Approaches to comparative sequence analysis: towards a functional view of vertebrate genomes

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Abstract
The identification of evolutionarily constrained sequences is an unbiased approach for finding functional sequences in genomes. However, their identification is strongly affected by upstream analyses. Genomes are sequenced to different levels of finishing, which affects downstream comparative analyses. Before genomic sequences can be aligned, segments of homologous collinearity must be identified. Errors at this stage can have a dramatic effect on the identification of constrained sequences. Base-pair sequence-alignment programs differentially handle the complexities of evolution, such as insertions/deletions and duplications. In addition, new approaches to identify regions of alignment uncertainty can be used. Current approaches that utilize evolutionary sequence constraint focus on regions that are deeply constrained. Newer approaches combined with sequences from more species can now be pursued to identify weakly and/or lineage-specific constrained sequences. The amount of detectable constrained sequence depends on the phylogenetic scope being pursued as well as the resolution and intensity of the desired detectable constraint. Large collaborative projects such as ENCODE are shedding light on the correlation between sequence constraint and sequence function. Additional methods are also available for determining the biological significance of constrained sequences.

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