Adaptive Evolution Coupled with Retrotransposon Exaptation Allowed for the Generation of a Human-Protein-Specific Coding Gene That Promotes Cancer Cell Proliferation and Metastasis in Both Haematological Malignancies and Solid Tumours: The Extraordinary Case ofMYEOVGene

Abstract

The incidence of cancer in human is high as compared to chimpanzee. However previous analysis has documented that numerous human cancer-related genes are highly conserved in chimpanzee. Till date whether human genome includes species-specific cancer-related genes that could potentially contribute to a higher cancer susceptibility remains obscure. This study focuses on MYEOV, an oncogene encoding for two protein isoforms, reported as causally involved in promoting cancer cell proliferation and metastasis in both haematological malignancies and solid tumours. First we document, via stringent in silico analysis, that MYEOV arose de novo in Catarrhini. We show that MYEOV short-isoform start codon was evolutionarily acquired after Catarrhini/Platyrrhini divergence. Throughout the course of Catarrhini evolution MYEOV acquired a gradually elongated translatable open reading frame (ORF), a gradually shortened translation-regulatory upstream ORF, and alternatively spliced mRNA variants. A point mutation introduced in human allowed for the acquisition of MYEOV long-isoform start codon. Second, we demonstrate the precious impact of exonized transposable elements on the creation of MYEOV gene structure. Third, we highlight that the initial part of MYEOV long-isoform coding DNA sequence was under positive selection pressure during Catarrhini evolution. MYEOV represents a Primate Orphan Gene that acquired, via ORF expansion, a human-protein-specific coding potential.

De novo gene birth

“…NYCM , a de novo gene unique to humans and chimpanzees, regulates the pathogenesis of neuroblastomas in mouse models [133], and the primate-specific PART1 , an lncRNA gene, has been identified as both a tumor suppressor and an oncogene in different contexts [44, 134, 135]. Several other human- or primate-specific de novo genes, including PBOV1 [136] , GR6 [137, 138] , MYEOV [139] , ELFN1-AS1 [140], and CLLU1 [45] , are also linked to cancer. Some have even suggested considering tumor-specifically expressed, evolutionary novel genes as their own class of genetic elements, noting that many such genes are under positive selection and may be neofunctionalized in the context of tumors [140].…”

Stochastic Gain and Loss of Novel Transcribed Open Reading Frames in the Human Lineage

“…2011 ), as well as involvement in diseases, such as cancer ( Samusik et al. 2013 ; Papamichos et al. 2015 ; Guerzoni and McLysaght 2016 ).…”

MYEOV overexpression induced by demethylation of its promoter contributes to pancreatic cancer progression via activation of the folate cycle/c-Myc/mTORC1 pathway

“…A comparative study of multiple animal genomes reported that the MYEOV gene is unique among primates only in Catarrhini. The report also notes that MYEOV has a very unusual feature as a cancer-related gene: the amino acid sequence significantly differs between humans and apes [ 13 ]. Analysis of MYEOV expression levels and promoter methylation status in several cancers in the TCGA showed that the promoter region was hypermethylated in normal tissues, while some tumors showed hypomethylation and overexpression.…”

“…However, the biological role of MYEOV is poorly understood. This may be due in part to the fact that MYEOV is an acquired gene in primates [ 13 ], making it difficult to conduct carcinogenesis in mouse models.…”