Dataset Information

Accurate prediction of orthologs in the presence of divergence after duplication.

ABSTRACT:

Motivation

When gene duplication occurs, one of the copies may become free of selective pressure and evolve at an accelerated pace. This has important consequences on the prediction of orthology relationships, since two orthologous genes separated by divergence after duplication may differ in both sequence and function. In this work, we make the distinction between the primary orthologs, which have not been affected by accelerated mutation rates on their evolutionary path, and the secondary orthologs, which have. Similarity-based prediction methods will tend to miss secondary orthologs, whereas phylogeny-based methods cannot separate primary and secondary orthologs. However, both types of orthology have applications in important areas such as gene function prediction and phylogenetic reconstruction, motivating the need for methods that can distinguish the two types.

Results

We formalize the notion of divergence after duplication and provide a theoretical basis for the inference of primary and secondary orthologs. We then put these ideas to practice with the Hybrid Prediction of Paralogs and Orthologs (HyPPO) framework, which combines ideas from both similarity and phylogeny approaches. We apply our method to simulated and empirical datasets and show that we achieve superior accuracy in predicting primary orthologs, secondary orthologs and paralogs.

Availability and implementation

HyPPO is a modular framework with a core developed in Python and is provided with a variety of C++?modules. The source code is available at https://github.com/manuellafond/HyPPO.

Supplementary information

Supplementary data are available at Bioinformatics online.

SUBMITTER: Lafond M

PROVIDER: S-EPMC6022570 | biostudies-literature | 2018 Jul

REPOSITORIES: biostudies-literature

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Publications

Accurate prediction of orthologs in the presence of divergence after duplication.

Lafond Manuel M Meghdari Miardan Mona M Sankoff David D

Bioinformatics (Oxford, England) 20180701 13

<h4>Motivation</h4>When gene duplication occurs, one of the copies may become free of selective pressure and evolve at an accelerated pace. This has important consequences on the prediction of orthology relationships, since two orthologous genes separated by divergence after duplication may differ in both sequence and function. In this work, we make the distinction between the primary orthologs, which have not been affected by accelerated mutation rates on their evolutionary path, and the second ...[more]

PMID: 29950018

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Project description:Despite over a billion years of evolutionary divergence, several thousand human genes possess clearly identifiable orthologs in yeast, and many have undergone lineage-specific duplications in one or both lineages. These duplicated genes may have been free to diverge in function since their expansion, and it is unclear how or at what rate ancestral functions are retained or partitioned among co-orthologs between species and within gene families. Thus, in order to investigate how ancestral functions are retained or lost post-duplication, we systematically replaced hundreds of essential yeast genes with their human orthologs from gene families that have undergone lineage-specific duplications, including those with single duplications (1 yeast gene to 2 human genes, 1:2) or higher-order expansions (1:>2) in the human lineage. We observe a variable pattern of replaceability across different ortholog classes, with an obvious trend toward differential replaceability inside gene families, and rarely observe replaceability by all members of a family. We quantify the ability of various properties of the orthologs to predict replaceability, showing that in the case of 1:2 orthologs, replaceability is predicted largely by the divergence and tissue-specific expression of the human co-orthologs, i.e., the human proteins that are less diverged from their yeast counterpart and more ubiquitously expressed across human tissues more often replace their single yeast ortholog. These trends were consistent with in silico simulations demonstrating that when only one ortholog can replace its corresponding yeast equivalent, it tends to be the least diverged of the pair. Replaceability of yeast genes having more than 2 human co-orthologs was marked by retention of orthologous interactions in functional or protein networks as well as by more ancestral subcellular localization. Overall, we performed >400 human gene replaceability assays, revealing 50 new human-yeast complementation pairs, thus opening up avenues to further functionally characterize these human genes in a simplified organismal context.

Dataset Information

Accurate prediction of orthologs in the presence of divergence after duplication.

Motivation

Results

Availability and implementation

Supplementary information

Publications

Accurate prediction of orthologs in the presence of divergence after duplication.

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