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Taylor’s Cycle & Genetic Code

Taylor’s Cycle & Genetic Code. vif,. p23. rev,. p19. 5' LTR. gag. 3' LTR. tat,. p14. pol. env. vpr vpu. p15 p16. nef. , p27. Case study: Selection on HIV-1 nef Gene.

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Taylor’s Cycle & Genetic Code

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  1. Taylor’s Cycle& Genetic Code

  2. vif, p23 rev, p19 5' LTR gag 3' LTR tat, p14 pol env vpr vpu p15 p16 nef , p27 Case study: Selection on HIV-1 nef Gene

  3. dN e dS along sequences by the Nei-Gojobori method (Nei & Kumar, 2000) are the total of synonymous (S) and non-synonynous (N) substitutions over the number of potentially synonimous (s) and non-synonimos (n) sites, respectively. Ex.: Phenylalanine (TTT), substitutions at the 1st and 2nd positions are non-synonimous 1 in 3 substitutions are synonimous (TTC): (s) is 0+0+1/3 and (n): 3-1/3=8/3. The proportion of synonymous (ps) and non-synonymous (pn) difference are ps = sd /S e pn = sn /N, respectively. To estimate (dS) and (dN) we can use Jukes-Cantor model:dS=-(3/4ln[1-(4/3)ps]dN=-(3/4ln[1-(4/3)pn] Pairwise determination of dN & dS dN/dS or >1 “Positive selection” dN/dS or  < 1 “Negative selection” dN/dS or  = 1 “Neutrality”

  4. Using the pairwise determination of dN & dS: Looking at comparisons

  5. Maximum likelihood determination of selected codon sites M0 assumes a single value of dN/dS for all codon sites. M1 (“Neutral”) 2 classes of codons: “conserved” (dN/dS= 0) and neutral (dN/dS= 1), distributed in diferent proportions (p0 e p1). M2 (“Selection”) adds a new codon class (p2) which can assume values greater than 1 for dN/dS ( 2). M3 (“Discrete”) assumes n categorias of códons for a given number of classes (K), the values of dN/ dS () per codon-class are gamma-distributed (K categories). For K=8, (Yang et al., 2000) we get  0 até  7 and (p0 até p7). The proportion p8, of sites with higher dN/dS indicates intense positive selection. M7 assumes 10 codon classes, with dN/dS being beta-distributed, with values lower than 1 (explicit negative selection model). M8 adds an eleventh class to model M7 with dN/dS greater than 1. LRT rationale : (i) M0 vs. M2 with 2 d.f.(ii) M0 vs. M3 with 4 d.f.(iii) M1 vs. M2 with 2 d.f.(iv) M1 vs. M3 with 4 d.f.(v) M2 vs. M3 with 3 d.f. (vi) M7 vs. M8 with 2 d.f.

  6. M2 better than M0 e M1 indicates positive selection (>1).M3 better than M1 and M2 points to which codons are positively selected. M0 vs. M2 e M1 vs. M2, since M2 gives conservative estimates of  (Yang, 2000), only then we can trust codons under selection found with M3 and M8. Pros:Yang method allows fitting adequate substitution models using different amino acids transition matrices and rates of heterogeneity when estimating  for each codon, Uses genealogical information (Felsenstein, 1973; Yang, 1994). Cons:May inflate dN, when (n < 20) and when phylogenetic signal is low (Suzuki & Nei, 2001). Considerations about the maximum likelihood method

  7. Using the maximum likelihood method

  8. Using the maximum likelihood method: data

  9. HIV-1 nef gene: Positively seleted sites

  10. HIV-1 Subtype B: Positively seleted sites

  11. Gene substitution and trees: A cladistic view

  12. Gene substitution in the HIV-1 nef gene

  13. Positive selection in the HIV-1 pol gene: immune pressure? 211 214 122, 123 135

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