Nonrandom spatial distribution of synonymous substitutions in the GP63 gene from Leishmania

In this work we analyze the variability in substitution rates in the GP63 g ene from Leishmania. By using a sliding window to estimate substitution rat es along the gene, we found that the rate of synonymous substitutions along the GP63 gene is highly correlated with both the rate of amino acid substi tution and codon bias. Furthermore, we show that comparisons involving gene s that represent independent phylogenctic lines yield very similar divergen ce/conservation patterns, thus suggesting that deterministic forces (i.e., nonstochastic forces such as selection) generated these patterns. We presen t evidence indicating that the variability in substitution rates is unambig uously related to functionally relevant features. In particular, there is a clear relationship between rates and the tertiary structure of the encoded protein since all divergent segments are located on the surface of the mol ecule and facing one side (almost parallel to thc cell membrane) on the exp osed surface of the organism. Remarkably, the protein segments encoded by t hese variable regions encircle die active site in a funnel-like distributio n. These results strongly suggest that the pattern of nucleotide divergence and, notably, of synonymous divergence is affected by functional constrain ts.