Biostatistics Advance Access published online on June 18, 2008
Biostatistics, doi:10.1093/biostatistics/kxn019
StepBrothers: inferring partially shared ancestries among recombinant viral sequences
Department of Biostatistics, UCLA School of Public Health, Los Angeles, CA 90095, USA
Departments of Statistics and Genetics, Development and Cell Biology, Iowa State University, Ames, IA 50011-3260, USA
Departments of Biomathematics and Human Genetics, David Geffen School of Medicine at UCLA, Los Angeles, CA 90095-1766, USA and Department of Biostatistics, UCLA School of Public Health, Los Angeles, CA 90095-1766, USA msuchard{at}ucla.edu
* To whom correspondence should be addressed.
Phylogeneticists have developed several statistical methods to infer recombination among molecular sequences that are evolutionarily related. Of these methods, Markov change-point models currently provide the most coherent framework. Yet, the Markov assumption is faulty in that the inferred relatedness of homologous sequences across regions divided by recombinant events is not independent, particularly for nonrecombinant sequences as they share the same history. To correct this limitation, we introduce a novel random tips (RT) model. The model springs from the idea that a recombinant sequence inherits its characters from an unknown number of ancestral full-length sequences, of which one only observes the incomplete portions. The RT model decomposes recombinant sequences into their ancestral portions and then augments each portion onto the data set as unique partially observed sequences. This data augmentation generates a random number of sequences related to each other through a single inferable tree with the same random number of tips. While intuitively pleasing, this single tree corrects the independence assumptions plaguing previous methods while permitting the detection of recombination. The single tree also allows for inference of the relative times of recombination events and generalizes to incorporate multiple recombinant sequences. This generalization answers important questions with which previous models struggle. For example, we demonstrate that a group of human immunodeficiency type 1 recombinant viruses from Argentina, previously thought to have the same recombinant history, actually consist of 2 groups: one, a clonal expansion of a reference sequence and another that predates the formation of the reference sequence. In another example, we demonstrate that 2 hepatitis B virus recombinant strains share similar splicing locations, suggesting a common descent of the 2 viruses. We implement and run both examples in a software package called StepBrothers, freely available to interested parties.
Keywords: Bayesian; Hepatitis B virus; Human Immunodeficiency Virus; Phylogeny; Recombination
Received October 16, 2007; revised March 21, 2008; accepted for publication May 16, 2008.