Download Genes and Genetic Disease

Genes and Genetic Disease
Chapter 2
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”
Gregor Mendel 1822-1884
St. Thomas Abbey Brno Czech Rep.
Mendelian Genetics
 Hugo de Vries & Carl Correns
1900 : independent
duplication of
1865 work
 “acknowledged Mendel’s work”
 Lucky…working 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
Watson-Crick Model of DNA Molecule
1953
 Genes = DNA (deoxyribonucleic acid)
3 basic components
Pentose sugar – deoxyribose
2. Phosphate molecule
3. 4 types of nitrogen bases
1.
pyrimidines: cytosine, thymine (C, T)
purines: adenine, guanine (A, G)
 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
DNA
Rosland Franklin: 1920-1958
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
DNA Replication
 Untwisting and unzipping of the DNA strand –
template
 Complementary base pairing by DNA polymerase
A –T
C–G
DNA Replication
Mutation
 Any inherited alteration of genetic material
“Chromosome aberrations”
 Base pair substitution (missense/stop)
A-T………..G-C
 Frame shift mutation – deletion or insertion
ATGCTACG……AT_CTACG or ATG G CTACG
SO -
insert the wrong amino acid(s) into the polypeptide
chain(s) → abnormal proteins (MUTATION)
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
Genes to Proteins
Dogma:
Transcription
DNA
Translation
RNA
NUCLEUS
RNA – 2 differences
1.- ribose sugar: added Oxygen
2.- uracil, rather than thymine
A–U
C–G
Proteins
CYTOPLASM
Transcription
 Messenger RNA – synthesized from DNA
template (RNA polyerase)
 single strand of DNA
 mRNA → cytoplasm
Transcription
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
remember:RNA- U:A, C:G
DNA- T:A, C:G
*Nobel Prize Chemistry 2009: Ramakrishnan, Steitz,
Yonath “structure of ribosomes”…new antibiotics!
**Transfer RNA
Translation
Chromosomes
 Abnormalities – leading cause mental retardation &
miscarriage
 Somatic cells
 46 chromosomes (23 pairs) –
Diploid
 Gametes
 23 chromosomes (1 member of pair) - Haploid
Chromosomes
 Meiosis – haploid cells from diploid cells :sperms &
eggs
(reduction division)
 Mitosis – forms somatic cells :new cells
 Figure 2-9
Karyotype
 Ordered display of chromosomes
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
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”
Chromosome Aberrations
 Disjunction – normal separation of chromosomes
during cell division
 Non-disjunction – failure of homologous
chromosomes to separate – meiosis / mitosis
 Usual cause of aneuploidy
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
Nondisjunction
Autosomal Aneuploidy
 Down Syndrome
 Trisomy 21
 1:800 live births
 Mentally retarded, low nasal bridge, epicanthal folds,
protruding tongue, poor muscle tone
 Risk ↑ with maternal age > 35
Down Syndrome
Blood Test for Down Syndrome6/2011
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
Turner Syndrome -45X, monosomy
Klinefelter Syndrome-47,XXY
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
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)
Genetics
 Gregor Mendel – 1865
 Austrian monk
 Garden peas
 Mendelian traits
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
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)
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
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
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
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.
Chromosome Theory of Inheritance
“Single Gene Disease – 4 mode of inheritance”
1) Autosomal dominant
2) Autosomal recessive
3) X-linked dominant
4) X-linked recessive
Pedigrees
 Used to study specific genetic disorders within families
 Begin with proband
Pedigrees
Single Gene Disorders
 Autosomal dominant – rare < 1:500
 Normal parent x affected heterozygote
 “Rare”
Single-Gene Disorders
 Autosomal dominant traits
Single-Gene Disorders
 Autosomal dominant trait pedigree
Single Gene Disorders
 Recurrence risk
AD – one parent with disease, one without risk :50%
risk
Single Gene Disorders
 Autosomal dominant
 Achondroplasia 4p16.3…FGFR3 Gene …80% new
mutations
 Marfan syndrome
 Neurofibromatosis
 Brachydactyly
 Noonan syndrome
 Huntington disease
15q 15-21
17q11
Wizard of Oz
Review
 Delayed age of onset
 Penetrance
 expressivity
Single Gene Disorders
Autosomal recessive
 Abnormal allele – recessive so must have 2 copies
(homozygous) for expression
 Recurrence risk 1:4
 ↑ with consanguinity (2 related individuals)
Autosomal Recessive Disorder
Single Gene Disorders
Autosomal recessive
 Albinism
 Cystic fibrosis 7q31
 Phenylketnuria 12q21
 Galactosemia
 Mucopolysaccharidosis
Albinism
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:
Duchenne’s Muscular Dystrophy
Color Blindness
Hemophilia
Sex-Linked Disorders
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