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Cellular Genetics and the Cell Cycle

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Foundations of Biomedical Science 1

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King's College London

Academic year: 2018/2019

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Cellular Genetics and the Cell Cycle

Lecture 1: Basics of Genetic Inheritance –

Inherited traits controlled by genes on chromosomes: 1. Monogenic disorders – CLJstiĐ fiďrosis, “CA, HuŶtiŶgtoŶ͛s 2. Polygenic disorders – Type II diabetes, Rheumatoid Arthritis, Schizophrenia Genotype can determine whether gene resistance will occur:  People ǁho doŶ͛t haǀe CCR5 Chemokine receptor are resistant to HIV-

Genotype controls drug response in individuals:  Form of cytochrome P450 (CYP2D6) control metabolism of 25% of drugs.  It converts codeine to active form (morphine)  Codeine is ineffective for individuals who are poor metabolisers

A persoŶ͛s genotype can determine which drugs are prescribed:  Herceptin: - 30% breast cancers feature overexpression of HER2 (human epidermal growth factor receptor) - Herceptin blocks Her2 activity (this means Herceptin is only effective against HER+ tumours, but not against tumours that doŶ͛t oǀeredžpress HE‘Ϯ )

Genes are discrete units of inheritance, distributed across chromosomes; composed of DNA wound around beads of protein (histones). DNA + histones = chromatin 1. 1 DNA in every nucleus; histones allow packaging into nucleus about 5 micrometres in diameter. 2. Result: each DNA molecule has been packaged into a mitotic chromosome that is 10,000 x shorter than extended length

Info in genes must be accessible:  30nm fibre arranged as loops  Regions of DNA can be unwound from nucleosomes (DNA coiled around histones)  Groups of genes can be expressed without disassembly of entire chromosome

Human Karyotype: 1. 46 chromosomes – 22 pairs of autosomes (any chromosome that is not sex chromosome) + 1 pair sex chromosome 2. Assessed by staining chromosomes from metaphase spreads  as chromosomes are short, fat and visible in this state 3. G-banding (stained w/ Giesma)  unique alternating and dark bands for each pair

Cytogenetics: study of genetic component of cell through viualisation and analysis of chromosomes

Human Chromosomes characterised by: 1. Size 2. Pattern of G bands 3. Location of centromere (region of chromosome where microtubules of spindle attach)

Chromosomal replication: 1. Mitosis: development, growth, replacing lost cells (wound healing). - Leads to production of 2 genetically identical cells with diploid chromosomes 2. Meiosis: transmission of genetic information to offspring - Haploid number of chromosomes so sexual reproduction occurs without doubling of genetic content  introduces variation owing to recombination between homologous chromosomes - Four sperm cells formed in males BUT only 1 egg cell in females (3 haploid sets of DNA lost)

Mitosis and Meiosis:

Y chromosome and maleness:  Suggested that sŵall regioŶ at eŶd of short arŵ is all that͛s Ŷeeded to ĐoŶfer ŵaleŶess - Some males are 46, XX ďut at top ϭ X is a short regioŶ froŵ ͚p͛ eŶd of Y - Some males are 46, XY but small region near long end of Y chromosome missing

47, XYY (XYY syndrome): 1. Asymptomatic 2. Increased growth velocity, above average height

Euploidy: Complete chromosome set Aneuploidy: one or more individual chromosomes present at an extra copy (or missing)

Aneuploidies caused by non-disjunction: failure of homologous chromosomes to separate properly during meiosis.

Necessary times to determine Karyotypes:  Enable foetal diagnosis of chromosome abnormalities  Amniocentesis usually carried out during weeks 15 -20 of pregnancy  Only offered when combined test in 1st trimester indicates significant risk baby will develop serious condition or abnormality (risk of miscarriage 1%)

Amniocentesis: 1. Foetal cells isolated 2. Q-PCR – count number of chromosomes 13,18,21: 1 day 3. Grown in medium culture 4. Karyotype developed (after 2 weeks)

Majority of aneuploid conceptions attributed to non-disjunction during oogenesis

Locus: chromosomal location (position of a gene) Allele: different version of a gene

Monogenic disorders display Mendelian inheritance: 1. Autosomal recessive e. cystic fibrosis - CTFR on chromosome 7 (Cystic Fibrosis Transmembrane Conductance Regulator) - C is normal that encodes functional CTFR, c is a mutant allele lacking 508th codon - You must have ͞ĐĐ͟ to express cystic fibrosis - Normal CTFR pumps Cl - ions out of cells, leading to water exiting cell by osmosis (this maintains free flowing mucus layer) - With ͞ĐĐ͟, loss of Cl - gradient  thicker mucus  lung infections, blockage of ducts in pancreas and intestines (50% reach 40th birthday) Pedigree for Autosomal Recessive:  Trait is rare in pedigree  Skips generations  Affects males and females equally  Trait transmitted by either sex  Freq. high  1/3 Africa and 1/25 North Europe

Autosomal Dominant e. HuŶtiŶgtoŶ͛s Disease
- Neurodegenerative disease caused by mutation at HD locus
- HD Đreates HuŶtiŶgtoŶ͛s proteiŶ. Normal HD has 28 repeats of CAG (glutamine) codon
- Mutant HD has >36 repeats of CAG  aggregation of protein, cytotoxicity and neuronal cell death Pedigree for Autosomal Dominant:  Trait is frequent & transmitted by either sex  People in every generation are affected. Affects males and females equally.
X-Linked Recessive e. Haemophilia A
- Haemophilia A (mutation in gene for blood clotting factor VIII on X chromosome)
- Will occur most freq. in males
- Cannot be passed from father to son
- All daughters of affected fathers are carriers. Half sons of carrier will be affected, and half her daughters will be carriers.
- Anhidrotic Ectodermal Dysplasia – defective sweat glands  heterozygous females have random patches with and without sweat glands
- Red-Green colour blindness
X-Linked Dominant
- Dominant gene carried on X chromosome
- Less common than X-linked recessive
- When son is affected, mother is always affected
Mitochondrial
- Condition always passed on through female line – Matrilineal
- Due to many mitochondria being passed into egg from ovary, all offspring of woman would be expected to inherit condition
- Affected male does not pass mitochondria onto his children

Complex Disorders:  Most human characteristics are not Mendelian but are polygenic  Many traits are polygenic and influenced by environment (multifactorial) - Cardiovascular disease - Diabetes Mellitus - Obesity - Mental illness

How to assess contribution made by genetics vs environment:  Compare concordance between Monozygotic (identical) twins and Dizygotic twins (non- identical)  Epigenetics = study of changes in organisms caused by modification of gene expression rather than alteration of genetic code

Lecture 2: Molecular Basis of Inheritance

DNA is the genetic material + polymer of nucleotides each consisting of:  Deoxyribose has H at position 2 on sugar ring (ribose has OH)  Phosphate Group  Nitrogenous Base

4 Nitrogen containing bases (DNA):  Guanine and Adenine = purines (2C ring structure)  Cytosine and Thymine = pyrimidines (1C ring structure). In RNA T replaced by Uracil

DNA is a polynucleotide:  Phosphodiester bonds string nucleotides together  ϯ͛ OH of sugar and 5͛ monophosphate of nucleotide  DNA polymerase catalyses this  by product is inorganic pyrophosphate (PPi)  There is polarity to chain as free 5͛ phosphate end and ϯ͛ OH end

Genome specifies non-coding RNA (ncRNA) required for exon-splicing and de-coding mRNA: 1. Message Processing - Small nuclear mRNAs (snRNAs) upto 360 nucleotides in length. Form complexes with proteins to form small ribonucleoprotein particles (snRNPs)  splice pre-mRNAs. 2. De-coding mRNA 3. >3000 genes that specify for long ncRNAs  most of unknown function

>3000 miRNA (micro RNAs) that regulate expression of specific genes: 1. Transcription from miRNA gene, to give hairpin stem loop precursor miRNA

Cut by nuclease
Export into cytoplasm and processing by nuclease
This leaves single strand of RNA that base pairs with a coding mRNA

Mutations in miRNA cause disease: 1. miR-96 causes hereditary progressive hearing loss 2. miR-184 causes hereditary keratoconus and cataract

Mitochondrial Genome:  Contain their own circular genome (mtDNA, encodes 13 polypeptides plus tRNA and rRNA)  Highly compact genome, no introns & no repetitive DNA.  Mitochondria inherited exclusively from mother Human diseases caused by mutations in mtDNA. Organs most affected are those that use high amounts of ATP:  MELAS – Myopathy, Encephalopathy, Lactic Acidosis, Stroke-like Episodes  LHON – Leďer͛s hereditary optic neuropathy

You can have 3 parent IVF where faulty mitochondria removed from egg.

Lecture 3: Maintenance and use of Genetic Information –

Eukaryotic Cell Cycle: Si gnal committing cell to replicate DNA received in G1. If no signal received, cell enters G0.

DNA replication: 1. DNA unwinds to expose bases 2. Daughter strands of DNA synthesised, using parent strand as template (complementary base pairing) 3. Semi conservative replication – each new DNA molecule contains one parent and one daughter strand

Initiation of replication by proteins interacting with DNA sequences at ͚OrigiŶ of ‘epliĐatioŶ͛: 1. Base pairs of double helix must be broken (strand unwinds) 2. DNA polymerase now has access to the bases and can synthesise new strands using parental ones as templates. 3. Ϯ ͞repliĐatioŶ forks are formed.

Replication Fork:  DNA unwound by helicase (bases exposed)  Single strand binding proteins prevent immediate reformation of double helix  DNA polymerase synthesises new strands using old ones as templates  DNA polymerase only sLJŶthesises DNA iŶ 5 to ϯ͛ direĐtioŶ  Helix unwinds further so replication can continue

One strand is synthesised continuously (leading st rand). Other must be synthesised discontinuously (lagging strand)

Pulling strands apart increases their winding about each other further down the molecule, introducing supercoiling.  Helix would eventually snap  Topoisomerase breaks a phosphodiester bond of one parental strand ahead of replication fork, providing degree of freedom around which remainder can unwind.

Beginning Synthesis:  DNA Polymerase can only add nucleotides to pre-existing chains, it cannot initiate synthesis  RNA polymerase can initiate RNA synthesis, so DNA synthesis begins with synthesis of short RNA primer  RNA primer 8-10 nucleotides long is synthesised by primase (RNA polymerase)  DNA polymerase takes over, edžteŶdiŶg ϯ͛ eŶd of priŵer ( 5͛ eŶd of DNA )

Events that join up adjacent Okazaki fragments: 1. DNA polymerase extends DNA in the 5͛ to ϯ͛ direĐtioŶ uŶtil it reaches the next RNA primer 2. Primer degraded by exonuclease, leaving a gap 3. DNA polymerase continues synthesis across gap 4. 2 Okazaki fragments now next to each other  missing phosphodiester bond put in place by DNA ligase.

Formation of lagging strand loop co-ordinates leading and lagging strands, despite synthesis proceeding in different directions topologically. Enzyme Function Helicase Unwinds DNA strand Topoisomerase Releases supercoils in DNA Single Strand Binding Protein Stabilises single stranded DNA Primase Makes RNA primer so DNA synthesis can begin DNA Polymerase Synthesises DNA Exonuclease Removes RNA primer DNA ligase Links adjacent Okazaki fragments

i. Ionizing radiation – causes single/double bond breaks ii. UV light – thymine dimers. UVC (180-290) sterilising agent most lethal vs. UVB (290-320) – major mutagenic fraction of sunlight b. Chemical: i. Nitrous acid: cytosine to uracil ii. Alkylating agents: guanine modification iii. Free radicals: strand breaks and base modification

Most damage is repaired:  Direct repair: Dealkylation by enzymes e. 0 6 -methylguanine-DNA methyltransferase (MTase)  06 -methylguanine to guanine.  Removal of damaged region followed by re-synthesis e. Nucleotide Excision Repair (NER) o Region around damaged base removed by nuclease and helicase action and then whole area resynthesized

DNA synthesis has high fidelity: 1. Overall error rate 10-7 per bp  10 -10 including repair enzymes

Constant Cell Division is a Feature of Intestinal Epithelia:  Intestinal walls composed of villi  Epithelial cell populations are in constant flux  each minute 5 million cells die and are replaced in colon  intestinal carcinomas

Accessing information in DNA:  Genes transcribed by RNA polymerase which binds to promoter, regulated by transcription factors  Regions that have actively transcribed genes must be decondensed

Chromatin modification:

Gene expression is tightly regulated: 1) Tissue specific expression: All somatic cells contain same DNA but are very different due to different genes being expressed in different tissues 2) External signals lead to changes in gene expression profile: during exercise glucose levels need to be raised so Glucocorticoid hormones released. When hormone no longer present, production of enzymes drops back to normal levels 3) Regulation in time and space: during development, genes need to be switched on and off at the right time and in the right place.

Lecture 4: Molecular Basis of Gene Transcription –

Coding Properties of Nucleic Acids: 1. A messenger exists that transmits information from the nucleus (where transcription occurs) to the cytoplasm (where translation occurs) 2. The genetic code is read in triplets 3. The amino acid sequence is linearly related to the DNA sequence

Transcription: RNA synthesis:  RNA polymerase enzymes make RNA  They synthesise RNA in the 5-3' direction (so the template strand is read in the 3-5' direction)  The 2 strands of DNA need to be separated as a template is required for RNA polymerase to synthesise RNA

RNA Polymerase: o DNA is being unwound to read the template strand to copy the other strand o Ribonucleoside triphosphates enter through the uptake channel to be used as building blocks for the RNA being synthesised in the active site of the polymerase

Prokaryotic Transcription:  The promotor region is the gene switch -> can turn expression on or off  The start site of transcription is indicated by a + 1 (the first nucleotide to be transcribed)  The UTRs: o They're important in transporting the mRNA to different positions in the cell o 5' UTR have signals for initiation + 3' UTR have signals for termination translation

Initiation:  RNA polymerase directed to start of transcription on dsDNA  2 motifs serve as anchor regions: -10 box + -35 box  Signa factor binds to -10 site (Pribnow box) + RNA polymerase binds to helper protein o RNA polymerase is a complex made of 4 subunits (aaBB)  RNA then directed to +1 to start transcription  Sigma factor dissociates after transcription starts

Elongation: reading DNA sequence on template strand and mRNA synthesis  Occurs at 50nt per second  ALL DONE THROUGH RNA POLYMERASE o Can unwind the helix itself

Termination:  Stops when RNA polymerase reaches transcriptional translation site o On mRNA there is a stretch of G followed by C  forms hairpin loop o G-C rich stem loop recognised by RNA polymerase and it falls off (stop signal)

Eukaryotic Transcription: 1. Splicing – occurs to remove introns a. Some heteronuclear RNAs (primary RNA transcripts) can be spliced in different ways  different protein product from single gene

AŵiŶo aĐids attaĐh to ϯ͛ eŶd of t‘NA: a. Aminoacyl-tRNA-synthetases load tRNA molecules with amino acids (specific synthetase for each AA) b. Energy for addition of AA and tRNA molecules comes from ATP hydrolysis to AMP c. Synthetase checks whether tRNA molecule is appropriate for AA being loaded d. Correct tRNA anticodon binding to mRNA codon ensures correct AA being inserted

The Ribosome: E-Coli (70s):  A site = accepting  P site = polymerisation  E site = exit  Small subunit is where contact made between mRNA and tRNA

Prokaryotic Translation: 1. Initiation o The initiation complex is formed, which consists of ribosome, mRNA and initiator tRNA (formylmethionine- tRNAfmet) o Initiation Factor proteins (IF1, IF2 & IF3) required o IF2 is activated by binding to the nucleotide GTP 2. Elongation o Activated amino acid binds to elongation factor (EF-Tu-GTP) o Then it enters the A site of the ribosome o Energy for proofreading is provided by hydrolysis of GTP to GDP o Peptide bonds form between amino acids in P and A site (no additional energy is needed for this) o EF-G-GTP binds and ribosome translocates (GTP hydrolysis) so that the A site is free again 3. Termination o Stop codon of mRNA is presented to the A site o Release factor (RF1 or RF2) binds o Hydrolysis of protein from tRNA occurs o Ribosome complex is disassembled o This requires IF3, Ribosomal recycling factor and GTP hydrolysis

Prokaryotic vs Eukaryotic Transcription/Translation:  Bacterial mRNA is polycistronic -> multiple proteins encoded by the same mRNA molecule  Eukaryotic mRNA is monocistronic -> only one protein is encoded

Prokaryotes Eukaryotes

mRNA is unmodified and translated as soon as its synthesised (or while being synthesised)

hnRNA is modified by capping, polyadenylation and splicing before being exported from the nucleus for translation

30S + 50S = 70S ribosome 40S + 60S = 80S ribosome

Shine-Dalgarno sequence binds with 16S RNA in 30S subunit for mRNA binding to ribosome

Interaction between 5' cap of mRNA and ribosome -> how the start codon (AUG) is found is unclear

Initiator tRNA is fmet-tRNAfmet Initiator tRNA is met-tRNAmet

Polycistronic mRNA code for more than one protein Monocistronic mRNA codes for one protein

Polyribosomes (cluster of ribosomes held together by mRNA during translation) are free in cytoplasm

Polyribosomes are free in cytoplasm OR can be bound to RER

Antibiotic - prokaryotic How it works Actinomycin (transcription inhib)

Binds to DNA at the transcription initiation complex and preventing elongation by RNA polymerase Rifamycin (transcription inhib)

Inhibits DNA-dependent RNA synthesis by binding to prokaryotic RNA polymerase

Streptomycin (translation inhib)

Affects translation initiation (30S subunit can't bind to mRNA) and causes the misreading of codons (don't start at correct place) Erythromycin (translation inhib)

Binds to 50S subunit and prevents translocation

Chloramphenicol (translation inhib)

Inhibits peptidyl transferase by binding on 50S subunit (ribosome can't carry out elongation of the peptide chain) Tetracyclines (translation inhib)

Inhibit binding of aminoacyl-tRNAs to the ribosome

Antibiotic - eukaryotic How it works Puromycin Causes premature chain termination during translation. Mimics tRNA (can affect both pro and eu) a-aminitin Inhibitor of eukaryotic RNA Polymerase II – deadly toxin Cycloheximide Interferes with translocation step during elongation – inhibits protein synthesis Diphtheria toxin Inhibits RNA translation by inactivating eukaryotic elongation-factor 2

Why prokaryotic antibiotics that interfere with mitochondrial protein synthesis can be used therapeutically without harming eukaryotic host:  Few drugs cross inner mitochondrial membrane  Mitochondria have low rate of transcription (slow rate of division and replacement)

Lecture 6: Manipulation of DNA, use in Therapy and Diagnosis –

Recombinant DNA technology:  Allows isolation and manipulation of DNA  Isolates sections of DNA and then creates multiple copies of these sections of DNA o ^^ - gene cloning

DNA Cloning:  Method required to isolate pieces of DNA – restriction enzymes/PCR  Method needed to copy pieces of DNA o E. insertion of isolated DNA into bacterial plasmids so they can be replicated  Done to amplify amount of DNA for manipulation

Restriction Enzymes: molecular scissors that cut DNA  Recognise specific nucleotide sequences in the DNA, bind to DNA at this point and cut both strands of sugar-phosphate backbone  Sequence forms palindrome – cut to leave sticky ends  To identify location of genes to aid their study, you need to generate maps of DNA clones o After, restriction enzymes used to cut out genomic sections to amplify

Agarose Gel Electrophoresis:  DNA visualised by adding ethidium bromide (binds DNA and fluoresces when exposed to UV) o Separate according to size: smaller fragments migrate quicker (larger = slower)

PCR uses: key diagnostic method for detection of bacteria and viruses in humans

DNA Microarrays:  (Gene chips) – use nucleic acid hybridisation to rapidly measure which genes are expressed in a tissue sample o Hybridisation occurs when complementary DNA strands anneal to each other  These can be used to compare gene expression in 2 samples (normal vs diseased cells)  Therefore they can be used to compare gene expression in cancer o GeŶes ǁho͛s edžpressioŶ leǀels ĐhaŶge ĐaŶ ďe ideŶtified  likely to be causative for cancer o Identification of specific changes allow personalised therapeutic approaches

Lecture 7: Introduction to Genetic Variation –

DNA Polymorphisms – neutral variations in DNA sequence in population

Types of Genetic Variation: 1. Single Nucleotide Polymorphisms a. Single base of DNA can exist in 2 forms b. Most common type of variation in genome 2. Repeat Polymorphisms a. ATTC carried by most people but some have 2 copies b. Different number of repeats 3. Structural variation a. Big chunks of chromosome (1000s of bps) inserted or deleted

SNPs:  Single base substitutions – most abundant type of polymorphism in human genome  Generally have 2 alleles  1/300 nucleotides on average

Haplotypes = series of SNP alleles along single chromosome Genotype = 2 alleles present at an SNP in an individual (looking at 2 chromosomes) Alleles = single copy, allele ATGC

Tandem Repeat Polymorphisms: when non-coding DNA is repetitive  Microsatellite markers are common short tandem repeats that are polymorphic (2 - nucleotides per unit)  ALS/MND: o Hexanucleotide repeat on chromosome 9 in the gene C9orf72 – GGGGCC o Most people carry 30 repeats but >100 repeats can increase risk

Structural Variation:  Segment of DNA can be absent in some chromosomes OR present in in multiple tandem copies = CNV (copy number variant) OR CNP (copy number polymorphism)  Some CNVs are benign and have no impact on health but others can increase risk of disease

Hardy-Weinberg Equilibrium: 1. Random mating 2. Random transmission 3. Random survival (survival doesn't depend on genotypes at this locus)

Heritability = proportion of phenotypic variation due to genetic differences between individuals

Lecture 8: Genetic Basis of Disease –

 Gene = distinct sequence of nucleotides forming part of chromosome, representing unit of genetic information  GeŶoŵe = aŶ orgaŶisŵ͛s Đoŵplete set of DNA  Allele = 2+ alternative forms of gene that arise by variation  Indel = insertion or deletion polymorphism in which series of nucleotides added/deleted

Common vs Rare Variant:  Common variant = genetic variant w/ minor allele frequency (MAF) > 1% in population aka SNPs  Rare variant = genetic variant w/ MAF < 1% in population aka (when pathogenic) mutations o MAF = frequency at which second most common allele occurs in given population

Genetic Diseases: 1. Mendelian Diseases = disorders caused by abnormality or mutation in the sequence of one gene 2. Complex (multifactorial) disease = disorders caused by combination of envt factors and mutations 3. Chromosomal diseases = disorders caused by abnormalities in chromosome structure 4. Mitochondrial diseases = disorders caused by mutations in non-chromosomal DNA of mitochondria Mendelian diseases Complex (multifactorial) diseases Monogenic Polygenic **‘are ** Common High penetrance (the extent to which a gene is expressed in the phenotype)

Variable penetrance

Autosomal dominant ,Autosomal recessive ,X-linked Variable and unclear modes of inheritance Minimal to mild environmental influence Gene-environment interactions Often involve gross perturbations in gene/protein function

Minor common variations Regulatory and modifying changes

Penetrance = proportion of individuals carrying particular variant (or allele) of a gene (genotype) that expresses an associated trait (phenotype)

Cystic Fibrosis: abnormal build up of mucus in lungs  breathing problems  Can lead to malnutrition, diabetes, osteoporosis, liver problems  CF has autosomal recessive inheritance pattern  Most common mutation = ΔF5ϬΘ o Deletion of 3 nucleotides  loss of AA (Phe) at 508th position

HuŶtiŶgtoŶ͛s Disease: progressiǀe ŶeurodegeŶeratiǀe disorder 5/100k people  Symptoms include o Chorea (rapid complex body movements that look purposeful but are involuntary) o Dystonia (neurological muscle disorder that results in muscle contraction that cause twisting and repetitive movements)  Mutation: CAG triplet repeat expansion  Autosomal dominant inheritance

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Cellular Genetics and the Cell Cycle

Module: Foundations of Biomedical Science 1

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University: King's College London

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1 | P a g e

Cellular Genetics and the Cell Cycle

Lecture 1: Basics of Genetic Inheritance –

Inherited traits controlled by genes on chromosomes:

1. Monogenic disorders – Cystic fibrosis, SCA, Huntington’s

2. Polygenic disorders – Type II diabetes, Rheumatoid Arthritis, Schizophrenia

Genotype can determine whether gene resistance will occur:

 People who don’t have CCR5 Chemokine receptor are resistant to HIV-1

Genotype controls drug response in individuals:

 Form of cytochrome P450 (CYP2D6) control metabolism of 25% of drugs.

 It converts codeine to active form (morphine)

 Codeine is ineffective for individuals who are poor metabolisers

A person’s genotype can determine which drugs are prescribed:

 Herceptin:

- 30% breast cancers feature overexpression of HER2 (human epidermal growth factor

receptor)

- Herceptin blocks Her2 activity (this means Herceptin is only effective against HER+

tumours, but not against tumours that don’t overexpress HER2)

Genes are discrete units of inheritance, distributed across chromosomes; composed of DNA

wound around beads of protein (histones). DNA + histones = chromatin

1. 1.8m DNA in every nucleus; histones allow packaging into nucleus about 5 micrometres in

diameter.

2. Result: each DNA molecule has been packaged into a mitotic chromosome that is 10,000 x

shorter than extended length

Info in genes must be accessible:

 30nm fibre arranged as loops

 Regions of DNA can be unwound from nucleosomes (DNA coiled around histones)

 Groups of genes can be expressed without disassembly of entire chromosome

Human Karyotype:

1. 46 chromosomes – 22 pairs of autosomes (any chromosome that is not sex chromosome) +

1 pair sex chromosome

2. Assessed by staining chromosomes from metaphase spreads  as chromosomes are short,

fat and visible in this state

3. G-banding (stained w/ Giesma)  unique alternating and dark bands for each pair

Cytogenetics: study of genetic component of cell through viualisation and analysis of

chromosomes

Human Chromosomes characterised by:

1. Size

2. Pattern of G bands

3. Location of centromere (region of

chromosome where microtubules of

spindle attach)