Research Papers:

Positive selection drives the evolution of endocrine regulatory bone morphogenetic protein system in mammals

Hafiz Ishfaq Ahmad _, Muhammad Jamil Ahmad, Muhammad Muzammal Adeel, Akhtar Rasool Asif and Xiaoyong Du

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Oncotarget. 2018; 9:18435-18445. https://doi.org/10.18632/oncotarget.24240

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Hafiz Ishfaq Ahmad1, Muhammad Jamil Ahmad1, Muhammad Muzammal Adeel3, Akhtar Rasool Asif2 and Xiaoyong Du1,3

1Key Laboratory of Agricultural Animal Genetics, Breeding and Reproduction of the Ministry of Education, College of Animal Science and Technology, Huazhong Agricultural University, Wuhan 430070, P.R. China

2University of Veterinary and Animal Sciences, Lahore, Sub Campus Jhang, Pakistan

3Hubei Key Laboratory of Agricultural Bioinformatics, College of Informatics, Huazhong Agricultural University, Wuhan 430070, P.R. China

Correspondence to:

Xiaoyong Du, email: [email protected]

Keywords: selection; BMPs; nucleotide substitutions; maximum likelihood; evolution

Received: July 14, 2017     Accepted: December 06, 2017     Epub: January 13, 2018     Published: April 06, 2018


The rapid evolution of reproductive proteins might be driven by positive Darwinian selection. The bone morphogenetic protein family is the largest within the transforming growth factor (TGF) superfamily. A little have been known about the molecular evolution of bone morphogenetic proteins exhibiting potential role in mammalian reproduction. In this study we investigated mammalian bone morphogenetic proteins using maximum likelihood approaches of codon substitutions to identify positive Darwinian selection in various species. The proportion of positively selected sites was tested by different likelihood models for individual codon, and M8 were found to be the best model. The percentage of positively elected sites under M8 are 2.20% with ω = 1.089 for BMP2, 1.6% with ω = 1.61 for BMP 4 0.53% for BMP15 with ω = 1.56 and 0.78% for GDF9 with ω = 1.93. The percentage of estimated selection sites under M8 is strong statistical confirmation that divergence of bone morphogenetic proteins is driven by Darwinian selection. For the proteins, model M8 was found significant for all proteins with ω > 1. To further test positive selection on particular amino acids, the evolutionary conservation of amino acid were measured based on phylogenetic linkage among sequences. For exploring the impact of these somatic substitution mutations in the selection region on human cancer, we identified one pathogenic mutation in human BMP4 and one in BMP15, possibly causing prostate cancer and six neutral mutations in BMPs. The comprehensive map of selection results allows the researchers to perform systematic approaches to detect the evolutionary footprints of selection on specific gene in specific species.

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