This web page was produced as an assignment for Genetics 677, an undergraduate course at UW-Madison.
RNAi and Phenotypes
A human disease is often found to be associated with a certain allele, or segment of DNA. One way to study human diseases is to examine its homologs. (A homolog is a DNA segment or gene that is conserved in another organism. For example, the human has many segments of DNA that are similar in sequence to DNA segments located in mice, Mus musculus). When a homolog is identified for a human disease it can be used to study that disease. One way to study the homolog is to use RNA interference (RNAi) to knockout (disable all functionality) the gene of interest. By knocking out a gene, phenotypes (physical traits) can be observed, often similar to the human disease.
Psoriasis phenotypes were identified using RNAi databases MGI and ZFIN for Mus musculus and Danio rerio, respectively. Other RNAi databases exist for other novel model organisms; however, HLA-C homologs only existed for the mouse and zebrafish RNAi databases.
Psoriasis phenotypes were identified using RNAi databases MGI and ZFIN for Mus musculus and Danio rerio, respectively. Other RNAi databases exist for other novel model organisms; however, HLA-C homologs only existed for the mouse and zebrafish RNAi databases.
Analysis
Of the HLA-C homologs, only the mouse and zebrafish had RNAi databases available. The phenotypes identified were NOT homologous to the HLA-C gene but were related to psoriasis. Psoriasis phenotypes were identified using RNAi databases MGI and ZFIN for Mus musculus and Danio rerio, respectively. The zebrafish and mouse are novel model organisms, thus the genetic tools (like RNAi) are widely available, unlike the other HLA-C homologs; therefore, phenotypic studies related to RNAi are limited/nonexistent for other HLA-C homologs.
Danio rerio (zebrafish) has a psoriasis-related strain known as m14, which was identified in ZFIN. Webb et al. (2008) identified phenotypes, from m14, relating to cell proliferation and epidermal development. The genes (markers) correlated with this mutant strain are NOT homologous to HLA-C in humans, but provides better insight to the complex disease of psoriasis, which involves many genes.
Using MGI, a gene (Itgb2) that is responsible for psoriasis-related phenotypes was identified; however, this gene is not the homolog of HLA-C. The Kess et al. 2006 paper was able to identify a component (PL/J) which is required to express psoriatic phenotypes. When Itgb2 lacks PL/J, Type I leukocyte adhesion deficiency (LAD) phenotypes are expressed. Luckily, the mouse model with Itgb2 has a PL/J background,which will prove useful for further psoriasis studies.
Danio rerio (zebrafish) has a psoriasis-related strain known as m14, which was identified in ZFIN. Webb et al. (2008) identified phenotypes, from m14, relating to cell proliferation and epidermal development. The genes (markers) correlated with this mutant strain are NOT homologous to HLA-C in humans, but provides better insight to the complex disease of psoriasis, which involves many genes.
Using MGI, a gene (Itgb2) that is responsible for psoriasis-related phenotypes was identified; however, this gene is not the homolog of HLA-C. The Kess et al. 2006 paper was able to identify a component (PL/J) which is required to express psoriatic phenotypes. When Itgb2 lacks PL/J, Type I leukocyte adhesion deficiency (LAD) phenotypes are expressed. Luckily, the mouse model with Itgb2 has a PL/J background,which will prove useful for further psoriasis studies.
Mus musculus Phenotypes
Kess et al. published a paper, which can be read here, in 2006 which identified loci susceptible to skin disease in a psoriasis mouse. Unfortunately the loci identified (Itgb2) was on chromosome 10 (Chr10, 39.72), which was different from the HLA-C homolog. Regardless, psoriasis is a complex disease and no gene alone is responsible for psoriasis, so any insight on the disease is beneficial.
Itgb2 has phenotypic effects only when PL/J is expressed in the background. Phenotypic effects related to psoriasis are located in the integument (skin), immune system, and, less commonly, the skeleton. Itgb2's phenotypic effects are more commonly related to LAD. The proposed disease model includes PL/J in the background, thus is a psoriatic model.
The picture to the left shows a wildtype mouse next to a Itgb2 homozygous mouse with PL/J in the background. Figure A compares a wildtype mouse (left) to a mildly diseased mouse (right). Figure B shows a severely psoriatic mouse. Figures C-F show cross sections of the epidermis; C and E are wildtype and D and F are Itgb2 with PL/J.
Itgb2 has phenotypic effects only when PL/J is expressed in the background. Phenotypic effects related to psoriasis are located in the integument (skin), immune system, and, less commonly, the skeleton. Itgb2's phenotypic effects are more commonly related to LAD. The proposed disease model includes PL/J in the background, thus is a psoriatic model.
The picture to the left shows a wildtype mouse next to a Itgb2 homozygous mouse with PL/J in the background. Figure A compares a wildtype mouse (left) to a mildly diseased mouse (right). Figure B shows a severely psoriatic mouse. Figures C-F show cross sections of the epidermis; C and E are wildtype and D and F are Itgb2 with PL/J.
Danio rerio Phenotypes
Webb et al. published a paper in 2008, which can be read here, showing abnormal epidermal phenotypes related to psoriasis. The left, top image shows how psoriasis embryos fail to stop proliferation (growing new tissue). The left, bottom image shows how the psoriasis strain contains dead/dying cells (green) in the epidermal aggregates.
The paper used a mutant psoriasis zebrafish strain known as m14, from the Driever Lab. m14 phenotypes include: increased cell proliferation, high number of epidermal cells, abnormal epidermis structure/morphology, disrupted epidermis development, disrupted keratinocyte differentiation, organism lethality, and abnormal pericardium edematous.
ZFIN identified 3 genes (markers) (actl6a-actin-like 6A, krt4-keratin 4, and psoriasis-psoriasis) related to psoriasis, none of which correspond to the HLA-C homolog.
The paper used a mutant psoriasis zebrafish strain known as m14, from the Driever Lab. m14 phenotypes include: increased cell proliferation, high number of epidermal cells, abnormal epidermis structure/morphology, disrupted epidermis development, disrupted keratinocyte differentiation, organism lethality, and abnormal pericardium edematous.
ZFIN identified 3 genes (markers) (actl6a-actin-like 6A, krt4-keratin 4, and psoriasis-psoriasis) related to psoriasis, none of which correspond to the HLA-C homolog.
References
1. MGI
2. ZFIN
3. Webb, et al. 2008. Psoriasis regulates epidermal development in zebrafish. Dev. Dyn. 237(4):1153-1164 (Journal)
4. Bullard DC, Proc Natl Acad Sci U S A 1996 Mar 5;93(5):2116-21. Copyright 1996 National Academy of Sciences, U.S.A. J:32126
5. Kess D et al., "Identification of susceptibility loci for skin disease in a murine psoriasis model." J Immunol 2006 Oct 1;177(7):4612-9
2. ZFIN
3. Webb, et al. 2008. Psoriasis regulates epidermal development in zebrafish. Dev. Dyn. 237(4):1153-1164 (Journal)
4. Bullard DC, Proc Natl Acad Sci U S A 1996 Mar 5;93(5):2116-21. Copyright 1996 National Academy of Sciences, U.S.A. J:32126
5. Kess D et al., "Identification of susceptibility loci for skin disease in a murine psoriasis model." J Immunol 2006 Oct 1;177(7):4612-9
_Site created by Valeri Lapacek
Genetics 677 Assignment, Spring 2012
University of Wisconsin-Madison
Last Updated: 5/23/2012
Genetics 677 Assignment, Spring 2012
University of Wisconsin-Madison
Last Updated: 5/23/2012