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CYNTENATOR manuscript accepted

CYNTENATOR: Progressive gene order alignment of 17 vertebrate genomes

Background

Whole genome gene order evolution in higher eukaryotes was initially considered as a random process. Gene order conservation or conserved synteny was seen as a feature of common descent and did not imply the existence of functional constraints. This view had to be revised in the light of results from sequencing dozens of vertebrate genomes. It became apparent, that other factors exist, which constrain gene order in some genomic regions over long evolutionary time periods. Outside of these regions, genomes diverge more rapidly in terms of gene content and order.

Method

We have developed CYNTENATOR, a progressive gene order alignment software, to identify genomic regions of conserved synteny over a large set of diverging species. CYNTENATOR does not depend on nucleotide level alignments and a priori homology assignment. Our software implements an improved scoring function, which utilizes the underlying phylogeny. In this manuscript, we report on our progressive gene order alignment approach, a comparison to previous software and an analysis of 17 vertebrate genomes for conservation in gene order. CYNTENATOR has a runtime complexity of O(n3) and a space complexity of O(n2) with n being the gene number in a genome. CYNTENATOR performs as good as state-of-the art software on simulated pairwise gene order comparisons, but is the only algorithm that works in practice for aligning dozens of vertebrate-sized gene orders. Lineage specific characterization of gene order across 17 vertebrate genomes revealed mechanisms for maintaining conserved synteny such as enhancers and coregulation by bidirectional promoters. Genes outside conserved synteny blocks show enrichments for responses to external stimuli such as immunity, olfactory response in primate genome comparisons. We even see significant gene enrichments for breakpoint regions of ancestral nodes close to the root of the phylogeny. Additionally, our analysis of transposable elements has revealed a significant accumulation of LINE-1 elements in mammalian breakpoint regions.

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