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Alu-J element represents a novel mechanism to the evolution of hemochorial placentation in primates

A research team led by professor Cheng Deng at Nanjing Normal University has made great progress in the research of the adaptive evolution and functionalization of G-protein coupled receptor (GPCR) in polypeptide hormone family.

The researchers found that the exonization and functionalization of an Alu-J element in the protein coding region of glycoprotein hormone alpha gene represent a novel mechanism to the evolution of hemochorial placentation in primates. The results were published Sept. 26 in the Molecular Biology and Evolution, one of the top journal in the field of evolutionary biology.

Haidi Chen, the doctoral candidate of the School of Life Sciences in NNU and Li Chen, the associate chief physician at Nanjing General Hospital are the two leading authors of the paper.

Approximately half of the human genome is derived from transposable elements, and primate-specific Alu sequences, 300 base-pair long each, are the dominant short interspersed nuclear elements (SINEs) in primate genomes. Alu elements frequently form new exons in primate genomes, and their migration in the genome allows the shaping of primate evolution. In particular, in the human genome, there are approximately one million copies of the Alu element, accounting for 10% of our genome, and 4% of human genes contain the Alu sequence in the coding regions, indicating exonization events.

“Alu elements contribute considerably to gene regulation and genome evolution in primates. The generation of new exons from Alu elements has been found in various human genes, and the regulatory function of the Alu exon has been investigated in many studies. However, the functionalization of Alu elements in protein coding regions remains unknown.” Haidi Chen said.

The research reported that an Alu-J element exonized in the glycoprotein hormone alpha (GPHA) gene and encoded an additional N-terminal peptide (Alu-J encoding peptide) of the mature GPHA peptide, leading to a splicing variant of Alu-GPHA in anthropoid primates approximately 35 million years ago. Interestingly, adaptive evolution of the Alu-J exon occurred in the human and ape lineages during anthropoid evolution.

The Alu-J encoding peptide is found to be a new biomarker in human early pregnancy and prolongs the serum half-life of human chorionic gonadotropin (HCG) circulation. Moreover, Alu-J encoding peptide enhances the bioactivity of HCG protein, both in vivo and in vitro. Additionally, a further study reveals that Alu-HCG shows better bioactivity with a longer serum half- life and as a more effective hormone in cell invasion/migration in vitro due to the Alu-J encoding peptide.

“Our study reveals the first example of an Alu element functioning as the encoding peptide to increase the whole protein stability and provides insight into the potential multi-functionalization of the Alu exon in the protein coding regions. Furthermore, with the chorionic gonadotropin (CG) linking with hemochorial placentation, the exonization and functionalization of the Alu-J exon in GPHA gene represent a novel mechanism to the evolution of hemochorial placentation in primates.” Li Chen said.

The graduate student Yun’e Wu and the undergraduate Hao Shen are the joint second authors of the paper. Cheng Deng, the professor of School of Life Sciences is the corresponding author.

This work was supported by the National Natural Science Foundation of China (grant 31401207), the Priority Academic Program Development of Jiangsu Higher Education Institutions (PAPD), the Natural Science Foundation from Jiangsu Province (grant BK20151546) and Jiangsu Distinguished Professor Funding (grant 15KJA180004).