Chapter 13 genetic counseling

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  • 1. Introduction to Biology Chapter 13Professor Zaki Sherif, MD., PhD Strayer University
  • 2. Essentials of Biology Sylvia S. Mader Chapter 13 Lecture OutlineCopyright © The McGraw-Hill Companies, Inc. Permission required for reproduction or display.
  • 3. 13.1 Counseling for chromosomal disorders• Genetic counseling – potential parents are advised on their risk of inherited disorders.• Counselor helps couple understand the mode of inheritance, medical consequences of disorder and decisions they might wish to make.• Karyotyping – visual display of chromosomes arranged by size, shape and banding pattern • Can be from white blood cells or fetal cells by amniocentesis or chorionic villus sampling
  • 4. Figure 13.2 Testing for chromosomal mutations Copyright © The McGraw-Hill Companies, Inc. Permission required for reproduction or display. c. Karyotype of a person with Down syndrome. Note the three number 21 chromosomes. © CNRI/SPL/Photo Researchers, Inc.
  • 5. • Amniocentesis  Sample of amniotic fluid taken  0.3% risk of spontaneous abortion  Not until 14-17th week of pregnancy
  • 6. Figure 13.2 continued Copyright © The McGraw-Hill Companies, Inc. Permission required for reproduction or display. amniotic cavity a. During amniocentesis, a long needle is used to withdraw amniotic fluid containing fetal cells.
  • 7. •Chorionic villus sampling Chorionic cells from where placenta will develop As early as 5th week of pregnancy Greater risk (0.8%) but earlier results
  • 8. Figure 13.2 continued Copyright © The McGraw-Hill Companies, Inc. Permission required for reproduction or display. chorionic villi b. During chorionic villi sampling, a suction tube is used to remove cells from the chorion, where the placenta will develop.
  • 9. • Chromosomal mutations  Karyotype reveals changes in chromosome number and differences in structure.  In humans only a few variations in number are typically seen. • Down syndrome, Turner syndrome, Klinefelter syndrome  Changes in chromosome structure more common • Due to breakage and failure to reunite properly • Results in deletion, duplication, translocation or inversion
  • 10. • Deletion  When a single break causes a chromosome to lose an end or 2 breaks result in the loss of an internal segment  Williams syndrome – chromosome 17 loses a tiny end piece.  Cri du chat – chromosome 5 loses an end piece.
  • 11. Figure 13.3 Deletion Copyright © The McGraw-Hill Companies, Inc. Permission required for reproduction or display. a b c d e f g h deletion a b c d e f g + h lost a.
  • 12. Figure 13.3 continued Copyright © The McGraw-Hill Companies, Inc. Permission required for reproduction or display.b. Courtesy The Williams Syndrome Association
  • 13. • Duplication  Chromosome segment repeated  Individual has more than 2 alleles for certain traits.  Inv dup 15 syndrome – inverted duplication of chromosome 15 • Inversion – segment joins in direction opposite from normal.
  • 14. Figure 13.4 Duplication Copyright © The McGraw-Hill Companies, Inc. Permission required for reproduction or display. a b c d e f g h duplication inversion a b c d e f f e d g h a. b. Courtesy Kathy Wise
  • 15. • Translocation  Exchange of chromosome segments between nonhomologous chromosomes  A person with both the involved chromosomes has a normal amount of genetic material and is healthy unless the exchange disrupts a gene.  5% of Down syndrome cases caused by a translocation in previous generation between chromosome 21 and 14 • Not related to parental age but is inherited
  • 16. • Alagille syndrome  Translocation between chromosome 2 and 20  Normal amount of genetic material but distinctive face, some abnormalities and severe itching  Translocation disrupted allele on chromosome 20  Father did not realize he had the syndrome until he had this child.
  • 17. Figure 13.5 Translocation Copyright © The McGraw-Hill Companies, Inc. Permission required for reproduction or display. a s a s b t b t c c u translocation u d v d v e w e w f x f x g y y g h z z h a.
  • 18. • Inversion  Segment of a chromosome is turned 180°  Reverse sequence of alleles can lead to altered gene activity if it disrupts control of gene expression.  Usually do not cause problems  During meiosis, crossing-over can lead to recombinant chromosomes. • Alignment only possible when inverted chromosome forms a loop
  • 19. Figure 13.6 Inversion Copyright © The McGraw-Hill Companies, Inc. Permission required for reproduction or display. A A a a A A g a B B b b crossing-over B B b inverted f C e e segments C C DC ce C D d DD dd d D A B c d a b e E E EE c c e f F Ec F F F f f gG G b f F G G g g a g G homologous nonsister duplication chromosomes chromatids and deletion in both
  • 20. Please note that due to differingoperating systems, some animationswill not appear until the presentation isviewed in Presentation Mode (SlideShow view). You may see blank slidesin the “Normal” or “Slide Sorter” views.All animations will appear after viewingin Presentation Mode and playing eachanimation. Most animations will requirethe latest version of the Flash Player,which is available athttp://get.adobe.com/flashplayer.
  • 21. 13.2 Counseling for Genetic Disorders• Even if no chromosomal abnormality is likely, amniocentesis might still be done to perform biochemical tests for over 400 different disorders caused by specific genes.• Counselor needs to know medical history of family to construct a pedigree• Determines what tests are warranted
  • 22. • Pedigree  Chart of a family’s history with regard to a particular genetic trait • Males are squares • Females are circles • Shading represents individuals expressing disorder. • Horizontal line between circle and square is a union. • Vertical line down represents children of that union.  Counselor may already know pattern of inheritance and then can predict chance that child born to a couple would have the abnormal phenotype.
  • 23. • Pedigrees for autosomal disorders  Autosomal recessive disorder • Child can be affected when neither parent is affected • Heterozygous parents are carriers • Parents can be tested before having children
  • 24. Figure 13.7 Autosomal recessive pedigree Copyright © The McGraw-Hill Companies, Inc. Permission required for reproduction or display. aa A? A? Aa Aa A? * Aa Aa A? A? aa aa A? Key: • Affected children can have aa = affected unaffected parents. Aa = carrier • Heterozygotes (Aa) have a (normal) normal phenotype. AA = normal A? = normal • Both males and females are (one allele unknown) affected with equal frequency.
  • 25. Autosomal dominant disorder •Child can be unaffected even when parents are heterozygous and therefore affected. •When both parents are unaffected, none of their children will have the condition. No dominant gene to pass on
  • 26. Figure 13.8 Autosomal dominant pedigree Copyright © The McGraw-Hill Companies, Inc. Permission required for reproduction or display. Aa Aa * aa Aa A? aa aa aa Aa Aa aa aa aa aa Key: • Affected children will have at least AA = affected one affected parent. Aa = affected • Heterozygotes (Aa) are affected. A? = affected • Both males and females are affected aa = normal with equal frequency.
  • 27. • Pedigree for sex-linked disorder  X-linked recessive disorder • Sons inherit trait from mother – son’s X comes from mother. • More males than females have disorder – allele on X is always expressed in males. • Females who have the condition inherited the mutant allele from both their mother and their father. • Conditions appear to pass from grandfather to grandson.
  • 28. Figure 13.9 X-linked recessive pedigree Copyright © The McGraw-Hill Companies, Inc. Permission required for reproduction or display. Key: XBXB XbY grandfather XBXB = Normal female XBY = Normal male XBXb = Carrier female XbY = Color-blind male XbXb = Color-blind female XBY XBXb daughter XBY XbXb • More males than females are affected. • An affected son can have parents who have the normal phenotype. XbY • For a female to have the characteristic, her father must also have it. Her mother must have it or be a carrier. XBY XBXB XBXb XbY grandson
  • 29.  X-linked dominant • Only a few traits • Daughters of affected males have the condition. • Affected females can pass condition to daughters and sons.  Depends on which X inherited from a carrier mother if father is normal Y chromosome • Only a few disorders • Present only in males and are passed to all sons but not daughters
  • 30. • Genetic disorders of interest Figure 13.10  Autosomal disorders Methemoglobinemia Copyright © The McGraw-Hill Companies, Inc. Permission required for reproduction or display. • Methemoglobinemia – lack enzyme to convert methemoglobin back to hemoglobin  Relatively harmless, bluish- purplish skin Courtesy of Division of Medical Toxicology, University of Virginia
  • 31. •Cystic fibrosis – Figure 13.11 Cystic fibrosisautosomal recessive Copyright © The McGraw-Hill Companies, Inc. Permission required for reproduction or display.disorder Most common lethal genetic disorder among Caucasians in US Chloride ion channel nebulizer defect causes abnormally thick mucus. percussion vest © Pat Pendarvis
  • 32. •Alkaptonuria – autosomal Figure 13.12 Alkaptonuriarecessive disorder Copyright © The McGraw-Hill Companies, Inc. Permission required for Lack function reproduction or display. homogentisate oxygenase gene Accumulation of homogentisic acid turns urine black. © O.J. Staats, M.D./Custom Medical Stock Photo
  • 33. • Sickle cell disease – Figure 13.13 Sickle cell autosomal recessive disease disorder Copyright © The McGraw-Hill Companies, Inc. Permission required for reproduction or display.  Single base change in globin gene changes 1 amino acid in hemoglobin.  Makes red blood cells sickle – leads to poor circulation, anemia, low resistance to infection• Marfan syndrome – autosomal dominant disorder  Defect in connective tissue protein  Problems in tissues expressing this protein ×2500 © Dr. Gopal Murti/SPL/Photo Researchers, Inc.
  • 34. •Huntington disease – Figure 13.14 Huntingtonautosomal dominant diseasedisorder Copyright © The McGraw-Hill Companies, Inc. Permission required for reproduction or display. Progressive degeneration of neurons in brain Mutation for huntingtin protein Patients appear normal until middle-aged – usually after having children. Many neurons in normal brain Test for presence of gene Loss of neurons in Huntington brain (both): Courtesy Dr. Hemachandra Reddy
  • 35.  X-linked recessive disorders • Color blindness  About 8% of Caucasian men have red-green color blindness. • Duchenne muscular dystrophy  Absence of protein dystrophin causes wasting away of muscles.  Therapy – immature muscle cells injected into muscles
  • 36. Figure 13.15 Muscular dystrophy Copyright © The McGraw-Hill Companies, Inc. Permission required for reproduction or display. fibrous normal tissue tissue (left, right): Courtesy Dr. Rabi Tawil; (center): Courtesy Muscular Dystrophy
  • 37. • Testing for genetic disorders  Testing for a protein • Some disorders caused by a missing enzyme  Test for quantity of enzyme produced  Testing the DNA • Genetic marker – relies on an abnormality in the DNA sequence due to presence of abnormal allele.  Fragments from restriction digest will differ from a normal person’s results.
  • 38. Figure 13.16 Use of a genetic marker to test for a geneticmutation Copyright © The McGraw-Hill Companies, Inc. Permission required for reproduction or display. enzyme cleavage sites enzyme cleavage sites normal affected allele allele fragments of DNA fragments of DNA a. Normal fragmentation pattern b. Genetic disorder fragmentation pattern
  • 39. • Genetic profiling  Individual’s complete genotype  DNA sample applied to DNA chip  DNA chip contains probes – single-stranded DNA that binds to complementary DNA from patient  Binding shows patient has particular mutated genes
  • 40. Figure 13.17 Use of a DNA chip to test for mutated genes Copyright © The McGraw-Hill Companies, Inc. Permission required for reproduction or display. fluorescent DN A did not bind to mutant alleleDN Amicroarray fluorescent DN A did bind to mutant allele mutant allelefluorescentgenomic DN A Testing subject’s DN A (chip): Courtesy of Mergen, Ltd
  • 41.  Testing the fetus Figure 13.18 Ultrasound • Ultrasound – helps Copyright © The McGraw-Hill Companies, Inc. Permission required for reproduction or display. evaluate fetal anatomy for serious abnormalities.  Uses high-frequency sound waves • Testing fetal cells  Cells from amniocentesis or chorionic villus sampling  Fetal cells can also be collected from mother’s blood. • PCR used to amplify DNA, no risk to fetus © Bernard Bennot/SPL/Photo Researchers, Inc.
  • 42.  Testing the embryo Figure 13.19 Testing the and egg embryo • Testing embryo – Copyright © The McGraw-Hill Companies, Inc. Permission required for reproduction or display. following IVF, 1 cell can be removed Embryonic cell is removed. from embryo without 8-celled embryo harm. Cell is genetically healthy. Embryo develops normally in uterus.
  • 43.  Testing the embryo and egg • Testing egg – meiosis results in single egg and 2 polar bodies. • Polar bodies can be used in genetic testing. • If a woman is a heterozygote, when the polar body has the defective allele, the egg must be normal.
  • 44. Copyright © The McGraw-Hill Companies, Inc. Permission required for reproduction or display. Figure 13.20 Testing the egg Egg Woman is heterozygous Polar body IVF is removed.Polar body containsmutant allele. Genetically healthy egg used for IVF. Embryo develops normally in uterus.
  • 45. 13.3 Gene Therapy• Insertion of genetic material into human cells for treatment of a disorder• 2 methods  Ex vivo – outside the body  In vivo – inside the body
  • 46. • Ex vivo  Treatment of SCIDS • Severe combined immunodeficiency • Lack enzyme involved in maturation of cells producing antibodies • Bone marrow are stem cells removed and infected with RNA retrovirus carrying gene for normal enzyme. • Cells are then retuned to patient.  Treatment of familial hypercholesterolemia • High levels of cholesterol lead to early fatal heart attacks. • Small portion of liver is removed and infected with retrovirus containing normal cholesterol receptor. • Tissue is returned to patient.
  • 47. Figure 13.21 Ex vivo gene therapy in humans Copyright © The McGraw-Hill Companies, Inc. Permission required for reproduction or display. defective gene 1 Remove bone marrow stem cells. bone marrow
  • 48. Figure 13.21 Ex vivo gene therapy in humans Copyright © The McGraw-Hill Companies, Inc. Permission required for reproduction or display. defective gene 1 Remove bone marrow stem cells. 2 Use a virus to carry the normal gene into bone marrow stem cells. bone marrow recombinant DNA normal gene retrovirus
  • 49. Figure 13.21 Ex vivo gene therapy in humans Copyright © The McGraw-Hill Companies, Inc. Permission required for reproduction or display. defective gene 1 Remove bone marrow stem cells. 2 Use a virus to carry the normal gene into bone marrow stem cells. bone marrow recombinant DNA normal gene virus 3 Recombinant DNA molecules carry the normal gene into the genome of stem cells. recombinant DNA normal gene
  • 50. Figure 13.21 Ex vivo gene therapy in humans Copyright © The McGraw-Hill Companies, Inc. Permission required for reproduction or display. defective gene 1 Remove bone marrow stem cells. 2 Use a virus to carry the normal gene into bone marrow stem cells. bone marrow recombinant DNA normal gene virus 3 Recombinant DNA molecules carry the normal gene into the genome of stem cells. 4 Return genetically engineered stem cells to the patient. recombinant DNA normal gene
  • 51. • In vivo  Cystic fibrosis treatment • Gene needed is sprayed into the nose or delivered to lower respiratory tract. • Use adenoviruses or liposomes to carry gene  Poor coronary circulation treatment • Vascular endothelial growth factor can cause growth of new blood vessels. • Genes coding for growth factor can be injected alone, or within a virus, into the heart to stimulate branching of coronary arteries.  Rheumatoid arthritis • Immune system destroys person’s own body. • Inject adenoviruses that contain anti-inflammatory genes into the affected joint
  • 52. Figure 13.23 Ex vivo gene therapy in humans Copyright © The McGraw-Hill Companies, Inc. Permission required for reproduction or display. Brain (gene transfer by injection)* • Huntington disease • Alzheimer disease • Parkinson disease • brain tumors Skin (gene transfer by modified blood cells)* • skin cancer Lungs (gene transfer by aerosol spray)* • cystic fibrosis • hereditary emphysema Liver (gene transfer by retroviral implants)** • familial hypercholesterolemia Blood (gene transfer by bone marrow transplant)** • sickle cell disease Endothelium (blood vessel lining) (gene transfer by implantation of genetically altered endothelium)** • hemophilia • diabetes mellitus Muscle (gene transfer by injection)* • Duchenne muscular dystrophy Joint (gene transfer by injection) • rheumatoid arthritis Bone marrow (gene transfer by implantation of genetically altered stem cells)** • ADA deficient SCID • sickle cell disease * in vivo ** ex vivo