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Identification of mammalian orthologs using local synteny.

ABSTRACT: BACKGROUND: 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. RESULTS: 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. CONCLUSIONS: 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.

SUBMITTER: Jun J

PROVIDER: S-EPMC2807883 | biostudies-literature | 2009

REPOSITORIES: biostudies-literature

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Identification of mammalian orthologs using local synteny.

Jun Jin J Mandoiu Ion I II Nelson Craig E CE

BMC genomics 20091223

<h4>Background</h4>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 ...[more]

PMID: 20030836

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Project description:BACKGROUND:The evolutionary history of genes serves as a cornerstone of contemporary biology. Most conserved sequences in mammalian genomes don't code for proteins, yielding a need to infer evolutionary history of sequences irrespective of what kind of functional element they may encode. Thus, sequence-, as opposed to gene-, centric modes of inferring paths of sequence evolution are increasingly relevant. Customarily, homologous sequences derived from the same direct ancestor, whose ancestral position in two genomes is usually conserved, are termed "primary" (or "positional") orthologs. Methods based solely on similarity don't reliably distinguish primary orthologs from other homologs; for this, genomic context is often essential. Context-dependent identification of orthologs traditionally relies on genomic context over length scales characteristic of conserved gene order or whole-genome sequence alignment, and can be computationally intensive. RESULTS:We demonstrate that short-range sequence context-as short as a single "maximal" match- distinguishes primary orthologs from other homologs across whole genomes. On mammalian whole genomes not preprocessed by repeat-masker, potential orthologs are extracted by genome intersection as "non-nested maximal matches:" maximal matches that are not nested into other maximal matches. It emerges that on both nucleotide and gene scales, non-nested maximal matches recapitulate primary or positional orthologs with high precision and high recall, while the corresponding computation consumes less than one thirtieth of the computation time required by commonly applied whole-genome alignment methods. In regions of genomes that would be masked by repeat-masker, non-nested maximal matches recover orthologs that are inaccessible to Lastz net alignment, for which repeat-masking is a prerequisite. mmRBHs, reciprocal best hits of genes containing non-nested maximal matches, yield novel putative orthologs, e.g. around 1000 pairs of genes for human-chimpanzee. CONCLUSIONS:We describe an intersection-based method that requires neither repeat-masking nor alignment to infer evolutionary history of sequences based on short-range genomic sequence context. Ortholog identification based on non-nested maximal matches is parameter-free, and less computationally intensive than many alignment-based methods. It is especially suitable for genome-wide identification of orthologs, and may be applicable to unassembled genomes. We are agnostic as to the reasons for its effectiveness, which may reflect local variation of mean mutation rate.

Dataset Information

Identification of mammalian orthologs using local synteny.

Publications

Identification of mammalian orthologs using local synteny.

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