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Enhanced Negative Regulation of the DHH Signaling Pathway as a Potential Mechanism of Ascrotal Testes in Laurasiatherians

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Abstract

Unsuccessful descent of testes in humans and other scrotal mammals can result in cryptorchidism, consequent abnormalities and a high risk of malignancy. However, many male adult mammals possessing natural ascrotal testes are as viable and healthy as other scrotal mammals. This study performed an evolutionary analysis on the desert hedgehog (DHH) signaling pathway, an important regulator for testicular development, mainly in laurasiatherians. Significant positive selection, accelerated evolutionary rates, and specific amino acid substitutions were identified in ascrotal species, some of which caused radical changes in physicochemical and biological properties. Considering that most signs of positive selection were identified in genes responsible for or related to negative regulation, we suggest that the enhanced negative regulation of the DHH signaling pathway drives, at least in part, the evolution of ascrotal testes in laurasiatherians and other mammals. This study could provide some novel insights into the evolution of natural healthy ‘cryptorchidism’ in mammals and into the convergent molecular evolution of the complex trait.

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Data Availability

All data generated or analysed during this study are included in this published article and its supplementary information files.

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Acknowledgements

We thank Mr. Xinrong Xu, Dr. Lei Shan, Dr. Di Sun, Mr. Weijian Guo due to their suggestion and technical support during this study.

Funding

This study was financially supported by the National Natural Science Foundation of China to WR (grant number 31872219 and 31370401) and SX (grant number 31570379); the Key Project of National Natural Science of China to GY (grant number 31630071); the National Key Programme of Research and Development, Ministry of Science and Technology to GY and SX (Grant number 2016YFC0503200); the Priority Academic Program Development of Jiangsu Higher Education Institutions (RAPD) to GY and SX.

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Authors and Affiliations

  1. Jiangsu Key Laboratory for Biodiversity and Biotechnology, School of Life Sciences, Nanjing Normal University, Nanjing, 210023, Jiangsu, China

    Simin Chai, Ran Tian, Ying Yang, Guang Yang, Shixia Xu & Wenhua Ren

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  1. Simin Chai
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  2. Ran Tian
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  3. Ying Yang
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  4. Guang Yang
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Contributions

GY, WR and SX conceived the project. SC designed and performed the evolutionary analyses. YY helped with analysis and organized the supplementary files. SC wrote the manuscript. GY and RT improved the manuscript. All authors read and approved the final manuscript.

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Correspondence to Wenhua Ren.

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Supplementary Information

Below is the link to the electronic supplementary material.

11692_2021_9542_MOESM1_ESM.tif

Supplementary file1 Figure S1. Specific AA substitutions in MEGF8 in ascrotal cetaceans shown in mammal dataset.pdf (TIF 6779 kb)

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Supplementary file2 Figure S2. Specific AA substitutions in MEGF8 in ascrotal eulipotyphlans shown in mammal dataset.pdf (TIF 3948 kb)

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Supplementary file3 Figure S3. Specific AA substitutions in MEGF8 in ascrotal megabats shown in mammal dataset.pdf (TIF 7444 kb)

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Supplementary file4 Figure S4. Specific AA substitutions in MEGF8 in ascrotal pinnipeds shown in mammal dataset.pdf (TIF 5189 kb)

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Supplementary file5 Figure S5. Specific AA substitutions in MEGF8 in ascrotal rhinoceros shown in mammal dataset.pdf (TIF 6687 kb)

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Supplementary file6 Figure S6. Ascrotal laurasiatherian specific substitutions in DHH in mammal dataset.pdf (TIF 4599 kb)

Supplementary file7 Table S1. Representative laurasiatherians in this study.xlsx (XLSX 11 kb)

Supplementary file8 Table S2. DHH signaling pathway genes in this study.xlsx (XLSX 10 kb)

Supplementary file9 Table S3. REGs in the DHH signaling pathway in scrotal laurasiatherians.xlsx (XLSX 28 kb)

Supplementary file10 Table S4. PSGs in the DHH signaling pathway in laurasiatherians.docx (DOCX 103 kb)

11692_2021_9542_MOESM11_ESM.docx

Supplementary file11 Table S5. PSG in the DHH signaling pathway across combined branches of ascrotal laurasiatherians.docx (DOCX 40 kb)

Supplementary file12 Table S6. PSG MEGF8 across combined asctoal mammals.xlsx (XLSX 25 kb)

Supplementary file13 Table S7. Convergent DHH signaling pathway genes in laurasiatherians.xlsx (XLSX 26 kb)

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Supplementary file14 Table S8. Number of specific substitutions in DHH signaling pathway genes in ascrotal laurasiatherians.xlsx (XLSX 45 kb)

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Supplementary file15 Table S9. Functional prediction of ascrotal laurasiatherian specific substitutions in DHH and MEGF8.xlsx (XLSX 49 kb)

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Chai, S., Tian, R., Yang, Y. et al. Enhanced Negative Regulation of the DHH Signaling Pathway as a Potential Mechanism of Ascrotal Testes in Laurasiatherians. Evol Biol 48, 335–345 (2021). https://doi.org/10.1007/s11692-021-09542-0

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