Mutation. Mutation provides raw material to evolution. Different kinds of mutations have different effects

Transcription

1 Mutation Mutation provides raw material to evolution Different kinds of mutations have different effects

2 Mutational Processes Point mutation single nucleotide changes coding changes (missense mutations) silent-site changes stop codons (nonsense mutations) control region changes Insertion and deletion Frameshift Larger events Duplication Inversion and translocation

3 Causes of Mutation Replication errors Chemical damage can include crosslinked bases, modified bases Radiation damage often single and double-strand breaks Transposition Viral insertion Unequal crossing-over

4 Mutation Rates Table taken from Farnsworth These are rates per locus, not per site; they were estimated by observing phenotypes. E. coli histidine auxotrophy 2x10 6 streptomycin sensitivity 1x10 8 phage T1 resistance 2 3x10 8 Drosophila males brown eyes 3x10 5 eyeless 6x10 5 yellow body 1.2x10 4 Corn colorless kernel 2x10 6 shrunken kernel 1.2x10 6 Human achondroplasia 1x10 5 aniridia 2.9x10 6 retinoblastoma 6 7x10 6 However, organisms such as HIV virus which do not proofread have mutation rates on the order of 10 3 or even higher.

5 Silent, coding, and control mutations The nature of the genetic code means that some mutations will be silent, meaning that they don t change the protein sequence. The structure of the code means that most first-position and all secondposition mutations are coding, whereas most third-position mutations are silent. In general, we expect silent mutations to have no fitness effect. This may not be true if the coding sequence also has control functions; the silent mutation may affect control of the gene.

6 Mutation Rates Silent and coding sites generally have the same underlying mutation rate However, many mutations at coding sites are lost This produces the appearance of a lower mutation rate It s really a higher loss rate

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8 The Standard Genetic Code First Position (5' end) U C A G Second Position U C A G UUU Phe UCU Ser UAU Tyr UGU Cys Third Position (3' end) UUC Phe UCC Ser UAC Tyr UGC Cys C UUA Leu UCA Ser UAA Stop UGA Stop A UUG Leu UCG Ser UAG Stop UGG Trp G CUU Leu CCU Pro CAU His CGU Arg U CUC Leu CCC Pro CAC His CGC Arg C CUA Leu CCA Pro CAA Gln CGA Arg A CUG Leu CCG Pro CAG Gln CGG Arg G AUU Ile ACU Thr AAU Asn AGU Ser U AUC Ile ACC Thr AAC Asn AGC Ser C AUA Ile ACA Thr AAA Lys AGA Arg A AUG Met Start ACG Thr AAG Lys AGG Arg G GUU Val GCU Ala GAU Asp GGU Gly U GUC Val GCC Ala GAC Asp GGC Gly C GUA Val GCA Ala GAA Glu GGA Gly A GUG Val GCG Ala GAG Glu GGG Gly G U Start Codon Stop Codon Nonpolar Side Chain

9 Codon bias Each organism uses some codons more often than others This bias varies among species Two possible causes: Mutation process may be asymmetrical Some trnas may be better or more abundant than others, so a gene which uses popular codons may be translated faster If the second idea is correct, this is a case where silent sites are not completely neutral

10 Mutation without selection Mutation rates at a locus are often asymmetrical, with more mutations to the nonfunctional state it is easier to break a gene than repair it. The mutation rate from normal to mutant is often written as µ and the reverse as ν. An equilibrium is reached at: pa = ν ν + µ Usually pa is very small at equilibrium. The evolutionary implication is that genes with no use, and therefore no selection, are expected to deteriorate. However, the process is very slow for normal mutation rates.

11 Mutation without selection Suppose there are 100 sites in a gene which will destroy function if they mutate, and each mutates with a probability of Reverse mutation has to hit the same site, and has to restore the old base pair. µ = 10 7 ν = 0.33x10 9 What happens in one generation? Allele A a Frequency before mutation Frequency after mutation (Note that the effect of reverse mutation is so tiny it can t be seen.)

12 Mutation without selection

13 Genomic deterioration Note the millions of generations in previous slide Are we damaging our gene pool by using medicine? Such effects would take a very long time 1 million human generations = 20 million years

14 McClintock s genome shock hypothesis Barbara McClintock showed that transposition in maize increases when the plant is stressed drought salt insects Her genome shock theory is that mutation gives the plant a chance to fix a bad situation If this is true, transposons could be beneficial Alternative is that a sick plant loses control of its transposons In this view they are harmful selfish DNA Hard to test this theory

15 How low can mutation rate go? The bacterium Deinococcus radiodurans was discovered growing on irradiated meat. It can withstand 1000 times as much radiation as a human cell. This is enough radiation to break its single chromosome into about 100 pieces. It arrests (stops dividing), repairs its chromosome, and continues. Very few mutations are produced.

16 Very good replication fidelity is possible The full genome of D. radiodurans has been sequenced recently. It has unusually large numbers of DNA-repair genes, but no new repair mechanisms have so far been discovered. The organism may have evolved this capability to deal with DNA damage during extreme drought and sunlight conditions. It is being studied as a cleanup bacterium for mixed chemical and radioactive wastes. It can t help with the radioactivity, but at least it isn t killed and can biodegrade the chemicals.

17 Very good replication fidelity is possible Presumably other cells could repair as well as D. radiodurans, but they don t. Is this because such repair is too expensive, or because having a higher mutation rate is actually an advantage? (I don t know the answer.)

18 Mutation rates in perspective Human genome has 6x10 9 bp. Point mutation rate around 1x10 9 per bp per generation Human population around 7 billion Every point mutation compatible with life exists somewhere Every human has several new point mutations