Genetic Conservation Across Species

The pandemic caused by the coronavirus disease known now as Covid-19 has brought up questions regarding the ability of viruses to “jump” to new species. How can humans contract a bat disease? Coronaviruses are common in bats, and this is the third coronavirus disease originating from bats that has been able to cause a pandemic in the last 100 years1. The other two diseases, severe acute respiratory syndrome (SARS)- CoV and Middle East respiratory syndrome (MERS)-CoV, killed 7742 and 7123 people respectively. Bats, like humans, are mammals. They produce milk, and they have hair, but there the similarities seem to end.

The answer to questions about cross-species viral susceptibility lies in conserved biological mechanisms. Many biological mechanisms are conserved across species. The closer species are on the phylogenic tree, the more likely they are to have conserved biology. Humans are much more likely to be susceptible to viruses from bats than they are to viruses that infect insects. Some biological mechanisms are found across all species. While those genes or mechanisms might not tell us anything about viral susceptibility, we can use them to learn about other disease mechanisms.

A transcription factor called mediator complex subunit 12 (MED12) is one example of a gene found in humans and many different species of animals. MED12 regulates many genes since it interacts with RNA polymerase II4. In humans, germline mutations (mutations you are born with) in MED12 can lead to intellectual disability and physical abnormalities5. Somatic mutations (mutations you acquire) in MED12 can lead to prostate cancer and uterine tumors6. MED12 is required for normal cardiac function, a discovery made through experiments conducted on mice7.

We can learn something new about MED12 from many different organisms. From zebrafish, we learn that Med12 (also known as Trap230) plays an important role in facial development, contributing to formation of the neural crest, cartilage, and ears8. We can even study the role of Med12 in the regulation of oxytocin (the cuddle hormone) in zebrafish9.

As we go down the evolutionary chain, we find even more discoveries in the fruit fly, Drosophila melanogaster. Fruit fly studies find roles for MED12 in steroid regulation and heart and muscle signaling10. Mutations in MED12 cause problems with eye development11. A research group from Texas A&M University used D. melanogaster to study MED12. They found that the gene is downregulated by insulin signaling in obese women, increasing the risk of uterine tumors12.

Answers to the inner workings of human bodies can even be found by observing the lowly yeast. Studies of Saccharomyces cerevisiae reveal that MED12 is part of a larger complex called the Srb8-11 module13. Yeast have been used to study the role of MED12 in drug resistance14 and to understand its role in oxidative stress15.

Whether you are studying viruses, cancer, or facial development, data can be mined from experiments conducted with almost any species. Understanding how genes and mechanisms are conserved helps us better understand human biology and will equip us to better contribute to human health and wellbeing in the future.

Detection of human MED12 in FFPE breast carcinoma by IHC.
Detection of human MED12 in FFPE breast carcinoma by IHC. Antibody: Rabbit anti-MED12 recombinant monoclonal [BLR084G] (A700-084). Secondary: HRP-conjugated goat anti-rabbit IgG (A120-501P). Substrate: DAB.
Detection of human MED12 by immunohistochemistry.
Detection of human MED12 by immunohistochemistry. Sample: FFPE section of human ovarian carcinoma. Antibody: Affinity purified rabbit anti-MED12 (Cat. No. A300-774 Lot2) used at a dilution of 1:1,000 (1µg/ml). Detection: DAB.
Detection of mouse MED12 by immunohistochemistry.
Detection of mouse MED12 by immunohistochemistry. Sample: FFPE section of mouse squamous cell carcinoma. Antibody: Affinity purified rabbit anti-MED12 (Cat. No. IHC-00180) used at a dilution of 1:250. Detection: DAB.

References

1. Li B, Si H-R, Zhu Y, Yang X-L, Anderson DE, Shi Z-L, Wang L-F and Zhou P. 2020. Discovery of Bat Coronaviruses through Surveillance and Probe Capture-Based Next-Generation Sequencing. mSphere. 5(1): e00807-00819.

2. Drosten C, Günther S, Preiser W, van der Werf S, Brodt HR, Becker S, Rabenau H, Panning M, Kolesnikova L, Fouchier RA, Berger A, Burguière AM, Cinatl J, Eickmann M, Escriou N, Grywna K, Kramme S, Manuguerra JC, Müller S, Rickerts V, Stürmer M, Vieth S, Klenk HD, Osterhaus AD, Schmitz H and Doerr HW. 2003. Identification of a novel coronavirus in patients with severe acute respiratory syndrome. N Engl J Med. May 15 348(20): 1967-1976.

3. Chafekar A and Fielding BC. 2018. MERS-CoV: Understanding the Latest Human Coronavirus Threat. Viruses. Feb 24 10(2).

4. Malik S and Roeder RG. 2010. The metazoan Mediator co-activator complex as an integrative hub for transcriptional regulation. Nat Rev Genet. Nov 11(11): 761-772.

5. Narayanan DL and Phadke SR. 2017. A novel variant in MED12 gene: Further delineation of phenotype. Am J Med Genet A. Aug 173(8): 2257-2260.

6. Kämpjärvi K, Kim NH, Keskitalo S, Clark AD, von Nandelstadh P, Turunen M, Heikkinen T, Park MJ, Mäkinen N, Kivinummi K, Lintula S, Hotakainen K, Nevanlinna H, Hokland P, Böhling T, Bützow R, Böhm J, Mecklin JP, Järvinen H, Kontro M, Visakorpi T, Taipale J, Varjosalo M, Boyer TG and Vahteristo P. 2016. Somatic MED12 mutations in prostate cancer and uterine leiomyomas promote tumorigenesis through distinct mechanisms. Prostate. Jan 76(1): 22-31.

7. Baskin KK, Makarewich CA, DeLeon SM, Ye W, Chen B, Beetz N, Schrewe H, Bassel-Duby R and Olson EN. 2017. MED12 regulates a transcriptional network of calcium-handling genes in the heart. JCI Insight. Jul 20 2(14).

8. Hong SK, Haldin CE, Lawson ND, Weinstein BM, Dawid IB and Hukriede NA. 2005. The zebrafish kohtalo/trap230 gene is required for the development of the brain, neural crest, and pronephric kidney. Proc Natl Acad Sci U S A. Dec 20 102(51): 18473-18478.

9. Spikol ED and Glasgow E. 2018. Separate roles for Med12 and Wnt signaling in regulation of oxytocin expression. Biol Open. Mar 28 7(3).

10. Lee JH, Bassel-Duby R and Olson EN. 2014. Heart- and muscle-derived signaling system dependent on MED13 and Wingless controls obesity in Drosophila. Proc Natl Acad Sci U S A. Jul 1 111(26): 9491-9496.

11. Treisman J. 2001. Drosophila homologues of the transcriptional coactivation complex subunits TRAP240 and TRAP230 are required for identical processes in eye-antennal disc development. Development. Feb 128(4): 603-615.

12. X, Liu M and Ji JY. 2019. Understanding Obesity as a Risk Factor for Uterine Tumors Using Drosophila. Adv Exp Med Biol. 1167: 129-155.

13. Zhu X, Wirén M, Sinha I, Rasmussen NN, Linder T, Holmberg S, Ekwall K and Gustafsson CM. 2006. Genome-wide occupancy profile of mediator and the Srb8-11 module reveals interactions with coding regions. Mol Cell. Apr 21 22(2): 169-178.

14. Shahi P, Gulshan K, Näär AM and Moye-Rowley WS. 2010. Differential roles of transcriptional mediator subunits in regulation of multidrug resistance gene expression in Saccharomyces cerevisiae. Mol Biol Cell. Jul 15 21(14): 2469-2482.

15. Willis SD, Stieg DC, Ong KL, Shah R, Strich AK, Grose JH and Cooper KF. 2018. Snf1 cooperates with the CWI MAPK pathway to mediate the degradation of Med13 following oxidative stress. Microb Cell. Jun 25 5(8): 357-370.