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Universal Genetic code table
Lecture Goals
1. Gene duplication – concerted evolution
2. Neutral theory and clocks
3. Epigenetics
2
Mitosis and meiosis
Meiosis: Metaphase I
Homologous Recombination
Homologous Recombination
DNA replication: repairs accidents at replication fork
Repairs double strand DNA (dsDNA) breaks
Occurs at meiosis (cross-overs)
Occurs at other times between highly similar sequences
Recombination -- Holliday Junction
Proposed by Dr. Holliday (Holliday R. 1964. A mechanisms for gene conversion in fungi.
Genet. Res. 5:282-304)
Holliday structures
ds-stranded breaks not uncommon
Meiosis
Created by topoisomerase-like enzymes
Mitosis
Radiation
Mutagens (e.g. chemicals)
Stalled replication forks
Specialized endonucleases (eg site-specific HO endonuclease in switching of yeast matting type (MAT) genes)
Gene Conversion
A special type of homologous recombination: Non-reciprocal transfer of genetic material from ‘donor’to ‘acceptor’
Initiated by double strand DNA (dsDNA) breaks
Outcome: portion of ‘donor’ sequence copied to ‘acceptor’and original ‘donor’ copy unchanged
donor acceptor
geneconversion
Gene Conversion is not uncommon
Yeast mating type switch (MAT) genes
Human repetitive sequence elements (Alu and LINE-1 sequences)*
Human gene families (e.g. MHC alleles, Rh blood group antigens, olfactory receptor genes)
Chicken B cells Ig gene diversification
Pathogen clonal antigenic variation (e.g. African Trypanosomes and Babesia bovis)
* Chen et al. 2007 Gene conversion: mechanisms, evolution and human disease Nature Reviews Genetics. 8: 762-775.
Lecture Goals
1. Gene duplication – concerted evolution
2. Neutral theory and clocks
3. Epigenetics
14
Neutral theory
• Proposed to explain considerable levels of molecular variation in populations
• Majority of mutations are effectively neutral and therefore subject to drift.
15
Terms to own
Genetic drift: Changes in the allele frequencies due to effects of chance on sampling between generations
16
Genetic drift
•Cause of drift: sampling error in finite population
17
Genetic Drift
• Drift simulations• More drift simulations
18
Practice this!
Genetic drift: more important in smaller populations
19
Terms to own
Genetic drift: Changes in the allele frequencies due to effects of chance on sampling between generations
Effective population size: “the number of breeding individuals in an idealized population that would show the same amount of dispersion of allele frequences under random genetic drift as the population under consideration” (Sewall Wright)
20
Effective population sizeEstimate of long term ‘relevant’ size of population.
21
Effective population size
• A population that has experienced a bottleneck will have a lower effective population size than a population of the same census size that has been stable.
• This is because alleles are lost due to genetic drift so it is as if you have fewer individuals following bottleneck as compared to idealized population.
22
Cheetahs23
Cheetahs: small Ne
24
Cheetahs: small Ne
25
Cheetahs: small Ne = skin graft26
Cheetahs: inbreeding depression
• Very low heterozygosity• 70% abnormal sperm and low sperm counts• Very high mortality to disease:
– 1982, Wildlife Safari in Oregon, 60 cheetahs– Coronavirus (e.g., SARS, common cold) killed 60%
(vs. 10% mortality in humans from SARS)
27
Motoo Kimura
1968 “Evolutionary Rate at the Molecular Level,” Nature 217: 624-626.
28
Neutral theory
• Let neutral mutation rate be µ (= new mutant copies of a gene per generation)
29
Neutral theory
• Let neutral mutation rate be µ (= new mutant copies of a gene per generation)
• How many mutations in a population?
30
Neutral theory
• Let neutral mutation rate be µ (= new mutant copies of a gene per generation)
• In a diploid population of size 2Ne, there will be 2Neµ new
mutations at a gene per generation
• What is probability of fixation? Loss?
31
Neutral theory
• Let neutral mutation rate be µ (= new mutant copies of a gene per generation)
• In a diploid population of size Ne, there will be 2Neµ new mutations at a gene per generation
• Since these mutations are neutral, the probability of eventual fixation of any one mutation is 1/2Ne, and probability of loss is 1 - (1/2Ne)
Most new neutral mutations will be lost by drift within a few generations, but occasionally a new mutation will increase infrequency and replace previously existing alleles
32
Random Walk: how long will it take for a “happy” man to fall of ledge?
33
Time to fixation34
Neutral theory
Average number of allelic fixations per generation
35
Neutral theory
Average number of allelic fixations per generation is equal to the number of new mutations per generation x the probability that any one mutation eventually becomes fixed
36
Neutral theory
Average number of allelic fixations per generation is equal to the number of new mutations per generation x the probability that any one mutation eventually becomes fixed
# new mutations per generation =
37
Neutral theory
Average number of allelic fixations per generation is equal to the number of new mutations per generation x the probability that any one mutation eventually becomes fixed
# new mutations per generation = 2Neµ
prob. fixation of a new mutation =
38
Neutral theory
Average number of allelic fixations per generation is equal to the number of new mutations per generation x the probability that any one mutation eventually becomes fixed
# new mutations per generation = 2Neµ
prob. fixation of a new mutation = 1/2Ne
39
Neutral theory
Average number of allelic fixations per generation is equal to the number of new mutations per generation x the probability that any one mutation eventually becomes fixed
# new mutations per generation = 2Neµ
prob. fixation of a new mutation = 1/2Ne
So, average # fixations per generation =
40
Neutral theory
Average number of allelic fixations per generation is equal to the number of new mutations per generation x the probability that any one mutation eventually becomes fixed
# new mutations per generation = 2Neµ
prob. fixation of a new mutation = 1/2Ne
So, average # fixations per generation = µ
41
Neutral theory
Average # allelic fixations per generation = µ
Average time between fixations =
42
Neutral theory
Average # allelic fixations per generation = µ
Average time between fixations = 1/µ
43
Neutral theory
Average # allelic fixations per generation = µ
Average time between fixations = 1/µ
This is the molecular clock!
44
• Your thoughts: neutral theory
Lecture Goals
1. Gene duplication – concerted evolution
2. Neutral theory and clocks
3. Epigenetics
46
47
Epigenetics• Epigenetics – quick history and definition• The Epigenome• Examples of Non-Mendelian inheritance
48
Epigenetics: a brief history • Epigenesis: organisms develop through
transitions from egg to adult
• Preformationism:
49
Epigenetics: brief history
50
Epigenetics: brief history • Epigenesis: organisms develop through
transitions from egg to adult
• Preformationism: organisms are fully-formed throughout life cycle
51
Epigenetics: brief history • Epigenesis: organisms develop through
transitions from egg to adult
• Preformationism: organisms are fully-formed throughout life cycle
• Epigenetics originally defined by Waddinton 1942: “branch of biology which studies the causal interactions between genes and their products which bring the phenotype into being”
52Epigenetics: Waddington
53
Epigenetics – a term to struggle with• Epigenetics is the study of heritable changes in gene
expression that occur without a change in DNA sequence
• Epigenetics describes phenomena underlying many examples of non-Mendelian inheritance
• ‘Epigenetics has always been all the weird and wonderful things that cannot be explained by genetics’ - Denise Barlow, Vienna Austria (discovered first imprinted gene)
54Epigenetics
Certainly NOT the exception:
1. Maternal Effects
2. Imprinting
3. Other Epigenetic Phenomena
55
Maternal Effect
A. E. Boycott (1920s)– First study of maternal effect– Water snail, Limnea peregra
• Shell and internal organs either right- or left-handed
56
Maternal Effect
A. E. Boycott (1920s)– Began with two different true-breeding strains
• One dextral, one sinistral
– Dextral ♀ x sinistral ♂ dextral offspring– Reciprocal cross sinistral offspring– Contradict a Mendelian pattern of inheritance
57
Maternal Effect
A. E. Boycott (1920s); Alfred Sturtevant (1923)– Sturtevant proposed that Boycott’s results could be
explained by a maternal effect gene• Dextral (D) is dominant to sinistral (d)• Phenotype of offspring is determined by genotype of
mother
Other Epigenetic PhenomenaMorphological evidence: Spirotrichea
Morphological evidence: Spirotrichea
Other Epigenetic Phenomena
Other Epigenetic Phenomena
• Trans-generational inheritance in Arabidopsis• Paramutation in mice
61Transgenerational memory - Arabidopsis
62
Transgenerational memory - Arabidopsis
63Arabidopsis: homologous recombination
64Transgenerational memory - Arabidopsis
65Homologous recombination
66
Mouse phenotype: kit
Kit null mutant (heterozygotes)
• Kit is a tyrosine kinase gene
67
68Kit mutant
69Kit null mutant (heterozygotes)
70Kit mutant
71Kit* (paramutated) = decrease polyA Kit RNA
72Kit knockout = increase aberrant Kit RNA
73Kit RNA microinjection: offspring!
Kit Summary
• Paramutation: Kit allele transforms phenotype of offspring (white tipped tail and feet)
• Associated with build up of aberrant RNAs that are specifically packaged in sperm
• Injection of these RNAs also causes phenotype
Challenges central dogma!
74
• Your thoughts: epigenetics