BMOL10030 - Section 5 & 6 (T. McMorrow & N. O’Sullivan Lectures) - Cancer Biology & Genetics

What is molecular genetics?

Molecular genetics is the field of biology that studies genes and their functions at the molecular level, focusing on the molecules of inheritance and the mechanisms behind inheritance patterns.

Why is molecular genetics important in biomedical science?

It underpins many biomedical fields, including cell biology, developmental biology, medicine, neuroscience, and pharmacology, explaining how gene changes can affect disease, diagnosis, treatment, and drug responses.

What is the difference between classical genetics and molecular genetics?

Classical genetics focuses on observable traits and inheritance, while molecular genetics focuses on DNA, genes, and the molecular mechanisms behind inheritance patterns.

What is DNA?

DNA is the genetic material that contains the instructions needed to build proteins, with human cells containing around 6 billion nucleotides of genomic DNA.

What is a protein-coding gene?

A protein-coding gene is a DNA sequence that contains the instructions to make a protein, which carries out many cellular processes required for life.

What is the central dogma?

The central dogma states that DNA replicates itself, is transcribed into RNA, and RNA is translated into protein, explaining how genetic information produces proteins.

Where does transcription occur?

Transcription occurs in the nucleus, where DNA is copied into messenger RNA.

Where does translation occur?

Translation occurs at ribosomes in the cytoplasm, where mRNA is used to build a protein from amino acids.

What is a codon?

A codon is a group of three bases in mRNA that specifies a particular amino acid, determining the amino acid sequence of the protein.

How does DNA sequence affect protein sequence?

The DNA sequence determines the mRNA sequence, which in turn determines the order of amino acids in a protein; changes in DNA can alter the protein produced.

What is a synonymous mutation?

A synonymous mutation is a DNA change that does not alter the amino acid sequence of the protein, also known as a silent mutation.

What is a non-synonymous mutation?

A non-synonymous mutation changes the amino acid sequence of the protein, potentially altering its shape, function, localization, or expression.

What is a nonsense mutation?

A nonsense mutation changes an amino acid codon into a stop codon, producing a shortened, usually non-functional protein.

What is a missense mutation?

A missense mutation changes one amino acid into a different amino acid, which can affect protein folding, shape, or function.

What are insertions and deletions?

Insertions add extra DNA bases, while deletions remove DNA bases; if they alter the reading frame, they can cause frameshift mutations.

What is a frameshift mutation?

A frameshift mutation changes the reading frame of the genetic code, altering every amino acid after the mutation and often producing a non-functional protein.

How can a single amino acid change cause disease?

A single amino acid change can alter protein shape and disrupt function, as seen in the GABAA receptor R43Q mutation associated with childhood febrile seizures.

What is a genotype?

A genotype is the genetic variant or DNA sequence an individual carries, influencing traits, disease risk, and drug response.

What is a phenotype?

A phenotype is the observable characteristic or disease presentation produced by a genotype and environmental influences.

What is a monogenic disease?

A monogenic disease is caused mainly by a mutation in a single gene, often easier to identify genetically than polygenic disorders.

What is a polygenic disease?

A polygenic disease is influenced by multiple gene variants and environmental factors, making these conditions harder to understand and model.

Why is identifying disease-causing variants difficult?

Humans share most of their DNA but have millions of genetic differences, making it challenging to identify which variants are linked to a disease phenotype.

What is linkage analysis used for?

Linkage analysis is used to identify DNA variations causing monogenic disorders by tracking inheritance of genetic markers through families.

What are GWAS used for?

Genome-wide association studies identify associations between DNA variants and polygenic traits or diseases by comparing genetic variation between affected and unaffected groups.

What is genetic regulation?

Genetic regulation controls when, where, and how strongly genes are expressed, allowing different cells to use the same genome in different ways.

What are promoters, enhancers, and repressors?

Promoters, enhancers, and repressors are regulatory non-coding DNA sequences that help control gene expression by influencing transcription.

What are transcription factors?

Transcription factors are proteins that bind DNA and regulate gene transcription, helping to switch genes on or off.

What are epigenetic signals?

Epigenetic signals are chemical or molecular changes that regulate gene expression without changing the DNA sequence, including DNA methylation and histone modification.

What is PCR?

PCR, or polymerase chain reaction, is a technique used to amplify DNA, with the product visualized on a gel.

What is DNA sequencing?

DNA sequencing determines the order of bases in DNA, with Sanger sequencing using modified PCR with labelled nucleotides.

What is gene expression analysis?

Gene expression analysis measures how much a gene is being expressed, with quantitative PCR measuring mRNA levels using fluorescence.

What is CRISPR-Cas9 gene editing?

CRISPR-Cas9 uses a guide RNA to direct the Cas9 enzyme to a specific DNA sequence, cutting the DNA for precise edits or gene knockouts.

What is a model organism?

A model organism is a non-human species used in the lab to investigate biological processes relevant to humans.

Why can model organisms teach us about human disease?

Many genes and biological processes are shared across species, revealing mechanisms relevant to humans.

Why is human disease research difficult?

Gene function is not fully understood, human populations are diverse, and human experimentation can be unethical or impossible.

What features make a good model organism?

Good model organisms have a short life cycle, many offspring, genetic tractability, and relevance to human disease mechanisms.

What does genetic tractability mean?

Genetic tractability means the organism's genome is known and can be manipulated for studying gene function.

Why are bacteria useful model organisms?

Bacteria are simple, fast-growing, and genetically tractable, useful for studying basic cellular processes.

Why is yeast useful as a model organism?

Yeast is simple, fast-growing, and eukaryotic, useful for studying cellular processes such as organelle organization.

What are limitations of bacteria and yeast models?

They lack the complexity of multicellular organisms and may not model tissue interactions or mammalian physiology well.

Why are worms, flies, and zebrafish useful models?

They are whole organisms with multiple tissues, short life cycles, and well-understood genetics, useful for studying development and behavior.

What is Caenorhabditis elegans?

Caenorhabditis elegans is a worm model organism useful for studying cell development and body patterning.

What is Drosophila melanogaster?

Drosophila melanogaster is the fruit fly, widely used to study genetics, development, behavior, and neurodegenerative disease.

What is Danio rerio?

Danio rerio is the zebrafish, useful for studying development and disease due to its well-understood genetics and accessible embryos.

Why are mice useful model organisms?

Mice are genetically similar to humans and have well-established disease models, often used to study various diseases.

What are limitations of mouse models?

Mouse models are more expensive, have longer lifespans than smaller organisms, raise ethical concerns, and their physiology is not identical to humans.

Why is choosing the right model organism important?

Different model organisms are suited to different questions, depending on the biological process, disease mechanism, and level of complexity being studied.

How did zebrafish help identify a human pigmentation gene?

Researchers studied golden zebrafish with lighter pigmentation and identified a mutation in the slc24a5 gene.

What is SLC24A5?

SLC24A5 is a human gene similar to the zebrafish slc24a5 gene, expressed in melanin-producing cells, contributing to differences in skin pigmentation.

What did the golden zebrafish model show?

It showed that mutation of slc24a5 reduces pigmentation, which translates to humans where SLC24A5 variation contributes to pigmentation differences.

How does the GABAA R43Q mutation affect neurons?

The R43Q mutation changes the shape of the GABAA receptor and reduces chloride ion flow into neurons, altering neuronal excitability.

Why were R43Q mice generated?

R43Q mice were generated to model the human GABAA mutation linked to epilepsy, allowing researchers to study disease mechanisms and test therapies.

What features do R43Q mice display?

R43Q mice show altered brainwave activity from around 22 days of age, seizure activity with increased body temperature, and reduced inhibitory current.

What does the R43Q mouse model suggest about epilepsy?

It suggests that reduced neuronal inhibition contributes to childhood epilepsy in patients with the GABAA R43Q mutation.

What is Warburg Micro Syndrome?

Warburg Micro Syndrome is a rare autosomal recessive genetic disorder causing neurological defects such as optical abnormalities, microcephaly, and progressive spasticity.

What genes are linked to Warburg Micro Syndrome?

Mutations in genes encoding proteins in the RAB18 pathway, including RAB18, Rab3GAP1, Rab3GAP2, and TBC1D20, can cause Warburg Micro Syndrome.

Why was a fly model made for Warburg Micro Syndrome?

A fly model was made because flies contain all Rab18 cycle genes and can be genetically manipulated to study neuronal defects.

How was the Rab3GAP1 fly model generated?

CRISPR-Cas9 was used to mutate the Rab3GAP1 gene in flies, producing germline mutations.

What happened in Rab3GAP1 knockout flies?

Rab3GAP1 knockout flies had a 5 base-pair deletion disrupting protein production, showing progressive locomotor defects.

Why are model organisms useful for rare diseases?

Model organisms allow researchers to study affected cells and tissues in ways not possible in human patients and test genetic or drug treatments.

What is precision medicine?

Precision medicine customizes healthcare based on an individual's genetic profile, lifestyle, and environment.

How does precision medicine differ from traditional medicine?

Traditional medicine often uses a one-size-fits-all approach, while precision medicine tailors treatment to the individual.

Why can patients respond differently to the same drug?

Patients can differ in genetics, lifestyle, and environment, affecting drug efficacy and toxicity.

What is pharmacokinetics?

Pharmacokinetics refers to what the body does to the drug, including absorption, distribution, metabolism, and elimination.

What is pharmacodynamics?

Pharmacodynamics refers to what the drug does to the body, including its effects on cells, tissues, and clinical outcomes.

How can genetic variation affect drug response?

Genetic variation can alter drug processing or target response, affecting efficacy and toxicity.

What technologies enable precision medicine?

Technologies include DNA sequencing, genomic databases, precise animal models, pharmacogenomic analysis, bioinformatics, and big data analysis.

How does DNA sequencing support precision medicine?

DNA sequencing identifies genetic variants in patients that can be linked to disease risk or drug response.

What are genomic databases?

Genomic databases store genetic information from large populations, such as the 1000 Genomes Project and UK Biobank.

How do genomic databases help researchers?

They allow correlation of genetic variants with disease traits and treatment responses.

How do animal models support precision medicine?

Animal models help study disease mechanisms and test therapies targeted to specific mutations.

What is pharmacogenomic analysis?

Pharmacogenomic analysis studies how genetic variation affects drug response, identifying which patients may benefit from treatment.

What is the role of GWAS in precision medicine?

GWAS identifies DNA variants that co-occur with drug response, guiding genotype-based treatment decisions.

How does bioinformatics support precision medicine?

Bioinformatics analyzes large biological datasets to find patterns, improving diagnosis and personalized treatment planning.

Why is cystic fibrosis an example of precision medicine?

Cystic fibrosis is caused by mutations in the CFTR gene, with different mutations affecting CFTR protein function.

What gene causes cystic fibrosis?

Cystic fibrosis is caused by mutations in the CFTR gene, which regulates chloride ion transport.

How many CFTR mutations are known?

There are over 2,000 known mutations in the CFTR gene.

What are traditional cystic fibrosis treatments?

Traditional treatments manage symptoms like respiratory infections and include antibiotics, mucolytics, and enzyme replacement therapy.

What are CFTR correctors?

CFTR correctors improve delivery of CFTR protein to the cell surface for mutations affecting trafficking.

What are CFTR potentiators?

CFTR potentiators increase opening of the chloride channel at the cell surface for mutations that reach the membrane.

What is Orkambi?

Orkambi is a precision treatment for cystic fibrosis patients with the F508del CFTR mutation.

Why is warfarin an example of precision medicine?

Warfarin dose requirements vary widely; genetic differences can guide safer starting doses.

What is warfarin used for?

Warfarin is an anticoagulant used to reduce the risk of thromboembolic events.

How does warfarin work?

Warfarin limits vitamin K availability, reducing blood clotting.

Why is warfarin dosing difficult?

There is large variation in the dose needed to reach the therapeutic range.

What is the traditional approach to warfarin dosing?

Traditional treatment starts with a low dose and titrates upward until the therapeutic level is reached.

What is VKORC1?

VKORC1 is vitamin K reductase, the drug target of warfarin.

How is warfarin metabolised?

Warfarin is metabolized in the liver by cytochrome P450 enzymes.

How can genotype-guided warfarin treatment improve outcomes?

Starting dose based on genotype can increase time in the therapeutic range and reduce excessive anticoagulation.

What is warfarin?

Warfarin is a medication that is catabolised in the liver by cytochrome P450 enzymes.

What is the overall goal of precision medicine?

The goal is to tailor treatment using genetic and biological information for more effective, safer, and personalised care.

What is cancer?

Cancer is a group of diseases in which cells divide abnormally without control and can invade other tissues.

What is oncology?

Oncology is the branch of medicine that studies cancerous diseases and provides cancer treatment.

Why are more people getting cancer?

Cancer risk increases with age, and people are living longer, reaching ages where cancer is more common.

How are most cancers named?

Most cancers are named after the organ or cell type in which they start.

What is a carcinoma?

A carcinoma is a cancer of the skin or tissues that line or cover internal organs.

What is a sarcoma?

A sarcoma is a cancer of bone, cartilage, fat, muscle, blood vessels, or other connective or supportive tissue.

What is leukaemia?

Leukaemia is a cancer of blood-forming tissue such as bone marrow.

What are lymphoma and myeloma?

Lymphoma and myeloma are cancers of immune system cells.

What are central nervous system cancers?

Central nervous system cancers are cancers of tissues in the brain and spinal cord.