Ryan's Post

Throughout the conduction of research on Ostegenesis Imperfecta I learned many interesting facts! I thought it was important to know that OI is an autosomal dominant defect that may give rise to 8 different types. I would have to agree with Dr. Monoco about exactly how much a doctor needs to know about evolution to be a good physician. I feel that a doctor should really only know aspects of evolution that pertain to human health. By this I mean that physicians should primarily know about the evolution of pathogens and antibiotics that are most useful in killing bacteria.

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Two Questions

1) Provide an estimate of h2 for the disorder. Based on this, discuss how much influence selection could have on this trait.
Most forms of OI are inherited dominantly meaning only one copy of the mutant gene is required for the expression of OI. Type I, the mild form of OI, is the most common disorder (about 4-5 people out of 100,000 people are affected). In type I OI, the mutation produces normal collagen and mutant collagen because the normal allele (from a normal parent) produces normal collagen and the mutant allele (from an OI parent) produces mutant collagen. Consequently, normal collagen combined with mutant collagen produces a mild form of OI. The most severe form of OI is type II in which only mutant collagen is produced; as a result, bones that are made become brittle. h² shows the amount of genetic variation that is due to additive effect. Since OI is a genetic disorder, h² should be high. The equation, R=h²S, shows that selection has a strong influence on this trait because the mutation reduces the fitness of the person with this disorder.

2) What effect might inbreeding have on this disorder?

Inbreeding increases homozygosity and decreases heterozygosity. Therefore, inbreeding will result in individuals with severe OI (Type II) or no OI (normal) and no mild forms of OI (Type I). The frequency of OI (Type II) in the population will increase and Type I (heterozygous genotype) will decrease.

http://ghr.nlm.nih.gov/condition=osteogenesisimperfecta

John's Response

I learned that there were different forms of OI and that the different types ranging in different levels of severity. Through evolution, it is amasing how there is such a great similarity between the chicken and human. And, a possibility for the their differences is a divergence from a common ancestor. Gene targeting can be a difficult process and it is impressive how gene therapy could target the defective genes with a hope to help the OI patient.

Dung's Response

Most mutations at the COL1A1 and COL1A2 results in Type I or Type IV which usually follows an autosomal dominant pedigree. This means that they can receive the allele from either parents. Mutations in CRTAP and LEPRE1 results in Type III and usually follows an autosomal recessive pedigree. This means that offsprings must receive the recessive allele from both parents.

I learned that OI has some medical advancements in improving the lives of patients with OI because we cannot control what genes are passed on from parent to offspring. Thus, we must help those that receive slightly deleterious or deleterious genes. This will enable OI patients to have equal chances of reproduction as the rest of normal people without the mutated genes.

Why does a doctor need to know evolution?
Doctors should be well aware of evolution because each individual is different from another. Since people tend to ask doctor's about their decision, doctors should be well versed in all aspects of biology and evolution is included. For example, a person that has a regular cold. The person asks the doctor if he can get antibiotics. What should the doctor say? Should he state that it is a regular cold and the immune system can easily handle it or should he prescribe him antibiotics which may mutate the bacteria and then become resistant to bacteria? As one can see, using antibiotics increases the likelihood of bacteria to becoming resistant to the drug because some bacterium cells survive and then reproduce which causes all of their offspring to have the antibiotic resistance. Therefore, it is imperative for doctors to know evolution as well because this will play a role in making decision when a patient asks for drugs for their problems.

Paper Questions

1. OI type I is selected against once the phenotype from the disease becomes apparent. In other words, natural selection acts upon the disease after reproduction age which is usually around twenties to thirties. Therefore, before menopause in women and age 60 in men, natural selection usually does not act upon the disease. During reproductive age, people with the genotype for OI type I has similar chances to everyone else for finding a mate since the phenotype for the disease is not apparent yet. Therefore, they could still pass on their genes to their offspring and remain in the population. Since the disease is autosomal dominant, only one dominant allele is required from the parent for the offspring to develop the disease. For example, if one affected heterozygous parent mates with a normal parent, half of their offspring will have the genotype for OI type I. The reason why the genes are remained in the population is because the phenotype is not expressed during reproductive age but rather later on in life. This enables them to reproduce as normal individuals and keeping in the gene in the gene pool.

2. In the essay, it states that the amino acid residues 328-429 from the chicken correspond exactly to those in humans. The similarity between the chicken and the human is most likely due to inheritance from a common ancestor. However, the sequence 430-447 in human is different from the chicken. According to the article, this difference might have been caused by divergence from a common ancestor more than 600 million years ago. There could have been a mutation in this segment of the gene that caused them to diverge at the location with the differences. Since this region of the genome sequence is similar, but in different species, they are considered as orthologous sequences.

3. The article stated that the repetitive structure of interstitial collagen genes is caused by serial duplication of the primordial 54-bp exon. There are two ways that this could have occurred. First, a possibility for duplication could have occurred by homologous exchange between the adjacent exons, mediated by chromosome pairing. Secondly, it could have been caused by non-homologous introns breaking and reuniting.

4. The process of transcription allows the RNA to form from the DNA. Translation is when the amino acids are formed from the codes of the RNA. After the proteins are translated, they fold according to the genetic code. By studying the folding of proteins, it is possible to compare the normal folding of proteins to the mis-folding of proteins to help understand the disease. By comparing the abnormal to the normal proteins, it is possible to pin-point the location of abnormality. Unlike OI type I, which is usually not acted upon by natural selection since the phenotype shows up in the later stage of life, the phenotype of type II shows up before birth. Since people with type II display the symptoms of osteogenesis imperfecta at throughout their life, natural selection acts against them which make it difficult for them to survive to reproductive age.

5. The reason why this method works is because viral vectors are the injection of viruses which contains genetic information. Basically, the idea is exposing a cell with a virus and once that virus infects that cell, it will block or silence production of a specific protein. In this case for OI, it is the production of proteins that makeup collagen fiber. If there was a regulatory gene mutation in a MSC, then the probability of MSC functioning properly is lowered because the proteins within the cell are changed. As a result, normal collagen are not formed by the MSC and will not help with OI.

Interview: Osteogenesis Imperfecta

1. Why did you choose to become a doctor in the field you chose?

My medical student Docent group was led by the chairman of the department of medicine.

2. Do you have any accounts of patients with osteogenesis imperfecta? Any other interesting stories?

My first exposure to OI was in 1984 as a medical student doing an internship in Columbia Missouri with a family practitioner. This particular patient that I met was extremely short and barrel chested and had blue sclerae due to collagen deficiency. He looked deformed to me. My Preceptor, Dr. Moranville, was the first person to expose me to this condition. It was at that time that I was first taught about OI – and his clinical presentation has stuck with me throughout the years, making it easier to remember the disorder.

3. Why should a doctor or researcher studying osteogenesis imperfecta know about evolution?

I don’t know the correlation here.

4. How important is the search for a cure?

As with any disease that affects both quality and quantity of life, it is important to attempt to understand the disease and work toward a cure to reduce the incidence of OI and save thousands of individuals from increased morbidity and mortality.

5. How might research in osteogenesis impefecta benefit research of other genetic diseases?

Research for OI is employing stem cell research and gene therapy which can be applied to other health conditions. Also the use of rehabilitation and bone healing/treatments could help us to understand how to better treat bone fractures in otherwise healthy individuals.

6. What misconceptions exist about osteogenesis imperfecta?

That these patients may be some type of dwarf given their short stature. Also, some people assume that there is some type of mental retardation associated with these individuals as well which is not the case.

7. How important is it for physicians to know about gene mutations?

I am not sure that every physician needs to understand gene mutations to be able to be a good primary care specialist. However, physicians should be aware of the condition and be able to recognize it and offer appropriate referrals for treatment/management.

8. What do you think about using grid computing in this search?

I only know a little about grid computing. I understand the concept and have participated in them a few years ago with such web portals such as Kazaa and Napster for music searching/downloading. It makes sense to me that if you were to use the power of many CPU processors to genetic information etcetera, then the power of these computers could speed up the process immensely. I would support the use of grid computing here and in any complex medical problem that requires massive computer processing power to facilitate the work and increase the rate of success and finding the answer/cure etc.