Xenolog classification

Abstract

Motivation: Orthology analysis is a fundamental tool in comparative genomics. Sophisticated methods have been developed to distinguish between orthologs and paralogs and to classify paralogs into subtypes depending on the duplication mechanism and timing, relative to speciation. However, no comparable framework exists for xenologs: gene pairs whose history, since their divergence, includes a horizontal transfer. Further, the diversity of gene pairs that meet this broad definition calls for classification of xenologs with similar properties into subtypes.

Results: We present a xenolog classification that uses phylogenetic reconciliation to assign each pair of genes to a class based on the event responsible for their divergence and the historical association between genes and species. Our classes distinguish between genes related through transfer alone and genes related through duplication and transfer. Further, they separate closely-related genes in distantly-related species from distantly-related genes in closely-related species. We present formal rules that assign gene pairs to specific xenolog classes, given a reconciled gene tree with an arbitrary number of duplications and transfers. These xenology classification rules have been implemented in software and tested on a collection of ∼13 000 prokaryotic gene families. In addition, we present a case study demonstrating the connection between xenolog classification and gene function prediction.

Availability and implementation: The xenolog classification rules have been implemented in N otung 2.9, a freely available phylogenetic reconciliation software package. http://www.cs.cmu.edu/~durand/Notung . Gene trees are available at http://dx.doi.org/10.7488/ds/1503 .

Contact: durand@cmu.edu.

Supplementary information: Supplementary data are available at Bioinformatics online.

Fig. 1.

Gene tree (thin black lines), with a duplication and a transfer from species Y to species X, embedded in a species tree (shown in gray). The cenancestor of the transfer is designated a_s. Species sets D, R and O are labeled below the leaves

Fig. 2.

Xenolog class hierarchy: (top) Gene tree with one transfer, shown in the context of the species tree. (bottom) The reconciled gene tree. Each leaf is annotated with its xenolog class. Nodes $g_1,g_2,g_3$ and g₄ are the common ancestors of $\widehat{g}$ and, respectively, the Primary, Sibling Donor, Sibling Recipient and Outgroup xenologs in the tree, as indicated by the labels on internal nodes. The labels on the path from $\widehat{g}$ to the root satisfy the hierarchy, $\mathrm{PX}{<}_X\mathrm{SDX}{<}_X\mathrm{SRX}{<}_X\mathrm{OX}$, consistent with Theorem 2.1

Fig. 3.

Paraxenolog classification: The gene tree in Figure 1, which contains a duplication followed by a transfer. Each leaf is annotated with its xenolog class. Each internal node on the path from $\widehat{g}$ to the root is labeled with the xenolog class of all genes in its right subtree (i.e. the subtree that does not contain a transfer.) The progression of labels satisfy the xenolog hierarchy, consistent with Theorem 2.1.

Fig. 4.

Xenolog classification with multiple transfers: (top) Gene tree with two comparable transfers (solid arrows) and the associated super-transfer (dashed arrow), shown in the context of the species tree. (bottom) The reconciled gene tree. Each leaf is annotated with its xenolog class. Genes g_X and g_U are classified with respect to t² and obey the hierarchy: $\text{MRCA}(\widehat{g},g_X){<}_G\text{MRCA}(\widehat{g},g_U)$ and $\mathcal{X}(\widehat{g},g_X)=\mathrm{PX}{<}_X\mathcal{X}(\widehat{g},g_U)=\mathrm{SDX}$. All other genes are classified with respect to the super-transfer, $t^{*}$. Their xenolog classes are consistent with the hierarchy (Theorem 2.1): $\text{MRCA}(\widehat{g},g_Y){<}_G\text{MRCA}(\widehat{g},g_Z){<}_G\text{MRCA}(\widehat{g},g_W){<}_G\text{MRCA}(\widehat{g},g_V)$ and $\mathrm{PX}{<}_X\mathrm{SDX}{<}_X\mathrm{SRX}{<}_X\mathrm{OX}$

Fig. 5.

Xenolog classification with incomparable transfers: (top) Gene tree with two incomparable transfers shown in the context of the species tree. Species sets associated with transfers $t^1$ and $t^2$ are shown below the leaves. (bottom) The reconciled gene tree. Each leaf is annotated with its xenolog class in reference to t² (top row) and t¹ (bottom row). Genes ${\widehat{g}}_1$ and ${\widehat{g}}_2$ are separated by both transfers. Since ${\widehat{g}}_2\in \Delta (g_d^1),\hspace{0.17em}\mathcal{X}({\widehat{g}}_1,g_2)=\mathrm{PX}$. In contrast, $\mathcal{X}({\widehat{g}}_2,g_1)=\mathrm{IX}$ since ${\widehat{g}}_1\cancel{\notin }\Delta (g_d^2)$. Xenolog classes for other genes are consistent with their relatedness in the gene tree (Theorem 2.1): $\text{MRCA}({\widehat{g}}_2,g_Y){<}_G\text{MRCA}({\widehat{g}}_2,g_Z){<}_G\text{MRCA}({\widehat{g}}_2,g_W)=\text{MRCA}({\widehat{g}}_2,g_X){<}_G\text{MRCA}({\widehat{g}}_2,g_V)$ and $\mathrm{PX}{<}_X\mathrm{SDX}{<}_X\mathrm{SRX}{<}_X\mathrm{OX}$

Fig. 6.

(left) Proportions of orthologs, paralogs and xenologs (all classes) in the 13 194-tree bacterial dataset. (right) Proportions of xenolog classes

Fig. 7.

Summary of the BIO4 gene family event history. Dashed lines represent lineages with a putative dual-function DTBS + DAPAS enzyme; solid lines represent lineages with a putative DTBS-only function. With respect to the gene $\widehat{g}$ in S.cerevisiae, all other fungal genes are SRX, α-proteobacterial genes are PX, and genes in Firmicutes are SDX