comparative computational biology
DESCRIPTION
Comparative computational biology. Positive selection. What is positive selection?. Positive selection is selection of a particular trait - and the increased frequency of an allele in a population. Intraspecific level Positive selection driving continuous adaptation to changes - PowerPoint PPT PresentationTRANSCRIPT
![Page 1: Comparative computational biology](https://reader035.vdocuments.site/reader035/viewer/2022081515/56816602550346895dd933a3/html5/thumbnails/1.jpg)
Comparative computational biology
Positive selection
![Page 2: Comparative computational biology](https://reader035.vdocuments.site/reader035/viewer/2022081515/56816602550346895dd933a3/html5/thumbnails/2.jpg)
What is positive selection?
![Page 3: Comparative computational biology](https://reader035.vdocuments.site/reader035/viewer/2022081515/56816602550346895dd933a3/html5/thumbnails/3.jpg)
Positive selection is selection of a particular trait
- and the increased frequency of an allele in a population
![Page 4: Comparative computational biology](https://reader035.vdocuments.site/reader035/viewer/2022081515/56816602550346895dd933a3/html5/thumbnails/4.jpg)
Species B Species CSpecies A
Recurrent adaptation
Intraspecific levelPositive selection driving continuous adaptation to changes
in the environment
![Page 5: Comparative computational biology](https://reader035.vdocuments.site/reader035/viewer/2022081515/56816602550346895dd933a3/html5/thumbnails/5.jpg)
Woolhouse et al, 2002. Nat. Genet
Positive selection and recurrent selective sweeps
Positive selection and dynamics of polymorphisms
Allele frequencies in host-pathogen interactions
Host
Pathogen
Fixation of alleles
![Page 6: Comparative computational biology](https://reader035.vdocuments.site/reader035/viewer/2022081515/56816602550346895dd933a3/html5/thumbnails/6.jpg)
Species B Species CSpecies A
Diversifying positive selection
Interspecific levelPositive selection driving divergence
![Page 7: Comparative computational biology](https://reader035.vdocuments.site/reader035/viewer/2022081515/56816602550346895dd933a3/html5/thumbnails/7.jpg)
![Page 8: Comparative computational biology](https://reader035.vdocuments.site/reader035/viewer/2022081515/56816602550346895dd933a3/html5/thumbnails/8.jpg)
Why is it interesting to identify traits which
have undergone or are under positive selection?
FunctionEvolution
Environment……
![Page 9: Comparative computational biology](https://reader035.vdocuments.site/reader035/viewer/2022081515/56816602550346895dd933a3/html5/thumbnails/9.jpg)
How can we detect positive selection?
by comparing homologous sequences from
different individuals and identify an unexpectedly high proportion of
non-neutral mutational changes
![Page 10: Comparative computational biology](https://reader035.vdocuments.site/reader035/viewer/2022081515/56816602550346895dd933a3/html5/thumbnails/10.jpg)
Positive selection acts on beneficial mutations
![Page 11: Comparative computational biology](https://reader035.vdocuments.site/reader035/viewer/2022081515/56816602550346895dd933a3/html5/thumbnails/11.jpg)
…… which give rise to changes in the amino acid
sequences of proteins
![Page 12: Comparative computational biology](https://reader035.vdocuments.site/reader035/viewer/2022081515/56816602550346895dd933a3/html5/thumbnails/12.jpg)
Rate of synonymous mutations dS or KS
Rate of non-synonymous mutations dN or KA
To measure positive selection:
![Page 13: Comparative computational biology](https://reader035.vdocuments.site/reader035/viewer/2022081515/56816602550346895dd933a3/html5/thumbnails/13.jpg)
1 2 3 4 5
Pro Phe Gly Leu PheSeq 1 CCC UUU GGG UUA UUUSeq 2 CCC UUC GAG CUA GUA
Pro Phe Ala Leu Val How many possible non-synonymous and
synonymous mutations??
![Page 14: Comparative computational biology](https://reader035.vdocuments.site/reader035/viewer/2022081515/56816602550346895dd933a3/html5/thumbnails/14.jpg)
![Page 15: Comparative computational biology](https://reader035.vdocuments.site/reader035/viewer/2022081515/56816602550346895dd933a3/html5/thumbnails/15.jpg)
We need to know the degeneracy of each codons to compute the number of possible synonymous mutations in codons (S):
ProlineCCUCCCCCACCG
Counted as S=0 (N=1)
A non-degenerate site (all possible nucleotides will result in an amino acid change):
A fourfold degenerate site (all possible nucleotides can be tolerated without an an amino acid change :
Counted as S=1 (N=0)Possible synonymous changes for proline:S = 0 + 0 + 1 = 1
![Page 16: Comparative computational biology](https://reader035.vdocuments.site/reader035/viewer/2022081515/56816602550346895dd933a3/html5/thumbnails/16.jpg)
We need to know the degeneracy of each codons to compute the number of possible synonymous mutations in codons (S):
PhenylalanineUUUUUC
Counted as S=0 (N=1)
A non-degenerate site (all possible nucleotides will result in an amino acid change):
A two-fold degenerate site (two possible nucleotides can be tolerated without an an amino acid change:
Counted as S=1/3 (N=2/3)Possible synonymous changes for phenylalanineS = 0 + 0 + 1/3 = 1/3
![Page 17: Comparative computational biology](https://reader035.vdocuments.site/reader035/viewer/2022081515/56816602550346895dd933a3/html5/thumbnails/17.jpg)
1. Proline S = 0 + 0 + 1 = 1
2. Phenylalanine S = 0 + 0 + 1/3 = 1/3
3. For Glycine S = 0 + 0 + 1 = 1, 4. Leucine for UUA, S = 1/3 + 0 + 1/3 = 2/3 for CUA, S = 1/3 + 0 + 1 = 4/3 Take the average of these: S = 1
5. Phenylalanine for UUU, S = 1/3 Valine, S = 1 Take average: S = 2/3 For the whole sequence: S = 1 + 1/3 + 1 + 1 + 2/3 = 4 N = total number of sites: 15 - 4 = 11
Counts of possible synonymous sites for each gene (S) 1 2 3
4 5Pro Phe Gly
Leu PheSeq 1 CCC UUU GGG UUA UUUSeq 2 CCC UUC GAG CUA GUA
Pro Phe Ala Leu Val
![Page 18: Comparative computational biology](https://reader035.vdocuments.site/reader035/viewer/2022081515/56816602550346895dd933a3/html5/thumbnails/18.jpg)
Counts of synonymous and non-synonymous changes for each gene (Sd and Nd)
1 2 3 4 5
Pro Phe Gly Leu PheSeq 1 CCC UUU GGG UUA UUUSeq 2 CCC UUC GAG CUA GUA
Pro Phe Ala Leu Val
Calculate Sd and Nd for each codon. 1. Sd = 0, Nd = 0
2. Sd = 1, Nd = 0
3. Sd = 0, Nd = 1
4. Sd = 1, Nd = 0
5. this could happen in two ways UUU --> GUU --> GUANd = 1 Sd = 1 Route 1: Sd = 1, Nd = 1
UUU --> UUA --> GUANd = 1 Nd = 1 Route 2: Sd = 0, Nd = 2 Average: Sd = 0.5, Nd = 1.5
Total Sd = 2.5, total Nd = 2.5
![Page 19: Comparative computational biology](https://reader035.vdocuments.site/reader035/viewer/2022081515/56816602550346895dd933a3/html5/thumbnails/19.jpg)
1 2 3 4 5
Pro Phe Gly Leu PheSeq 1 CCC UUU GGG UUA UUUSeq 2 CCC UUC GAG CUA GUA
Pro Phe Ala Leu Val Possible synonymous sites: 4
Possible non-synonymous sites: 11Synonymous changes: 2.5Non-synonymous changes: 2.5
Synonymous rate: KS=Sd / S = 2.5/4 = 0.625
Non-synonymous rate: KA= Nd / N = 2.5/11 = 0.227
Finally, we can compute the rates of syn and non-syn changes
![Page 20: Comparative computational biology](https://reader035.vdocuments.site/reader035/viewer/2022081515/56816602550346895dd933a3/html5/thumbnails/20.jpg)
Evaluating the effect of positive selection by computing
the RATIO of syn and non-syn changes
Neutral evolution
Purifying selection
Positive selection
f.ex. immune related genes
f.ex. housekeeping genes
f.ex. pseudogenes
Ks or dS
Ka or dN
KA or dN: rate of non-synonymous divergence
KS or dS: rate of synonymous divergence
KA>KS
KA<KS
KA=KS
![Page 21: Comparative computational biology](https://reader035.vdocuments.site/reader035/viewer/2022081515/56816602550346895dd933a3/html5/thumbnails/21.jpg)
1 2 3 4 5
Pro Phe Gly Leu PheSeq 1 CCC UUU GGG UUA UUUSeq 2 CCC UUC GAG CUA GUA
Pro Phe Ala Leu Val Possible synonymous sites: 4
Possible non-synonymous sites: 11Synonymous changes: 2.5Non-synonymous changes: 2.5
Synonymous rate: KS=Sd / S = 2.5/4 = 0.625
Non-synonymous rate: KA= Nd / N = 2.5/11 = 0.227
Finally, we can compute the rates of syn and non-syn changes
Ka/Ks = 0.36
![Page 22: Comparative computational biology](https://reader035.vdocuments.site/reader035/viewer/2022081515/56816602550346895dd933a3/html5/thumbnails/22.jpg)
Species A Species B Species C
PN / Ps
Positive selection affects gene evolution during species divergence and during evolution of a population
Ka/Ks
Within species:
Non-synonymous proportion of polymorphisms: P N = Nd / N
Synonymous proportion of polymorphisms: PS = Sd / S
![Page 23: Comparative computational biology](https://reader035.vdocuments.site/reader035/viewer/2022081515/56816602550346895dd933a3/html5/thumbnails/23.jpg)
Species A Species B Species C
PN / Ps
Positive selection affects gene evolution during species divergence and during evolution of a population
Ka/Ks
We can use the two ratios Ka/Ks and Pn/Ps
to infer when selection has acted (or is acting)
Past selection (during speciation)
Present day selection (adaptation)
![Page 24: Comparative computational biology](https://reader035.vdocuments.site/reader035/viewer/2022081515/56816602550346895dd933a3/html5/thumbnails/24.jpg)
McDonald Kreitman (MK) test to contrast within and between species variation
![Page 25: Comparative computational biology](https://reader035.vdocuments.site/reader035/viewer/2022081515/56816602550346895dd933a3/html5/thumbnails/25.jpg)
Question: Are adaptive mutations in the alcohol dehydrogenase in Drosophila species a result of species divergence or current positive selection?
![Page 26: Comparative computational biology](https://reader035.vdocuments.site/reader035/viewer/2022081515/56816602550346895dd933a3/html5/thumbnails/26.jpg)
Repl: Nonsynonymous, Syn: SynonymousFixed: Substitution, Poly: Polymorphisms
Drosophila dataset alcohol dehydrogenase
![Page 27: Comparative computational biology](https://reader035.vdocuments.site/reader035/viewer/2022081515/56816602550346895dd933a3/html5/thumbnails/27.jpg)
The proportion of non-synonymous fixed differences between species much higher than the proportion of non-synonymous polymorphisms
MK test contrasts within and between species synonymous and non-synonymous differences
Contingency table can be tested by a G-test
![Page 28: Comparative computational biology](https://reader035.vdocuments.site/reader035/viewer/2022081515/56816602550346895dd933a3/html5/thumbnails/28.jpg)
Conclusion from MK-test:
Adh locus in Drosophila has accumulated
adaptive mutations (been under positive
selection) when the Drosophila species
diverged
![Page 29: Comparative computational biology](https://reader035.vdocuments.site/reader035/viewer/2022081515/56816602550346895dd933a3/html5/thumbnails/29.jpg)
![Page 30: Comparative computational biology](https://reader035.vdocuments.site/reader035/viewer/2022081515/56816602550346895dd933a3/html5/thumbnails/30.jpg)
One problem with the “counting methods”
Sometimes the signal of selection is not very strong
![Page 31: Comparative computational biology](https://reader035.vdocuments.site/reader035/viewer/2022081515/56816602550346895dd933a3/html5/thumbnails/31.jpg)
Positive selection on one or few particular codonsor in one particular branch
Evolutionary model to detect selection in particular codons or branches