it. 22 POLYMORPHISMS 23 Types of polymorphism Single nucleotide substitution (SNPs, single nucleotide polimorphism): replacement of one nucleotide by another Microsatellites or minisatellites: these tandem repeats have high levels of polymorphism Polymorphisms of the number of copies 24 SNPs SNPs occur every 300-1000 bases in the human genome Two of every three SNPs consists in the replacement of a cytosine for thymine SNPs can occur in coding and non-coding regions of the genome Many SNPs have no effect on cell function, but others may predispose to disease or adverse drug reactions 25 Classification of SNPs Coding SNPs – Synonyms: when the change in a single base is not a change in the resulting amino acid – No synonyms: when the change in a single base is a change in the resulting amino acid Noncoding SNPs that influence gene expression Noncoding SNPs silent 26 Microsatellites and minisatellites Repetitions of 2-6 nucleotides (micro) and 6-64 nucleotides (mini) Very common human genetic variation. Usually it has no effect. 27 Exception: diseases related to trinucleotide repeats 28 Polymorphisms of the number of copies Variations in the number of copies of long genome segments The affected regions are too small to be seen cytogenetically and too long to be sequenced 29 Summary Mutation Polymorphism Usually causes a disease Causes increased risk, but Follows a Mendelian not direct disease inheritance pattern There is not a clear pattern There are not frequent in of inheritance population It is common in the population 30 References Robert L. Nussbaum, 2007. Thompson & Thompson Genetics in Medicine. 7th Edition. Saunders. Peter D Turnpenny, 2011. Emery's Elements of Medical Genetics. 14th Edition. Churchill Livingstone. Saunders Elsevier , 2007​. US National Library of Medicine. Genetics Home Reference (http://ghr.nlm.nih.gov) 31