1. Chapter 4 and 5 Genes and Genetic Diseases Mosby items and derived items © 2010, 2006 by Mosby, Inc., an affiliate of Elsevier Inc.

2. Genes and Genetic Diseases Chapter 4 Mosby items and derived items © 2010, 2006 by Mosby, Inc, an affiliate of Elsevier Inc.

3. Objectives 1. Identify the different mechanisms of mutation. 2. Identify the major Chromosomal abnormalities and give examples of each. 3. Differentiate between autosomal dominant, autosomal recessive, and x- linked recessive inheritance modes. 4. Describe sex-limited and sex-linked traits and give an example of each. 5. Discuss the concept of mutifactorial inheritance. 3

4. 4 Identify the different mechanisms of mutation: Definitions Genetics—the study of biologic heredity ◦Gene—basic unit of heredity Genomics—the field of genetics concerned with the structural and functional studies of the genome ◦Genome—DNA representing all of the genes for a given species

5. 5 DNA Organization Chromosome ◦Temporary but consistent state of DNA ◦Composed of two longitudinal sister chromatids

6. 6 Chromosomes Gametes: sperm and egg ◦Contain 23 chromosomes ◦Haploid cells  One member of each chromosome pair Somatic cells: all other cells ◦Contain 46 chromosomes (23 pairs) ◦Diploid cells: one from father and one from mother to each chromosome pair

7. 7 Chromosomes Autosomes ◦The first 22 of the 23 pairs of chromosomes in males and females ◦The two members are virtually identical and thus said to be homologous Sex chromosomes ◦Remaining pair of chromosomes ◦In females, it is a homologous pair (XX) ◦In males, it is a nonhomologous pair (XY)

8. 8 Karyotype Ordered display of chromosomes

9. 9 Mutation Any inherited alteration of genetic material ◦Mutations in somatic cells are not transmitted to offspring ◦Mutations in gametes are transmitted to offspring

10. 10 Mutagen Agent known to increase the frequency of mutations ◦Radiation ◦Chemicals

11. Consequences of Mutations Gain of function ◦Associated with dominant disorders Loss of function ◦Associated with recessive disorders 11

12. 2. Identify the major Chromosomal abnormalities and give examples of each. 12

13. 13 Chromosome Abnormalities Euploid cells: eu= “normal” ◦Cells that have a multiple of the normal number of chromosomes ◦Haploid and diploid cells are euploid forms When a euploid cell has more than the diploid number, it is called a polyploid cell ◦Triploidy: a zygote having three copies of each chromosome (69) ◦Tetraploidy: four copies of each (92 total) Triploid and tetraploid fetuses don’t survive

14. 14 Chromosome Abnormalities Disjunction ◦Normal separation of chromosomes during cell division Nondisjunction ◦Usually the cause of aneuploidy  Aneuploidy-does not contain 23 chromosomes ◦ Trisomy- 3 copies of one chromosome ◦ Monosomy-one copy of chromosome  Loss of genetic material has >consequence than duplication of material.

15. 15 Nondisjunction

16. 16 Chromosome Abnormalities Aneuploidy ◦A somatic cell that does not contain a multiple of 23 chromosomes ◦A cell containing three copies of one chromosome is trisomic (trisomy) ◦Monosomy is the presence of only one copy of any chromosome ◦Monosomy is often fatal, but infants can survive with trisomy of certain chromosomes  “It is better to have extra than less”

17. 17 Chromosomal Disorders Leading cause of mental retardation and miscarriage Incidence of chromosomal abnormalities ◦1/12 conceptions ◦Approximately 95% of conceptions with chromosome disorders result in miscarriage ◦50% of first-trimester miscarriages associated with a major chromosomal abnormality ◦1/150 live births with a major diagnosable chromosomal abnormality

18. 18 Autosomal Aneuploidy Down syndrome ◦Best-known example of aneuploidy  Trisomy 21 ◦1:800 live births ◦Mentally retarded, low nasal bridge, epicanthal folds, protruding tongue, poor muscle tone ◦Risk increases with maternal age ◦Increased risk of congenital heart disease, gastrointestinal disease, and leukemia

19. 19 Down Syndrome

20. 20 Other Autosomal Aneuploidies Trisomy 13 and 18 ◦More severe clinical manifestations than trisomy 21 ◦Death in early infancy is common

21. 21 Sex Chromosome Aneuploidy One of the most common is trisomy X. This is a female that has three X chromosomes. Termed “metafemale” ◦Symptoms are variable: sterility, menstrual irregularity, and/or mental retardation ◦Symptoms worsen with each additional X

22. 22 Sex Chromosome Aneuploidy Turner syndrome ◦Females with only one X chromosome ◦Characteristics  Absence of ovaries (sterile), Underdeveloped breasts; wide nipples  Short stature (~ 4'7")  Webbing of the neck  X is usually inherited from mother

23. 23 Sex Chromosome Aneuploidy Klinefelter syndrome ◦Individuals with at least two Xs and one Y chromosome ◦Characteristics  Male appearance  Develop female-like breasts  Small testes  Sparse body hair  Long limbs ◦Some individuals can be XXXY and XXXXY. The abnormalities will increase with each X.

24. 24 Alterations in Chromosome Structure Deletion ◦ Loss of a sequence of DNA from a chromosome Inversion ◦Chromosomal rearrangement in which a segment of a chromosome is reversed end to end

25. 25 Alterations in Chromosome Structure Translocation ◦Transfer of one chromosome segment to another Ring chromosome ◦Structurally abnormal chromosome in which the telomere of each chromosome arm has been deleted and the broken arms have joined

26. 26 Alterations in Chromosome Structure Chromosome breakage ◦If a chromosome break does occur, physiologic mechanisms usually repair the break, but the breaks often heal in a way that alters the structure of the chromosome ◦Agents of chromosome breakage  Ionizing radiation, chemicals, and viruses

27. Alterations in Chromosome Structure Breakage or loss of DNA Cri du chat syndrome ◦“Cry of the cat” ◦Deletion of short arm of chromosome 5 (5p-) ◦Low birth weight, metal retardation, and microcephaly 27

28. 28 Alterations in Chromosome Structure Fragile X syndrome ◦Site on the long arm of the X chromosome ◦2nd in occurrence to Down syndrome ◦Males > Females because they have only one X chromosome ◦Clinical Manifestations:  Mental retardation  Long face, large mandible, mitral valve prolapse, hyperextendable joints, high arched palate, macro-orchidism

29. 29 Genetics Gregor Mendel ◦Austrian monk ◦Garden pea experiments ◦Mendelian traits

30. 30 Genes Basic units of heredity Sequences of chromosomal DNA coding for the production of a functional product All genes are contained in each cell of the body

31. Elements of Genetics Genotype ◦Gene composition Phenotype ◦Outward appearance Dominant ◦Observable effects Recessive ◦Hidden effects Carrier ◦Has diseased gene but phenotypically normal 31

32. 32 Genes Allele: alternate version of a gene at a locus ◦Each individual possesses two alleles for each gene ◦Homozygous: possessing identical alleles of a given gene ◦Heterozygous: possessing two different alleles of a given gene

33. 33 Genetics Homozygous ◦Loci on a pair of chromosomes have identical alleles ◦Example  O blood type (OO) Heterozygous ◦Loci on a pair of chromosomes have different alleles ◦Example  AB blood type (A and B alleles on pair of loci)

34. 34 Genetics Genotype (“what they have”) ◦The genetic makeup of an organism Phenotype (“what they demonstrate”) ◦The observable, detectable, or outward appearance of the genetics of an organism Example ◦A person with the A blood type could be AA or AO. A is the phenotype; AA or AO is the genotype.

35. 35 Genetics Carrier ◦A carrier is one that has a disease gene but is phenotypically normal ◦For a person to demonstrate a recessive disease, the pair of recessive genes must be inherited ◦Example  Ss = sickle cell anemia carrier  ss = demonstrates sickle cell disease

36. 36 Single-Gene Disorders Recurrence risk ◦The probability that parents of a child with a genetic disease will have yet another child with the same disease ◦Recurrence risk of an autosomal dominant trait: 50:50  When one parent is affected by an autosomal dominant disease and the other is normal, the occurrence and recurrence risks for each child are one half

37. 37 Autosomal Dominant Disorders Characteristics of autosomal dominant disorders ◦Condition is expressed equally in males and females ◦Approximately half of children of an affected heterozygous individual will express the condition  Homozygous affected individuals are rare ◦No generational skipping

38. Autosomal Dominant Males=Females No skipped generations Transmit to ½ of offspring Recurrence risk is the probability of disease in subsequent offspring. May have delayed age of onset. ◦Huntington’s Chorea 38

39. Autosomal Recessive Disorders Characteristics ◦Condition expressed males = females ◦Affected individuals most often the offspring of asymptomatic heterozygous carrier parents  Approximately 1/4 of offspring will be affected  1/2 will be asymptomatic carriers  and 1/4 will be unaffected ◦Generational skipping may occur ◦Consanguinity may be present  Mating of two related individuals  Dramatically increases the recurrence risk of recessive disorders 39

40. 40 Sex-Linked Disorders Disorders involve X and Y chromosomes X-linked disorders usually expressed by males because females have another X chromosome to mask the abnormal allele ◦Most are recessive Y-linked disorders uncommon because Y chromosome contains relatively few genes ◦Father-son transmission present ◦No father-daughter transmission

41. 41 X-Linked Recessive Disorders Hemophilia ◦Bleeding disorders resulting from a congenital deficiency of coagulation factors ◦Mutations associated with factor VIII deficiency Duchenne Muscular Dystrophy ◦Progressive proximal muscle weakness

42. 42 Multifactorial Inheritance Environmental influenced traits ◦Polygenic traits ◦Several genes acting together Examples ◦Height ◦IQ

43. Genes, Environment, and Common Diseases Chapter 5 Mosby items and derived items © 2010, 2006 by Mosby, Inc., an affiliate of Elsevier Inc.

44. 44 Disease in Populations Incidence rate ◦Number of new cases of a disease reported during a specific period (typically 1 year) divided by the number of individuals in the population Prevalence rate ◦Proportion of the population affected by a disease at a specific point in time Relative risk ◦Incidence rate of a disease among individuals exposed to a risk factor divided by the incidence rate of a disease among individuals not exposed to a risk factor

45. 45 Multifactorial Inheritance Characteristics of multifactorial disorders ◦Result from hereditary and environmental factors ◦Hereditary component is polygenic  Individual involved genes follow mendelian principles  Many genes act together to influence the expressed trait

46. 46 Recurrence Risks Recurrence risks vary due to environment and lifestyle factors among populations. Recurrence risk is higher if: ◦more than one family member is affected ◦the expression of the disease is more severe, recurrence risk is higher ◦the less commonly affected sex Recurrence risk for the disease usually decreases rapidly in remotely related relatives

47. 47 Nature and Nurture Nature ◦Genetics Nurture ◦Environment-lifestyle Twin studies used to study nature vs nurture ◦Monozygotic (identical) ◦Dizygotic (fraternal) ◦Concordant trait  Both members of a twin pair share a trait ◦Discordant trait  A twin pair does not share a trait

48. 48 Nature and Nurture Adoption studies ◦Children born to parents who have a disease but are then subsequently adopted by parents lacking the disease are studied for the recurrence of the disease

49. 49 Genetics of Common Diseases Congenital malformations ◦Congenital diseases are present at birth or shortly after birth ◦Most congenital diseases are multifactorial

50. 50 Adult Multifactorial Diseases Coronary heart disease ◦Potential mycocardial infarction caused by atherosclerosis ◦Risk increases if:  There are more affected relatives  Affected relatives are female rather than male  Age of onset is younger than 55 years ◦Autosomal dominant familial hypercholesterolemia, high-fat diet, lack of exercise, smoking, and obesity

51. 51 Hypertension Risk factor for heart disease, stroke, and kidney disease 20% to 40% of blood pressure variations are genetic; this means that 60% to 80% are environmental Causes of hypertension ◦Sodium intake, lack of exercise, stress, obesity, smoking, and high-fat intake

52. 52 Breast Cancer Affects 12% of American women who live to 85 If a woman has a first-degree relative with breast cancer, her risk doubles Recurrence risk increases if age of onset in the affected relative is early and if the cancer is bilateral

53. 53 Colorectal Cancer 1 in 20 Americans will develop colorectal cancer ◦Second only to lung cancer Risk factors ◦Genetics ◦High-fat and low-fiber diet are contributors

54. 54 Diabetes Leading cause of blindness, heart disease, and kidney failure Two major types ◦Type 1 (insulin-dependent diabetes mellitus) ◦Type 2 (non–insulin-dependent diabetes mellitus)

55. 55 Type 1 Diabetes Autoimmune destruction of insulin- producing beta cells in the pancreas ◦T cell activation and autoantibody production Onset before 40 years of age Higher incidence with offspring of diabetic fathers

56. 56 Type 2 Diabetes 80% to 90% of all diabetes cases Neither HLA nor autoantibodies commonly seen in type 2 Person has insulin resistance or diminished insulin production Risk factors ◦High carbohydrate diet and obesity

57. 57 Obesity Body mass index >30 ◦BMI = W/H 2 (weight in kg and height in meters) Obesity is a substantial risk factor for heart disease, stroke, and type 2 diabetes Adoptive studies ◦Body weights of adopted individuals correlated significantly with their natural parents’ body weights Twin studies ◦Higher concordance in MZ twins than DZ twins

58. 58 Alzheimer Disease Progressive dementia and loss of memory Formation of amyloid plaques and neurofibrillary tangles in the brain Risk of developing AD doubles in individuals who have an affected first- degree relative Mutations in any of three genes that affect amyloid-beta deposition

59. 59 Alcoholism Risk is 3 to 5 times higher in individuals with an alcoholic parent Adoption studies ◦Offspring of nonalcoholic parents, when reared by alcoholic parents, did not have an increased risk

60. 60 Psychiatric Disorders Schizophrenia ◦Severe emotional disorder characterized by delusions, hallucinations, and bizarre, withdrawn, or inappropriate behavior ◦Recurrence risk among the offspring of one affected parent is 10 times higher than the general population ◦Twin and adoption studies indicate that genetic factors are likely to be involved Bipolar affective disorder ◦Genetics ◦Minimal environmental influence

61. The End Do you have Turning Technology turned on? 61

62. Klinefelter’s syndrome is an example of a(n) Autosomal recessive disorder Autosomal dominant disorder Chromosomal disorder Multifactorial inheritance disorder 62 Answer Now 20

63. Type 2 diabetes is: Highly correlated with reduced BMI. Caused by an absence of insulin production. Usually more prevalent in individuals less than 40 years of age. Often treated with lifestyle modification including diet and exercise. 63 Answer Now 20

64. The relative risk indicates the: Number of new cases of a disease in a specific time period. 2. Proportion of a population with a disease at one time point. 3. Chance of developing a disease relative to an exposure. 4. Ability of a causative factor to produce a disease. 64 Answer Now 20

65. Down Syndrome is/are: Mutations on three chromosomes Translocation of one copy of chromosome 21 Nondisjunction of one copy of chromosome 21 Three copies of chromosome 21 65 Answer Now 20

66. The following diet contributes to the risk for Colorectal Cancer: Low-fat and low fiber Low-fat and high fiber High-fat and low fiber High-fat and high fiber 66 Answer Now 20