Hardy-Weinberg Lab

Hardy-Weinberg Equilibrium Model Planner

This document exists to help you plan your approach as you work on your Hardy-Weinberg Model. Some time spent thinking about what you are going to do, and how you are going to do it, can go a long way toward helping you create the best model you can.  

1.  Pick a question to investigate.  Remember that the idea of your model is to help illustrate how some source of evolutionary pressure can affect the distribution of alleles in a population.  There is really no limit to what you could decide to look at.  Certainly, it’s very possible to model any of the major evolutionary pressures (natural selection, genetic drift, gene flow, sexual selection) in the spreadsheet model.  But don’t feel limited.  Also, don’t feel overwhelmed.  There is nothing wrong with simple.  Use the space below to write down some ideas about the question(s) you are interested in investigating.  If you do have multiple questions, you’ll need to make a choice before moving into #2 (or maybe you’ll revise your choice if the rest of this isn’t working out like you hoped it would).

Why is polydactyly a dominant trait, but is not a common trait amongst most human populations?

2.  Determine the ingredients.  What are you going to need to do to your model to help you analyze your question?  You’ve already got a good foundation in the model that we created in class.  It would be silly to start from scratch.  But you are going to need to figure out what you are going to have to do to change/expand your model for your purpose.  Sketch some ideas in the space below.  Keep them general.

-We would use “A” as dominant alleles and “B” as recessive alleles.

-I will make the assumption that all the organisms in our hypothetical populations are diploid.

-Gametes for the next few generations would be would be random.

-I need to determine how the allele frequencies might change from generation to generation.

-Many people mistaken “dominant” for common. The presence of polydactyl can be caused by a dominant mutation, however, it only occurs in .31-6.18 births of 1000, which may vary depending on ethnicity. That means although mutation is dominant, it is very unlikely to have that gene mutation.

3.  Quantify your ideas.  You are going to have to translate the ideas that you have into the language of the spreadsheet.  Maybe you need to alter equations or add additional ones.  This step is quite possibly the most difficult one.  Don’t get discouraged.  Spend some time and think about what you are doing before you start making changes to your foundational model.  Remember to simplify things as much as possible.  It may even be helpful for you to sketch out your spreadsheet model here.

-The determination of a person obtaining polydactyly is based according to family history. Polydactyl tends to be a strong family trait that usually does not skip generations and for that reason, the chance of passing on this traits is 50%, this only being if the parent has polydactyly. Discrepancies between percentages would have to be due to the fact if perhaps a parent has polydactyly but as a recessive trait, therefore lowering possibilities. This can occur even when your family has no family history of polydactyl, again chances are highly varied.

Lets consider the scenario that a father has heterozygous dominant for the trait of polydactyly (Rr) and the mother is is heterozygous as well but not for the trait (Rr). The probability of the child having polydactyly would be 25%.

4.  Implement your changes.  Now is the time to actually make the changes to your model.  Here are a few points to keep in mind:

• Feel free to run off a “copy” of your foundational model, and make your changes to that instead.  Just select the sheet tab at the bottom of the spreadsheet, and use the duplicate option.  You can also rename sheets, and do all sorts of other things from that menu.
• Remember that color and borders are your friends.  They help keep you organized.

• Make model into 1000 people in population and see if it changes.
• Perhaps with bigger populations the allele frequency will change.
• Will polydactyl be more common or less common in larger populations?

POPULATION: 20

Population: 1000

What can we conclude?

Prompt: Your job is to explain and justify the mechanism by which a specific disease is caused by a defective signaling pathway and investigate one drug that works by blocking a signaling pathway.

Celiac Disease

What is Celiac Disease?

Celiac Disease is an auto-immune system that may occur in genetically predisposed people where the ingestion of gluten results in the damage of the small intestine. Specifically the damage on the small intestines happens to the villi, which are small finger like outgrowths that line the small intestine that help nutrient absorption, therefore due to this disease people are unable to absorb nutrients properly if gluten is ingested.  It is generally estimated that 1 out of every 100 people in the world are affected by this disease, although most people are left undiagnosed due to its specificity. Something also important about this disease is the fact that is it hereditary, meaning if relatives have this disease your likelihood of obtaining is increased.

Symptoms: 

-Digestive problems (things like bloating, pain, gas, diarrhea, weight loss, pale stool, etc.)

-Severe skin rash known as dermatitis herpetiformis 

-Iron deficiency anemia (low blood count)

-Musculoskeletal problems (muscle cramps bone and joint pain)

Long Term affects of this disease are:

-Iron deficiency anemia 

-Pancreatic insufficiency

-Lactose intolerance 

-Gall bladder malfunction

-Infertility and miscarriages

-Vitamin and mineral deficiencies

-Intestinal lymphomas

-Neurological manifestations

-Early onset osteoporosis and osteopenia

- Central and peripheral nervous system disorders

Which pathway is defective? 

PPAR (Peroxisome Proliferator-Activated Receptors) signaling pathway:  It was concluded in a study that the down-regulation of proteins involved in the PPAR signaling were highly associated with the cause of Celiac disease. The study analyzed the intestinal mucosa proteome alterations using two dimensional difference gel electrophoresis, they tested Celiac Disease patients of varying degrees of histological abnormalities defined by Marsh criteria and controls (Stanford experiment from the school of medicine). There was basically two groups of patients, those with Type 0-I of Celiac Disease known as Group A and the other patients were group B, with Types II-III Celiac Disease. It resulted that in Group B there were many down-regulated proteins that were directly implicated in the peroxisome proliferator-activated receptor signaling pathway. This signal pathways was defective due to the fact that the deregulation of those proteins occurred in apoptosis/survival pathways, which resulted in more severe tissue damage in Group B patients.Meaning that there was no a destruction of the cell, therefore creating a defect in the signaling pathway. Furthermore, the studies also showed that IgMs( antibodies) were found to be very strongly increased in Group B, illustrating that more antibodies were needed because something went wrong in the signaling pathway.

The Experimental Drug: NVP-BEZ235

The experimental drug NVP-BEZ235 is being tested in the laboratory at University of California, Los Angeles and has shown that this drug blocks two crucial cancer cell signaling pathways that inhibits the growth of ovarian cells. This is an extremely important drug because it could potentially be used after chemotherapy and all sort of other conventional treatments are not working to reduce the size of ovarian cancer cells. It is able to re-sensitize the ability of the cells to work through these therapies.

 Doctors have become very hopeful of this drug, as exemplified below:
"We were very encourage to find that NPV-BEZ235 could re-sensitize the ovarian cancer cells to standard platinum treatment," Dorgio said. "In addition, we found this drug to be more effective in inhibiting ovarian cancer cell growth than other drugs that target only one checkpoint, mTOR, in this pathway. We believe that NVP-BEZ235 has superior efficacy because of the dual effect on P13Kinase and mTOR."

Only the structural form of this drug is available at this point.

This new found drug has been experimented throughout various diseases and has proved to have great results in other inhibition of signaling pathways. It is said that this drug is a novel and potent dual  P13Kinase/mTOR inhibitor that is currently in phase of 1/2 clinical trials for advanced solid tumors. It is able to inhibit ATM and DNA-PKcs, two of the major kinases responding to ionization radiation- induced DNA double stand breaks, therefore has potential to act as an effective radiosensitizer for GBMs in the clinic. Overall the idea of this drug brings great results in the area regarding cancer, it sparks a hope for future advancements in the field of cancer research and treatment. 

Works Cited

Ferretti, Gianna, Tiziana Bacchetti, Simona Masciangelo, and Letizia Saturni. "Celiac Disease, Inflammation and Oxidative Damage: A Nutrigenetic Approach." Nutrients 4.12 (2012): 243-57. Web.

Mukherjee, B., N. Tomimatsu, K. Amancherla, C. Camacho, and S. Burma. "Abstract 3745: The Dual PI3K/mTOR Inhibitor NVP-BEZ235 Is a Potent Inhibitor of ATM- and DNA-PKcs-mediated DNA Damage Responses." Cancer Research 72.8 Supplement (2012): 3745. Web.

Simula, Maria P., Renato Cannizzaro, Vincenzo Canzonieri, Alessandro Pavan, Stefania Maiero, Giuseppe Toffolio, and Valli De Re. "PPAR Signaling Pathway and Cancer-Related Proteins Are Involved in Celiac Disease-Associated Tissue Damage." Molecular Medicine. NCBI, 3 Mar. 2012. Web. 9 Nov. 2014.

Sollid, Ludvig M., and Chaitan Khosla. "Future Therapeutic Options for Celiac Disease." Nature Clinical Practice Gastroenterology & Hepatology 2.3 (2005): 140-47. Web.

University of California - Los Angeles Health Sciences. "Experimental Drug Inhibits Cell Signaling Pathway and Slows Ovarian Cancer Growth." ScienceDaily. ScienceDaily, 18 Apr. 2011. Web. 10 Nov. 2014.

"What Is Celiac Disease? - Celiac Disease Foundation." Celiac Disease Foundation. Celiac Disease Foundation, May 2013. Web. 09 Nov. 2014.