Is Sequence Alignment an Art or a Science?

Abstract

Aligning multiple nucleotide sequences is a prerequisite for many if not most comparative sequence analyses in evolutionary biology. These alignments are often recognized as representing the homology relations of the aligned nucleotides, but this is a necessary requirement only for phylogenetic analyses. Unfortunately, existing computer programs for sequence alignment are not based explicitly on detecting the homology of nucleotides, and so there is a notable gap in the existing bioinformatics repertoire. If homology is the goal, then current alignment procedures may be more art than science. To resolve this issue, I present a simple conceptual scheme relating the traditional criteria for homology to the features of nucleotide sequences. These relations can then be used as optimization criteria for nucleotide sequence alignments. I point out the way in which current computer programs for multiple sequence alignment relate to these criteria, noting that each of them usually implements only one criterion. This explains the apparent dissatisfaction with computerized sequence alignment in phylogenetics, as any program that truly tried to produce alignments based on homology would need to simultaneously optimize all of the criteria.