Week 2 Genetics & Health Notes

Chromosomes & Disease: Genetic Cockups!

Human Chromosomes:
• What are they?
o Highly compacted linear pieces of DNA
o Contain many different genes
o Only visible during M-Phase once the replicated chromosomes have condensed.
o Vary in size; 50-250Mbase-pairs

• Chromosome Number:
o Varies between species
o Similar species have similar chromosome numbers
§ Eg. Chimps – 48 , Humans – 46
o Chromosome number ≠ sophistication
• Cell Function:
o Normal people are born with 2x sets of 23 chromosomes
§ 1 set from mum
§ 1 set from dad
o 2 Sex Chromosomes:
§ X&Y
§ XX = Female
• X from Dad
• X from Mum
§ XY = Male
• X from Mum
• Y from Dad
o 44 Autosomes (all others):
o Genes:
§ Sequences of DNA that encode proteins.
§ Different genes have different functions.
• Some genes are expressed in all cell types.
• Most cells only express genes relevant to their function.
o Pairs of identical chromosomes are paired & numbered by length & banding patterns

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Human Sex Determination:
DAD MUM

Female Male

Chromosome Nomenclature:
• Bands
o Chromosomes show distinct banding patterns
o Due to gene rich and gene poor regions
o Regions = heterochromatin (dark) and euchromatin (light)
§ Heterochromatin (Dark):
• Genes that have been turned off and packed away
• Genes that the cell doesn’t need for its specific functions
§ Euchromatin (Light):
• Genes that are unpacked and readily transcribed into proteins
• These genes are critical to the cell’s specific function.

• Chromosome Charting:
o Arms
§ Long = ‘q’
§ Short = ‘p’
o Regions
§ 2 regions/arm
§ Divided evenly
o Bands
§ Centromere = Band 10
§ Counts upward both ways toward the centromere
o Centromere
§ Where the 2 sister chromatids are anchored
together
o Telomere
§ Repeated sequences of non-coding DNA at the Very
ends of each chromosome arm.

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• Chromosome Shapes:
1. Metacentric:
§ Arms of similar length
2. Submetacentric:
§ Centromere at approx 1/3
3. Acrocentric:
§ Centromere very close to telomere
4. Telocentric:
§ Centromere at the telomere

• Writing Chromosomes:
o 46, XX = normal Female
o 46, XY = normal Male
o 47, XX, +10 = abnormal Female - extra 10th chromosome.
o 45, XY, -22 = abnormal Male – missing 22nd chromosome.
o More:

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Extracting Chromosomes – G-Banding Ideogram:
• Extract cells
• Centrifuge - Collect cells
• Grow cells in culture – amplify numbers
• Treat with spindle-inhibitor à arrests cells in metaphase
• Treat with Protease and stain with Giemsa.
• Drop cells onto slide – flattens cell à spreads chromosomes
• Analyse by computer – pair identical chromosomes.
• Result: Human Karyotype

Origins of Abnormal Karyotypes:

• Errors in Cell Division
o During Meiosis of Mitosis
o Gains/losses of parts of chromosomes
o Rearrangements between chromosomes
o Gains/losses of whole chromosomes
o 2 Classes:
§ Constitutional Chromosome Abnormalities
• During Gametogenesis
• Found in every cell of the body
§ Acquired Chromosome Abnormalities
• During Embryogenesis
• Found only in clusters of cells
• Individuals are a ‘mosaic’ of normal & abnormal cells

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5 Main Causes of Abnormal Karyotypes:
1. Anaphase Lag
§ During anaphase
§ One chromosome fails to migrate to the pole of the spindle
§ That chromosome then fails to be enclosed by the new nuclear envelope
§ Chromosome is lost and gets degraded
§ Results in 1x normal cell + 1x cell with a missing/extra chromosome
§ Leads to monosomies & trisomies

2. Chromosome Mis-Segregation (Nondisjunction)

§ Error during meiosis
§ Where chromosomes aren’t divided equally among the gametes.
§ Results in either: gametes with extra or missing chromosomes.
§ If such gametes are fertilized à mosomies & trisomies

3. Replication Failure (Meiotic/Mitotic)..and..

4. Dispermy
§ Results in polyploidy.
§ How this can happen:
• Error in Gametogenesis
o Chromosomes duplicate but the germ cell fails to divide à diploid gamete.
• Error at Fertilisation
o Eg. Dispermy à 2 sperm simultaneously fertilise egg. àtriploid embryo
• Error in Embryogenesis
o Errors during early mitotic cell divisions
o Chromosomes duplicate by the embryonic cell/s fail to divide àtriploid
mosaic embryo
5. Incorrect DNA Repair
§ Cellular DNA damage happens regularly
§ Usually DNA repair mechanisms work well
§ Sometimes, DNA damage is incorrectly repared.

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Classes of DNA Damage:
• Translocations:
o Insertional:

o Reciprocal:

o Robertsonian:
(Centric Fusions of Acrocentric Chromosomes)

• Inversions:
o A segment of the chromosome has been flipped
o No gain / loss of genetic material
o If breakpoints don’t disrupt genes àno abnormality
o 2 Kinds:
§ Pericentric
§ Paracentric

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• Deletions:
o A region of a chromosome is deleted
o Deletion size: proportional to: Severity of abnormality.
o Eg. William’s syndrome = DNA loss on Chr. 7

• Duplications:
o A region of a chromosome is doubled
o If duplication occurs outside a coding region & doesn’t result in a frameshift àno abnormalities.

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Aneuploidy Vs. Polyploidy
• Aneuploidy:
o The addition/loss of a chromosome from the normal (euploid) 23pairs.
o Common cause: Nondisjunction – failure of chromosomes to separate properly during meiosis
o Generally manifests as a trisomy - 3 sets of a chromosome.
§ Most trisomies are lethal except on the small chromosomes.
• Eg. Chr.21 – Down’s Syndrome;
• Chr.18 – Edward’s Syndrome.
o Rarely as a monosomy – loss of a chromosome.
§ All embryonically lethal – except on sex chromosomes.

o Aneuploidy of Sex Chromosomes:

§ Males must cope with a single X-chromosome.
§ Evolution developed a mechanism: dosage compensation
§ Females only use one of their X-chromosomes.
§ One X-chromosome in each cell is randomly hypercondensed (inactivated) àBarr Bodies.
§ Therefore all females are mosaics. (eg. Dermal dysplasia)
• Barr Bodies: areas of heterochromatin

• Polyploidy:
o Addition of whole sets of chromosomes.
o Eg. 3 copies of every chromosome (or 4, or 5, etc)
o Almost always embryonically lethal & results in spontaneous miscarriage.

Ø Spontaneous miscarriage/abortion:
o Most of early miscarriages are due to genetic abnormality

Overview of Common Genetic Diseases

47, XY, +18: Edward’s Syndrome
• Trisomy 18
• Rarely survive beyond infancy

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47, XY, +21: Down’s Syndrome
• Trisomy 21
• Risk of Down’s syndrome increases exponentially with maternal age.

Klinefelter’s Syndrome 47, XXY

Diplo-Y (Super-Male) 47,XYY.

Turner’s Syndrome:
• Most die during gestation
• Survivors are mostly mosaics

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 Week 5 Genetics & Health Notes
Autosomal Recessive Disorders

Is a Mutation Dominant Or Recessive?

• Broad Generalisations:
o Dominant
§ Affect structural proteins
§ Gain-of-function
o Recessive
§ Affect enzymes
§ Loss-of-function

What Determines The Effect of a Mutation?

• Coding Regions:
o Alter/truncate amino acid sequence
o Therefore altering protein shape & function.
• Regulatory Sequences:
o Change quantity or pattern of expression.
o May even stop expression completely.

Notation for Mutations:

• @ DNA Level: Eg. (76 A>T)
o Capitals
o Number = first nucleotide affected
• @ RNA Level: Eg. (76 a>u)
o Lower-case
o Number = first nucleotide affected
• @ Protein Level: Eg. (T.26.P)
o Capitals
o Letter 1: first amino acid changed.
o Number: position of amino acid in mature protein (codon number)
o Letter 2: what the 1st amino acid changed to.

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Classes of Gene Mutations:

• Single Base Substitutions:

o Errors in DNA replication/repair
§ Synonymous Mutations à(silent – change occurs in wobble position. Ie. Same amino acid)

§ Missense Mutations à (change not in wobble position. Ie. Codes for different amino acid)
• Conservative: The new amino acid is chemically similar to its predecessor.
o May preserve protein function
• Non-Conservative: The new amino acid is chemically different to its predecessor.
o Generally screws protein function

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 § Nonsense Mutations à (Code for a stop codon. Ie. Can truncate protein)

• Insertions:
o One or more extra nucleotides
o May alter splicing if in introns.
o May cause frameshift

• Deletions:
o Total erasure of 1 or more bases.
o Up to millions of BP’s
o May encompass multiple genes.
o May cause frameshift

• Dynamic Mutations:
o Tandem repeats that change size each cell cycle
o Either increase/decrease

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Levels of Gene Function à Disease:
• Some have a high threshold – only show symptoms with significant loss of gene function.
• Some have a low threshold – show symptoms with little loss of gene function
• Some symptoms vary in severity (proportional to amount of loss of gene function)
• Some effect different body systems @ different thresholds.

Classic Autosomal Recessive Disorders:

• Metabolism:
o Phenylketonuria: (similar to Maple-Syrup Urine Disease)
§ Enzyme that breaks down phenylalanine isn’t functioning.
• Normally converts phenylalanine to another amino acid & tyrosine
§ Phenylalanine & its breakdown chemicals (from other enzyme routes) accumulate in blood.
§ Symptoms:
• Mousy odour to urine
• Vomiting
• Rashes
• Irritability
• Small head
• Severe brain damage – if left too long untreated.
§ Diagnosis:
• Heel-prick test – newborn screening
§ Management:
• Manage diet – avoid high protein foods
• Maintain blood-phenylalanine levels (some is needed for normal growth)
• Offspring of affected mothers – mental retardation – elevated phenylalanine inhibits
foetal neural development.
§ Compound Heterozygotes:
• Patients with 2 different defective alleles, both contributing to the disease
phenotype.
• Compound heterozygotes of recessive disorders are usually
affected.

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• Blood Cell Function:
o Thalassemia:
§ Absence of synthesis of one of the globin chains
§ Usually via deletions that block globin protein production
§ Alpha-thalassemia = absence of alpha-globin (more common in Asians)
§ Beta-thalassemia = absence of beta-globin (more common in Caucasians)
§ Symptoms:
• Babies become anaemic
• Become pale
• Don’t sleep well
• No appetite
• If untreated – usually fatal (usually die between 1 & 8yrs)

o Sickle Cell Disease:

§ Mutant allele codes for faulty beta-chain haemoglobin subunit.
§ Mis-shapen red blood cell
§ More common areas affected by malaria – malarial parasites grow poorly in homozygous &
sickle cell carriers.

o Haemochromatosis:
§ Iron Overload – hyperabsorption of iron.
§ Caused by mutations in the HFE Gene.
§ Iron builds up in organs (particularly: heart/liver/pancreas) and cause failure.
§ Symptoms: (usually men age 30-50 / women 50+)
• Joint pain
• Fatigue
• Abdominal pain
• Heart problems
• Symptoms often occur after irreversible organ damage.
§ Long-Term Effects:
• Arthritis/Liver disease/Heart abnormalities/Impotence/Early menopause/Bronze or
grey complexion/Possible diabetes

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 • Membrane Function:
o Cystic Fibrosis:
§ Defective Cl- Transporter in some cells (mostly exocrine glands)
§ Defective gene = CFTR
§ Q arm of Chromosome 7
§ Lungs:
• Thicker mucus secretion
• Ciliated cells can’t move mucus up trachea
• Mucus + dust + particles + bacteria àtrapped in lungs àfrequent lung infections.
§ Pancreas:
• Pancreatic duct clogs up – formation of cysts – eventually become fibrous
• Hinders proper digestion (no pancreatic enzymes àduodenum)
§ Intestine:
• Not enough digestive enzymes – mainly for fats
• Malnourishment
• Fatty stools
§ Reproductive Ducts:
• Male vas-deferens blocks à sterility
§ Sweat Glands:
• Secrete salt to induce H2O flow but salt isn’t actively
reabsorbed.
• Results in salt-residue on skin & salt deficit in body.
§ Treatment:
• Enzyme tablets with meals
• Electrolyte fluid – replenish lost NaCl
• Vitamin supplements
• Percussion – clear lungs

Gene Therapy:
• Using a genetically modified vector (viruses) to insert therapeutic genes into cells with defective genes.

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