Last updated: Sun May 3 18:00:03 PDT 2009 Mon May 4 01:00:03 UTC 2009

Date of last work unit 2009-05-03 16:02:02 Total score 2346 Overall rank (if points are combined) 777861 of 1230329 Active processors (within 50 days) 1 Active processors (within 7 days) 1

Contributions by team and project:

Donator	shoemakej
Team	Default (includes all those WU returned without valid team number) (0)
Score	2376
Donator Rank	717861 of 1230329
WU	3
Date of last work unit	2009-05-03 16:02:02
Active processors (within 50 days)	1
Active processors (within 7 days)	1

Detailed listing for projects 0-999

Detailed listing for projects 1000-1999

Detailed listing for projects 2000-2999

Detailed listing for projects 3000-3999

Detailed listing for projects 4000-4999

Detailed listing for projects 5000-5999

1. What is the estimate of h^2?

Narrow sense heritability is the proportion of the phenotypic variation that is due to the additive effect of the variation in the genes of the human. It is found by dividing the additive genetic variation of a trait by the phenotypic variation of a trait-

VA / VP = VA / (VA+VD+VE).
The narrow sense heritability estimate for Huntington's Disease is 50%, as a child with a HD parent has a 50% chance of inheriting the allele. There is no environmental variation to be factored in, as HD is a genetic autosomal dominant disease.

2. How much influence does selection have on this trait?

Research suggests that selection is weak on Huntington’s in human populations. The weak selection coupled with mutation keeps it from becoming extinct. Huntington's is a genetic disease that easily evades natural selection because it is often “invisible” to natural selection. This occurs because it does not normally affect people until after reproduction. The reason for its escape from selection is because the disease has a late-onset period. As a result, Huntington’s survives into future generations despite its deleterious effects. Huntington's is rare but it is not entirely eliminated because selection does a relatively poor job of weeding these alleles out, while mutation continues creating new ones.

(http://evolution.berkeley.edu/evolibrary/article/_0_0/medicine_05)

3. What effect would inbreeding have on this trait?

Inbreeding would increase the chance of Huntington’s because it would make the dominant allele more frequent. Looking at the figure below one may infer that when the dominant allele is present then the chances of the offspring carrying Huntington’s double. If inbreeding were to occur, it could make it possible for an offspring in the next generation to have two Huntington alleles. This would only occur if the two with Huntington’s were to inbreed with one another. As inbreeding continues to occur it will increase the likelihood of the disease to be present in the population over time.

(http://evolution.berkeley.edu/evolibrary/article/_0_0/medicine_05)

Questions About Huntington's

1. The PNAS paper entitled “Potent inhibition of huntingtin aggregation and cytotoxicity by a disulfide bond-free single-domain intracellular antibody” (Colby et al. 2004) describes a potential treatment that uses “intrabodies” (intracellular antibodies) to bind the toxic fragment of the huntingtin protein and inactive it or prevent its misfolding. Could this treatment be modeled using grid-computing? The intrabody would have to be introduced using gene therapy. How would this work?

Grid-computing can be used to model potential treatments that use “intrabodies” to bind the toxic fragment of the huntingtin protein and inactivate it or prevent its misfolding. There are two possible ways that gene therapy could be either to inactive or prevent misfolding. The first way requires the introduction of the intrabody to the toxic fragment of the protein that has been misfolded. The intrabody would be placed on the misfolded protein and would correct for the errors that lead to Huntington’s disease. The second way would require the placement of the intrabody onto the protein prior to any potential misfolding. This method would prevent the problem of misfolding before it had a chance to occur. Grid-computing would act as a simulation of the protein folding and configure how likely it would be that these treatments would be effective. The data collected across these shared computer systems would provide information regarding when treatments would need to be used in order to stop Huntington’s disease in its tracks. The information could tell researchers whether this form of gene therapy would be worthwhile in human beings.

2. In an evolutionary sense, why is it informative to study Huntington's and its implications in mice?

It is informative to study Huntington’s and its implications in mice because of their close evolution relation to humans. Their body plans, physiology, and genome share many of the same features. It is evident that mice and humans share orthologous genes, meaning homologous sequences (from a recent common ancestor) that have been separated by a speciation event. Due to these genes, the neurons that are affected by Huntington’s in mice most likely follow similar pathways and probably function in the same ways in humans. A study by Gonitel et al., 2008 demonstrates this similarity by examining how mutations form repetitive CAG sequences which creates unique neuronal populations in both mice and HD patients. It is also shown how both mice and humans share the MSH3 gene which differentiates neurons from nonneuronal cells.

3. Apply Darwin's four postulates to the traditional view of neuron selection.

1. Individuals within a species are variable.

   -In an individuals body there are several different kinds of neurons

2. At least some of these variations are hereditary

   -Some neurons will be passed on to future generations, and if the neurons are infected with HD, these defective genes will be passed on

3. In every generation there are more offspring produced than survive

   -The favorable neurons will outlive the nonfavorable neurons since there are not enough resources for all of them to survive

4. Natural Selection operates on populations

   -The neurons that survive are more adaptable to their environment and have higher fitness. The neurons that have been infected by Huntington’s keep repeating and changing so that they continue to survive in their environment.

4. Now add the selective pressure of MSH3 and instability and describe how this violates the assumptions we have made in class about “important” mutations.

MSH3 accounts for the instablility in Huntington's mice, while the factors that cause the cell-specific differences in CAG repeat instability are unknown. Nothing is known about the distribution of MSH3 in the brain. However, cells withouth MSH3 are unable to cause CAG repeat size in adults. Therefore, this protien accounts for the expansion of the sequences. This violates the assumptions we have made about important mutations because mutations must occur by reproductive age in order to be passed on to future generations. But the repeat sequence cannot be modulated in adulthood in cells that lack MSH3.

5. Is Huntington’s Disease itself subject to selection? Why or why not?

Huntington’s disease largely escapes the pressures of selection because the onset of the disease, in most cases, does not appear until the individual is past reproduction age. Late-onset Huntington’s is especially immune to selection because the alleles are almost invisible to the selection process because of the age when Huntington’s hits. Although Huntington’s is a deadly disease and the CAG repeats are almost always deleterious the alleles still get passed on to future generations. The only way selection could affect Huntington’s is because of its anticipation factor. It has been shown that an increase in the number of repeats also increases the severity and onset of symptoms. If the analogous repeat lengths were to be inherited there would be a difference of several decades in age of onset, and this would be strongly selected against if the age were to be before reproduction age. Although it is very unlikely that selection could eliminate this disease because it is mutation based and some get the disease without any family history of it.

6. Why is it important to study protein folding/misfolding in Huntington’s, even though we know its cause (trinucleotide repeats)?

Studying protein misfolding is very important in searching for a cure for Huntington’s. Although the cause of Huntington’s is already known a cure has still yet to be found and the answer may be found in dealing with the aggregate proteins. Figuring out why the repeats cause the proteins to clump may lead to a drug which eliminates this effect. Also, one of the factors for the pathogenicity of the disease is the cellular context. The instability of the disease is largely due to the misfolding of proteins.

Interview

On Wednesday, February 11, we conducted a phone interview with Dr. Lorraine Edwards, a neurologist from Hastings, Nebraska who practices at Central Nebraska Neurology. She is very well informed on Huntington's Disease and has seen and treated the disease first hand. The interview was very helpful in furthering our understanding of HD. The following is the transcript of the phone interview:

1. Why did you choose this field?
In Med School, she was in a summer research project that dealt with Huntington's and really enjoyed it, so from them on she decided to push Huntington's.

2. Do you have any accounts of patients with HD? Any interesting stories?
Yes, Huntington's disease(HD) is quite variable, she has seen cases of it in 40 year olds as well as people in their 70's and 80's. One man who had HD developed it when he was young, but he loved to play the guitar. He had a great deal of trouble walking but could still play his guitar. When he could no longer hang onto the guitar, he was brought a keyboard so he could still play the music, even though he could hardly walk or talk. Another gentleman couldn't walk or drive but could still ride his bike, which he really enjoyed doing. This was his means of transportation, although he had difficulty stopping and starting. Often times people don't find out they have HD until they are older and many times they have already passed it onto their children. One woman had HD all throughout her family. She got married and had a baby, and at age 44 developed symptoms of HD. When her husband realized the onset of the disease had started, he took their six year old child and abandoned her. She progressed quickly and could not walk, and it was later found out that HD was not only present in all her sisters but also her father's family. Another story occurred when a parent and a child both had HD and were experiencing symptoms at the same time. The child had worse symptoms because of anticipation. The child's symptoms were more closely resembled Parkinson's.

3.Why should a doctor studying HD know about evolution?
Because of the different nature of the way the gene is affected/expressed in each generation is different. It becomes worse with each passing generation. Natural selection has not been seen to play a role in the elimination of the disease because most individuals find out they have the disease after child-bearing years.

4. Why should they know about protein misfolding?
Because it is the misfolding of proteins that leads to the development of the disease. The first step in finding a cure is making a correction in the error of folding.

5. How important is the search for a cure?
Very important, a cure should be found soon because we have already established the exact location on chromosome 4 where the problem lies. They are very close to finding a cure for the genetic mistake that causes the disease.

6. What do you think about using grid computing in this search?
Not sure

7. What misconceptions exist about HD?
People with HD often die early and their children do not know they have a 50/50 chance of getting the disease. Especially in the past, many families will keep the disease a secret. They feel it is easy to sweep the issue under the rug rather then be upfront and honest with their family history. Doctors are not allowed to pass on the information to the children of their high risk. All doctors can do is recommend family counseling.

8. What are the symptoms of HD?
Chorea-movement disorder-develops from a mild disorder to inability to walk, many often end up in wheelchairs
Slurred speech, difficulty swallowing (some patients have a feeding tube), depression, paranoia, dementia

9. From the time the symptoms start, generally how quickly do they progress?
People who develop symptoms of HD in their 60's and 70's have milder symptoms for a longer time frame. They can live for up to 20 years living a normal life after they have discovered they have Huntington's. Normally though in the first 5-7 years jerky movements associated with the disease become more pronounced. After 10 years many patients then start to experience the dementia phase, although on average they experience less dementia. Those who develop Huntington's at a younger age, around their 40's, develop the symptoms much faster and to a higher degree. The jerky movements will become very strong and the onset of dementia normally occurs in less then 10 years and is very severe. Most of these types of patients die within 10 years of diagnosis.

10. What actually causes the death of HD patients?
A person with HD will often die of pneumonia or other respiratory complications due to the inhalation of saliva or food that gets trapped in the lungs and develops an infection.

11. How many cases of HD have you seen? Is it common? Has it become more popular?
It is very rare, in 15 years seen a dozen cases/worked on in Nebraska as well as Rochester, NY, has not become more common in that time period.

12. Are certain regions more likely to develop this disease? Does gender effect it?
Certain regions in the United States have not been more prone to it. Gender does not affect it because it is an autosomal disorder.

13. What do people do to treat their symptoms?
Medicines can be taken to tone down the movements, treat the depression, which is often portrayed by anxiety or OCD, and control the drooling that can occur. People with HD are most often in wheelchairs.

Diseases and Misfolding of Proteins

Description

We are using the grid-computation method, sharing tasks over multiple computers, in order to learn about the molecular nature of diseases that are caused from errors in protein folding. Using this method, we are doing work with the Folding@home project. The aim of theFolding@home project is to better understand protein folding, what happens when proteins do not fold correctly, and the diseases that result from this protein misfolding. Once the causes of protein misfolding are discovered, cures for diseases such as Alzheimer's disease, Huntington's disease, cystic fibrosis, BSE , and cancers could find a cure. Misfolding of proteins causes clumps of proteins to gather in the brain, causing diseases. Proteins fold very quickly, some as fast as a millionth of a second. The link to the folding@home website is: http://folding.stanford.edu/English/Main Folding@home has had many successes related to protein misfolding. http://folding.stanford.edu/English/Papers, describes the results of the work that has been done so far.
Huntington's Disease (HD)
One of the diseases that Folding@home is currently focusing on is Huntington’s Disease. This disease results from the aggregation of various proteins. If proteins contain long enough strands that contain numerous repeats of the amino acid, glutamine aggregates begin to form, causing the disease. This abnormally long of a repeated section of the amino acid glutamine in the DNA sequence has been thought to stem from an inherited gene and has been give the name, huntingtin gene. A healthy person has a string of 9 to 39 glutamines; whereas, Huntington's patients have 36 to 121 glutamines. http://www.aboutdementia.com/articles/about-huntingtons/huntingtons-causes.php

Folding@home is examining the structure of poly-glutamine aggregates and is attempting to predict as the pathway that forms these aggregates. The goal of these Huntington’s studies is to find drug design approaches so Huntington’s can be find a method to stop the disease from forming the aggregate pathway. The link to the folding@home website is: http://folding.stanford.edu/English/Papers

Huntington's Disease effects the brain in a way that causes physical symptoms throughout the entire body.