This web page was produced as an assignment for Genetics 677, an undergraduate course at UW-Madison.
What is a phenotype?
A rough definition of a phenotype is the visible result of having a certain gene, but in this case I am interested in what we see when we mutate or lose a gene. Some mutations are spontaneous, but researchers are also able to induce mutations by using a variety of chemicals. Another very powerful tool RNAi or RNA interference. RNAi is a cellular process in which small pieces of complementary RNA can bind messenger RNA to prevent its translation into protein. Researchers Andrew Fire and Craig Mello recieved the Nobel Prize in 2006 for discovering that RNAi could be used as a research tool to knock down genes by inserting double stranded RNA homologous to the gene they wished to eliminate the function of. [1]
MiceMice are a convenient model organism to look at since their Ank1 gene is actually an ortholog of the human ANK1 gene, meaning that the proteins perform the same function. There have been 3 mutant alleles found in mice that can cause similar effects in mice to those found in humans with Hereditary Spherocytosis; 2 of them are chemically induced mutations and the other is a spontaneous mutation. [2]
ZebrafishThough there is no known phenotype of and Ank1 knock out or mutation in zebrafish, there have been hereditary spherocytosis studies done in them. A variety of anemic zebrafish have been observed, some of them with spherocytes. One type of anemic zebrafish with spherocytes, riesling, had its mutation sequenced and appears to have a mutation in the Spectrin β gene, which can also cause hereditary spherocytosis in humans. [3,4]
C. elegansWorms such as C. elegans don't actually have blood, however they do have a gene that is a homolog of human ANK1. That gene is unc-44 which creates the UNC-44 protein that contains all the same domains as the human ANK1 protein. [5] When this gene is knocked out in C. elegans, the worms are small and have difficulties in axon guidance and other neural system processes. [6] Though these are interesting alternate phenotypes involved with a protein similar to ANK1, it would be kind of a stretch to try and relate them back to spherocytosis.
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Chosen Model
Since both zebrafish and mice have blood and show spherocytosis phenotypes, they both make excellent choices for studying hereditary spherocytosis. However, it would be advantageous to start studies in zebrafish due to their shorter life cycles and cost effectiveness to do larger studies. Many drug studies are done in zebrafish since it is as simple as adding a compound to the water the fish live in. After something interesting is found in zebrafish, it is possible to pursue the discovery further with more expensive and time consuming mouse studies to see if the model is also applicable to mammals.
References
- The Nobel Prize in Physiology or Medicine 2006 Advanced Information. http://web.archive.org/web/20070120113455/http://nobelprize.org/nobel_prizes/medicine/laureates/2006/adv.html
- Mouse Genome Informatics. ANK1. Last update May 8, 2013. http://www.informatics.jax.org/marker/MGI:88024
- Liem and Gallagher. 2005. Molecular mechanisms in the inherited red cell membrane disorders. Science Direct Vol 2. Issue 4. 539-545. http://dx.doi.org/10.1016/j.ddmec.2005.11.004
- Weinstein, B.M., Schier, A.F., Abdelilah, S., Malicki, J., Solnica-Krezel, L., Stemple, D.L., Stainier, D.Y., Zwartkruis, F., Driever, W., and Fishman, M.C. 1996. Hematopoietic mutations in the zebrafish. Development 123:303-309
- SMART database. Retrieved May 15, 2013. http://smart.embl-heidelberg.de
- WormBase Version WS236. Unc-44. Retrieved May 15, 2013. http://www.wormbase.org/species/c_elegans/gene/WBGene00006780?query=unc-44#0a-9e6-10