User:Sharkeyr/sandbox

Summary of the Five Pillars of Wikipedia
The Five Pillars of Wikipedia discuss the guidelines for contributions to the site.
 * First, wikipedia is not for people to try to draw an audience to get their opinions across. It is a reference, just like any other encyclopedia or almanac. Even though it is up to users to add content, it all must comply to those mindsets.
 * Second, all articles, or updates to articles, need to have a neutral tone. It is not a place to put emphasis on a viewpoint, it is just to relay the information of exactly what happened.
 * Third, everyone has access to Wikipedia, but it still is important to remember not to plagiarize, because it is still held to copy write laws. If you want to use facts from another book they must be summarized and sited.
 * Fourth, everyone using wikipedia must respect each other. There should be no attacking another contributor. If an issue arises, the talk page has a conflict resolution section.
 * Finally, the fifth pillar is that there are no hard-fast rules on Wikipedia. As times change, rules may also become modified to reflect what is current. Mistakes can be corrected, as old versions of pages are saved, and because other people can contribute, it is likely any mistake will be corrected by someone else.

Article Assessment
We are looking to update a stub article, which is just a simple introduction to the topic. There are no references and very little information available in the article. The goal of this class assignment is to update the stub article to somewhere between a B level and GA level article. A B level article has a good deal of information and some references, although possibly incomplete. You are able to get a good amount of information out of the article, but things like pictures and charts may not be included and the formatting may not be perfect. A GA or good article is a step above a B level article and has good information and references. It is just below the quality of an actual encyclopedia. The main problems are generally editing/formatting, and this may be helped out by having a peer review or comparing it to featured articles. To get an article to be between a B and GA level, the content must be complete and easily understood by an reader. The formatting needs to be close to perfect and references need to be very complete and include footnotes/references within the text as opposed to just the list at the bottom of the article.

Pubmed Article summary
Several studies have been performed to determine what telomere length affects. One study aimed to look at telomere lenght and Body Mass Index (BMI) and type 2 diabetes. There was no significant difference found in people with type 2 diabetes or a higher BMI and a shortened telomere length. Another study looked at women who express the APOE gene to determine if telomere length was associated, as well as whether or not hormone therapy had any affect on the telomere length. In this study APOE expression did play a role in telomere length, which expression indicating telomere shortening over the study period. Hormone therapy seemed to have a positive effect, with telomeres maintaining more of their length despite APOE expression during the 2 year study. While the first study appeared to show no shortening of the telomere based on BMI, it was a very specific population being monitored, with only middle aged and older European women being enrolled in the study. The study involving hormone therapy also was compiled of middle aged and older women, with no specific nationality described.

notes on references
Identification of somatic mutations in human prostate cancer by RNA-Seq XiaoLin Xu, KaiChang Zhu, Feng Liu, Yue Wang, JianGuo Shen, Jizhong Jin, Zhong Wang, Lin Chen, Jiadong Li, Min Xu, Identification of somatic mutations in human prostate cancer by RNA-Seq, Gene, Available online 19 February 2013, ISSN 0378-1119, 10.1016/j.gene.2013.01.046. (http://www.sciencedirect.com/science/article/pii/S0378111913001194) -RNA-seq uses parallel sequencing to find Single nucleotide varients in transcribed regions - frameshift mutation (in/del) disrupts ORF in TNFSF10 which prohibits apoptosis and allows tumors to progress - prostate cancer has environmental triggers but also genetic component. - of tested coding regions 116 varients found, 61 were damaging by altering amino acids or causing frameshift mutations - method included mapping short regions of DNA and DNA sequencing

New Approaches to Treatment of Primary Immunodeficiencies: Fixing Mutations With Chemicals Hu, Hailiang, and Richard A. Gatti. "New Approaches to Treatment of Primary Immunodeficiencies: Fixing Mutations with Chemicals." Current Opinion in Allergy and Clinical Immunology 8.6 (2008): 540-46

-	Primary Immunodeficiencys (PIDs) are inherited, lead to increase risk of infection -	120 currently observed genes and 150 current known mutations play a role in PIDs -	current treatment is gene therapy, but it is risky and difficult, possibly leading to diseases such as leukemia -	frameshift mutations alter reading frame, changing downstream codons o	lead to loss of protein, change of protein or insertion of new protein -	no pharmacogenetic approaches currently available for repair -	gene therapy includes modified zinc finger nuclease fusion protein to cleave either side of the mutation, essentially removing it from the DNA strand -	antisense-oligonucleotide mediated exon skipping – skip exon with mutation to generate in frame mutation and functional protein o	Duchnne muscular dystrophy (PRO051) o	Lessening of symptoms, not cure for disease o	More practical for repetitive genes, ie structure proteins -	Revertant mosaicism- naturally occurring but can repair frameshift mutation o	Reverse mutation or second-site mutations o	Neutralizes mutant phenotype o	X-linked SCID, Wiskott–Aldrich syndrome, Fanconi anemias, and Bloom syndrome -	Reversion may be cause by intragenic recombination, mitotic gene conversion, second site DNA slipping, site-specific reversion -	Learning more about these processes could potentially lead to pharmaceutical drug development

Host RNA polymerase II makes minimal contributions to retroviral frame-shift mutations Zhang, J. "Host RNA Polymerase II Makes Minimal Contributions to Retroviral Frame-shift Mutations." Journal of General Virology 85.8 (2004): 2389-395. -transcription needs DNA polymerase and RNA polymerase II, these can both introduce mutations into the sequence - in vitro models can’t determine at which stage errors are introduced -reverse transcriptase is thought to cause more mutations based on the fact that HIV mutation rates are higher than things like T cell leukemia, based on determining mutations after 1 round of transcription - prokaryotic and wheat RNA polymerase II error frequency rates can be determined ( between 10-4 and 10-5, and 1x10-3 respectively) but human rates cannot -frameshift mutation is one of the most common in retrovirus replication -GFP was inserted into vector, if insertion was in-frame no mutation is present and host emits green. If insertion is off-frame, frameshift mutation present, green intensity reduced, backward frameshift mutation - Adenosine nucleotides inserted, 1 at a time, error rate 0-3 after 1 round of transcription error rate 11%, indicative of error being caused by reverse transcriptase, each addition caused more mutation, less green light 10 A inserts 3% error rate, 16A 13% error -	RNA polymerase II accounts for 3-13% of frameshift mutations, 10A insert accounted for 0-3% of mutation, but frameshift mutation rate for sequence was 11% showing that RNA polymerase II not responsible for majority -	Reverse transcription causes majority of frameshift mutations -	Frameshift mutations may be very important in HIV evolution

FRAMESHIFT MUTATION: DETERMINANTS OF SPECIFICITY. Ripley, L. S. "FRAMESHIFT MUTATION: DETERMINANTS OF SPECIFICITY." Annual Review Of Genetics 24, (December 1990): 189-213. Academic Search Complete, EBSCOhost (accessed March 9, 2013).

Two Frameshift Mutations in the Cystic Fibrosis Gene Iannuzzi MC, Stern RC, Collins FS, Hon CT, Hidaka N, Strong T, Becker L, Drumm ML, White MB, Gerrard B, et al. Two frameshift mutations in the cystic fibrosis gene. Am J Hum Genet. 1991 Feb;48(2):227–231. -	Majority of cystic fibrosis occurs because of ∆F508 deletion of entire amino acid, but several other mutations possible -	Cystic fibrosis on CFTR gene (CF transmembrane conductance regulator) -	2 frameshift mutations on exon 7 CF1213delT and CF1154-insTC o	in patients with frameshift mutation observed both have at least 1 other CF mutation o	both have mild impairment of lung function o	observed through Sanger sequencing o	observed to be less than 1% of 128 patients teste

Predicting the effects of frameshifting indels Hu Jing, Ng Pauline C. Predicting the effects of frameshifting indels. Genome Biology.2012:13:R9 http://genomebiology.com/content/pdf/gb-2012-13-2-r9.pdf -	insertions and delitions of less than 20 bp account for 24% of mutations in disease o	frameshift mutations are caused by in/dels not divisible by 3 -	harder to study than SNPs or structure varients o	Sanger sequencing and next gen sequencing commonly used but difficult to get quality data o	Sanger sequencing identified 1.96 million indels that did not overlap other databases -	Frameshift mutations commonly thought to be loss of function, but some new trends found in humans o	Generally are found at end of protein o	Occur in hypothetical and olfactory genes •	Suggestive that some FS mutations are possibly neutral -	SIFT algorithm predicts effect of amino acid substitutions o	SIFT indel algorithm predects effects of indels •	84% accurate o	FS indels thought to be damaging to the gene negatively correlates with allele frequency o	Have both functional and non functional forms -	method for determination involves comparing DNA damaging FS mutations to Human Genome Mutation Database (HGMD) o	neutral indels determined from pairwise alignments with other species o	20 feature decision tree to determine damaging effects •	4 features most important – 1. fraction of affected conserved DNA bases, 2. Indel location relative to transcript 3. Fraction of affected conserved amino acids 4. Minimum distance of indel to exon boundry o	classification rules •	1. If the percente of affected conserved DNA low, indel doesn’t affect gene function •	2. If the max. relative indel location is not near the end of the exon sequence, indel is still neutral if percentage of affected conserved DNA bases is low •	3. If the percentage of affected conserved DNA bases is low, the max fraction of lost conserved amino acids is low, and max indel position is near end of cDNA, then indel is predicted neutral •	4. If more than 6.2% of conserved bases affected, indel is in the middle of cDNA and middle of the exon, likely gene damaging -	Most frameshift mutations in humans thought to be damaging after SIFT indel analysis and comparison to 100G and CGI data sets o	Many genes with gene damaging indels are overrepresented and under relaxed selection o	Bottleneck population – no time for purifying •	European and Asian populations o	Positive selection -	Maynard Olsen “less is more” theory 1999 o	Gene loss can be an advantage for survival

A frameshift mutation in NOD2 associated with susceptibility to Crohn's disease Ogura Y, Bonen DK, Inohara N, et al. A frameshift mutation in NOD2 associated with susceptibility to Crohn's disease. Nature. 2001;411(6837):603-6. -	3020insC truncates NOD2 protein and is associated with Chrons disease -	normal protein responsive to bacterial lipposaccharides, truncated protein not -	leads to premature stop codon

Image List-Frameshift Mutation
1.	Molecular Biology and Biochemistry background http://en.wikipedia.org/wiki/File:Cdmb.svg

http://en.wikipedia.org/wiki/File:Translation-genetics.png

http://en.wikipedia.org/wiki/File:Rna-codons-protein.png

http://en.wikipedia.org/wiki/File:GeneticCode21-version-2.png

http://en.wikipedia.org/wiki/File:Peptide_bond.jpg

http://commons.wikimedia.org/wiki/File:Protein-structure.png

2.	Mechanism

http://commons.wikimedia.org/wiki/File:Frameshift_mutation.jpg

http://commons.wikimedia.org/wiki/File:Point_mutations-en.png

3.	Frame shift causes-Research

4.	Diseases-Research

http://commons.wikimedia.org/wiki/File:Patterns_of_Crohn%27s_Disease.svg

http://commons.wikimedia.org/wiki/File:Tay-sachsUMich.jpg

http://commons.wikimedia.org/wiki/File:Cystic_fibrosis_manifestations.svg

http://commons.wikimedia.org/wiki/File:Prostate_Cancer.jpg

5.	Positive Uses-Research

Preliminary Outline-Frameshift Mutation
Lead: Introductory Text….

……..Frameshift mutation is an intriguing topic, as a simple/small change in a nucleotide can cause such large/complex outcomes. Frame shift mutation is the deletion or insertion of nucleotides.….. Expand the original lead paragraph ideas and add more refs.

Contents…..

1.	Molecular Biology and Biochemistry background


 * Central dogma (add image?)
 * Brief background on translation (rRNA, tRNA processes)
 * Importance of the triplet codon in translation (add image?)
 * Movement/deletion of the stop codon to alter entire protein
 * Protein: structure and function (add image?)

2.	Mechanism


 * Description of frameshift mutation (add image?)
 * Is it heredity or environmental mutation
 * Debate why this is different than a point mutation (add image?)

3.	Frame shift causes-Research
 * Research attempts into what exactly cause the shift (deletion or insertion)
 * Methods for finding frameshift mutations
 * RNA editing (gRNAs) Dscam gene- exon 6 (add images?)

4.	Diseases-Research
 * Diseases: research into causes and cures (cancers, cystic fibrosis) (add images?)
 * Keep concepts from “thermodynamic” section of original article

5.	Positive Uses-Research
 * Identification of frameshift mutations that can lead to improved treatments
 * Any positive uses for this type of mutation (nylonase?)

6.	See also…..

7.	FootNotes……
 * Mutation, Transcription (genetics), Translation (biology), codon, protein, reading frame, point mutation, crohn’s disease, BRCA2, ubiquitin

8.	References……
 * In line citations with link to Diberri tool for references

9.	Further Reading…..
 * Textbook references

10.	External links…..
 * Books etc…..ie. DNA repair & Mutagenesis (textbook)


 * Keep the same list as in the original article

Summary of Improvements
To improve this article we are looking to broaden the basic ideas already highlighted. We would like to add in information regarding the formation of frameshift mutations and how they effect the reading frame/proteins. We would also like to look into the mechanism of the mutation, i.e. genetic or environmental causes, and also how it differs from other point mutations. From there we would like to expand into research on the cause of frame mutations. This will lead into the clinical relevancy of frame mutations, such as role in disease. Finally we would like to talk about frameshift mutations as a positive factor in dealing with improving treatments, and the role frameshift mutations play/have played in evolution, i.e. nylonase.