“You’re lucky nobody was injured. Your base pairs are out of alignment and that has your reading frames all messed up. ⎯ Doc, have you been trying to do your own repair work?” Mutation (mostly) and recombination “Whatever the cause may be for each slight difference in the offspring from their parents ⎯ and a cause for each must exist ⎯ it is the steady accumulation, through natural selection, of such differences, when beneficial to the individual that give rise to all the more important modification of structure …” We make a strict separation between the process that generates mutation and the processes that influence evolutionary fate of such variation 1
Mutations arise by: 1. Error in repair (missincorporation, spontaneous decay, etc.) 2. Error in replication (including steps in recombination) Two broad categories of mutation: 1. Point (nucleotides) mutations 2. Insertions, deletions, or other rearrangements (scale is hugely variable) The fate of a mutation is either: 1. Fixation in a population 2. Loss from a population Polymorphism: genetic variation due to the transitory period where a mutation has not yet been fixed or lost from a population. Mutation: A genetic variant resulting from a mutation event. Holds no meaning about the evolutionary fate of a genetic variant. Substitution: A mutation that has completed the process of being fixed in a population. mutation vs. substitution 2
Purines: Adenine and Guanine Within category: Transition (ts) A G Two rates: Between categories: ts > tv Transversion (tv) C T Pyrimidines: Cytosine and thymine Within category: Transition (ts) Two broad categories of change among codons 1. Synonymous (silent) 2. Nonsynonymous (replacement) 3
Changes among codons can be classified according to nucleotide change Ser Ter Seq 1 ATG CTG GTC AAG TTG AGA AGT TAA Synonymous transition ↓ (1) (A) Seq 2 ATG CTG GTC AAG TTG AGA AGC TAA Ser Leu Ter Seq 1 ATG CTG GTC AAG TTG AGA AGT TAA Nonsynonymous transversion ↓ (2) (B) Seq 2 ATG GTG GTC AAG TTG AGA ACT TAA Val Lys Ter Seq 1 ATG CTG GTC AAG TTG AGA AGT TAA ↓ Nonsense transversion (3) Seq 2 ATG CTG GTC TAG Ter Two sequences showing the different types of mutations (1) synonymous mutation, (2) nonsynonymous mutation, (3) nonsense mutation, (A) transition, (B) transversion. Structure of code determines some effects of mutation on protein Because of the structure of the code, transitions are more likely to be synonymous than transversions. Most degenerate sites are at the occur at third codon positions; here, all transitions are synonymous whereas only some transversion are synonymous 4
Mutational pathways among codons: our first hints at modelling T T G T T A (L e u) (L e u) TTC T C T (Phe) (Se r) T T T T AT G T T (Phe ) (T yr) (Va l) T G T AT T (C ys) C T T (I le ) (L e u) Mutational pathways among codons: our first hints at modelling Relative proportion of different types of mutations in hypothetical protein coding sequence. Expected number of changes (proportion) 1 st positions 2 nd positions 3 rd positions Type All 3 Positions Total mutations 549 (100) 183 (100) 183 (100) 183 (100) Synonymous 134 (25) 8 (4) 0 (0) 126 (69) Nonsyonymous 392 (71) 166 (91) 176 (96) 50 (27) nonsense 23 (4) 9 (5) 7 (4) 7 (4) 3 x 3 x 61 = 549 mutational pathways Assumptions: (1) ts = tv; and (2) codon frequencies = 1/61; complelty neutral evolution 5
Mutational pathways among codons: our fist hints at modelling 0.34 0.32 0.3 0.28 0.26 0.24 0.22 0.2 0 5 10 15 20 Transition/transversion rate ratio ( α/β ) Insertion-deletion events (Indels) 1. Nucleotide indels 2. Genic (exon) indels 3. Chromosomal segments 4. Genomic compliment 6
Insertion-deletion events (Indels): nucleotides insert T 1 ↓ 23 Leu Arg Ser Ter Seq 1 ATG CTG AAG TTG AGA AGT TAA … ↓ Seq 2 ATG CTG A T A GTT GAG AAG TTA AGA Val Glu Lys Leu Arg The insertion of a T causes the amino acids encoded beyond the insertion to change and since no stop codon is found it would continue until one is reached resulting in a longer polypeptide. Frame–shift mutations are highly deleterious (consider hemoglobin) • common in non-coding sequences and loop regions RNA encoding genes • rare in coding sequences and stem regions Insertion-deletion events (Indels): chromosome segments 7
Insertion-deletion events (Indels): chromosome segments Insertion-deletion events (Indels): chromosome segments 8
Insertion-deletion events (Indels): chromosome segments • Occur in viruses, prokaryotes and eukaryotes • Very deleterious if breaks occur within genes • Position effect variegation (PEV) Insertion-deletion events (Indels): genomic scale events Haploidy: the condition of having only ½ ( n ) the of the two haploid sets (2 n ) of chromosomes. • normal in some species; e.g., drone honeybees Polyploidy: the condition of having more than two haploid sets of chromsomes (>2 n ) in some multiple of n . • lethal in most animals; but, known in a few reptiles and fish • as much as 70% of modern angiosperms have polyploid origins Autopolyploidy: polyploids having all sets of chromosomes from the same species Allopolypoidy: polyploids having sets of chromosomes originated in different species Aneuploidy: a change in number of chromosomes. • e.g., trisomy 21 9
Phenotypic effect of mutation 1. Deleterious (vast majority of mutations; R. A. Fisher, 1930’s) 2. Slightly deleterious (Tamoko Ohta [1972]) 3. Neutral (M. Kimura [1969]; King and Jukes[1969]) 4. Slightly beneficial (Darwin [1859] and R. A. Fisher [1930’], rare but important; Ohta [1970’s] more common, less important in finite population sizes) 5. Major beneficial effects (Episodic; Mendelians; LGT) F IVE KEY QUESTIONS ABOUT MUTATION : W Wh ha at t i is s t th he e n na at tu ur ra al l r ra at te e o of f m mu ut ta at ti io on n? ? W Wh ha at t a ar re e t th he e e ef ff fe ec ct ts s o of f m mu ut ta at ti io on n o on n f fi it tn ne es ss s? ? I Is s m mu ut ta at ti io on n r ra at te e i it ts se el lf f u un nd de er r g ge en ne et ti ic c c co on nt tr ro ol l? ? I Is s t th he e m mu ut ta at ti io on n r ra at te e s su ub bj je ec ct t t to o n na at tu ur ra al l s se el le ec ct ti io on n? ? I Is s e ev vo ol lu ut ti io on n e ev ve er r l li im mi it te ed d b by y t th he e a av va ai il la ab bi il li it ty y o of f n ne ew w m mu ut ta at ti io on ns s? ? 10
What is the natural rate of mutation? What is the natural rate of mutation? Note that mutation rate is measured in different ways 1. The rate of nucleotide substitution at sites believed to be free from natural selection pressure (neutral). 2. The rate at which new mutations occur at a gene locus (or per genome) per generation. 3. The rate of accumulation of lethal or deleterious mutations on a chromosome. 4. The rate at which new phenotypic variance is generated by mutation. ….Be careful ! Two approaches to measuring mutation rates: 1. Direct 2. Indirect What is the natural rate of mutation? What is the natural rate of mutation? Direct methods: 1. Quantify the number of new mutation that occur within the timeframe of the study. 1. Visible effect on phenotype in lab population 2. Phenotypic effect from dominant mutants in a pedigree 2. Requires very large numbers; mutation is slow 10 -1 to 10 -10 Microorganisms: Mice: 8 x 10 -4 Fruitflies: ~4 x 10 -6 per bp Human genealogies: 10 -6 10 -6 Typical rate: 11
What is the natural rate of mutation? What is the natural rate of mutation? Indirect methods: 1. Estimate the number of substitutions along lineages since they shared a common ancestor. 2. Must be neutral (substitutions used as a proxy for mutations 3. Date of common ancestor must be known; must convert to generations 4. If substitutions are not neutral, rates will be influences by: 1. Strength and type of selection We will deal with these issues later in the course 2. Effective population size What is the natural rate of mutation? What is the natural rate of mutation? Indirect methods: Substitution rate is not the same as mutation rate when the mutations are subject to natural selection pressure New mutations natural selection Cause the sieve effect and genetic drift to differ in different acts as a “sieve” lineages Fixation in a population The substitution rate can be used as an indirect measure of the mutation rate if the mutations are selectively neutral 12
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