OMSI Science Pub - Genetics


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"Genetic Testing: Do You Really Want To Know What's In Your Genes?"

This Science Pub took place at the Bagdad Theater in Portland, Oregon, on Monday, July 6, 2009. It was presented by Dr. Lisa Sardinia, Associate Professor at Pacific University and Associate director of the Pacific Institute for Ethics and Social Policy.

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  • Categories of genetic testing. Samples for genetic testing. Genetic testing methods. Issues.
  • not mutually exclusive categories
  • New mother is concerned because her newborn son is having trouble feeding. The pediatrician notes that the baby is somewhat "floppy" and has weak facial muscles. Upon questioning, the mother says her own father died suddenly of heart block as a young man, and that she herself has recently developed muscle weakness in her hands and feet. The doctor suspects the baby has the congenital form of myotonic dystrophy, a genetic disorder that usually presents in adulthood. The doctor offers molecular genetic testing as a way to confirm the diagnosis. A 50-year-old man recently diagnosed with diabetes complains to his internist that he has started to have joint pains. The doctor asks if the man has traveled to the tropics recently, because his skin looks more darkly tanned than usual. After blood iron studies are abnormal, the doctor does molecular genetic testing, and the results show that the man has hereditary hemochromatosis. This is a treatable genetic disorder in which too much dietary iron is absorbed, resulting in excess iron storage and damage to various organs and tissues. After having a unit of blood drawn every week for a year, the man's joint pains and tanned coloring have disappeared, and his diabetes is easier to control.
  • A 38-year-old woman is diagnosed with FAP after she was found to have colon cancer. FAP is a genetic disorder characterized by hundreds to thousands of colonic polyps by the late teens or early twenties and progression to colon cancer in almost every case. The woman has a twin son and daughter who are ten years old. Her oncologist tells her that recommendations for people at risk for FAP include sigmoidoscopy every one to two years beginning at age 10-12 years. The family chooses to first do DNA testing to see if either twin has inherited the disorder. The woman’s daughter does not have the familial mutation, but her son does. Although early-onset Alzheimer’s disease has a pretty clear genetic component, the much more common form of Alzheimer’s disease, which presents after the age of 60, is less clearcut. One gene, the ApoE gene, has been found to be associated with development of Alzheimer’s disease, but the connection is tenuous.
  • some examples include cystic fibrosis, sickle cell anemia, and Tay-Sachs disease.
  • neonates are screened for a number of extremely rare genetic disorders. These disorders all have more or less effective treatments, that is, in all these cases, treatment will have a positive effect, if not a cure. The diseases are so rare that cumulatively, only 1 in 2000 infants will test positive for any of them.
  • Your genes decide virtually everything about you: whether you are tall or not the color of your hair the color of your skin whether you are good at sports how you respond to environmental triggers whether you are more likely to develop certain diseases
  • Each of your cells contains two sets of chromosomes - one set came from your mother while the other came from your father - male sperm and the female egg carry a single set of 23 chromosomes each - 22 autosomes and an X or Y sex chromosome. If you are female you inherited an X chromosome from each parent - if you are male you inherited an X chromosome from your mother and a Y from your father.
  • fluorescent in situ hybridization FISH uses fluorescent probes that bind to only those parts of the chromosome with which they show a high degree of sequence similarity. Fluorescence microscopy can be used to find out where the fluorescent probe bound to the chromosomes. Examples of diseases that are diagnosed using FISH include Prader-Willi syndrome , Angelman syndrome , 22q13 deletion syndrome , chronic myelogenous leukemia , acute lymphoblastic leukemia , Cri-du-chat , Velocardiofacial syndrome , and Down syndrome .
  • cystic fibrosis: 1604 mutations one mutation is most common, accounts for 75% of all cases of CF--in Caucasians
  • Huntington disease is a progressive neurodegenerative genetic disorder that does not manifest symptoms until, usually, the 5th to 6th decade of life. The problem is in a gene that contains the directions for a protein called huntingtin. This gene has a section of repeated DNA words, so that several copies of the same amino acid appear in the protein. But the enzymes that copy DNA sometimes get confused and slip, increasing the number of repeats and therefore increasing the number of the same amino acid (glutamine). When a certain number of repeated amino acids is reached, the protein misfolds and starts to build up in the cell, eventually killling it. If you have even a single copy of this gene, from either parent, you WILL develop HD. No treatment, no cure. If you have one copy of this gene, you have a 50% chance of passing it on to offspring and you won’t know you’ve got it, that is, you won’t get symptoms, until, usually, after you’ve reproduced. There is a test. Won’t test anyone under 18 but prenatal testing is allowed.
  • All diseases discussed so far are rare. The most common diseases, the most common causes of death, are caused by multiple genes interacting with their environment. Environment of a gene includes other genes, proteins in the cell, other cells around it, hormones released by other cells, then stuff from outside the body.
  • All cancer is genetic. Not all cancer is inherited. Some genes are caretaker genes. Control cell division, repair damaged DNA. What happens when the caretaker genes are knocked out? The one universal characteristic of cancer cells is inappropriate cell division. Most mutations occur during cell division. If no repair occurs, more mutations accumulate, leading eventually from benign cancer cells to malignant cancer cells. Many pathways. You have two copies of all genes, including the caretaker genes.
  • When one caretaker gene is knocked out in one cell, no problem. When the second copy is mutated, cancer. Inherited susceptibility to cancer.
  • Apolipoprotein E has many functions in the body. When it is synthesized by the liver as part of VLDL it functions in the transport of triglycerides to the liver tissue. It is also incorporated into HDL (as HDL-E) and functions in cholesterol distribution among cells. It is also incorporated into intestinally synthesized cholymicrons and transports dietary triglycerides and cholesterol. It is involved in lipid metabolism by mediating the receptor binding of apo-E lipoproteins to the LDL receptor. Receptor binding begins the cellular uptake of lipoproteins to be used in intracellular cholesterol metabolism (where they can be used, for example, as components of cell membranes). Three different forms, ApoE2, ApoE3 and ApoE4. You could have two copies of ApoE2, two of ApoE3 or two of ApoE4, or you could have one ApoE2 and one ApoE3, one ApoE2 and one ApoE4 or one ApoE3 and one ApoE4. Clearly you could see how mutations in this gene could affect develop of atherosclerosis or heart disease. But what about Alzheimer’s disease? You can find the protein in the neurofibrillary tangles found in the brains of people with Alzheimer’s disease. Analysis of apolipoprotein E alleles in Alzheimer disease and controls demonstrated that there was a highly significant association of apolipoprotein E4 and late-onset familial Alzheimer disease.
  • A genome-wide association study is an approach that involves rapidly scanning markers across the complete sets of DNA, or genomes, of many people to find genetic variations associated with a particular disease. PPARG peroxisome proliferator-activated receptor gamma The most well studied candidate gene of insulin resistance; The target of the oral diabetic drugs Thiazolidinediones (TZDs); KCNJ11 and ABCC8 KCNJ11 (potassium inwardly-rectifying channel, subfamily J, member 11), ABCC8 (sulfonylurea receptor, SUR1) These two closely linkly genes encodes the K + -ATP channel complex in the pancreatic β-cell surface (2); The drug targets of oral diabetic drugs, Sulfonylureas and Meglitinides; TCF7L2 transcription factor 7-like 2   A component of the Wnt signaling pathway; The IDE/HHEX locus IDE (insulin-degrading enzyme) and HHEX (hematopoietically expressed homeobox);   SLC30A8 solute carrier family 30 (zinc transporter), member 8 The gene has critical roles in insulin secretion(15); CDKAL1 cyclin-dependent kinase 5 (CDK5) regulatory subunit associated protein 1-like 1(9-14)   CDKN2A/B cyclin-dependent kinase inhibitor 2A and 2B(9-14)   IGF2BP2 insulin-like growth factor 2 mRNA binding protein 2(9-14) FTO/ RPGRIP1L FTO (fat mass and obesity associated) and RPGRIP1L (retinitis pigmentosa GTPase regulator interacting protein 1 like) (9-14)   KCNQ1 potassium voltage-gated channel, KQT-like subfamily, member 1
  • OMSI Science Pub - Genetics

    1. 2. Lisa Sardinia, J.D., Ph.D. Associate Professor, Pacific University Associate Director, Pacific Institute for Ethics & Social Policy Genetic Testing: Do You Really Want to Know What’s in Your Genes?
    2. 3. What are the types of genetic testing? <ul><li>Diagnostic </li></ul><ul><li>Predictive </li></ul><ul><li>Carrier </li></ul><ul><li>Newborn </li></ul><ul><li>Prenatal </li></ul><ul><li>Pre-implantation </li></ul><ul><li>Forensic </li></ul>
    3. 4. Diagnostic Genetic Testing <ul><li>identify or rule out a specific genetic or chromosomal condition </li></ul><ul><li>often used to confirm a diagnosis based on physical signs and symptoms </li></ul>congenital myotonic dystrophy hemochromatosis
    4. 5. Predictive Genetic Testing <ul><li>detects gene mutations associated with disorders that appear later in life </li></ul><ul><li>frequently provides a probability, not a certainty, that a disorder will occur </li></ul>familial adenomatous polyposis ApoE4 & Alzheimer’s Disease
    5. 6. Carrier Screening <ul><li>identifies people who carry one copy of a gene mutation that, when present in two copies, causes a genetic disorder </li></ul><ul><li>provides info on a couple’s risk of having a child with a genetic disorder </li></ul>
    6. 7. Newborn Screening <ul><li>used just after birth to identify genetic disorders that can be treated early in life </li></ul><ul><li>All states test for phenylketonuria & congenital hypothyroidism </li></ul><ul><li>Oregon tests for 34 disorders </li></ul>
    7. 8. Prenatal Genetic Testing <ul><li>used to detect genetic or chromosomal disorders in a fetus during pregnancy </li></ul><ul><li>hundreds of tests available--few are routine </li></ul>
    8. 9. Preimplantation Genetic Diagnosis <ul><li>detects genetic changes in embryos produced by IVF </li></ul><ul><li>testing done prior to implantation/pregnancy </li></ul>
    9. 10. Forensic DNA Testing <ul><li>uses DNA sequences to identify an individual for legal purposes </li></ul><ul><li>not used to detect gene mutations associated with a disease </li></ul>
    10. 11. How is genetic testing done? <ul><li>We need to make a short digression here…. </li></ul>
    11. 12. What is a gene? <ul><li>basic physical & functional unit of heredity </li></ul><ul><li>made up of DNA </li></ul><ul><li>composed of subunits called bases (A, C, G, T) </li></ul><ul><li>vary in size from a few hundred DNA bases to more than 2 million bases </li></ul><ul><li>The Human Genome Project has estimated that humans have between 20,000 and 25,000 genes </li></ul>
    12. 13. Where are genes? <ul><li>In every cell, wound up to form chromosomes </li></ul>
    13. 14. What does a gene do? <ul><li>contains instructions to build all the proteins that make our bodies function </li></ul><ul><li>passes genetic information to offspring </li></ul>
    14. 15. For example… <ul><li>Red blood cells transport oxygen throughout our bodies using a protein called hemoglobin </li></ul>
    15. 16. <ul><li>If the hemoglobin gene is normal, the instructions will be used to make a normal hemoglobin protein </li></ul><ul><li>But if the instructions are changed, or mutated , changes in the hemoglobin protein could result </li></ul><ul><li>One such mutation causes the disorder sickle cell anemia </li></ul>
    16. 17. Genes can be inherited…
    17. 18. Back to genetic testing <ul><li>the goal is to provide information about a person’s genes and chromosomes, including gene variants that can result in disorders </li></ul>
    18. 19. So, once again, how is genetic testing done? <ul><li>Tissues tested include: </li></ul><ul><ul><li>blood </li></ul></ul><ul><ul><li>skin </li></ul></ul><ul><ul><li>cheek cells </li></ul></ul><ul><ul><li>hair follicles </li></ul></ul><ul><ul><li>embryonic cells </li></ul></ul><ul><ul><li>placental tissue </li></ul></ul><ul><ul><li>amniotic fluid </li></ul></ul>
    19. 20. Methods of Genetic Testing <ul><li>Cytogenetic analysis </li></ul><ul><li>DNA Analysis </li></ul>
    20. 21. Cytogenetic Analysis normal karyotype trisomy 21 Down syndrome
    21. 22. FISH
    22. 23. DNA Analysis
    23. 24. DNA Analysis
    24. 25. Complications….
    25. 26. Carrier frequency of cystic fibrosis Ethnicity Carrier frequency Caucasian (non-Hispanic) 1/25 Ashkenazi Jewish 1/25 Hispanic American 1/46 African American 1/65 CF carrier risk after a negative result for 32 mutations Ethnicity Carrier frequency Caucasian (non-Hispanic) 1/240 Ashkenazi Jewish 1/800 Hispanic American 1/146-1/167 African American 1/207
    26. 27. Tricky stuff-- Predictive genetic testing
    27. 28. Trickier stuff-- Predictive genetic testing…. with probabilities <ul><li>Cancer </li></ul><ul><li>Alzheimer’s disease </li></ul><ul><li>Type II diabetes </li></ul>
    28. 29. Cancer
    29. 30. Two-hit hypothesis
    30. 31. Alzheimer’s disease: Apolipoprotein E
    31. 32. Type II diabetes: Genome-wide association study
    32. 33. I am my genome
    33. 34. Brave new world?
    34. 35. Want more? <ul><li>Pacific Institute for Ethics & Social Policy </li></ul><ul><li>Fall Programming </li></ul><ul><li>Genetic Testing: Science—Ethics—Public Policy </li></ul><ul><ul><ul><li>Community seminars (September-November) </li></ul></ul></ul><ul><ul><ul><li>Town Hall panel discussion (November 18th) </li></ul></ul></ul><ul><li> </li></ul>