Notes in 3- Mutations and Genetics

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Published	02/10/2024	{{c1::Phenotype}} = Outward, physical manifestation of organism {{c1::Genotype}} = Full hereditary information of organism (even if not expre…
Published	02/10/2024	Proteins are all functionally different because of their structure Protein structure depends on {{c1::primary structure}} and therefore on specifi…
Published	02/10/2024	DNA is a chain of {{c1::nucleotide monomers}}Each nucleotide contains: {{c2::Sugar}} {{c2::Base}} {{c2::Phosphate group}}
Published	02/10/2024	DNA has a {{c1::double helix}} structure with base pairs and a sugar phosphate backbone.The polynucleotide chains run {{c1::anti-parallel}} to one ano…
Published	02/10/2024	Base-pairing is this way because of:- {{c1::Hydrogen bonding}} between pairs- {{c1::DNA polymerase}} and its function
Published	02/10/2024	{{c1::Nucleus}} is the largest organelle in the cell. Contains most of the cell’s genetic material (DNA) DNA Replication and the first steps in dec…
Published	02/10/2024	Each nucleus ~ 5 - 10 μm in diameter {{c1::Nucleolus}} can take up to 25% of its volume (Site of transcription and assembly of rRNA) 2 m DNA…
Published	02/10/2024	In the nucleus the DNA molecule is packaged into thread-like structures called {{c1::chromosomes}}. They are a single piece of DNA containing many…
Published	02/10/2024	Double helix to ChromosomeExplain the packaging and condensation!
Published	02/10/2024	{{c1::Chromatin}} is the name given to the mixture of DNA, proteins and RNA that package DNA within the nucleus. It is divided between {{c2::heter…
Published	02/10/2024	Chromatin is divided between: {{c2::Heterochromatin}} → (darker & condensed & transcriptionally inactive) {{c2::Euchromatin}}&n…
Published	02/10/2024	{{c1::Transcription & Replication}} both require the two strands of DNA to separate temporarily to allow enzymes access to the DNA template.&…
Published	02/10/2024	Nucleosomes and folding of chromatin pose barriers to enzymes→ cells have means of opening up chromatin or removing histonesThere are two …
Published	02/10/2024	DNA Replication is {{c1::semi-conservative}}i.e. one-half is old; one-half is new.DNA Replication is {{c1::bi-directional}}i.e. replication in two dir…
Published	02/10/2024	DNA Replication (usage of DNA polymerase)[1] Proteins unzip the double helix by breaking the hydrogen bonds[2] New nucleotide molecules are then paire…
Published	02/10/2024	Explain the process of DNA replication
Published	02/10/2024	Mitotic Chromosomes line up in the middle during {{c1::Metaphase}}→ allows organisation and equal splitting between the two newly formed daughter cell…
Published	02/10/2024	General Info
Published	02/10/2024	Repeated sequences that do not code for proteins are called {{c1::junk DNA}}, they make up at least {{c1::50%}} of the human genome
Published	02/10/2024	Genes contain two regions:Coding regions → {{c1::Exons}}Non-coding regions → {{c1::Introns}}The way they are spliced gives rise to complexity- We have…
Published	02/10/2024	{{c1::Genetic Code}} describes how base sequences are converted into amino acids Each set of 3 bases is called a {{c2::codon}}→ specifies a particula…
Published	02/10/2024	{{c1::Redundancy/Degeneracy}} of the genetic code→ the number of codons is greater than the number of amino acids→ Most amino acids are encoded by mor…
Published	02/10/2024	{{c1::Sickle cell anaemia}} is an inherited blood disorder where a single nucleotide substitution leads to a pathological phenotype by chang…
Published	02/10/2024	The major role of RNA is to participate in {{c1::Protein synthesis (Translation)}}
Published	02/10/2024	{{c1::Transcription}}: DNA → mRNA{{c1::Translation}}: mRNA → Protein
Published	02/10/2024	{{c1::Alternative Splicing}} is a process by which the exons of the RNA produced by transcription of a gene (a primary gene transcript or pre-mRN…
Published	02/10/2024	How can a single gene code for multiple proteins?
Published	02/10/2024	Genetic Reading Frames are bound by a start codon and a termination codon.{{c1::Intitiation codon}} determines the reading frame of the RNA sequence.A…
Published	02/10/2024	Describe the central dogma
Published	02/10/2024	{{c1::tRNA}} is a type of RNA that acts as an adapter molecule between the coded amino acid and the mRNA. Major role is to translate mRNA sequence in…
Published	02/10/2024	{{c1::rRNA}} is a type of RNA that combines with proteins to form a ribosome• Produced in the nucleus & transport to cytoplasm
Published	02/10/2024	Several ribosomes can translate mRNA at one time creating what is known as a {{c1::polysome}}
Published	02/10/2024	Incidence of chromosomal abnormalities
Published	02/10/2024	Chromosomal abnormalities• {{c1::Numerical}}→ wrong number of chromosomes in a karyotype • {{c1::Structural}}→ large scale rearrangement of chromosome…
Published	02/10/2024	50% of First trimester miscarriages are related to {{c1::Trisomy}}→ three copies of chromosomes instead of two.
Published	02/10/2024	{{c1::Monosomy}} is the state of having a single copy of a chromosome pair instead of the usual two copiesA {{c1::Trisomy}} is a chromosomal cond…
Published	02/10/2024	Incidence of chromosomal abnormalities Liveborn infants
Published	02/10/2024	Numerical abnormalities
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Published	02/10/2024	Origins of chromosome abnormalities: non-disjunction→ failure of disjunction during meiosis[1] failure of a pair of {{c1::homologous chromosomes}} to …
Published	02/10/2024	Why does down syndrome incidence go up with increasing maternal age?
Published	02/10/2024	{{c1::Nondisjunction}} is the failure of homologous chromosomes or sister chromatids to separate properly during cell division.Origin:
Published	02/10/2024	Autosomal aneuploidy syndromes (Down syndrome) → {{c1::Trisomy 21}} – Incidence: 1 in 650 to 1 in 700 • Increases with advancing maternal age – C…
Published	02/10/2024	Autosomal aneuploidy syndromes (Patau syndrome) → {{c1::Trisomy 13}} – Incidence: 1 in 5000 – Multiple dysmorphic features and mental retardation…
Published	02/10/2024	Autosomal aneuploidy syndromes (Edwards syndrome) → {{c1::Trisomy 18}} – Incidence: 1 in 3000 – Severe developmental problems; most patients die …
Published	02/10/2024	Sex chromosomes aneuploidy syndromes (Turner syndrome) → {{c1::45,X}} – Incidence: 1 in 5000 to 1 in 10000 (liveborn) – Incidence at conception m…
Published	02/10/2024	Sex chromosomes aneuploidy syndromes (Klinefelter syndrome) → {{c1::47,XXY}} – Incidence: 1 in 1000 – Tall stature, long limbs – Male but inferti…
Published	02/10/2024	{{c1::Structural}} abnormalities are characterized by gross large scale rearrangement in the karyotype.• Balanced or unbalanced rearrangementsCan…
Published	02/10/2024	{{c1::Balanced translocation}} is when the same amount and number of copies of the original DNA are still present after a part of a chromoso…
Published	02/10/2024	{{c1::Unbalanced translocation}} is when a different amount and number of copies of the original DNA are present after a part of a…
Published	02/10/2024	{{c1::Reciprocal}} translocation carrier: involving breaks in two chromosomes with formation of two new derivative chromosomes
Published	02/10/2024	{{c1::Robertsonian}} translocation: involves fusion of two acrocentric chromosomes
Published	02/10/2024	{{c1::Robertsonian}} translocation carrier: has fusion of two acrocentric chromosomesPredisposed to Trisomy 21 (Down syndrome) & miscarr…
Published	02/10/2024	{{c1::Deletions}} is a type of structural abnormality where a part of a chromosome is left out during DNA replication.
Published	02/10/2024	{{c1::Inversion}} is a type of structural abnormality where a chromosome rearrangement occurs in which a segment of a chromosome is reversed end …
Published	02/10/2024	Genetic mutations:• {{c1::Germline}} or {{c1::somatic}} • Gene disruption / disease-associated • Polymorphism   – No phenotypic effect   – F…
Published	02/10/2024	Types of mutations:[A] Non-coding→ could affect promoters or regulatory molecules [B] Coding[1] {{c1::Silent}}– e.g. CGA (Arg) to CGC (Arg)[2] {{…
Published	02/10/2024	Mutation nomenclature
Published	02/10/2024	Detecting mutations:• Polymerase chain reaction (PCR) • Gel electrophoresis • Restriction fragment length polymorphism (RFLP) analysis • Amplification…
Published	02/10/2024	{{c1::Polymerase chain reaction (PCR)}}→ aim is to amplify a specific piece of double stranded DNA for analysisWhat do we need for PCR?• Sequence info…
Published	02/10/2024	PCR Technique:[1] {{c1::Denature}}→ when the double-stranded template DNA is heated to separate it into two single strands.[2] {{c1::Anneal}}→ wh…
Published	02/10/2024	{{c1::Gel electrophoresis}} is a technique used to separate DNA fragments by size.• Apply an electric field • DNA is negatively charged • Separate thr…
Published	02/10/2024	Advantages of PCR Gel:• Speed • Ease of use • Sensitive • Robust
Published	02/10/2024	PCR applications:• DNA cloning• DNA sequencing• In vitro mutagenesis• Gene identification• Gene expression studies• Forensic medicine• Typin…
Published	02/10/2024	ARMS (Amplification Refractory Mutation System) → allele-specific PCRNormal primer base pairing → AmplificationMutant primer base pairing → Ampli…
Published	02/10/2024	Amplification Refractory Mutation System (ARMS) analysisonly normal alleles → {{c1::amplification with normal primers}}normal & mutant allele…
Published	02/10/2024	Advantages of Amplification Refractory Mutation System (ARMS)• Cheap • Labelling not required • Electrophoresis required • Primer design critical…
Published	02/10/2024	{{c1::Restriction endonucleases}}→ Enzymes from bacterial cells that degrade DNA of invading viruses• Protective mechanism • Recognise specific D…
Published	02/10/2024	{{c1::Restriction fragment length polymorphism (RFLP) analysis}}→ Test whether samples contain mutant or normal allele- Restriction enzyme that recogn…
Published	02/10/2024	Sickle cell anaemia diagnosis using RFLPOn electrophoresis gel:normal = 1.1 kbcarrier = 1.1 kb & 1.3 kbaffected = 1.3 kb
Published	02/10/2024	Advantages / disadvantages of RFLP• Simple • Cheap • Non-radioactive • Requires gel electrophoresis • Not always feasible
Published	02/10/2024	DNA sequencing (Gold Standard)• Chain termination method (Sanger sequencing) • Use of {{c1::dideoxynucleotides}} → causes chain termination &…
Published	02/10/2024	{{c1::Dideoxynucleotides}} are chain-elongating inhibitors of DNA polymerase, used in the Sanger method for DNA sequencing.
Published	02/10/2024	Advantages of Sanger method for DNA sequencing:• Gold standard for mutation detection • Automation and high throughputDisadvantages of Sanger method f…
Published	02/10/2024	Choice of method for detecting mutations:• Direct test • Quick and easy • Cheap • Sensitivity • Specificity
Published	02/10/2024	{{c1::Fitness}} means the relative ability of organisms to survive (long enough) to pass on their genes.Factors that influence it:[1] Alleles  &n…
Published	02/10/2024	• Mutation in {{c1::recessive}} genes rarely affects carriers – notable common recessive diseases   • Sickle cell disease   • Thalassaemia …
Published	02/10/2024	De novo mutation common in {{c1::dominant}} disorders esp. where disease reduces reproductive fitness   e.g. common cause of severe lea…
Published	02/10/2024	Genotype frequencies in a {{c1::recessive}} condition
Published	02/10/2024	Allele frequencies in a {{c1::recessive}} conditionp + q = 1.0
Published	02/10/2024	First & Second generation
Published	02/10/2024	Genotype and allele frequencies of offspringRelative frequencies remain {{c1::constant}}→ p2 + 2pq + q2 = 1Dominant conditions (alleles) do …
Published	02/10/2024	Hardy-Weinberg equilibrium (HWE)• {{c1::Allele frequencies}} remain {{c2::constant}} generation to generation. • Relative proportion of {{c1::gen…
Published	02/10/2024	Assumptions underlying HWE: - Mutation can be ignored - Migration is negligible (No gene flow) - Mating is random - No selective pressure - Popul…
Published	02/10/2024	Mutation and Migration (Gene flow) → Mutations increase the proportion of new alleles. → Introduction of new alleles as a result of {{c1::migrat…
Published	02/10/2024	{{c1::Non-random}} mating leads to increased mutant alleles, thereby increasing proportion of affected homozygotes.[1] {{c2::Assortative mating}}…
Published	02/10/2024	{{c1::Founder effect}} - new migration from physical or cultural isolationleads to a change in the frequency of an allele within a population.It occur…
Published	02/10/2024	{{c1::Natural selection}} a gradual process by which biological traits become either more or less common in a population.[1] {{c2::Negative}} sel…
Published	02/10/2024	Negative vs Positive selectionWhat are the differences?
Published	02/10/2024	Heterozygote advantages in a recessive disorder
Published	02/10/2024	Large populations can balance out fluctuations, but small populations can exhibit “{{c1::genetic drift}}” and cause “{{c1::founder effect}}”.{{c1…
Published	02/10/2024	{{c1::Genetic drift}} - random fluctuation of one allele transmitted to high proportion of offspring by chance.Mutations (alleles) are wides…
Published	02/10/2024	The {{c1::bottleneck effect}} is a sharp reduction in the size of a population due to environmental events such as famines, earthquakes, floods, fires…
Published	02/10/2024	Explain the founder effect and bottle neck effecte.g. when a volcano erupts and reduces the population size
Published	02/10/2024	Cultural & geographic founder mutations [1] – {{c1::Dominant}}    • Hereditary breast cancer gene mutations BRCA1/2 – Ashkenazi jew…
Published	02/10/2024	Examples of founder effects:[1] Cystic fibrosis in the Faroes – All one mutation – CF More common than elsewhere in Europe[2] Ellis-van Creveld syndr…
Published	02/10/2024	Applications of HWE:• Useful for calculating risk in genetic counselling • Useful for planning population based carrier screening programmes
Published	02/10/2024	Determine Carrier Frequency
Published	02/10/2024	{{c1::Cancer}} is the most common genetic disease of somatic cells• Most cancers happen by ‘chance’ or due to environmental factors • A small proporti…
Published	02/10/2024	Cancer Arises From Gene Mutations:[1] {{c1::Somatic}} mutations• Occur in nongermline tissues • Are nonheritable[2] {{c1::Germline}} mutations• Prese…
Published	02/10/2024	Tumors Are {{c1::Clonal}} Expansions
Published	02/10/2024	Genetic processes associated with Cancer • {{c1::Oncogenes}} • {{c1::Tumour suppressor genes}} • {{c1::DNA damage-response genes}}
Published	02/10/2024	{{c1::Proto-oncogenes}} – normal gene that codes for proteins to regulate cell growth and differentiation.• Mutations can change it into an oncogene •…
Published	02/10/2024	{{c1::Oncogenes}} are dominant genes in effect, they are derived from a mutation in proto-oncogenes.→ accelerate cell division→ one mutation sufficien…
Published	02/10/2024	{{c1::Tumour suppressor genes}} are recessive genes in effect that inhibit cell cycle or promote apoptosis or both→ The cell's brakes for cell growth→…
Published	02/10/2024	Why are individuals with inherited tumour suppressor gene mutation more susceptible to cancer than normal individuals?
Published	02/10/2024	{{c1::DNA damage-response genes}} are genes responsible for repair mechanisms for DNA• Cancer arises when both genes fail, speeding the accumulation o…
Published	02/10/2024	Hereditary nonpolyposis colorectal cancer (HNPCC) results from failure of {{c1::MisMatch Repair genes (MMR)}}
Published	02/10/2024	{{c1::Microsatellite instability (MSI)}} is the condition of predisposition to mutation (genetic hypermutability) that results fro…
Published	02/10/2024	{{c1::Mismatch repair genes (MMR)}} are genes that correct errors that spontaneously occur during DNA replication like single base mismatches or short…
Published	02/10/2024	{{c1::Microsatellites}} (aka Simple Sequence Repeats SSR) are repeated sequences of DNA, can be made of repeating units of 1 – 6 base pairs
Published	02/10/2024	Cancer Types:[1] {{c1::BENIGN}} – lacks ability to metastasize. Rarely or never become cancerous. Can still cause negative health effec…
Published	02/10/2024	Some Dominantly Inherited Cancer Syndromes
Published	02/10/2024	Cancer can be caused by Mutations in:[1] {{c1::Proto-oncogenes}} → Oncogenes[2] {{c1::Tumour suppressor genes}}[3] {{c1::Mismatch repair genes}}Other …
Published	02/10/2024	{{c1::De Novo Mutations}} are new mutations that occur in germ cell of parent→ with no family history of hereditary cancer syndrome
Published	02/10/2024	Features of {{c1::Retinoblastoma}}• Most common eye tumor in children• 1 in 20,000 children • Occurs in heritable and nonheritable forms • Identifyin…
Published	02/10/2024	Nonheritable vs Heritable Retinoblastoma (germline mutations in RB1 gene) – ‘two hit hypothesis’
Published	02/10/2024	Risk Factors for Breast Cancer• Ageing • Family history • Early {{c1::menarche}}→ the first occurrence of menstruation. • Late menopause• {{c1::Nullip…
Published	02/10/2024	Genes contributing to familial breast cancer
Published	02/10/2024	Genes contributing to familial ovarian cancer
Published	02/10/2024	{{c1::BRCA1}}-Associated Cancers: Lifetime Risk
Published	02/10/2024	{{c1::BRCA2}}-Associated Cancers: Lifetime Risk
Published	02/10/2024	Risk Factors for Colorectal Cancer (CRC)• Ageing • Personal history of CRC or adenomas • High-fat, low-fibre diet • Inflammatory bowel disease • Famil…
Published	02/10/2024	Why do clinicians look/screen for HNPCC widely?
Published	02/10/2024	Adenoma to Carcinoma Sequence
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Published	02/10/2024	Hereditary Colorectal Cancer (CRC) syndromes:[1] {{c1::Non-polyposis}} → (few to no adenomas)HNPCC (hereditary non-polyposis  colon cancer /…
Published	02/10/2024	Clinical Features of HNPCC[1] Early but variable age at CRC diagnosis (~45 yrs)[2] Tumor site throughout colon rather than descending colon [3] E…
Published	02/10/2024	Clinical Features of Familial Adenomatous Polyposis (FAP)[1] Estimated penetrance for adenomas >90% [2] Risk of extracolonic tumors (upper GI,…
Published	02/10/2024	Clinical Features of Attenuated FAP & Recessive MYH polyposis[1] Later onset (CRC ~age 50) [2] Few colonic adenomas [3] Not associated with CHRPE …
Published	02/10/2024	Multiple {{c1::modifier genes}} of lower genetic risk• May explain families with history of cancer and no identified mutation • May explain differenc…
Published	02/10/2024	Managing cancer risk in Adenomatous Polyposis syndromes• Surveillance → (colonoscopy) • Surgery • Chemoprevention → (aspirin)
Published	02/10/2024
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