* Your assessment is very important for improving the workof artificial intelligence, which forms the content of this project
Download mutations - Université d`Ottawa
Cell-free fetal DNA wikipedia , lookup
Saethre–Chotzen syndrome wikipedia , lookup
Adaptive evolution in the human genome wikipedia , lookup
Designer baby wikipedia , lookup
Non-coding DNA wikipedia , lookup
Neuronal ceroid lipofuscinosis wikipedia , lookup
Dominance (genetics) wikipedia , lookup
Polymorphism (biology) wikipedia , lookup
Genome (book) wikipedia , lookup
Genetic engineering wikipedia , lookup
Cre-Lox recombination wikipedia , lookup
Epigenetics of neurodegenerative diseases wikipedia , lookup
Therapeutic gene modulation wikipedia , lookup
History of genetic engineering wikipedia , lookup
Artificial gene synthesis wikipedia , lookup
Site-specific recombinase technology wikipedia , lookup
Human genetic variation wikipedia , lookup
Genome editing wikipedia , lookup
No-SCAR (Scarless Cas9 Assisted Recombineering) Genome Editing wikipedia , lookup
Deoxyribozyme wikipedia , lookup
Oncogenomics wikipedia , lookup
Helitron (biology) wikipedia , lookup
Genetic code wikipedia , lookup
Microsatellite wikipedia , lookup
Genetic drift wikipedia , lookup
Koinophilia wikipedia , lookup
Frameshift mutation wikipedia , lookup
Population genetics wikipedia , lookup
MUTATIONS - any detectable change in DNA sequence eg. errors in DNA replication/repair - inherited ones of interest in evolutionary studies Deleterious - will be selected against and lost (purifying selection) Advantageous - will be fixed in population by natural selection - rare occurrence Neutral - will have not effect on phenotype - may be fixed in population by genetic drift TYPES OF MUTATIONS 1. Point mutations Transition Transversion = purine to purine or pyrimidine to pyrimidine = purine to pyrimidine How many possible transitions? transversions? p.38 “In animal nuclear DNA, ~ 60-70% of all point mutations are TRANSITIONS, whereas if random expect 33%” Missense mutation - different aa specified by codon Nonsense mutation - change from sense codon to stop codon Non-synonymous - amino acid altered Synonymous - “silent” change 2. Insertions or deletions (“indels”) - frameshift mutations within coding sequences Fig. 1.12 Short insertions or deletions (short “indels”) eg. if slippage during DNA replication -rapid evolution change in copy number of short tandem repeats microsatellites Fig.1.18 Do you agree or disagree with the following statement? “A synonymous mutation may not always be silent.” see p.27 Fig. 6.23 “Triplet repeat expansion” mutations - increased copy number of tandem repeats of triplets within gene (or regulatory region) - certain human genetic (neurodegenerative) diseases - repeat number strongly correlates with age of onset of disease and severity >200 7-22 5’ UTR Repeat copy number in normal = green; red = disease condition Karp p.435 intron 200 - >2000 5-40 3’ UTR Fragile X syndrome female male male II-1 asymptomatic hemizygous carrier daughter III-1 asymptomatic, but expanded repeat in germ line wt mutant Snustad Fig. 5.12 3. Inversions, translocations, etc. Inversion through chromosome breakage & rejoining Fig. 1.20 - shown as single stranded, but both DNA strands inverted - if recombination between direct repeats B C A B A A Fig. 1.20 D C D - if recombination between indirect repeats in genome D B C Fig. 1.17 MUTATIONS vs POLYMORPHISMS? Polymorphisms - two or more natural variants (alleles, phenotypes, sequence variants) which occur at “significant” frequencies in a population if present in < 2% population, called “mutation or “mutant allele” Alleles - alternative forms of a gene (or DNA sequence) at a particular locus (chromosomal site) - frequency in population determined by natural selection and random genetic drift if allele frequency = 1, FIXATION if allele frequency = 0, EXTINCTION (LOSS) Dynamics of gene substitution Advantageous mutations Neutral mutations _ t = mean conditional fixation time 1/K = mean time between 2 consecutive fixation events K = rate of substitution (# mutations fixed per unit time) Fig. 2.7 SELECTIONIST THEORY (Neo-Darwinian) Natural selection for advantageous mutations which improve fitness is primary source of genetic variation “Survival of the fittest” NEUTRAL THEORY OF MOLECULAR EVOLUTION (Kimura) At molecular level, most evolutionary changes occur by random genetic drift of alleles which are selectively neutral (or nearly so) “Survival of the luckiest” BUT …. presence of different neutral alleles in population important eg. if environment changes, certain alleles may be advantageous & selected Some observations leading to Kimura’s theory 1. Relatively high rate of amino acid sequence evolution - variable among proteins, but in many cases about 0.5 – 1.5 x 10-9 changes per non-synonymous (ie. amino acid-altering) site per year (Table 4.1) 2. Relatively constant rate of evolution for given protein over time - based on pairwise comparisons of proteins (eg a-globin) among species (Figure 4.15) “Molecular clock” 3. Rate of evolution can differ along protein sequence - functionally important regions (eg active site of enzyme) change at slower rate (Figure 4.5) 4. High degree of genetic variation (polymorphisms) within populations (Figure 2.9) Polymorphic sites in Drosophila Adh gene Fig. 2.9 Asterisk = site of Lys-for-Thr replacement responsible for mobility difference between fast (F) and slow (S) electrophoretic alleles Interpretation of data shown in figure? Bromham & Penny “The modern molecular clock” Nature Rev Genet 4:216, 2003 Selectionist theory: assumption that all mutations affect fitness Neutral theory: for most proteins, neutral mutations exceed advantageous ones (and more neutral sites would produce a faster overall rate of change Nearly neutral theory: fate of mutations with only slightly positive or negative effect on fitness will depend on factors like population size