A phylogenetic method linking nucleotide substitution rates to rates of continuous trait evolution

Abstract

Genomes contain conserved non-coding sequences that perform important biological functions, such as gene regulation. We present a phylogenetic method, PhyloAcc-C, that associates nucleotide substitution rates with changes in a continuous trait of interest. The method takes as input a multiple sequence alignment of conserved elements, continuous trait data observed in extant species, and a background phylogeny and substitution process. Gibbs sampling is used to assign rate categories (background, conserved, accelerated) to lineages and explore whether the assigned rate categories are associated with increases or decreases in the rate of trait evolution. We test our method using simulations and then illustrate its application using mammalian body size and lifespan data previously analyzed with respect to protein coding genes. Like other studies, we find processes such as tumor suppression, telomere maintenance, and p53 regulation to be related to changes in longevity and body size. In addition, we also find that skeletal genes, and developmental processes, such as sprouting angiogenesis, are relevant.

Fig 1. Simulated versus recovered (median) log(β₃/β₂) under model using 80 bp alignments.

A. fully bifurcating ultrametric tree with 128 tips and all branch lengths set to 0.1; B. branch lengths are doubled to 0.2; C. tip count is doubled with respect to A, but branch lengths are reduced to 0.09 to keep root to tip distance similar; D. branch lengths and topology as per mammalian tree (see S1 Text).

Fig 2. PhyloAcc-C fit to the LLL loci with the highest BF in favour of the full model (VCE277691).

A. the mammalian phylogeny (input data, see S1 Text) is scaled according to the posterior distribution of rate multipliers r and coloured by the posterior distribution of conservation state z (black = neutral, blue = conserved, red = accelerated). Next to the tree the LLL trait and CNE alignment (both are also input data) are shown. The corresponding posterior distribution of the trait (i.e. an ancestral reconstruction) is shown in Fig A in S1 Text. B. the prior (dashed) and posterior (solid) distribution of the rate multipliers r₂ (blue, conserved) and r₃ (red, accelerated). C. the prior (dashed) and posterior (solid) distribution of log(β₃/β₂). In this case the posterior distribution suggests a positive value so that faster nucleotide evolution is associated with faster trait evolution, but see S1 Text for VCE351367 where the opposite is true. D. posterior distribution of trait change from tip to immediate ancestor, normalized by branch length and coloured by posterior conservation state. Again note that an accelerated conservation state (red) is associated with bigger trait moves and a conserved conservation state (blue) is associated with smaller ones.

Fig 3. BF versus estimated (median) log(β₃/β₂) for 136,859 mammalian LLL loci.

Orange loci are those having BF ≥ 30 and that were submitted as GREAT foreground during analysis. The two loci with the highest BF in favour of the full model are labelled. Note VCE277691 (see Fig 2) and VCE351367 (see S1 Text) have effects with opposite signs.