Pan-cancer surveys indicate cell cycle-related roles of primate-specific genes in tumors and embryonic cerebrum

Abstract

Background Despite having been extensively studied, it remains largely unclear why humans bear a particularly high risk of cancer. The antagonistic pleiotropy hypothesis predicts that primate-specific genes (PSGs) tend to promote tumorigenesis, while the molecular atavism hypothesis predicts that PSGs involved in tumors may represent recently derived duplicates of unicellular genes. However, these predictions have not been tested. Results By taking advantage of pan-cancer genomic data, we find the upregulation of PSGs across 13 cancer types, which is facilitated by copy-number gain and promoter hypomethylation. Meta-analyses indicate that upregulated PSGs (uPSGs) tend to promote tumorigenesis and to play cell cycle-related roles. The cell cycle-related uPSGs predominantly represent derived duplicates of unicellular genes. We prioritize 15 uPSGs and perform an in-depth analysis of one unicellular gene-derived duplicate involved in the cell cycle, DDX11. Genome-wide screening data and knockdown experiments demonstrate that DDX11 is broadly essential across cancer cell lines. Importantly, non-neutral amino acid substitution patterns and increased expression indicate that DDX11 has been under positive selection. Finally, we find that cell cycle-related uPSGs are also preferentially upregulated in the highly proliferative embryonic cerebrum. Conclusions Consistent with the predictions of the atavism and antagonistic pleiotropy hypotheses, primate-specific genes, especially those PSGs derived from cell cycle-related genes that emerged in unicellular ancestors, contribute to the early proliferation of the human cerebrum at the cost of hitchhiking by similarly highly proliferative cancer cells.

Carcino-Evo-Devo, A Theory of the Evolutionary Role of Hereditary Tumors

“…We have described individual genes, such as PBOV1 [25,27,29] and ELFN1-AS1 [23,26], and whole classes of tumor-specifically expressed, evolutionarily novel (TSEEN) genes, such as CT antigen genes [28] and ncRNA genes [32,35]. Many of our findings have been confirmed by other authors with references to our priorities [107][108][109][110][111][112][113][114]. In [38], the author suggested considering TSEEN genes as a new superclass of novel and evolving genes with tumor-specific or predominant expression, with several classes and families of TSEEN genes, which includes TSEEN genes of various phyla of organisms.…”

Disruption of metazoan gene regulatory networks in cancer alters the balance of co-expression between genes of unicellular and multicellular origins

“…Mixed UC-MC modules with high Novelty scores also showed a trend of higher expression in tumours and higher prevalence of known driver genes relative to UC-Enriched and MC-Enriched modules. Somatic mutations may act to force the common expression of pairs of unicellular and multicellular genes that would not normally be co-expressed in healthy somatic tissues 16,24 . Amplifications in particular can alter expression of multiple genes simultaneously and thereby rapidly disrupt metazoan GRNs, perhaps explaining their strong enrichment in Mixed UC-MC modules.…”

“…In earlier work, we found pervasive down-regulation of genes of multicellular origin and selective upregulation of genes of unicellular origin across solid cancers 5,12 , since independently confirmed 13 . Similar approaches showed both genetic and transcriptional alterations accumulate in genes involved in multicellularity during selection for accelerated growth and metastatic potential in breast cancer xenografts 14 , in highly conserved genes in myeloma upon exposure to chemotherapy 15 and in recently-evolved paralogs of cell cycle control genes in cancer cell lines 16 . An example of the functional impacts is the stress-induced activation of error prone, stress-activated DNA repair mechanisms conserved with bacteria in a range of tumours, facilitating drug resistance 17,18 and leaving detectable mutational signatures 19,20 .…”

Evolutionarily new genes in humans with disease phenotypes reveal functional enrichment patterns shaped by adaptive innovation and sexual selection.

“…The most phylogenetically distant branch at which the shared syntenic block was detected marks the time when a human gene originated. In comparison to the method based on the similarity of protein families, namely the phylostratigraphic dating (Neme and Tautz 2013), this method employed in GenTree is robust to recent gene duplications (Shao et al 2019), despite its under-estimation of the number of young genes (Ma et al 2022). We obtained gene age for human Y genes through the analysis of 15 representative mammals (Cortez et al 2014).…”

“…Here, we found that at least 42% of primate-specific disease genes affecting the nervous systems could impact phenotypes related to brain size and intellectual development. For example, DDX11 is critical in pathology of microcephaly (Pirozzi et al 2018;Lerner et al 2020;van Schie et al 2020;Ma et al 2022). The NOTCH2NLA, NOTCH2NLB, and NOTCH2NLC may promote human brain size enlargement, due to their functions in neuronal intranuclear inclusion disease (NIID), microcephaly, and macrocephaly (Fiddes et al 2018;Suzuki et al 2018;Liu et al 2022).…”