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Cdx ParaHox genes acquired distinct developmental roles after gene duplication in vertebrate evolution.

Marlétaz F, Maeso I, Faas L, Isaacs HV, Holland PW - BMC Biol. (2015)

Bottom Line: We found that one paralogue, Cdx4, has a much stronger effect on gene expression than the others, including a strong regulatory effect on FGF and Wnt genes.The data also reveal a colinear-like effect of Cdx genes on Hox genes, with repression of Hox paralogy groups 1 and 2, and activation increasing from Hox group 5 to 11.We therefore suggest that developmental programmes were extensively rewired after whole genome duplication in the early evolution of vertebrates.

View Article: PubMed Central - PubMed

Affiliation: Department of Zoology, University of Oxford, South Parks Road, Oxford, OX1 3PS, UK. ferdinand.marletaz@gmail.com.

ABSTRACT

Background: The functional consequences of whole genome duplications in vertebrate evolution are not fully understood. It remains unclear, for instance, why paralogues were retained in some gene families but extensively lost in others. Cdx homeobox genes encode conserved transcription factors controlling posterior development across diverse bilaterians. These genes are part of the ParaHox gene cluster. Multiple Cdx copies were retained after genome duplication, raising questions about how functional divergence, overlap, and redundancy respectively contributed to their retention and evolutionary fate.

Results: We examined the degree of regulatory and functional overlap between the three vertebrate Cdx genes using single and triple morpholino knock-down in Xenopus tropicalis followed by RNA-seq. We found that one paralogue, Cdx4, has a much stronger effect on gene expression than the others, including a strong regulatory effect on FGF and Wnt genes. Functional annotation revealed distinct and overlapping roles and subtly different temporal windows of action for each gene. The data also reveal a colinear-like effect of Cdx genes on Hox genes, with repression of Hox paralogy groups 1 and 2, and activation increasing from Hox group 5 to 11. We also highlight cases in which duplicated genes regulate distinct paralogous targets revealing pathway elaboration after whole genome duplication.

Conclusions: Despite shared core pathways, Cdx paralogues have acquired distinct regulatory roles during development. This implies that the degree of functional overlap between paralogues is relatively low and that gene expression pattern alone should be used with caution when investigating the functional evolution of duplicated genes. We therefore suggest that developmental programmes were extensively rewired after whole genome duplication in the early evolution of vertebrates.

No MeSH data available.


K-mean clustering of multiple Cdx MOs effects. a Heatmap representation of gene expression fold-changes triggered by the three Cdx MOs and the co-injection triple MOs. Genes are arranged according to k-mean clustering and 12 clusters (left) are delineated to capture the diversity of responses to treatments. b Detail of gene expression response to Cdx MOs in the 12 selected clusters. The average response is plotted as a bold line while response of each member gene of the cluster is plotted in a thin grey line
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Fig3: K-mean clustering of multiple Cdx MOs effects. a Heatmap representation of gene expression fold-changes triggered by the three Cdx MOs and the co-injection triple MOs. Genes are arranged according to k-mean clustering and 12 clusters (left) are delineated to capture the diversity of responses to treatments. b Detail of gene expression response to Cdx MOs in the 12 selected clusters. The average response is plotted as a bold line while response of each member gene of the cluster is plotted in a thin grey line

Mentions: To identify differentially regulated gene sets, we applied a clustering procedure on expression fold-change in the distinct MO treatments, using all genes that are differentially expressed in at least one condition (Fig. 3). These analyses revealed diverse gene sets with markedly different response pattern to distinct Cdx MOs. For example, genes in clusters 6 and 8 are strongly up-regulated by disruption of Cdx4 function, but not at all are affected by Cdx1 or Cdx2 disruption. Similarly, cluster 5 and 7 genes show specific down-regulation with Cdx4 disruption. In contrast, clusters 1, 2, 9, and 10 are up- or down-regulated by disruption of any of the three Cdx genes, albeit more strongly by Cdx4 disruption. Cluster 12 genes respond to interference of Cdx1 and Cdx4, but not Cdx2; cluster 11 genes are affected by Cdx1 and Cdx2 but not Cdx4. We examined functional categories associated with these diverse responses by performing term enrichment analyses on each of these gene sets (Additional file 4: Table S3). We found clear functional distinctiveness of some clusters: cluster 1 is closely associated with Wnt signalling (14 genes, P = 0.03), cluster 2 is enriched in genes involved in embryo development (12 genes, P = 0.01), and cluster 8 in chromatin organization-related genes (230 genes, P = 0.009). While most clusters are enriched in one or a few terms, cluster 9 captures several specific developmental processes, such as angiogenesis and digestive tract development, that are classically associated with Cdx function.Fig. 3


Cdx ParaHox genes acquired distinct developmental roles after gene duplication in vertebrate evolution.

Marlétaz F, Maeso I, Faas L, Isaacs HV, Holland PW - BMC Biol. (2015)

K-mean clustering of multiple Cdx MOs effects. a Heatmap representation of gene expression fold-changes triggered by the three Cdx MOs and the co-injection triple MOs. Genes are arranged according to k-mean clustering and 12 clusters (left) are delineated to capture the diversity of responses to treatments. b Detail of gene expression response to Cdx MOs in the 12 selected clusters. The average response is plotted as a bold line while response of each member gene of the cluster is plotted in a thin grey line
© Copyright Policy - open-access
Related In: Results  -  Collection

License 1 - License 2
Show All Figures
getmorefigures.php?uid=PMC4522105&req=5

Fig3: K-mean clustering of multiple Cdx MOs effects. a Heatmap representation of gene expression fold-changes triggered by the three Cdx MOs and the co-injection triple MOs. Genes are arranged according to k-mean clustering and 12 clusters (left) are delineated to capture the diversity of responses to treatments. b Detail of gene expression response to Cdx MOs in the 12 selected clusters. The average response is plotted as a bold line while response of each member gene of the cluster is plotted in a thin grey line
Mentions: To identify differentially regulated gene sets, we applied a clustering procedure on expression fold-change in the distinct MO treatments, using all genes that are differentially expressed in at least one condition (Fig. 3). These analyses revealed diverse gene sets with markedly different response pattern to distinct Cdx MOs. For example, genes in clusters 6 and 8 are strongly up-regulated by disruption of Cdx4 function, but not at all are affected by Cdx1 or Cdx2 disruption. Similarly, cluster 5 and 7 genes show specific down-regulation with Cdx4 disruption. In contrast, clusters 1, 2, 9, and 10 are up- or down-regulated by disruption of any of the three Cdx genes, albeit more strongly by Cdx4 disruption. Cluster 12 genes respond to interference of Cdx1 and Cdx4, but not Cdx2; cluster 11 genes are affected by Cdx1 and Cdx2 but not Cdx4. We examined functional categories associated with these diverse responses by performing term enrichment analyses on each of these gene sets (Additional file 4: Table S3). We found clear functional distinctiveness of some clusters: cluster 1 is closely associated with Wnt signalling (14 genes, P = 0.03), cluster 2 is enriched in genes involved in embryo development (12 genes, P = 0.01), and cluster 8 in chromatin organization-related genes (230 genes, P = 0.009). While most clusters are enriched in one or a few terms, cluster 9 captures several specific developmental processes, such as angiogenesis and digestive tract development, that are classically associated with Cdx function.Fig. 3

Bottom Line: We found that one paralogue, Cdx4, has a much stronger effect on gene expression than the others, including a strong regulatory effect on FGF and Wnt genes.The data also reveal a colinear-like effect of Cdx genes on Hox genes, with repression of Hox paralogy groups 1 and 2, and activation increasing from Hox group 5 to 11.We therefore suggest that developmental programmes were extensively rewired after whole genome duplication in the early evolution of vertebrates.

View Article: PubMed Central - PubMed

Affiliation: Department of Zoology, University of Oxford, South Parks Road, Oxford, OX1 3PS, UK. ferdinand.marletaz@gmail.com.

ABSTRACT

Background: The functional consequences of whole genome duplications in vertebrate evolution are not fully understood. It remains unclear, for instance, why paralogues were retained in some gene families but extensively lost in others. Cdx homeobox genes encode conserved transcription factors controlling posterior development across diverse bilaterians. These genes are part of the ParaHox gene cluster. Multiple Cdx copies were retained after genome duplication, raising questions about how functional divergence, overlap, and redundancy respectively contributed to their retention and evolutionary fate.

Results: We examined the degree of regulatory and functional overlap between the three vertebrate Cdx genes using single and triple morpholino knock-down in Xenopus tropicalis followed by RNA-seq. We found that one paralogue, Cdx4, has a much stronger effect on gene expression than the others, including a strong regulatory effect on FGF and Wnt genes. Functional annotation revealed distinct and overlapping roles and subtly different temporal windows of action for each gene. The data also reveal a colinear-like effect of Cdx genes on Hox genes, with repression of Hox paralogy groups 1 and 2, and activation increasing from Hox group 5 to 11. We also highlight cases in which duplicated genes regulate distinct paralogous targets revealing pathway elaboration after whole genome duplication.

Conclusions: Despite shared core pathways, Cdx paralogues have acquired distinct regulatory roles during development. This implies that the degree of functional overlap between paralogues is relatively low and that gene expression pattern alone should be used with caution when investigating the functional evolution of duplicated genes. We therefore suggest that developmental programmes were extensively rewired after whole genome duplication in the early evolution of vertebrates.

No MeSH data available.