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Pervasive duplication of tumor suppressors in Afrotherians during the evolution of large bodies and reduced cancer risk

Vazquez, Juan M, Lynch, Vincent J·2021·eLife
DOI 10.7554/elife.65041PMC PMC7952090

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Abstract

The risk of developing cancer is correlated with body size and lifespan within species. Between species, however, there is no correlation between cancer and either body size or lifespan, indicating that large, long-lived species have evolved enhanced cancer protection mechanisms. Elephants and their relatives (Proboscideans) are a particularly interesting lineage for the exploration of mechanisms underlying the evolution of augmented cancer resistance because they evolved large bodies recently within a clade of smaller-bodied species (Afrotherians). Here, we explore the contribution of gene duplication to body size and cancer risk in Afrotherians. Unexpectedly, we found that tumor suppressor duplication was pervasive in Afrotherian genomes, rather than restricted to Proboscideans. Proboscideans, however, have duplicates in unique pathways that may underlie some aspects of their remarkable anti-cancer cell biology. These data suggest that duplication of tumor suppressor genes facilitated the evolution of increased body size by compensating for decreasing intrinsic cancer risk.

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Figure 1. Large-bodied Afrotherians are nested within species with smaller body sizes (Tacutu et al., 2013; Puttick and Thomas, 2015). (A) Phylogenetic relationships between Eutherian orders, examples of each order are given in parenthesis. Horizontal branch lengths are proportional to time since divergence between lineages (see scale, Millions of Ago [MYA]). The clades Atlantogenata and Boreoeutheria are indicated, the order Proboscidea is colored blue, Sirenia is colored orange, and Hyracoidea is colored red. (B) Phylogenetic relationships of extant and recently extinct Atlantogenatans with available genomes are shown along with clade names and maximum body sizes. Note that horizontal branch lengths are arbitrary, species indicated with skull and crossbones are extinct, and those in parentheses do not have genomes. The order Proboscidea is colored blue, Sirenia is colored orange, and Hyracoidea is colored red.
Figure 1. Large-bodied Afrotherians are nested within species with smaller body sizes (Tacutu et al., 2013; Puttick and Thomas, 2015). (A) Phylogenetic relationships between Eutherian orders, examples of each order are given in parenthesis. Horizontal branch lengths are proportional to time since divergence between lineages (see scale, Millions of Ago [MYA]). The clades Atlantogenata and Boreoeutheria are indicated, the order Proboscidea is colored blue, Sirenia is colored orange, and Hyracoidea is colored red. (B) Phylogenetic relationships of extant and recently extinct Atlantogenatans with available genomes are shown along with clade names and maximum body sizes. Note that horizontal branch lengths are arbitrary, species indicated with skull and crossbones are extinct, and those in parentheses do not have genomes. The order Proboscidea is colored blue, Sirenia is colored orange, and Hyracoidea is colored red.CC BY · PubMed Central
Figure 2. Convergent evolution of large-bodied, cancer resistant Afrotherians. (A) Atlantogenatan phylogeny, with branch lengths scaled by log2 change in body size (left) or log2 change in intrinsic cancer risk (right). Branches are colored according to ancestral state reconstruction of body mass or estimated intrinsic cancer risk. Clades and lineages leading to extant Proboscideans and dwarf elephants are labeled. (B) Extant and ancestral body size (left), lifespan (middle), and estimated intrinsic cancer risk reconstructions; data are shown as mean (dot) and 95% confidence interval (CI, whiskers).
Figure 2. Convergent evolution of large-bodied, cancer resistant Afrotherians. (A) Atlantogenatan phylogeny, with branch lengths scaled by log2 change in body size (left) or log2 change in intrinsic cancer risk (right). Branches are colored according to ancestral state reconstruction of body mass or estimated intrinsic cancer risk. Clades and lineages leading to extant Proboscideans and dwarf elephants are labeled. (B) Extant and ancestral body size (left), lifespan (middle), and estimated intrinsic cancer risk reconstructions; data are shown as mean (dot) and 95% confidence interval (CI, whiskers).CC BY · PubMed Central
Figure 3. Pervasive duplication of tumor suppressors in Atlantogenata. (A) Afrotherian phylogeny indicating the number of genes duplicated in each lineage, inferred by maximum likelihood with Bayesian posterior probability (BPP) ≥0.80. Branches are colored according to log2 change in body size. Inset, phylogeny with branch lengths proportional to gene expression changes per gene. (B) Upset plot of cancer related Reactome pathways enriched in each Afrotherian lineage; lineages in which the cancer pathway enrichment percentage is less than background are shown in gray. Note that Upset plots are Euler diagrams showing intersections between sets; lines indicate intersections in pathway terms between lineages connected by that line (for example, the line connecting the points for Aardvark and Tenrec indicate pathway indications for those two lineages), and empty sets are not shown. (C) Wordcloud of pathways enriched exclusively in the Proboscidean stem-lineage (purple), shared between Proboscidea and Tethytheria (blue), or shared between Proboscidea and any other lineage (green).
Figure 3. Pervasive duplication of tumor suppressors in Atlantogenata. (A) Afrotherian phylogeny indicating the number of genes duplicated in each lineage, inferred by maximum likelihood with Bayesian posterior probability (BPP) ≥0.80. Branches are colored according to log2 change in body size. Inset, phylogeny with branch lengths proportional to gene expression changes per gene. (B) Upset plot of cancer related Reactome pathways enriched in each Afrotherian lineage; lineages in which the cancer pathway enrichment percentage is less than background are shown in gray. Note that Upset plots are Euler diagrams showing intersections between sets; lines indicate intersections in pathway terms between lineages connected by that line (for example, the line connecting the points for Aardvark and Tenrec indicate pathway indications for those two lineages), and empty sets are not shown. (C) Wordcloud of pathways enriched exclusively in the Proboscidean stem-lineage (purple), shared between Proboscidea and Tethytheria (blue), or shared between Proboscidea and any other lineage (green).CC BY · PubMed Central
Figure 3—figure supplement 1. Estimated Copy Number by Coverage (ECNC) consolidates fragmented genes while accounting for missing domains in homologs. (A) A single, contiguous gene homolog in a target genome with 100% query length coverage has an ECNC of 1.0. (B) Two contiguous gene homologs each with 100% query length coverage have an ECNC of 2.0. (C) A single gene homolog, split across multiple scaffolds and contigs in a fragmented target genome; BLAT identifies each fragment as a single hit. Per nucleotide of query sequence, there is only one corresponding nucleotide over all the hits, thus the ECNC is 1.0. (D) Two gene homologs, one fragmented and one contiguous. 100% of nucleotides in the query sequence are represented between all hits; however, every nucleotide in the query has two matching nucleotides in the target genome, thus the ECNC is 2.0. (E) One true gene homolog in the target genome, plus multiple hits of a conserved domain that span 20% of the query sequence. While 100% of the query sequence is represented in total, 20% of the nucleotides have four hits. Thus, the ECNC for this gene is 1.45. (F) Two real gene homologs; one hit is contiguous, one hit is fragmented in two, and the tail end of both sequences was not identified by BLAT due to sequence divergence. Only 75% of the query sequence was covered in total between the hits, but for that 75%, each nucleotide has two hits. As such, ECNC is equal to 2.0 for this gene.
Figure 3—figure supplement 1. Estimated Copy Number by Coverage (ECNC) consolidates fragmented genes while accounting for missing domains in homologs. (A) A single, contiguous gene homolog in a target genome with 100% query length coverage has an ECNC of 1.0. (B) Two contiguous gene homologs each with 100% query length coverage have an ECNC of 2.0. (C) A single gene homolog, split across multiple scaffolds and contigs in a fragmented target genome; BLAT identifies each fragment as a single hit. Per nucleotide of query sequence, there is only one corresponding nucleotide over all the hits, thus the ECNC is 1.0. (D) Two gene homologs, one fragmented and one contiguous. 100% of nucleotides in the query sequence are represented between all hits; however, every nucleotide in the query has two matching nucleotides in the target genome, thus the ECNC is 2.0. (E) One true gene homolog in the target genome, plus multiple hits of a conserved domain that span 20% of the query sequence. While 100% of the query sequence is represented in total, 20% of the nucleotides have four hits. Thus, the ECNC for this gene is 1.45. (F) Two real gene homologs; one hit is contiguous, one hit is fragmented in two, and the tail end of both sequences was not identified by BLAT due to sequence divergence. Only 75% of the query sequence was covered in total between the hits, but for that 75%, each nucleotide has two hits. As such, ECNC is equal to 2.0 for this gene.CC BY · PubMed Central
Figure 3—figure supplement 2. Correlations between genome quality metrics and ECNC metrics. Gene copy number metrics, and the genome quality metrics most strongly associated with them, are highlighted in red.
Figure 3—figure supplement 2. Correlations between genome quality metrics and ECNC metrics. Gene copy number metrics, and the genome quality metrics most strongly associated with them, are highlighted in red.CC BY · PubMed Central
Figure 4. Duplications in the African savannah elephant (Loxodonta africana) are enriched for TP53-related and other tumor suppressor processes. (A) Upset plot of cancer-related Reactome pathways in African savannah elephant, highlighting shared genes in each set, and the pathway class represented by the combinations (see Figure 3 for a description of Upset plots). (B) Inverted Upset plot from A showing the pathways shared by genes highlighted by WEBGESTALT in each pathway. (C) Cladogram of Afrotheria with sequenced genomes. Exemplar tumor suppressor duplicates are mapped onto lineages in which those genes are duplicated. Dots represent a duplication event of the color-coded genes. Note that we are unable to determine duplication status for some genes in Proboscideans because of assembly gaps in ancient genomes (indicated with skull and crossbones); these genes appear to be independently duplicated in extant species (African Forest, African Savanah, and Asian elephants) because they are missing from ancient genomes, biasing ancestral reconstructions of duplication status. (D) Gene expression levels of genes from panel C that have two or more expressed duplicates.
Figure 4. Duplications in the African savannah elephant (Loxodonta africana) are enriched for TP53-related and other tumor suppressor processes. (A) Upset plot of cancer-related Reactome pathways in African savannah elephant, highlighting shared genes in each set, and the pathway class represented by the combinations (see Figure 3 for a description of Upset plots). (B) Inverted Upset plot from A showing the pathways shared by genes highlighted by WEBGESTALT in each pathway. (C) Cladogram of Afrotheria with sequenced genomes. Exemplar tumor suppressor duplicates are mapped onto lineages in which those genes are duplicated. Dots represent a duplication event of the color-coded genes. Note that we are unable to determine duplication status for some genes in Proboscideans because of assembly gaps in ancient genomes (indicated with skull and crossbones); these genes appear to be independently duplicated in extant species (African Forest, African Savanah, and Asian elephants) because they are missing from ancient genomes, biasing ancestral reconstructions of duplication status. (D) Gene expression levels of genes from panel C that have two or more expressed duplicates.CC BY · PubMed Central

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Authors
Vazquez, J. M., & Lynch, V. J.
Venue
eLife
Publisher
eLife Sciences Publications, Ltd
Published
2021-01-29
Volume
10
ISSN
2050-084X
DOI
10.7554/elife.65041
PMC
PMC7952090
Cited by
61
References
10
Language
en
Licence
Funders
University of Chicago

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Vazquez, J. M., & Lynch, V. J. (2021). Pervasive duplication of tumor suppressors in Afrotherians during the evolution of large bodies and reduced cancer risk. eLife. https://doi.org/10.7554/elife.65041