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A thorough investigation on the effects of DNA packaging on phenotype

Anthony Serra

on 23 June 2011

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Transcript of Epigenetics

As part of the 3 year pilot program, the HEP already mapped the MVPs of the Major Histocompatibility Complex (MHC) - A region of chromosome 6 associated with the most human diseases (2003).
DNA is wrapped around histone proteins. While this is happening, one unit is called a nucleosome, and nucleosomes cannot be transcribed.
In Genomic Imprinting, a particular DNA sequence is tagged during the sperm or egg's lifetime, potentially leading to the same gene have alternate phenotypic effects.
Today, only chromosomes 6, 20, and 22 are mapped. A History of the EpiGenome Project. Termed HEP, this officially started by Stephen Beck and Alexander Olek in 2000 at France.
The first researchers were Wellcome Trust Sanger Institute and Epigenomics AG.
The Human Genome Project … ‘provided the blueprint for life, but the epigenome will tell us how this whole thing gets executed’. -Olek
Unlike the HGP, the HEP is an interconnected network of private and public teams which minimizes competition.
Goal is to map the Methylation Variable Positions (MVP). Basic Elements to Know Procedure DNA segments are treated with sodium bisulfite, converting all non-methylated cytosine into uracile.
Amplify sample using PCR and bisulfite-specific primers.
Sequence the location of methylation by comparing location of cytosine on untreated segment and the location of uracil on treated segment. Real Life Experiments Reguarding the Epigenome Professors Yehuda and Seckl traced the generations of women in their last trimester who lived in New York during the time of the assault on the Twin Towers. It was found that a low level of the stress hormone cortisol was present in the saliva of both the women and their children, an indication that these kids will not be able to cope well with stress. Investigation of the third generation will be necessary to prove this is an inherited condition rather than due to high levels of cortisol in the womb. Mike Skinner exposed pregnant rats to high levels of pesticides, the results were that the offspring developed an array of diseases, including tumors, kidney dysfunction, and immune deficiencies from generation to generation. This may seem obvious, but it is critical to think why it had this long-term effect. It is apparent that the life choices of one generation can alter the epigenome for future generations. Should individuals make life style choices under the consideration of the impact it might have on future generations? Will (grand)parents be blamed for illness in the child? Paramutation Paramutable vs Paramutagenic The exposure of one allele to another by coexisting in the same genome nullifies its effect for generations.
Example in Zea mays* (corn): The B-I gene encodes for an enzyme responsible for pigmentation, the b gene is entirely recessive to it. However, there is also the B' gene which codes for very little amounts of the pigment and prevents typical pigmentation of the B-I gene, in the individual and offspring. Human Epigenome Project
(HEP) Anthony Serra Gene Silencing DNA Methylation Histone Modification All cells in the body contain the same genes, so silencing of some is vital for the differentiation of different body cells.
The random silencing of X Chromosomes in mammalian females into barr bodies is the extreme silencing. Methyl groups, R-CH3, modify DNA
Methylation specifically targets cytosine adjacent to guanine, a site referred to as the CpG site.
Three enzymes, called DNA methyltransferases (DNMTs), are capable of adding Methyl groups to DNA.
Methylation can sometimes differentiate between paternal and maternal sources (imprinting). Histones are proteins which wrap DNA and compact it into heterochromatin: untranslatable, compact DNA.
Two major modifications involve Acetyl groups (-COCH3) and methyl groups, both of which bind to the amino acid lysine.
In Acetylation, acetyls are added and genes cannot be expressed. In Deacetylation, the opposite is true.
Methylation is used more as a marker. Important Processes on Gene Expression Should environmental fluxes in previous generations be considered in insurance premiums, considering it does effect the general health and life expectancy of that individual? Should pregnant women be prevented from working during the last trimester to prevent potential exposure to harmful chemicals? Epigenetics could highlight social inequality - i.e. those most threatened are those with the least hospitable homes and working environments. Would this lead to discrimination? Should laws that protect privacy by implemented? Bioethics related to Epigenetics "At the heart of this new field is a simple but contentious idea – that genes have a ‘memory’. That the lives of your grandparents – the air they breathed, the food they ate, even the things they saw – can directly affect you, decades later, despite your never experiencing these things yourself. And that what you do in your lifetime could in turn affect your grandchildren." - Mike Bell Identical twins differentiating in the presence and absence of autism symptoms.
Difference between Angleman's Syndrome and Prader-Willi Syndrome despite the same chromosomal difference.
Beckwith-Wiedeman Syndrom (BWS) shows no difference in DNA than that of a "normal" person, however, unusual methylation causes a gene on chromosome 11 that regulates growth to become dysfunctional. This occurs more frequently during IVF births, suggesting an environmental stimuli. Evidence Supporting Epigenetic Effect on Phenotype: Parental Imprinting In mammals, it was discovered app. 10 years ago that certain genes are only expressed if it was inherited from a particular parent.
The imprinted allele (that which is not expressed) are more methylated than the opposite allele.
Paternal Imprinting - Expressed only if inherited from the mother, despite paternal allele. Ex. The Mus musculus* (mouse) gene H19.
Maternal Imprinting - Expressed only if inherited from the father, despite maternal allele. Ex. The Mus musculus* (mouse) gene Igf2. Implications of Epigenetics on Evolution The Epigenome is remarkably less stable than the Genome, and so has a much higher rate for mutation, which can both increase "genetic" variability and be directly influenced by the environment.
Because the environment can influence phenotype in this way, there can be a higher expected frequency of new heritable variants caused by epigenetic factors.
Greatly increases the current populations dynamics model, increasing complexity of mathematical formula involved in evolutionary theory.
Evolution can now be viewed in two major processes, the slow, stable DNA sequence, and the rapid, unstable epigenome. Connection Between Epigenetics and Cancer The connection between cancer and epigenetics was first discovered in 1983, the first time the epigenome was associated with illness.
Cancerous tissue samples often show less DNA methylation than normal tissue from the same patient, suggesting a heightened amount of gene expression as a potential cause of cancer.
CpG islands near the promoter, which are in high concentration, are often hypermethylated in cancer cells, shutting off entire genes, often that code for cell-cycle regulating enzymes.
Hypermethylation can lead to increased rate of DNA mutation and microsatellite (repeated sequences of DNA) instability. This is currently under experimentation to (dis)prove connection to cancer, though it is suspected that it does. Phenotypic Plasticity Described as the ability of the same genotype to produce different phenotypes in reguard to the environment.
Ex. The flower color of Hydrangea arborescens* is dependent upon the pH level of the soil.
When this trait influenced by the environment can be passed on to offspring, it is reffered to as the maternal effect, which basically shares a deffinition with epigenetic inheritance. Connection Between Epigenetics and Cloning Recent evidence suggests that cloning from somatic cells is particularly difficult due to the necessity of artificially "creating" a methylation imprint. Studies have shown that their is a tight correlation between the epigenetic transfer success and the clone's survival. Epigenetic Disorders and Mental Disability Diseases, syndromes, conditions, ect. that are caused by epigenetic abnormalities typically leads to mental disability and 'autism'-like behavior.
The most common is Fragile-X syndrome, which effect app. 1 in 4,000 males and 1 in 8,000 females.
Although this is caused by a gene mutation (repitioin of Cgc Islands), it is the hypermethylation disruptance that causes symptoms. Works Cited
Beck, PhD, Stephan. (2006). "UCL Cancer Institute." UCL – London's Global University. Retrieved from: http://www.ucl.ac.uk/cancer/research-groups/medical-genomics/hep_data/.
Bell, Mike. (2010). "Epigenetics – the Ghost in Your Genes." The Wellbeing Journey. Retrieved from: http://wellbeingjourney.co.uk/2010/10/14/epigenetics-the-ghost-in-your-genes/.
Bradbury, Jane. (2003). "PLoS Biology: Human Epigenome Project—Up and Running." PLoS Biology : Publishing Science, Accelerating Research. Retrieved from: http://www.plosbiology.org/article/info:doi/10.1371/journal.pbio.0000082.
"Epigenetics – The Ghost in Your Genes « BioethicsBytes." BioethicsBytes. (2011). Retrieved from: http://bioethicsbytes.wordpress.com/2008/06/30/epigenetics-the-ghost-in-your-genes/.
Freeman, W. H. "Epigenetic Inheritance - Modern Genetic Analysis - NCBI Bookshelf." (1999). Retrieved from: http://www.ncbi.nlm.nih.gov/books/NBK21276/.
"Human Epigenome Pilot Project." Human Epigenome Consortium. (2008). Retrieved from: http://www.epigenome.org/index.php?page=normalization1.
Simmons PhD, Danielle. "Epigenetic Influences and Disease | Learn Science at Scitable." Nature Publishing Group : Science Journals, Jobs, and Information. (2008). Retrieved from: http://www.nature.com/scitable/topicpage/epigenetic-influences-and-disease-895. Photos Cited
"Bees, Obesity and Epigenetics « Andreality." Andreality. (2011). Retrieved from: http://andreality.wordpress.com/2011/04/25/bees-obesity-and-epigenetics/.
"Stefanie Seitz : Connecting the Histone Acetyltransferase Complex SAS-I to the Centromere in S. Cerevisiae." Edoc - Dokumenten- Und Publikationsserver Der Humboldt-Universität Zu Berlin. (2005). Retrieved from: http://edoc.hu-berlin.de/dissertationen/seitz-stefanie-2004-10-20/HTML/chapter1.html.
"Epigenetics - How Major Experiences We Have May Have an Effect on Our DNA | SciShark.com." SciShark.com - Delicious Science for Hungry Sharks. (2011). Retrieved from: http://www.scishark.com/2011/03/epigenetics/.
"Entrepreneurship and Epigenetics." PHARMACEUTICALS AND HEALTHCARE. (2011). Retrieved from: http://pharmaceuticalshealthcare.blogspot.com/2011/02/entrepreneurship-and-epigenetics.html. Make Brochure on Epigenetic experimentation! * Binomial nomenclature incapable of being used with this format. Atypical Gene Expression Practical Application Epigenetic Experimentation Characteristics of Field Experiments Chemical manipulation of epigenetic factors through demethylating agents or endocrine-disruptors can be used to see epigenetic impact. Tight manipulation of environments of identical individuals to see if extremes trigger epigenetic responses. What Does This Mean to the Scientific Community?
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