Genes and Genetic Disease

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Genes and Genetic Disease

• Chapter 2

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• Genetic Perspective
• Microscopic studies 1800s nucleus might
  contain important information for inheritance
• Gregor Mendel 1865
• Austrian monk
• Garden peas
• Dominant, recessive
• Homozygous, heterozygous
• hallmark of understanding inheritance
• Apparent chromosomes (nucleus) contain genes
  basic unit of inheritance

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Gregor Mendel 1822-1884
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St. Thomas Abbey Brno Czech Rep.
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Mendelian Genetics

• Hugo de Vries Carl Correns 1900
  independent duplication of 1865 work
• acknowledged Mendels work
• Luckyworking with characteristics that were
  coded by single genes
• Principles
• Segregation one gene(of a pair) per
  gamete(sperm/egg)
• Independent assortment transmission of one gene
  does not affect the transmission of another

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• Watson-Crick Model of DNA Molecule
• 1953
• Genes DNA (deoxyribonucleic acid)
• 3 basic components
• 1. Pentose sugar deoxyribose
• 2. Phosphate molecule
• 3. 4 types of nitrogen bases
• pyrimidines cytosine, thymine (C, T)
• purines adenine, guanine (A, G)

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• Double-helix model
• twisted ladder with chemical bands as the
  rungs
• A T rungs of the
• G C ladder
• DNA subunit consists of
• Deoxyribose molecule
• Phosphate group
• One base (A, T, C or G)
• Called NUCLEOTIDE

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DNA
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Rosland Franklin 1920-1958
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• DNA as the Genetic Code
• Proteins structural, functional (receptors
  enzymes)
• Amino acids ? polypeptides ? one/more ? protein
  (tissues, enzymes, receptors)
• 20 different amino acids
• 4 bases (A-T, C-G) specify which amino acid is
  placed into the polypeptide
• Group of 3 bases each amino acid termed CODON

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• DNA Replication
• Untwisting and unzipping of the DNA strand
  template
• Complementary base pairing by DNA polymerase
• A T
• C G

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DNA Replication
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• Mutation
• Any inherited alteration of genetic material
• Chromosome aberrations
• Base pair substitution (missense/stop) A-T..G
  -C
• Frame shift mutation deletion or insertion
• ATGCTACGAT_CTACG or ATG G CTACG
• SO - insert the wrong amino acid(s) into the
  polypeptide chain(s) ? abnormal proteins
  (MUTATION)

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• Mutations
• Spontaneous absence of known mutagen
• Hot spots chromosome areas with ? rates
  cytosine followed by guanine ? large percentage
  of disease causing mutations
• Radiation chemicals - ? frequency

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• Genes to Proteins
• Dogma
• Transcription
  Translation
• DNA RNA
  Proteins
• NUCLEUS
  
  CYTOPLASM
• RNA 2 differences
• 1.- ribose sugar added Oxygen
• 2.- uracil, rather than thymine
• A U
• C G

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• Transcription
• Messenger RNA synthesized from DNA
• template (RNA polyerase)
• single strand of DNA
• mRNA ? cytoplasm

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Transcription
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• Translation
• RNA directs synthesis of polypeptides at the
  ribosome
• tRNA contains a sequence of nucleotides
  (anticodon) complementary to the triad of
  nucleotides on the mRNA strand (codon)
• mRNA UGC tRNA ACG
• rememberRNA- UA, CG
  DNA- TA, CG
  
• Nobel Prize Chemistry 2009 Ramakrishnan,
  Steitz, Yonath structure of ribosomesnew
  antibiotics!
• Transfer RNA

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Translation
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• Chromosomes
• Abnormalities leading cause mental retardation
  miscarriage
• Somatic cells
• 46 chromosomes (23 pairs) Diploid
• Gametes
• 23 chromosomes (1 member of pair) - Haploid

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• Chromosomes
• Meiosis haploid cells from diploid cells
  sperms eggs
• (reduction division)
• Mitosis forms somatic cells new cells
• Figure 2-9

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Karyotype

• Ordered display of chromosomes

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• Chromosome Aberrations
• Euploid cells
• Contains a multiple of the normal number of
  chromosomes (23)
• Haploid and diploid
• Polyploid cells
• Triploid 3 copies of 23(haploid) ? 69
  chromosomes
• Tetraploid 4 copies 23(haploid) ? 92 chromosomes

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• Chromosome Aberrations
• Aneuploidy
• Somatic cell does not contain a multiple of 23
  chromosomes
• 3 copies of one ? trisomy (may survive)
• 1 copy only ? monosomy (lethal)
• More is better

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• Chromosome Aberrations
• Disjunction normal separation of chromosomes
  during cell division
• Non-disjunction failure of homologous
  chromosomes to separate meiosis / mitosis
• Usual cause of aneuploidy

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• Chromosomes
• Autosomes
• First 22 of the 23 pairs
• Two members are identical and said to be
  homologous
• Sex chromosomes
• Remaining pair
• Females XX homologous
• Males XY non-homologous

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Nondisjunction
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• Autosomal Aneuploidy
• Down Syndrome
• Trisomy 21
• 1800 live births
• Mentally retarded, low nasal bridge, epicanthal
  folds, protruding tongue, poor muscle tone
• Risk ? with maternal age gt 35

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Down Syndrome
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Blood Test for Down Syndrome-6/2011
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• Sex Chromosome Aneuploidy
• 1 in 500 males / 1 in 900 females
• Females trisomy X
• Females single X total 45 chromosomes
• Turner Syndrome
• Males two x and one Y (47 chromosomes)
• Klinefelter Syndrome

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Turner Syndrome -45X, monosomy
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Klinefelter Syndrome-47,XXY
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• Abnormalities of Chromosome Structure
• Breakage repair may alter structure
• Loss Cri du chat syndrome deletion short arm
  5 ? low birth weight mental retardation and
  microcephaly
• Duplication less serious
• Inversion balanced no apparent effect
• Translocation interchange of material between
  two non-homologous chromosomes
• Robertsonian fusion at centromere ? single
  chromosome

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• Abnormalities of Chromosome Structure
• Fragile sites areas that develop breaks or gaps
• Fragile X syndrome long arm X chromosome
• Mental retardation
• Male (XY) verses female (XX)

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• Genetics
• Gregor Mendel 1865
• Austrian monk
• Garden peas
• Mendelian traits

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• Genetics
• trait caused by a single gene ? mendelian trait
• Locus gene location on a chromosome
• Allele different form of a particular gene at
  the given locus
• Example Hgb A verses Hgb S
• Polymorphism two or more alleles at a locus

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• Genetics
• humans are diploid one chromosome from mom one
  from dad 23 23 46
• 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 B genes on a pair
  of loci)

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• Genetics
• Genotype genetic makeup of the organism
• Phenotype observable, detectable or outward
  appearance of the genetics of an organism
• Example A blood type could be AA or AO
• A phenotype
• AA/AO genotype

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• Genetics
• Dominant/Recessive two alleles are found
  together, observable allele is dominant, other
  allele is recessive and not observable
• A large letter dominant
• a small letter recessive
• Alleles can be co-dominant
• Example AB blood type

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• Genetics
• Carrier - one that has a disease gene but is
  phenotypically normal
• to demonstrate a recessive disease the pair of
  recessive genes must be inherited
• Example Dd Heterozygous carrier
• dd Homozygous _ disease

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• Genetics
• Mendel 1865
• Principle of segregation homologous genes
  separate, reproductive cells carry only one gene
  (meiosis)
• Principle of independent assortment hereditary
  transmission of one gene does not affect the
  transmission of another.

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• Chromosome Theory of Inheritance
• Single Gene Disease 4 mode of inheritance
• Autosomal dominant
• Autosomal recessive
• X-linked dominant
• X-linked recessive

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• Pedigrees
• Used to study specific genetic disorders within
  families
• Begin with proband

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Pedigrees
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• Single Gene Disorders
• Autosomal dominant rare lt 1500
• Normal parent x affected heterozygote
• Rare

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Single-Gene Disorders

• Autosomal dominant traits

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Single-Gene Disorders

• Autosomal dominant trait pedigree

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• Single Gene Disorders
• Recurrence risk
• AD one parent with disease, one without risk
  50 risk

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• Single Gene Disorders
• Autosomal dominant
• Achondroplasia 4p16.3FGFR3 Gene 80 new
  mutations
• Marfan syndrome 15q 15-21
• Neurofibromatosis 17q11
• Brachydactyly
• Noonan syndrome
• Huntington disease

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Wizard of Oz
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• Review
• Delayed age of onset
• Penetrance
• expressivity

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• Single Gene Disorders
• Autosomal recessive
• Abnormal allele recessive so must have 2 copies
  (homozygous) for expression
• Recurrence risk 14
• ? with consanguinity (2 related individuals)

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Autosomal Recessive Disorder
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• Single Gene Disorders
• Autosomal recessive
• Albinism
• Cystic fibrosis 7q31
• Phenylketnuria 12q21
• Galactosemia
• Mucopolysaccharidosis

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Albinism
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• Sex Linked Disorders
• X chromosome, Y has only a few dozen genes
• Male expression (XY), females have another X (XX)
• Most disorders are recessive fathers cannot
  transmit to sons, but can to daughters
  Disease Duchennes Muscular
  Dystrophy Color Blindness Hemophilia

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Sex-Linked Disorders
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• Review Multi-factorial Inheritance
• Diseases
• Cleft lip palate
• Neural tube defects
• Clubfoot
• Some congenital heart disease Figure
  2-31 Example of Diseases A Gene Map