Description

This track shows a measure of evolutionary conservation in $organism, human and mouse, based on a phylogenetic hidden Markov model (phastCons). Multiz alignments of the following assemblies were used to generate this annotation: $organism $date ($db), human May 2004 (hg17), and mouse May 2004 (mm5).

In full display mode, this track shows the overall conservation score across all species as well as pairwise alignments of human and mouse, each aligned to the $organism genome. The pairwise alignments are shown in dense display mode using a grayscale density gradient. The checkboxes in the track configuration section allow the exclusion of species from the pairwise display; however, this does not remove them from the conservation score display.

When zoomed-in to the base-display level, the track shows the base composition of each alignment. The numbers and symbols on the "$organism gap" line indicate the lengths of gaps in the $organism sequence at those alignment positions. If the gap size is greater than 9, the "+" symbol is displayed. To view detailed information about the alignments at a specific position, zoom in the display to 30,000 or fewer bases, then click on the alignment.

This track may be configured in a variety of ways to highlight different aspects of the displayed information. Click the "Graph configuration help" link for an explanation of the configuration options.

Methods

Best-in-genome blastz pairwise alignments of $organism-human and $organism-mouse were multiply aligned using multiz. The resulting multiple alignments were then assigned conservation scores by phastCons.

The phastCons program computes conservation scores based on a phylo-HMM, a type of probabilistic model that describes both the process of DNA substitution at each site in a genome and the way this process changes from one site to the next (Felsenstein and Churchill 1996, Yang 1995, Siepel and Haussler 2003, Siepel and Haussler 2004). In this case, a two-state phylo-HMM was used, with a state for conserved regions and a state for non-conserved regions. The value plotted at each site is the posterior probability that the corresponding alignment column was "generated" by the conserved state of the phylo-HMM. These scores reflect the phylogeny (including branch lengths) of the species in question, a continuous-time Markov model of the nucleotide substitution process, and a tendency for conservation levels to be autocorrelated along the genome (i.e., to be similar at adjacent sites). The general reversible (REV) substitution model was used, and variation of substitution rates within each major category of sites (conserved and non-conserved) was allowed for using Yang's (1994) discrete gamma model. Note that, unlike many conservation-scoring programs, phastCons does not rely on a sliding window of fixed size, so short highly-conserved regions and long moderately conserved regions can both obtain high scores.

PhastCons currently treats alignment gaps as missing data, which sometimes has the effect of producing undesirably high conservation scores in gappy regions of the alignment. We are looking at several possible ways of improving the handling of alignment gaps.

Credits

This track was created at UCSC using the following programs:

References

Phylo-HMM

Felsenstein J and Churchill GA (1996). A hidden Markov model approach to variation among sites in rate of evolution. Mol Biol Evol 13:93-104.

Siepel A and Haussler D (2003). Combining phylogenetic and hidden Markov models in biosequence analysis. In Proceedings of the Seventh Annual International Conference on Computational Molecular Biology (RECOMB 2003), pp. 277-286.

Siepel A and Haussler D (2004). Phylogenetic hidden Markov models. In R. Nielsen, ed., Statistical Methods in Molecular Evolution, Springer (in press).

Yang Z (1994). Maximum likelihood phylogenetic estimation from DNA sequences with variable rates over sites: approximate methods, J Mol Evol 39:306-314.

Yang Z (1995). A space-time process model for the evolution of DNA sequences. Genetics, 139:993-1005.

Chain/Net

Kent WJ, Baertsch R, Hinrichs A, Miller W, and Haussler D (2003). Evolution's cauldron: Duplication, deletion, and rearrangement in the mouse and human genomes. Proc Natl Acad Sci USA 100(20):11484-11489 Sep 30 2003.

Multiz

Blanchette M, Kent WJ, Riemer C, Elnitski L, Smit AFA, Roskin KM, Baertsch R, Rosenbloom K, Clawson H, Green ED, Haussler D, Miller W. (2004). Aligning Multiple Genomic Sequences with the Threaded Blockset Aligner. Genome Res. 14(4):708-15.

Blastz

Chiaromonte F, Yap VB, and Miller W (2002). Scoring pairwise genomic sequence alignments. Pac Symp Biocomput 2002;:115-26.

Schwartz S, Kent WJ, Smit A, Zhang Z, Baertsch R, Hardison R, Haussler D, and Miller W. (2003). Human-Mouse Alignments with BLASTZ. Genome Res. 13(1):103-7.