Fixations of the HIV-1 env gene refute neutralism: New evidence for pan-selective evolution

Abstract

We examined 103 nucleotide sequences of the HIV-1 env gene, sampled from 35 countries and tested: I) the random (neutral) distribution of the number of nucleotide changes; II) the proportion of bases at molecular equilibrium; III) the neutral expected homogeneity of the distribution of new fixated bases; IV) the hypothesis of the neighbor influence on the mutation rates in a site. The expected random number of fixations per site was estimated by Bose-Einstein statistics, and the expected frequencies of bases by matrices of mutation-fixation rates. The homogeneity of new fixations was analyzed using χ 2 and trinomial tests for homogeneity. Fixations of the central base in trinucleotides were used to test the neighbor influence on base substitutions. Neither the number of fixations nor the frequencies of bases fitted the expected neutral distribution. There was a highly significant heterogeneity in the distribution of new fixations, and several sites showed more transversions than transitions, showing that each nucleotide site has its own pattern of change. These three independent results make the neutral theory, the nearly neutral and the neighbor influence hypotheses untenable and indicate that evolution of env is rather highly selective.

Heterogeneous periodicity of drosophila mtDNA: new refutations of neutral and nearly neutral evolution

“…Our study seeks to know the sequence information for tertiary or quaternary DNA structures (in relation to non-DNA molecules). We seek to affi rm or refute neutral, nearly neutral or selective evolution (Valenzuela and Santos, 1996, Valenzuela, 1997, 2007, 2010aValenzuela et al, 2010). Unexpectedly, we found a very high correlation between both bases of a dinucleotide separated by 0, 1, 2 …K (K= 35) nucleotide sites in the whole genome of the HIV-1 virus, and in one env gene of this virus (Valenzuela, 2009).…”

“…Neutralists answered fast (Jukes, 1976;Kimura and Ohta, 1977) proposing that the neighbor infl uence of bases on mutation rates could explain this order. However, this is an intuitive, ad hoc hypothesis that was never demonstrated and, as we saw, mutation plus the neighbor infl uence cannot produce the meaningful order we see in life (Valenzuela 2009(Valenzuela , 2010aValenzuela et al, 2010). It is very often proposed that the genetic code implies a constraint that explains the order.…”

“…, 2007Valenzuela et al, 2010). Recurrent forward and backward mutations make neutral fixation impossible (Wright 1931;Feller 1951;Valenzuela 2000Valenzuela , 2002aValenzuela et al, 2010).…”

“…The expected number of dinucleotides is obtained by the frequency of the first base, times the frequency of the second base, times the total number of dinucleotides. Taking the observed frequencies of bases is the best estimate of the expected historical action of mutation rates and all the possible neighbor influences (as average) because these frequencies should be considered as the expected equilibrium frequencies under neutral evolution (see Valenzuela et al, 2010). APPENDIX 2 presents dinucleotides ordered according to the significance of their deviation from randomness.…”

“…This argument falls into rational circularity, because the cause that originated and maintains the genetic code is sent to the unexplained, non-analyzable or un-debatable set of evolutionary processes (constraints). Recurrent mutation inexorably destroys any nucleotide sequence (also sequential constraints), as is evidenced regularly by the cancers, aging and genetic diseases of living beings (Valenzuela, 2007(Valenzuela, , 2009Valenzuela et al, 2010).…”