been lost in modern proteins. It also allows insights into the biology and ecology of extinct organisms. Although the majority of ancestral reconstructions have dealt with proteins, it has also been used to test evolutionary mechanisms at the level of bacterial genomes and primate gene sequences. Vaccine design RNA viruses such as the human immunodeficiency virus (HIV) evolve at an extremely rapid rate, orders of magnitude faster than mammals or birds. For these organisms, ancestral reconstruction can be applied on a much shorter time scale; for example, in order to reconstruct the global or regional progenitor of an epidemic that has spanned decades rather than millions of years. A team around Brian Gaschen proposed that such reconstructed strains be used as targets for vaccine design efforts, as opposed to sequences isolated from patients in the present day. Because HIV is extremely diverse, a vaccine designed to work on one patient's viral population might not work for a different patient, because the evolutionary distance between these two viruses may be large. However, their most recent common ancestor is closer to each of the two viruses than they are to each other. Thus, a vaccine designed for a common ancestor could have a better chance of being effective for a larger proportion of circulating strains. Another team took this idea further by developing a center-of-tree reconstruction method to produce a sequence whose total evolutionary distance to contemporary strains is as small as possible. Strictly speaking, this method was not ancestral reconstruction, as the center-of-tree (COT) sequence does not necessarily represent a sequence that has ever existed in the evolutionary history of the virus. However, Rolland and colleagues did find that, in the case of HIV, the COT virus was functional when synthesized. Similar experiments with synthetic ancestral sequences obtained by maximum likelihood reconstruction have likewise shown that these ancestors are both functional and immunogenic, lending some credibility to these methods. Furthermore, ancestral reconstruction can potentially be used to infer the genetic sequence of the transmitted HIV variants that have gone on to establish the next infection, with the objective of identifying distinguishing characteristics of these variants (as a non-random selection of the transmitted population of viruses) that may be targeted for vaccine design. Genome rearrangements Rather than inferring the ancestral DNA sequence, one may be interested in the larger-scale molecular structure and content of an ancestral genome. This problem is often approached