GENES AND GENETIC DISEASES Paula Ruedebusch ARNP DNP

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GENES AND GENETIC DISEASES Paula Ruedebusch, ARNP, DNP

GENES AND GENETIC DISEASES Paula Ruedebusch, ARNP, DNP

DNA Pentose sugar (deoxyribose) Phosphate molecule Four nitrogenous bases: Pyrimidines: cytosine and thymine Purines:

DNA Pentose sugar (deoxyribose) Phosphate molecule Four nitrogenous bases: Pyrimidines: cytosine and thymine Purines: adenine and guanine Double helix model Nucleotide 2

DNA (CONT’D) 3

DNA (CONT’D) 3

DNA VIDEO https: //www. youtube. com/watch? v=itsb 2 Sq. R-R 0 4

DNA VIDEO https: //www. youtube. com/watch? v=itsb 2 Sq. R-R 0 4

PROTEINS One or more polypeptides Composed of amino acids Twenty amino acids Directed by

PROTEINS One or more polypeptides Composed of amino acids Twenty amino acids Directed by sequence of bases (codons) 5

DNA REPLICATION Untwisting and unzipping of the DNA strand Single strand acts as a

DNA REPLICATION Untwisting and unzipping of the DNA strand Single strand acts as a template Complementary base pairing by DNA polymerase Adenine-thymine; cytosine-guanine 6

DNA 7

DNA 7

MUTATION Any inherited alteration of genetic material Chromosome-aberrations Base pair substitution One base pair

MUTATION Any inherited alteration of genetic material Chromosome-aberrations Base pair substitution One base pair is substituted for another Frameshift mutation Insertion or deletion of one or more base pairs Causes a change in the entire “reading frame” 8

MUTATION VIDEO https: //www. youtube. com/watch? v=qx. XRKVomp. I 8 9

MUTATION VIDEO https: //www. youtube. com/watch? v=qx. XRKVomp. I 8 9

MUTATION (CONT’D) Spontaneous mutation Mutation that occurs in absence of exposure to known mutagens

MUTATION (CONT’D) Spontaneous mutation Mutation that occurs in absence of exposure to known mutagens Mutational hot spots Areas of the chromosomes that have high mutation rates A cytosine base followed by a guanine is known to account for a disproportionately large percentage of disease-causing mutations 10

MUTAGEN Agent known to increase the frequency of mutations Radiation Chemicals Nitrogen mustard, vinyl

MUTAGEN Agent known to increase the frequency of mutations Radiation Chemicals Nitrogen mustard, vinyl chloride, alkylating agents, formaldehyde, sodium nitrite 11

TRANSCRIPTION RNA is synthesized from the DNA template RNA polymerase binds to promoter site

TRANSCRIPTION RNA is synthesized from the DNA template RNA polymerase binds to promoter site Results in the formation of messenger RNA (m. RNA) RNA polymerase detaches m. RNA moves out of the nucleus and into the cytoplasm Transcription continues until termination sequence is reached 12

TRANSCRIPTION (CONT’D) Transcription Video: https: //www. youtube. com/watch? v=Wsof. H 466 lqk 13

TRANSCRIPTION (CONT’D) Transcription Video: https: //www. youtube. com/watch? v=Wsof. H 466 lqk 13

TRANSLATION Process by which RNA directs the synthesis of a polypeptide via interaction with

TRANSLATION Process by which RNA directs the synthesis of a polypeptide via interaction with t. RNA Site of protein synthesis is the ribosome t. RNA contains a sequence of nucleotides (anticodon) complementary to the triad of nucleotides on the m. RNA strand (codon) The ribosome moves along the m. RNA sequence to translate the amino acid sequence 14

TRANSLATION (CONT’D) Translation Video: https: //www. youtube. com/watch? v=5 b. LEDd-PSTQ 15

TRANSLATION (CONT’D) Translation Video: https: //www. youtube. com/watch? v=5 b. LEDd-PSTQ 15

CHROMOSOMES Somatic cells: Contain 46 chromosomes (23 pairs) Diploid cells Gametes: Contain 23 chromosomes

CHROMOSOMES Somatic cells: Contain 46 chromosomes (23 pairs) Diploid cells Gametes: Contain 23 chromosomes Haploid cells One member of each chromosome pair 16

GAMETES VS. SOMATIC CELLS 17

GAMETES VS. SOMATIC CELLS 17

CHROMOSOMES (CONT’D) Meiosis Formation of haploid cells from diploid cells Mitosis Formation of somatic

CHROMOSOMES (CONT’D) Meiosis Formation of haploid cells from diploid cells Mitosis Formation of somatic cells 18

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CHROMOSOMES (CONT’D) Autosomes The first 22 of the 23 pairs of chromosomes in males

CHROMOSOMES (CONT’D) 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) Karyotype (karyogram) 20

KARYOTYPE Ordered display of chromosomes 21

KARYOTYPE Ordered display of chromosomes 21

CHROMOSOME ABERRATIONS Euploid cells have a multiple of the normal number of chromosomes Haploid

CHROMOSOME ABERRATIONS Euploid cells 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) Neither triploid nor tetraploid fetuses survive 22

CHROMOSOME ABERRATIONS (CONT’D) Aneuploidy A somatic cell that does not contain a multiple of

CHROMOSOME ABERRATIONS (CONT’D) 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 lethal, but infants can survive with trisomy of certain chromosomes “It is better to have extra than less” 23

CHROMOSOME ABERRATIONS (CONT’D) Disjunction Normal separation of chromosomes during cell division Nondisjunction Usually the

CHROMOSOME ABERRATIONS (CONT’D) Disjunction Normal separation of chromosomes during cell division Nondisjunction Usually the cause of aneuploidy Failure of homologous chromosomes or sister chromatids to separate normally during meiosis or mitosis 24

NONDISJUNCTION 25

NONDISJUNCTION 25

AUTOSOMAL ANEUPLOIDY Partial trisomy Only an extra portion of a chromosome is present in

AUTOSOMAL ANEUPLOIDY Partial trisomy Only an extra portion of a chromosome is present in each cell Chromosomal mosaics Trisomies occurring only in some cells of the body 26

AUTOSOMAL ANEUPLOIDY (CONT’D) Down syndrome Best known example of aneuploidy Trisomy 21 1: 800

AUTOSOMAL ANEUPLOIDY (CONT’D) 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 >35 27

DOWN SYNDROME 28

DOWN SYNDROME 28

SEX CHROMOSOME ANEUPLOIDY One of the most common is trisomy X (a female that

SEX CHROMOSOME ANEUPLOIDY One of the most common is trisomy X (a female that has three X chromosomes) Symptoms are variable: sterility, menstrual irregularity, and/or mental retardation Symptoms worsen with each additional X 29

SEX CHROMOSOME ANEUPLOIDY (CONT’D) Turner syndrome Females with only one X chromosome Characteristics: Underdeveloped

SEX CHROMOSOME ANEUPLOIDY (CONT’D) Turner syndrome Females with only one X chromosome Characteristics: Underdeveloped ovaries (sterile) Short stature (~ 4'7") Webbing of the neck Edema Underdeveloped breasts; wide nipples High number of aborted fetuses X is usually inherited from mother 30

TURNER SYNDROME KARYOTYPE 31

TURNER SYNDROME KARYOTYPE 31

SEX CHROMOSOME ANEUPLOIDY Klinefelter syndrome Individuals with at least two Xs and one Y

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 XXY and XXXY The abnormalities increase with each X 32

KLINEFELTER SYNDROME 33

KLINEFELTER SYNDROME 33

ABNORMALITIES IN CHROMOSOME STRUCTURE Chromosome breakage If a chromosome break does occur, physiologic mechanisms

ABNORMALITIES IN CHROMOSOME STRUCTURE Chromosome breakage If a chromosome break does occur, physiologic mechanisms will usually repair the break, but the breaks often heal in a way that alters the structure of the chromosome Clastogens Ionizing radiation, chemicals, and viruses 34

ABNORMALITIES IN CHROMOSOME STRUCTURE (CONT’D) Breakage or loss of DNA (deletions) Cri du chat

ABNORMALITIES IN CHROMOSOME STRUCTURE (CONT’D) Breakage or loss of DNA (deletions) Cri du chat syndrome “Cry of the cat” Deletion of short arm of chromosome 5 Low birth weight, metal retardation, and microcephaly 35

CRI-DU-CHAT DNA 36

CRI-DU-CHAT DNA 36

ABNORMALITIES IN CHROMOSOME STRUCTURE (CONT’D) 37

ABNORMALITIES IN CHROMOSOME STRUCTURE (CONT’D) 37

ABNORMALITIES IN CHROMOSOME STRUCTURE (CONT’D) Duplication Presence of a repeated gene or gene sequence

ABNORMALITIES IN CHROMOSOME STRUCTURE (CONT’D) Duplication Presence of a repeated gene or gene sequence Less serious consequences because better to have more genetic material than less (deletion) Duplication in the same region as cri du chat causes mental retardation but no physical abnormalities 38

ALTERATIONS IN CHROMOSOME STRUCTURE Inversions Two breaks on a chromosome Reversal of the gene

ALTERATIONS IN CHROMOSOME STRUCTURE Inversions Two breaks on a chromosome Reversal of the gene order Usually occurs from a breakage that gets reversed during reattachment ABCDEFG may become ABEDCFG Position effect 39

ABNORMALITIES IN CHROMOSOME STRUCTURE Translocations The interchanging of material between nonhomologous chromosomes Reciprocal translocation

ABNORMALITIES IN CHROMOSOME STRUCTURE Translocations The interchanging of material between nonhomologous chromosomes Reciprocal translocation occurs when two chromosomes break and the segments are rejoined in an abnormal arrangement Robertsonian translocation occurs when fusion at centromere, forming a single chromosome 40

ABNORMALITIES IN CHROMOSOME STRUCTURE (CONT’D) Fragile sites areas on chromosomes that develop distinctive breaks

ABNORMALITIES IN CHROMOSOME STRUCTURE (CONT’D) Fragile sites areas on chromosomes that develop distinctive breaks or gaps when cells are cultured No apparent relationship to disease 41

ABNORMALITIES IN CHROMOSOME STRUCTURE (CONT’D) Fragile X syndrome Site on the long arm of

ABNORMALITIES IN CHROMOSOME STRUCTURE (CONT’D) Fragile X syndrome Site on the long arm of the X chromosome Associated with mental retardation; second in occurrence to Down syndrome Higher incidence in males because they have only one X chromosome 42

FRAGILE X SYNDROME 43

FRAGILE X SYNDROME 43

FRAGILE X SYNDROME DIAGNOSIS 44

FRAGILE X SYNDROME DIAGNOSIS 44

GENETIC DISORDERS WEBSITE www. genefacts. org - Useful for information Diagnostics Management Counseling -

GENETIC DISORDERS WEBSITE www. genefacts. org - Useful for information Diagnostics Management Counseling - 45

GENETICS Locus Position of a gene along a chromosome Allele A different form of

GENETICS Locus Position of a gene along a chromosome Allele A different form of a particular gene at a given locus Example: Hgb A vs. Hgb S Polymorphism Locus that has two or more alleles that occur with appreciable frequency 46

GENETICS (CONT’D) Homozygous Loci on a pair of chromosomes have identical genes Example O

GENETICS (CONT’D) Homozygous Loci on a pair of chromosomes have identical genes Example O blood type (OO) Heterozygous Loci on a pair of chromosomes have different genes Example AB blood type (A and B genes on pair of loci) 47

GENETICS (CONT’D) Genotype (“what they have”) The genetic makeup of an organism Phenotype (“what

GENETICS (CONT’D) 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 48

GENOTYPE VS. PHENOTYPE 49

GENOTYPE VS. PHENOTYPE 49

GENETICS (CONT’D) If two alleles are found together, the allele that is observable is

GENETICS (CONT’D) If two alleles are found together, the allele that is observable is dominant, and the one whose effects are hidden is recessive In genetics, the dominant allele is represented by a capital letter, and the recessive by a lowercase letter Alleles can be codominant 50

CODOMINANCE EXAMPLES 51

CODOMINANCE EXAMPLES 51

GENETICS (CONT’D) Carrier A carrier is one who has a disease gene but is

GENETICS (CONT’D) Carrier A carrier is one who 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 52

CARRIERS 53

CARRIERS 53

GENETICS (CONT’D) Transmission of genetic disease Mode of inheritance Principle of segregation Principle of

GENETICS (CONT’D) Transmission of genetic disease Mode of inheritance Principle of segregation Principle of individual assortment Chromosome theory of inheritance 54

PEDIGREES Used to study specific genetic disorders within families Begins with the proband 55

PEDIGREES Used to study specific genetic disorders within families Begins with the proband 55

PEDIGREES (CONT’D) 56

PEDIGREES (CONT’D) 56

SINGLE-GENE DISORDERS Autosomal dominant disorder Abnormal allele is dominant, normal allele is recessive, and

SINGLE-GENE DISORDERS Autosomal dominant disorder Abnormal allele is dominant, normal allele is recessive, and the genes exist on a pair of autosomes 57

SINGLE-GENE DISORDERS (CONT’D) 58

SINGLE-GENE DISORDERS (CONT’D) 58

AUTOSOMAL DOMINANT EXAMPLES AND VIDEO Myotonic dystrophy Marfan Syndrome Huntington disease Familial hypercholesterolaemia https:

AUTOSOMAL DOMINANT EXAMPLES AND VIDEO Myotonic dystrophy Marfan Syndrome Huntington disease Familial hypercholesterolaemia https: //www. youtube. com/watch? v=dw-ra. R 6 E 9 z. U 59

PENETRANCE The percentage of individuals with a specific genotype who also express the expected

PENETRANCE The percentage of individuals with a specific genotype who also express the expected phenotype Incomplete penetrance Individual who has the gene for a disease but does not express the disease Retinoblastoma (eye tumor in children) demonstrates incomplete penetrance (90%) 60

EXPRESSIVITY Expressivity is the extent of variation in phenotype associated with a particular genotype

EXPRESSIVITY Expressivity is the extent of variation in phenotype associated with a particular genotype This can be caused by modifier genes Examples: von Recklinghausen disease Autosomal dominant Long arm of chromosome 17 Disease varies from dark spots on the skin to malignant neurofibromas, scoliosis, gliomas, neuromas, etc. 61

EXPRESSIVITY EXAMPLE: NEUROFIBROMATOSIS 62

EXPRESSIVITY EXAMPLE: NEUROFIBROMATOSIS 62

SINGLE-GENE DISORDERS Epigenetics Same DNA sequence can produce different phenotypes due to chemical modification

SINGLE-GENE DISORDERS Epigenetics Same DNA sequence can produce different phenotypes due to chemical modification that alters expression of genes 63

SINGLE-GENE DISORDERS (CONT’D) Autosomal recessive disorder Abnormal allele is recessive and a person must

SINGLE-GENE DISORDERS (CONT’D) Autosomal recessive disorder Abnormal allele is recessive and a person must be homozygous for the abnormal trait to express the disease The trait usually appears in the children, not the parents, and it affects the genders equally because it is present on a pair of autosomes Cystic fibrosis gene encodes a chloride ion channel in some epithelial cells that alters sodium balance 64

CYSTIC FIBROSIS 65

CYSTIC FIBROSIS 65

CYSTIC FIBROSIS TX 66

CYSTIC FIBROSIS TX 66

SINGLE-GENE DISORDERS (CONT’D) Autosomal recessive disorder recurrence risk Recurrence risk of an autosomal dominant

SINGLE-GENE DISORDERS (CONT’D) Autosomal recessive disorder recurrence risk Recurrence risk of an autosomal dominant trait When two parents are carriers of an autosomal recessive disease, the occurrence and recurrence risks for each child are 25% 67

Sickle Cell Anemia: 68

Sickle Cell Anemia: 68

AUTOSOMAL RECESSIVE DISEASE VIDEO https: //www. youtube. com/watch? v=o. E 9 BUuv 2 p.

AUTOSOMAL RECESSIVE DISEASE VIDEO https: //www. youtube. com/watch? v=o. E 9 BUuv 2 p. To 69

CONSANGUINITY Mating of two related individuals Dramatically increases the recurrence risk of recessive disorders

CONSANGUINITY Mating of two related individuals Dramatically increases the recurrence risk of recessive disorders 70

SEX-LINKED DISORDERS The Y chromosome contains only a few dozen genes, so most sex-linked

SEX-LINKED DISORDERS The Y chromosome contains only a few dozen genes, so most sex-linked traits are located on the X chromosome and are said to be X-linked Sex-linked (X-linked) disorders are usually expressed by males because females have another X chromosome to mask the abnormal gene 71

X-LINKED RECESSIVE 72

X-LINKED RECESSIVE 72

SEX-LINKED DISORDERS (CONT’D) X-linked recessive Most X-linked disorders are recessive Affected males cannot transmit

SEX-LINKED DISORDERS (CONT’D) X-linked recessive Most X-linked disorders are recessive Affected males cannot transmit the genes to sons, but they can to all daughters Sons of female carriers have a 50% risk of being affected Examples: hemophilia, color-blindness 73

SEX-LINKED DISORDERS (CONT’D) 74

SEX-LINKED DISORDERS (CONT’D) 74

RECURRENCE RISKS Recurrence risks of multifactorial diseases can change substantially between populations Recurrence risk

RECURRENCE RISKS Recurrence risks of multifactorial diseases can change substantially between populations Recurrence risk becomes higher if more than one family member is affected Empirical risks have been derived via direct observation 75

RECURRENCE RISKS (CONT’D) If the expression of the disease in the proband is more

RECURRENCE RISKS (CONT’D) If the expression of the disease in the proband is more severe, the recurrence risk is higher The recurrence risk is higher if the proband is of the less commonly affected sex The recurrence risk for the disease usually decreases rapidly in more remotely related relatives 76

TEST YOURSELF! 1. Which of the following statements is TRUE? A. B. C. D.

TEST YOURSELF! 1. Which of the following statements is TRUE? A. B. C. D. RNA is double-stranded. DNA is replicated in the cytoplasm. RNA contains the same bases as DNA. A mutation is an inherited alteration of DNA. 77

TEST YOURSELF! 2. Which term best describes an allele with an observable effect? A.

TEST YOURSELF! 2. Which term best describes an allele with an observable effect? A. B. C. D. Carrier Dominant Recessive Homozygous 78