Although it is widely accepted that the presence of taxonomically-restricted genes in different species make those genomes unique from all other species, it is not known if, or how, these species-specific genes might confer species-specific biological responsiveness to fundamental processes like inflammation and fibrosis.
Our laboratories have shown how the emergence of uniquely-human genes during hominid evolution may contribute to the appearance and progression of complex human inflammatory diseases.
First, we showed that uniquely-human genes are over-represented and regulated in immune cells like monocytes, lymphocytes and progenitor cells of bone marrow.
Second, we showed how the open reading frames encoded by these genes (once thought to be “pseudogenes”) can produce species-specific ligands (e.g. c2orf40TRG), receptors (e.g. CHRFAM7A), signal transduction molecules (e.g. TBC1D3) and even candidate transcription factors (e.g. TPTEP1).
Finally, we also showed how each of these genes can be implicated in human inflammatory disease, from injury and regeneration to cancer and tissue repair.
Having shown that these genes can have new biological activities unto themselves, gauge the activities of genes common to all species or compensate for the activity of their “parental” gene(s), we are evaluating how they arise and what they do in the hominid genome.
The mechanisms that explain their appearance in the human genome are common to all species. They include
(2) partial gene duplication and rearrangement,
(3) differential mRNA splicing and,
(4) the endogenization of foreign DNA.
Their effects on human biology include modulating human monocytes, lymphocytes and epithelial cell migration and trafficking, altering responsiveness to secretogogues, changing the drug sensitivity of human cells, alter resilience and inhibiting colony formation.
Because uniquely-human genes have the potential to create uniquely human signaling pathways that, by definition are absent in other species, we propose that their identity, their expression and their contributions to human disease need to be better understood so as to fully understand the development, progression and resolution of human inflammatory disease and the mechanisms that govern human tissue repair and regeneration.
1: Baird A, Costantini T, Coimbra R, Eliceiri BP. Injury, inflammation and the emergence of human-specific genes. Wound Repair Regen. 2016 May;24(3):602-6. doi: 10.1111/wrr.12422. Epub 2016 Apr 4. PubMed PMID: 26874655.
2: Costantini TW, Dang X, Coimbra R, Eliceiri BP, Baird A. CHRFAM7A, a human-specific and partially duplicated α7-nicotinic acetylcholine receptor gene with the potential to specify a human-specific inflammatory response to injury. Leukoc Biol. 2015 Feb;97(2):247-57. doi: 10.1189/jlb.4RU0814-381R. PubMed PMID: 25473097
3: Costantini TW, Dang X, Yurchyshyna MV, Coimbra R, Eliceiri BP, Baird A. A Human-Specific α7-Nicotinic Acetylcholine Receptor Gene in Human Leukocytes: Identification, Regulation and the Consequences of CHRFAM7A Expression. Mol Med. 2015 Apr 3;21:323-36. doi: 10.2119/molmed.2015.00018. PubMed PMID: 25860877
4: Baird A, Coimbra R, Dang X, Eliceiri BP, Costantini TW. Up-regulation of the human-specific CHRFAM7A gene in inflammatory bowel disease. BBA Clin. 2016 Jan;5:66-71. doi: 10.1016/j.bbacli.2015.12.003. eCollection 2016 Jun. PubMed PMID:27051591
5: Dang X, Eliceiri BP, Baird A, Costantini TW. CHRFAM7A: a human-specific 7-nicotinic acetylcholine receptor gene shows differential responsiveness of human intestinal epithelial cells to LPS. FASEB J. 2015 Jun;29(6):2292-302. doi: 10.1096/fj.14-268037. Epub 2015 Feb 13. PubMed PMID: 25681457
6: Costantini TW, Meads M, Dang X, Coimbra R, Torbett BE, Baird A, Eliceiri BP. The Response to Burn Injury in Mice With Human Hematolymphoid Systems. Ann Surg. 2016 Jan;263(1):199-204. doi: 10.1097/SLA.0000000000001123. PubMed PMID:25575256.