Chapter 2

Genes and Genetic Disease

Genetic PerspectiveMicroscopic studies – 1800s –

nucleus might contain important information for inheritance

Gregor Mendel 1865Austrian monkGarden peas

Dominant, recessiveHomozygous, 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 GeneticsHugo de Vries & Carl Correns 1900 :

independent duplication of 1865 work

“acknowledged Mendel’s work”Lucky…working with characteristics that

were coded by single genesPrinciples:

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

1953Genes = DNA (deoxyribonucleic acid)

3 basic components

1. Pentose sugar – deoxyribose

2. Phosphate molecule3. 4 types of nitrogen bases

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 theG – C ladder

DNA subunit consists ofDeoxyribose moleculePhosphate groupOne base (A, T, C or G)

Called NUCLEOTIDE

DNA

Rosland Franklin: 1920-1958

DNA as the Genetic CodeProteins – 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 polypeptideGroup of 3 bases – each amino acid termed

CODON

DNA ReplicationUntwisting and unzipping of the DNA

strand – templateComplementary base pairing by DNA

polymeraseA – TC – G

DNA Replication

MutationAny 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 ProteinsDogma: Transcription Translation

DNA RNA Proteins

NUCLEUS CYTOPLASM

RNA – 2 differences1.- ribose sugar: added Oxygen2.- uracil, rather than thymine

A – UC – G

TranscriptionMessenger RNA – synthesized from DNA

template (RNA polyerase) single strand of DNA

mRNA → cytoplasm

Transcription

Translation*RNA directs synthesis of polypeptides at the

ribosometRNA **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

ChromosomesAbnormalities – leading cause mental

retardation & miscarriageSomatic cells

46 chromosomes (23 pairs) – Diploid

Gametes23 chromosomes (1 member of pair) - Haploid

ChromosomesMeiosis – haploid cells from diploid

cells :sperms & eggs (reduction division)

Mitosis – forms somatic cells :new cells

Figure 2-9

KaryotypeOrdered display of chromosomes

Chromosome Aberrations Euploid cells

Contains a multiple of the normal number of chromosomes (23)

Haploid and diploid

Polyploid cellsTriploid – 3 copies of 23(haploid) → 69

chromosomesTetraploid – 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 / mitosisUsual cause of aneuploidy

ChromosomesAutosomes

First 22 of the 23 pairsTwo members are identical and said to be

homologousSex chromosomes

Remaining pairFemales – XX – homologousMales – XY – non-homologous

Nondisjunction

Autosomal AneuploidyDown Syndrome

Trisomy 211:800 live birthsMentally retarded, low nasal bridge,

epicanthal folds, protruding tongue, poor muscle tone

Risk ↑ with maternal age > 35

Down Syndrome

Blood Test for Down Syndrome-6/2011

Sex Chromosome Aneuploidy1 in 500 males / 1 in 900 females

Females trisomy X

Females single X – total 45 chromosomesTurner 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 seriousInversion – balanced – no apparent effectTranslocation – interchange of material

between two non-homologous chromosomesRobertsonian – fusion at centromere → single

chromosome

Abnormalities of Chromosome Structure

Fragile sites – areas that develop breaks or gaps

Fragile X syndrome – long arm X chromosomeMental retardationMale (XY) verses female (XX)

Genetics Gregor Mendel – 1865

Austrian monkGarden peasMendelian traits

Genetics“trait caused by a single gene →

mendelian trait”Locus – gene location on a chromosomeAllele – 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 genesExample: O blood type (OO)

Heterozygous – loci on a pair of chromosomes have different genesExample: 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 organismExample: A blood type – could be AA or AO

A – phenotypeAA/AO – genotype

GeneticsDominant/Recessive – two alleles are

found together, observable allele is dominant, other allele is recessive and not observable

A – large letter = dominanta – small letter = recessiveAlleles can be co-dominant

Example: AB blood type

GeneticsCarrier - one that has a disease gene but

is phenotypically normalto demonstrate a recessive disease the

pair of recessive genes must be inherited Example: Dd Heterozygous – carrier

dd Homozygous _ disease

GeneticsMendel 1865Principle 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 dominant2) Autosomal recessive3) X-linked dominant4) X-linked recessive

PedigreesUsed to study specific genetic disorders

within familiesBegin with proband

Pedigrees

Single Gene Disorders Autosomal dominant – rare <

1:500Normal parent x affected heterozygote “Rare”

Single-Gene DisordersAutosomal dominant traits

Single-Gene DisordersAutosomal dominant trait pedigree

Single Gene DisordersRecurrence risk

AD – one parent with disease, one without risk :50% risk

Single Gene DisordersAutosomal dominant

Achondroplasia 4p16.3…FGFR3 Gene …80% new mutations

Marfan syndrome 15q 15-21Neurofibromatosis 17q11BrachydactylyNoonan syndromeHuntington disease

Wizard of Oz

ReviewDelayed age of onsetPenetranceexpressivity

Single Gene DisordersAutosomal 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 DisordersAutosomal recessive

AlbinismCystic fibrosis 7q31Phenylketnuria 12q21GalactosemiaMucopolysaccharidosis

Albinism

Sex Linked DisordersX – chromosome, Y has only a few dozen

genesMale expression (XY), females have

another X (XX)Most disorders are recessive – fathers cannot

transmit to sons, but can to daughters

Disease:

Duchenne’s Muscular DystrophyColor BlindnessHemophilia

Sex-Linked Disorders

Review – Multi-factorial Inheritance

DiseasesCleft lip & palateNeural tube defectsClubfootSome congenital heart disease

Figure 2-31 Example of Diseases: A Gene Map