Simplified workflow of phylogenomic approaches. Workflow is shown for (A) the classical approach based on multiple sequence alignment, and (B) an alternative approach based on alignment-free methods, for a simple analysis example of homologous sequences 1, 2, 3 and 4, with a known phylogeny as a reference (shown on top). Sequence fragments that share the same ancestry across all four sequences (i.e. are highly similar among one another) are shown in the same colour (red, blue, yellow and orange regions in each sequence). In this example, the yellow and blue regions of sequences 2 and 4 have undergone rearrangement relative to 1 and 3. The dark yellow (in 1 and 2) and light yellow (in 3 and 4) regions are similar to each other. While the classical approach based on multiple sequence alignment (gaps introduced as dashed lines) yields an inaccurate phylogeny, the alternative alignment-free approach (grouping of sub-sequences) is not affected by the sequence rearrangement in 2 and 4, and yields the correct phylogeny. The difference between the two resulting phylogenetic trees is highlighted in red.