phylogenetic tree (i.e., a biased phylogenetic tree due to ignoring recombination can bias the reconstructed ancestral sequences ). In contrast, some researchers advocate a more computationally intensive Bayesian approach that accounts for uncertainty in tree reconstruction by evaluating ancestral reconstructions over many trees. History The concept of ancestral reconstruction is often credited to Emile Zuckerkandl and Linus Pauling. Motivated by the development of techniques for determining the primary (amino acid) sequence of proteins by Frederick Sanger in 1955, Zuckerkandl and Pauling postulated that such sequences could be used to infer not only the phylogeny relating the observed protein sequences, but also the ancestral protein sequence at the earliest point (root) of this tree. However, the idea of reconstructing ancestors from measurable biological characteristics had already been developing in the field of cladistics, one of the precursors of modern phylogenetics. Cladistic methods, which appeared as early as 1901, infer the evolutionary relationships of species on the basis of the distribution of shared characteristics, of which some are inferred to be descended from common ancestors. Furthermore, Theodosius Dobzhansky and Alfred Sturtevant articulated the principles of ancestral reconstruction in a phylogenetic context in 1938, when inferring the evolutionary history of chromosomal inversions in Drosophila pseudoobscura. Thus, ancestral reconstruction has its roots in several disciplines. Today, computational methods for ancestral reconstruction continue to be extended and applied in a diversity of settings, so that ancestral states are being inferred not only for biological characteristics and the molecular sequences, but also for the structure or catalytic properties of ancient versus modern proteins, the geographic location of populations and species (phylogeography) and the higher-order structure of genomes. Methods and algorithms Any attempt at ancestral reconstruction begins with a phylogeny. In general, a phylogeny is a tree-based hypothesis about the order in which populations (referred to as taxa) are related by descent from common ancestors. Observed taxa are represented by the tips or terminal nodes of the tree that are progressively connected by branches to their common ancestors, which are represented by the branching points of the tree that are usually referred to as the ancestral or internal nodes. Eventually, all lineages converge to the most recent common ancestor of the entire sample of taxa. In the context of ancestral reconstruction, a phylogeny is often treated as though it were a known quantity (with Bayesian approaches being an important exception). Because there can be an enormous number