The power of phylogenetic comparison in revealing protein function

Positive selection, that is, fixation of advantageous mutations driven by natural selection, has been an exciting topic to evolutionary biologists, because adaptive changes in genes and genomes are ultimately responsible for evolutionary innovations and species differences. In recent years, detecting signals of natural selection has also become a powerful approach for molecular biologists, biochemists, and virologists to understand the functions of new genes. In a recent issue of PNAS, Sawyer et al. (1) described a remarkable study in which phylogenetic sequence comparison identified a small segment of the primate TRIM5α protein to be under positive selection, and functional analysis using mutagenesis confirmed the importance of the segment in species-specific retroviral inhibition.

TRIM5α is a protein in the cellular antiviral defense system in primates and can restrict retroviruses such as HIV-1 and simian immunodeficiency virus in a species-specific manner. The protein was identified recently because the rhesus monkey TRIM5α restricts reverse transcription of HIV-1, whereas the native human TRIM5α does not (2). Sawyer et al. (1) sequenced the TRIM5α gene from a number of primate species, including hominoids and Old and New World monkeys. Their phylogenetic analysis estimating evolutionary rates identified amino acid positions in the protein at which natural selection appears to have actively promoted amino acid substitutions. In particular, a 13-aa “patch” in the SPRY domain had a concentration of positively selected sites, implicating it as an antiviral interface. By creating chimeric TRIM5α genes, Sawyer et al. demonstrated that this patch is responsible for most of the species-specific antiretroviral activity. Previous studies using phylogenetic approaches have identified a number of genes under positive selection, especially genes involved in host–pathogen interactions. However, this study is unique in that there was no a priori information, structural or otherwise, concerning which part of the protein acts as the interaction interface …