Parallel evolution of reduced cancer risk and tumor suppressor duplications in Xenarthra
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Curated by eLife
eLife Assessment:
This study is a useful extension of previous work on the relationship between body size and cancer risk and the mechanisms by which large-bodied mammals reduce their cancer risk. Through solid analyses of the genomes and several aspects of the cell biology of sloths, armadillos and their relatives, the study explores whether the evolution of large body size in their relatives (some extinct) was correlated with genomic changes such as the duplication of tumor suppressor genes, experimentally demonstrating that cells of Xenarthrans (sloths, armadillos, anteaters) are exceptionally sensitive to DNA damage. The study concerns a topic of great interest and contributes to our understanding of how cancer risk has evolved in mammals.
(This preprint has been reviewed by eLife. We include the public reviews from the reviewers here; the authors also receive private feedback with suggested changes to the manuscript. Reviewer #1 agreed to share their name with the authors.)
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Abstract
The risk of developing cancer is correlated with body size and lifespan within species, but there is no correlation between cancer and either body size or lifespan between species indicating that large, long-lived species have evolved enhanced cancer protection mechanisms. Previously we showed that several large bodied Afrotherian lineages evolved reduced intrinsic cancer risk, particularly elephants and their extinct relatives ( Proboscideans ), coincident with pervasive duplication of tumor suppressor genes (Vazquez and Lynch, 2021). Unexpectedly, we also found that Xenarthrans (sloths, armadillos, and anteaters) evolved very low intrinsic cancer risk. Here, we show that: (1) several Xenarthran lineages independently evolved large bodies, long lifespans, and reduced intrinsic cancer risk; (2) the reduced cancer risk in the stem lineages of Xenarthra and Pilosa coincided with bursts of tumor suppressor gene duplications; (3) cells from sloths proliferate extremely slowly while Xenarthran cells induce apoptosis at very low doses of DNA damaging agents; and (4) the prevalence of cancer is extremely low Xenarthrans , and cancer is nearly absent from armadillos. These data implicate the duplication of tumor suppressor genes in the evolution of remarkably large body sizes and decreased cancer risk in Xenarthrans and suggest they are a remarkably cancer-resistant group of mammals.
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eLife Assessment:
This study is a useful extension of previous work on the relationship between body size and cancer risk and the mechanisms by which large-bodied mammals reduce their cancer risk. Through solid analyses of the genomes and several aspects of the cell biology of sloths, armadillos and their relatives, the study explores whether the evolution of large body size in their relatives (some extinct) was correlated with genomic changes such as the duplication of tumor suppressor genes, experimentally demonstrating that cells of Xenarthrans (sloths, armadillos, anteaters) are exceptionally sensitive to DNA damage. The study concerns a topic of great interest and contributes to our understanding of how cancer risk has evolved in mammals.
(This preprint has been reviewed by eLife. We include the public reviews from the reviewers …
eLife Assessment:
This study is a useful extension of previous work on the relationship between body size and cancer risk and the mechanisms by which large-bodied mammals reduce their cancer risk. Through solid analyses of the genomes and several aspects of the cell biology of sloths, armadillos and their relatives, the study explores whether the evolution of large body size in their relatives (some extinct) was correlated with genomic changes such as the duplication of tumor suppressor genes, experimentally demonstrating that cells of Xenarthrans (sloths, armadillos, anteaters) are exceptionally sensitive to DNA damage. The study concerns a topic of great interest and contributes to our understanding of how cancer risk has evolved in mammals.
(This preprint has been reviewed by eLife. We include the public reviews from the reviewers here; the authors also receive private feedback with suggested changes to the manuscript. Reviewer #1 agreed to share their name with the authors.)
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Reviewer #1 (Public Review):
In this paper the authors reconstruct the ancestral states of the body sizes and genomes of Xenarthrans (sloths, armadillos, anteaters) to understand whether duplications of genes that reduce cancer risk are associated with large body size, as has previously been found in Proboscideans (elephants and mammoths). The strong points of the paper are that Xenarthran cells are particularly sensitive to DNA damage, which induces cell death, and that nine-banded armadillos have strikingly little cancer. They also present comparative evidence on the doubling times of cells in culture, but their conclusions are compromised by the small sample size - one individual - for sloths. The data on which their inferences are based do not yet allow them to decide whether large body size evolved before the gene duplications that …
Reviewer #1 (Public Review):
In this paper the authors reconstruct the ancestral states of the body sizes and genomes of Xenarthrans (sloths, armadillos, anteaters) to understand whether duplications of genes that reduce cancer risk are associated with large body size, as has previously been found in Proboscideans (elephants and mammoths). The strong points of the paper are that Xenarthran cells are particularly sensitive to DNA damage, which induces cell death, and that nine-banded armadillos have strikingly little cancer. They also present comparative evidence on the doubling times of cells in culture, but their conclusions are compromised by the small sample size - one individual - for sloths. The data on which their inferences are based do not yet allow them to decide whether large body size evolved before the gene duplications that reduce cancer risk, or vice versa. The main impact of this work is likely to be additional focus on nine-banded armadillos in cancer research, with an emphasis on the discovery of the mechanisms mediating the effects. It should also spur attempts to recover genomes from soft tissues of large-bodied Xenarthran fossils; that may be possible for giant ground sloths.
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Reviewer #2 (Public Review):
In this manuscript, the authors examine the genomes and several aspects of the cell biology of sloths, armadillos and their relatives to explore whether the evolution of large body size in their relatives (some extinct) was correlated with genomic changes such as the duplication of tumor suppressor genes. This is a paper on a topic of great interest and contributions to our understanding of how disease risk has evolved in mammals.
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