Frequent branch-specific changes of protein substitution rates in closely related lineages

Since its inception, the investigation of protein divergence has revolved around a more or less constant rate of sequence information decay that led to the formation of the molecular clock model for sequence evolution. We use here the classical approach of amino acid sequence comparisons to examine the overall divergence of proteins and the possibility of lineage-specific acceleration. By generating and analysing a high-confidence dataset of 13,160 syntenic orthologs from four ape species, including humans, we found that only less than 1% of the ortholog families are entirely in line with the clock model in each of their branches. The most common departure from the expected decay rate involves higher than expected substitutions on just one or two branches of the individual families. However, when taken as aggregate, even a small set of families conform well with the clock assumptions. We identified ADCYAP1 as the most divergent human protein-coding gene with 10% human-specific substitutions. Such lineage-specific highly accelerated genes were not limited to humans but appear as a general pattern that accompanies the formation of species. Our analysis uncovers a much more dynamic history of substitution rate changes in most protein families than usually assumed. Such fluctuations can result in bursts of rapid acceleration followed by periods of strong conservation that effectively cancel each other. Although this gives an impression of a long-term constant rate, the actual history of protein sequence evolution appears to be more complicated.