  We describe a new global multiple alignment program capable of aligning a
large number of genomic regions. Our progressive alignment approach
incorporates the following ideas: maximum-likelihood inference of ancestral
sequences, automatic guide-tree construction, protein based anchoring of
ab-initio gene predictions, and constraints derived from a global homology map
of the sequences. We have implemented these ideas in the MAVID program, which
is able to accurately align multiple genomic regions up to megabases long.
MAVID is able to effectively align divergent sequences, as well as incomplete
unfinished sequences. We demonstrate the capabilities of the program on the
benchmark CFTR region which consists of 1.8Mb of human sequence and 20
orthologous regions in marsupials, birds, fish, and mammals. Finally, we
describe two large MAVID alignments: an alignment of all the available HIV
genomes and a multiple alignment of the entire human, mouse and rat genomes.
