So far we have concentrated on the intrinsic properties of single sequences, such as CpG islands in DNA, or on pairwise alignment of sequences. However, functional biological sequences typically come in families, and many of the most powerful sequence analysis methods are based on identifying the relationship of an individual sequence to a sequence family. Sequences in a family will have diverged from each other in their primary sequence during evolution, having separated either by a duplication in the genome, or by speciation giving rise to corresponding sequences in related organisms. In either case they normally maintain the same or a related function. Therefore, identifying that a sequence belongs to a family, and aligning it to the other members, often allows inferences about its function.

If you already have a set of sequences belonging to a family, you can perform a database search for more members using pairwise alignment with one of the known family members as the query sequence. To be more thorough, you could even search with all the known members one by one. However, pairwise searching with any one of the members may not find sequences distantly related to the ones you have already. An alternative approach is to use statistical features of the whole set of sequences in the search. Similarly, even when family membership is clear, accurate alignment can be often be improved significantly by concentrating on features that are conserved in the whole family.