Identification of mammalian orthologs using local synteny

<p>Abstract</p> <p>Background</p> <p>Accurate determination of orthology is central to comparative genomics. For vertebrates in particular, very large gene families, high rates of gene duplication and loss, multiple mechanisms of gene duplication, and high rates of retrotransposition all combine to make inference of orthology between genes difficult. Many methods have been developed to identify orthologous genes, mostly based upon analysis of the inferred protein sequence of the genes. More recently, methods have been proposed that use genomic context in addition to protein sequence to improve orthology assignment in vertebrates. Such methods have been most successfully implemented in fungal genomes and have long been used in prokaryotic genomes, where gene order is far less variable than in vertebrates. However, to our knowledge, no explicit comparison of synteny and sequence based definitions of orthology has been reported in vertebrates, or, more specifically, in mammals.</p> <p>Results</p> <p>We test a simple method for the measurement and utilization of gene order (local synteny) in the identification of mammalian orthologs by investigating the agreement between coding sequence based orthology (Inparanoid) and local synteny based orthology. In the 5 mammalian genomes studied, 93% of the sampled inter-species pairs were found to be concordant between the two orthology methods, illustrating that local synteny is a robust substitute to coding sequence for identifying orthologs. However, 7% of pairs were found to be discordant between local synteny and Inparanoid. These cases of discordance result from evolutionary events including retrotransposition and genome rearrangements.</p> <p>Conclusions</p> <p>By analyzing cases of discordance between local synteny and Inparanoid we show that local synteny can distinguish between true orthologs and recent retrogenes, can resolve ambiguous many-to-many orthology relationships into one-to-one ortholog pairs, and might be used to identify cases of non-orthologous gene displacement by retroduplicated paralogs.</p

A parsimony approach to genome-wide ortholog assignment

Abstract. The assignment of orthologous genes between a pair of genomes is a fundamental and challenging problem in comparative genomics, since many computational methods for solving various biological problems critically rely on bona fide orthologs as input. While it is usually done using sequence similarity search, we recently proposed a new combinatorial approach that combines sequence similarity and genome rearrangement. This paper continues the development of the approach and unites genome rearrangement events and (post-speciation) duplication events in a single framework under the parsimony principle. In this framework, orthologous genes are assumed to correspond to each other in the most parsimonious evolutionary scenario involving both genome rearrangement and (post-speciation) gene duplication. Besides several original algorithmic contributions, the enhanced method allows for the detection of inparalogs. Following this approach, we have implemented a high-throughput system for ortholog assignment on a genome scale, called MSOAR, and applied it to the genomes of human and mouse. As the result will show, MSOAR is able to find 99 more true orthologs than the INPARANOID program did. We have also compared MSOAR with the iterated exemplar algorithm on simulated data and found that MSOAR performed very well in terms of assignment accuracy. These test results indiate that our approach is very promising for genome-wide ortholog assignment.