Lecture 10 - DNA, replication and mutation.pdf

Genetics in human Coley Tosto [email protected] health and disease (adapted from Dr. Amy Osborne) Why is it important to understand genetics? How are we different? Our genomes are different from e.g. monkeys and cucumbers The human genome is 3 billion base pai...

Genetics in human Coley Tosto [email protected] health and disease (adapted from Dr. Amy Osborne) Why is it important to understand genetics? How are we different? Our genomes are different from e.g. monkeys and cucumbers The human genome is 3 billion base pairs. The differences between our genomes are why we’re different to each other Genes control our phenotypes – genes can vary! This can create disease. We can use genes to predict disease risk. But this depends on variation. So where does variation come from? Why is it important to understand genetics? How are we different? Our genomes are different from e.g. monkeys and cucumbers The human genome is 3 billion base pairs. The differences between our genomes are why we’re different to each other Genes control our phenotypes – genes can vary! This can create disease. We can use genes to predict disease risk. But this depends on variation. So where does variation come from? Why is it important to understand genetics? How are we different? Our genomes are different from e.g. monkeys and cucumbers The human genome is 3 billion base pairs. The differences between our genomes are why we’re different to each other Genes control our phenotypes – genes can vary! This can create disease. We can use genes to predict disease risk. But this depends on variation. So where does variation come from? Your next 3 lectures  Monday 1pm DNA and the basics of replication (14.3)  Wednesday 12pm Meiosis (11.1, 11.2), chromosomal basis of inherited disorders (13.2)  Thursday 10am Inheritance, characters and traits (12.1, 12.2, 12.3) Textbook (online, open access)  https://openstax.org/details/books/biology-2e Learning objectives – DNA and the basis of replication  Describe the structure of DNA (14.2)  Describe the genetic code and how the nucleotide sequence prescribes the amino acid and the protein sequence (15.1)  Discuss the different types of mutation in DNA (14.6)  Explain DNA repair mechanisms (14.6) The building blocks of DNA are... Nucleotides Nucleotides are made up of: Nitrogenous base Pentose sugar Phosphate group Purines – adenine and guanine Pyrimidines – cytosine and thymine DNA is a double helix of nucleotides Two strands that twist around each other. The sugar and phosphate of the nucleotides form the backbone (sides) of the ‘ladder’ The ‘rungs’ are paired bases: A pairs with T C pairs with G Hydrogen bonds hold the strands together DNA is a double helix of nucleotides Two strands that twist around each other. The sugar and phosphate of the nucleotides form the backbone (sides) of the ‘ladder’ The ‘rungs’ are paired bases: A pairs with T C pairs with G Hydrogen bonds hold the strands together DNA is a double helix of nucleotides Two strands that twist around each other. The sugar and phosphate of the nucleotides form the backbone (sides) of the ‘ladder’ The ‘rungs’ are paired bases: A pairs with T C pairs with G Hydrogen bonds hold the strands Hydrogen bonds together Genes make proteins  DNA is the blueprint for proteins  Proteins have crucial functions in our bodies – we could not live without them.  Some functions of proteins – enzymes, hormones, nutrient transport, antibodies, energy. Central dogma recap Our genes are encoded by bases DNA transcribed into messenger RNA, which is translated into an amino acid sequence that makes a protein. Genetic variation is responsible for disease, so genetics helps us understand the origins of disease. Central dogma recap Our genes are encoded by bases DNA transcribed into messenger RNA, which is translated into an amino acid sequence that makes a protein. Genetic variation is responsible for disease, so genetics helps us understand the origins of disease. The genetic code is degenerate and universal Three bases = codon 64 possible codons, but only 20 amino acids! ‘Reading frames’ are important for the ‘sense’ of the message and the composition of the protein Insertions of 1 or 2 nucleotides disrupts the protein code. The genetic code is degenerate and universal Three bases = codon 64 possible codons, but only 20 amino acids! ‘Reading frames’ are important for the ‘sense’ of the message and the composition of the protein Insertions of 1 or 2 nucleotides disrupts the protein code. The genetic code is degenerate and universal Three bases = codon 64 possible codons, but only 20 amino acids! ‘Reading frames’ are important for the ‘sense’ of the message and the composition of the protein Insertions of 1 or 2 nucleotides disrupts the protein code. Time out DNA Replication DNA needs to be accessible to replicate. It is unwound from its histone proteins ‘Initiator proteins’ bind to DNA to signal helicase to unzip the DNA strand DNA primase binds and creates primers for DNA polymerase to attach to – now synthesis can start! DNA is replicated 5’ to 3’ (leading and lagging strands). DNA Replication DNA needs to be accessible to replicate. It is unwound from its histone proteins ‘Initiator proteins’ bind to DNA to signal helicase to unzip the DNA strand DNA primase binds and creates primers for DNA polymerase to attach to – now synthesis can start! DNA is replicated 5’ to 3’ (leading and lagging strands). DNA Replication DNA needs to be accessible to replicate. It is unwound from its histone proteins ‘Initiator proteins’ bind to DNA to signal helicase to unzip the DNA strand DNA primase binds and creates primers for DNA polymerase to attach to – now synthesis can start! DNA is replicated 5’ to 3’ (leading and lagging strands). Replication fork DNA Replication DNA needs to be accessible to replicate. It is unwound from its histone proteins ‘Initiator proteins’ bind to DNA to signal helicase to unzip the DNA strand DNA primase binds and creates primers for DNA polymerase to attach to – now synthesis can start! DNA is replicated 5’ to 3’ (leading and lagging strands). Replication fork DNA Replication DNA needs to be accessible to replicate. It is unwound from its histone proteins ‘Initiator proteins’ bind to DNA to signal helicase to unzip the DNA strand DNA primase binds and creates primers for DNA polymerase to attach to – now synthesis can start! DNA is replicated 5’ to 3’ (leading and lagging strands). DNA repair - proofreading A wrong base can be incorporated This is a mutation DNA polymerase can repair mistakes DNA pol can cut phosphodiester bonds and release the wrong nucleotide (3’ endonuclease action) Replaced with the correct one The gap is sealed with DNA ligase DNA repair - proofreading A wrong base can be incorporated This is a mutation DNA polymerase can repair mistakes DNA pol can cut phosphodiester bonds and release the wrong nucleotide (3’ endonuclease action) Replaced with the correct one The gap is sealed with DNA ligase DNA repair - proofreading A wrong base can be incorporated This is a mutation DNA polymerase can repair mistakes DNA pol can cut phosphodiester bonds and release the wrong nucleotide (3’ endonuclease action) Replaced with the correct one The gap is sealed with DNA ligase Not only synthesises your DNA strands! It can recognise when the wrong base is incorporated and correct it! DNA repair – nucleotide excision repair Removes damaged bases Nuclease (repair enzymes) cut the DNA strand DNA pol repairs the gap Ligase re-seals the DNA strand This is how bases damaged by UV are repaired. DNA repair – nucleotide excision repair Removes damaged bases Nuclease (repair enzymes) cut the DNA strand DNA pol repairs the gap Ligase re-seals the DNA strand This is how bases damaged by UV are repaired. DNA repair – nucleotide excision repair Removes damaged bases Pyrimidine dimer Nuclease (repair enzymes) cut the DNA strand DNA pol repairs the gap Ligase re-seals the DNA strand This is how bases damaged by UV are repaired. Xeroderma pigmentosa – a DNA repair disorder Skin highly sensitive to UV rays – pyrimidine dimers form easily This is because sufferers lack the repair mechanisms to fix the damage DNA double helix is distorted, DNA replication is impaired May lead to an increased risk of skin cancer Time out Other sources and types of mutations Mutations can come from damage to DNA This has various sources (external, internal) Can be induced by the environment Or can be spontaneous Induced Spontaneous Other sources and types of mutations Mutations can come from damage to DNA UV light Error in DNA repair This has various sources (external, Error in internal) Radiation replication Can be induced by the environment Chemicals Error in transcription Or can be spontaneous Induced Spontaneous Other sources and types of mutations Other sources and types of mutations Point mutations affect a single base pair Can be silent, missense or nonsense Some can be repetitive Some can add (insertion) or remove (deletion) a base Some can move (translocate) DNA from one chromosome to another Other sources and types of mutations Point mutations affect a single base pair Can be silent, missense or nonsense Some can be repetitive Some can add (insertion) or remove (deletion) a base Some can move (translocate) DNA from one chromosome to another Other sources and types of mutations Point mutations affect a single base pair Can be silent, missense or nonsense Some can be repetitive Some can add (insertion) or remove (deletion) a base Some can move (translocate) DNA from one chromosome to another Other sources and types of mutations Point mutations affect a single base pair Can be silent, missense or nonsense Some can be repetitive Some can add (insertion) or remove (deletion) a base Some can move (translocate) DNA from one chromosome to another Other sources and types of mutations Point mutations affect a single base pair Can be silent, missense or nonsense Some can be repetitive Some can add (insertion) or remove (deletion) a base Some can move (translocate) DNA from one chromosome to another Other sources and types of mutations Point mutations affect a single base pair Can be silent, missense or nonsense Some can be repetitive Some can add (insertion) or remove (deletion) a base Some can move (translocate) DNA from one chromosome to another Mutations in DNA repair genes Mutations in repair genes Pancreatic, colon and colorectal cancer Can affect germ cells or somatic cells (spontaneous or hereditary) BRCA1/2 are DNA repair genes Repair breaks caused by radiation, environmental exposures, and through errors in cell division BRCA1/2 maintain genome stability Mutations in DNA repair genes Mutations in repair genes Pancreatic, colon and colorectal cancer Can affect germ cells or somatic cells (spontaneous or hereditary) BRCA1/2 are DNA repair genes Repair breaks caused by radiation, environmental exposures, and through errors in cell division BRCA1/2 maintain genome stability Mutations in DNA repair genes Mutations in repair genes Pancreatic, colon and colorectal cancer Can affect germ cells or somatic cells (spontaneous or hereditary) BRCA1/2 are DNA repair genes Repair breaks caused by radiation, environmental exposures, and through errors in cell division BRCA1/2 maintain genome stability Mutations in DNA repair genes Mutations in repair genes Pancreatic, colon and colorectal cancer Can affect germ cells or somatic cells (spontaneous or hereditary) BRCA1/2 are DNA repair genes Repair breaks caused by radiation, environmental exposures, and through errors in cell division BRCA1/2 maintain genome stability Next time…. Meiosis and chromosomal disease