Abstract
PBOV1 is a known human protein-coding gene with an uncharacterized function. We have previously found that PBOV1 lacks orthologs in non-primate genomes and is expressed in a wide range of tumor types. Here we report that PBOV1 protein-coding sequence is human-specific and has originated de novo in the primate evolution through a series of frame-shift and stop codon mutations. We profiled PBOV1 expression in multiple cancer and normal tissue samples and found that it was expressed in 19 out of 34 tumors of various origins but completely lacked expression in any of the normal adult or fetal human tissues. We found that, unlike the cancer/testis antigens that are typically controlled by CpG island-containing promoters, PBOV1 was expressed from a GC-poor TATA-containing promoter which was not influenced by CpG demethylation and was inactive in testis. Our analysis of public microarray data suggests that PBOV1 activation in tumors could be dependent on the Hedgehog signaling pathway. Despite the recent de novo origin and the lack of identifiable functional signatures, a missense SNP in the PBOV1 coding sequence has been previously associated with an increased risk of breast cancer. Using publicly available microarray datasets, we found that high levels of PBOV1 expression in breast cancer and glioma samples were significantly associated with a positive outcome of the cancer disease. We also found that PBOV1 was highly expressed in primary but not in recurrent high-grade gliomas, suggesting the presence of a negative selection against PBOV1-expressing cancer cells. Our findings could contribute to the understanding of the mechanisms behind de novo gene origin and the possible role of tumors in this process.
Highlights
The origin of novel genes in the evolution of multicellular organisms has long been postulated to play a fundamental role in the development of new functions [1]
PBOV1 protein-coding sequence originated de novo in human evolution and appears to evolve neutrally According to hg19 version of Human UCSC Genome Browser
PBOV1 is transcribed from the strand that is opposite to BIG3
Summary
The origin of novel genes in the evolution of multicellular organisms has long been postulated to play a fundamental role in the development of new functions [1]. There are several wellestablished mechanisms of novel gene origin. Duplication and divergence, retroposition, gene fusion, exon shuffling and horizontal gene transfer all rely on reuse of the pre-existing genetic material (see [2] for review). It has been proposed that some protein-coding genes might have originated de novo from non-coding genomic regions through a series of mutations leading to the appearance of a novel protein-coding transcript. The resulting proteins might be fixed in the evolution either as a result of genetic drift or due to an accidental positive contribution to the organism fitness. The positive selection following the fixation might further enhance the functionality of such proteins
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