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Tom Haffie

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Lecture Two: HIV – TED Talk IS Outcomes general mechanisms by which vaccines protect against diseases. – vaccine trains body in advance how to recognize and neutralize an invader – vaccines make catch or ammo to defeat infection once contracted – creates small immunity to infection why developing a vaccine against HIV is relatively challenging, compared to other diseases. – HIV mutates furiously and attacks cells that destroy it why people are encouraged to get a flu vaccine each year (as opposed to one time only). – flu virus constantly mutating and changing shape – flu vaccine changes with the strain of mutant flu that is most prevalent at the time Lecture Outcomes general global distribution of HIV infections. – first world has low rates of infection – south sahara, south africa incredibly prevalent – extremely lower life expectancy – 33.3 million estimated to be living with HIV general temporal trends in HIV infection rates. – # of people living with HIV plateauing after an increase – death rate decreasing due to medications factors that explain why no cure or universal vaccine has been developed for HIV/AIDS. – HIV continues to mutate and evolve – body has no natural immunity to HIV – – retroviruses do not store genetic information as DNA, but RNA – no proofreading enzymes associated with reverse transcription – high frequency of errors – mutation rate is astronomical – 1 million times higher then rate in humans, ample opportunity for mutation reasons why viruses are not considered “alive”. – can't self reproduce – needs a host – no metabolic processes – not made up of cells, much smaller then cells – no cellular machinery/infrastructure reasons why anti-viral drug therapies often have serious side effects. – viruses require cellular machinery / infrastructure to reproduce – can't kill viruses without taking out host cells / host tissue major steps in life cycle of HIV. – HIV specializes in immune cells – codes for nine proteins, uses host's genome for everything else – in replicating its' cells, HIV kills immune cells and host dies of secondary condition 1. the glycoprotien on the surface of HIV attaches to protein receptors on the cellular membrane 2. viral contents enter cell via endocytosis 3. reverse transcriptase catalyzes the synthesis of DNA from the viral RNA 4. the RT synthesis a second complementary strand of DNA 5. the double stranded viral DNA is spliced into the host cell's DNA by integrase 6. transcription results in the production of RNA, RNA serves as genome for new virons, translated to produce viral proteins 7. HIV particles are assembled in macrophages, buds out of cell w/o rupturing 8. in T cells HIV exits the cell by rupturing it, killing the cell specific role of integrase and reverse transcriptase in retroviral life cycle. – reverse transcriptase transcribes RNA to DNA – integrase splices viral DNA into host DNA – transcription, then translation, new virons assemble and bud off or lyse out (killing host cell) mechanism of action of AZT. – AZT mimics thymidine and inhibits reverse transcriptase – RT is stalled because AZT has no attachment site for the next nucleotide – inhibits transcription reasons why effectiveness of AZT decreases over time. – when a virus is newly transmitted, very susceptible to AZT – AZT resistance begins to emerge after six months of use – virus mutates which allows it to recognize AZT and thymadine – with high mutation rate, generations occur rapidly – inevitable through RT that beneficial mutation is found – resistance is hereditary, mother to daughter viron – in the presence of AZT, resistant forms are more likely to reproduce then susceptible forms b/c not all virons reproduce rationale for multi-drug (drug cocktail) approach to treating viral infections. – resistance to one drug is inevitable, to many drugs is less likely – entry inhibitors slow down viron from entering cell – non-nucleoside reverse transcriptase inhibitors – nucleoside RT inhibitors – integrase inhibitors – protease inhibitors principles of evolution of HIV: variation, heritability, differential reproduction, change in genotype of population. – some people HIV resistant after repeated exposure or slower contraction time from HIV to AIDS – evolution can be very fast (months) – even non-living things can evolve – HIV evolution involves themes such as: mutation, natural selection, evolutionary history, and humans as an evolutionary force and as the products of evolution role of CCR5-Δ32 mutation in human resistance to HIV infection. – resistance due to deletion of protein receptor on immune system – missing 32 amino acids – one copy of CCR5-Δ32 = protection from HIV – two copies of CCR5-Δ32 = impervious to contracting HIV global distribution of CCR5-Δ32 allele. – relatively high frequency in Europe (Scandinavia, Jews) – frequency in sub sahara africa is very low likely explanations of modern distribution of CCR5-Δ32 allele. – selection pressure to HIV? (very unlikely) – not enough time, less of a selection force in north western Europe not imposed by virus – selectively favoured in N. Europe during historical epidemics (plague, small pox) – chance and history? Lecture Three: Origins – 3.1 – 3.3a BED IS Outcomes characteristics shared by all life. – all life forms display order – harnesses and utilizes energy – reproduces – responds to stimuli – exhibits homeostasis – grows and develops – evolves way in which properties of life are "emergent". – each of the characteristics of life depicted results from a hierarchy of interactions that begins with atoms – atoms --- molecules --- macromolecules --- cells – they come about or emerge from simpler reactions characteristics of the "habitable zone" of a solar system. – because of the importance of water for development of life, region around star where temperatures would allow for liquid water is termed habitable conditions of a primitive Earth. – almost complete absence of oxygen gas – reducing atmosphere: – presence of large concentration of H+, CH4, NH3 – contains an abundance of free electrons = RXN's = larger/complex organic molecules – oxidizing atmosphere: – large O2 concentration = no electron rich molecules formed – 02 oxidizes into water – lack of O2 also meant no ozone layer – therefore UV light hit the surface = biological molecules types of molecules that were, and were not, synthesized by the Millar-Urey experiment. – reducing atmosphere simulated including water vapour --- H2O(l) – large assortment of organic compounds: urea, amino acids, lactic / formic / acetic acid – 16% of carbon from CH4 --- organic compounds +HCN +formaldehyde = all the building blocks of complex biological molecules – amino acids, fatty acids, purine and pyrimidine components of nucleic acids, sugars, ribose, glucose, fructose – polymers did not exist importance of liposomes in evolution of first cells. – created membrane define compartments – genetic material system --- proteins – energy transferring pathways liposome: lipid vesicle, similar to a cell membrane – selectively permeable – can swell/contract based on osmotic conditions – clay catalyzes formation of lipid vesicles – active surface with membrane characteristics of mimivirus that suggest it should be considered to be alive. – more then 900 protein coding genes – builds viral factory, hijacks machinery characteristics of virophage. – viruses that can sicken and infect bacteria Lecture Outcomes age of the Earth. – 4.6 million years age of start of life on Earth. – four billion years ago for emergence of life, developed fast after, Earth had to cool domains of life. – Eubacteria: major forms of bacteria and the cyanobacteria, earliest organisms known as fossils – Archaea: (Acheabacteria) unicells with cell walls made up of different molecules than those of Eubacteria, often lives in extreme environments (hot sulfur springs / extreme salt []'s ) – Eukaryotes: unicellular (slime molds, ciliates, etc) & multicellular organisms (fungi, plants & animals) characteristics of LUCA – last universal common ancestor – common cellular ancestor before the diverging of the three domains of life characteristics shared by all domains of life. – able to reproduce – DNA/RNA as genetic material – metabolic processes 1. cells made up of lipids (cellular membrane) 2. genetic system based on DNA 3. DNA to RNA to Protein transcription and translation 4. common system of protein assembly 5. ATP as cellular form of energy 6. glucose & glycolysis reason why the term “prokaryote” is inappropriate. – “prokaryotes” no single group of organisms – archea/bacteria do not share similar characteristics or ancestry – “pro” means before, eukaryotes predate prokaryotes – no evidence prokaryotes came before eukaryotes – suggest directionality, simple to complex organisms reductive evolution explanation for rise of bacteria and archaea. advantages of evolutionary simplification (streamlining). – evolution does not have to go simple to complex – reductive evolution (bacteria / archea got rid of nuclear envelope) – “streamlining” – can save energy, rate of reproduction is faster, extremophiles (bacteria or archea) can inhibit areas eukaryotes can't relationship between homochirality and life – chirality: “handedness,” optical isomers – can't superimpose, mirror images – amino acids / sugars can appear in chiral forms – same physical and chemical properties – vastly different biological properties – homochirality essential to the evolution of life – only uses one form, two forms of everything doesn't make evolutionary sense – before LUCA maybe used both – LUCA, only one – only one form can bind to receptors reasons why we think RNA was the first of the three molecules of the Central Dogma to evolve. force that drives RNA folding. – information carrier – fidelity high – can do things proteins can't do – as a functional molecule can fold like a protein into a 3D shape – uses H bonding to drive folding characteristics of a ribozyme. – antisense RNA molecule with catalytic properties – can catalyze a reaction – catalyzes removal of H from 2' oxygen – O become reactive to phosphate – forces substrate into conformation that favours catalyzation – cleaves 5' end just like enzymes – precursor to tRNA processing – intron excision – mRNA processing – transfer of amino group from tRNA to growing peptide chain mechanism whereby a ribozyme cleaves RNA. – a ribozyme is an RNA molecule with a well define tertiary structure that enables it to preform a chemical reaction – they funciton by binding to target RNA moeity by base pairing and inactivate it by cleaving the phosphodiester backbone at the specific cutting site characteristics of amino transferase activity. – peptidyl transferase activity based on RNA – an enzyme that catalyzes the reaction between an alpha amino acid and a specified carbon on a keto acid reasons why a ribosome is considered a ribozyme. – the ribosome acts as an intermediate b/w RNA and protein – it is composed of about two thirds RNA and one third protein – the RNA component of the ribosome, not the protein, that actually catalyzes that incorporation of amino acids onto a growing peptide chain advantage that protein has over RNA as a catalyst. – Proteins are far more versatile than RNA molecules – the catalytic power of most enzymes is much greater then that of a ribozyme – the rate of catalysis of most ribozymes is one-tenth to one-one hundredth that of enzymes – while the number of ribozymes is very small, a typical cell can synthesize a huge array of different proteins RNA molecule is composed of only four nucleotides – amino acids can interact chemically with each other in bonding arrangements not possible b/w nucleotides – proteins are the dominant structural and functional molecule of a modern cell advantage that DNA has over RNA as a repository for genetic information. chemical basis for the advantage that DNA has over RNA as a repository for genetic information. – each strand of DNA is more stable and less likely to degrade than a strand of RNA – 2' hydroxyl group on DNA more stable then RNA – RNA will degrade b/c of reactivity of OH – just H in DNA is much more stable – the base uracil in RNA is not found in DNA, thymine replaces uracil in DNA – the conversion of C to U mutation common in DNA – by using thymine in DNA any uracil is easily recognized as damaged cytosine that needs to be repaired – DNA is double stranded, so in the case of mutation to one of the strands the information contained on the complementary strand can be used to repair the damaged strand – hydroxyl, H changes shape of ribose to make more likely shape of double stranded molecule – important for evolutionary change – complimentary strands allow for reproduction ribonucleic protein (RNA & protein) – ribosome, good illustration – earliest cells were only RNA – replication is error prone therefore good for evolutionary – only four bases in RNA therefor limited ribonucleicprotien – important in evolution of life Lecture Four: BioDiversity – chapter eight EPP IS Outcomes approximate times by which the first cells, and the first eukaryotic cells, had appeared. – first single celled methane producing bacteria existed more then 3.5 bya (archea) – single celled cyanobacteria stromalites 3.5 bya – eukaryotic cells arose 2.5 bya two-kingdom, five-kingdom and three-kingdom (three domain) systems for classifying living things. two kingdom: – life was classified into Plantea and Animalia – assignment based on structure and function, type of metabolism and movement – then life divided into Prokaryotes and Eukaryotes – Prokaryotes: single celled organisms, reproduce by binary fission, lack membranous structures and organelles, – Eukaryotes: multi celled organisms, reproduce by mitotic cell division, contains organelles such as endoplasmic ritulum, mitochondira etc. five kingdom: – prokaryotes – fungi – protists – plants – animals main characteristics distinguishing members of the Eubacteria, Archaea, Eukaryota domains of life. Eubacteria: – major forms of bacteria and the cyanobacteria – Archea: unicells with cell walls (diff then that of EB), live in extreme condtions Eukaryota: unicellular organisms, plants and animals meaning of horizontal gene transfer and why this makes it challenging to recreate the universal tree of life. – horizontal gene transfer: the transfer and incorporation of one organism's or species DNA into the DNA of a different organism or species – most common between closely related unicellular organisms – HGT obscures phylogenic relationships when otherwise distantly related organisms share a gene or sequence obtained through HGT and not a common ancestry monophyletic vs. polyphyletic groupings of organisms. – monophyletic: derived from a single common ancestor – polyphyletic: multiple origins, used for groups that have more then one (often multiple origins) Lecture Outcomes most recent common ancestor (MRCA) for a given group(s), given a phylogenetic tree. – mathematical modelling estimates about 3000 years ago – many MRCA's for each gorup why the idea that “humans are descended from chimps” is inaccurate. – 5-6 million years ago humans shared last descendant with chimps – we did not descend from chips, we share ancestry to chimps – lineage diverged, not evolved order of main branching events in tree of life (dates not testable). 1. Chimps (5-6 million) 2. Gorillas (7-8 million) ~ African Great Apes 3. Orang utans ~ Asian Great Apes 4. Gibbons (18 million) 5. Old World monkeys (25 million) ~ Africa / Asia 6. New World Monkeys (40 million) ~ South America 7. Tarsiers (58 million) 8. Lemurs and Lorises (63 million) ➢ end cretaceous mass extinction (65 million) 9. Rodents and Rabbits 10. Laurasiatheres 11. Marsupials (140 million) 12. Monotremes (180 million) 13. Reptiles (530 million) 14. Amphibians 15. Lungfish 16. Coelacanths 17. Ray-finned Fish 18. Sharks 19. Jawless Fish 20. Protosomes 21. Fungi 22. Amoebozoans 23. Plants 24. Archaea 25. Bacteria / LUCA cause of global catastrophe associated with mass extinction 65 mya. – 1/2 of species on Earth went extinct, including dinosaurs – end-Cretaceous mass extinction (asteroid?) relative proportion of protostome vs. deuterostome species. – more protostomes then deuerostomes – protosomes are insects and they outnumber deuerostomes information provided by genetic relatedness vs. traditional groupings of organisms (“reptiles”, “fish”) – birds are actually a type of reptile – snakes / lizards have recent ancestor with birds > turtles distribution of multi-cellularity in tree of life. why estimating numbers of species is uncertain. – reconstructing patterns of relatedness and estimating number of species is challenging – HGT (horizontal gene transfer) role of similarities due to common descent (DNA genome) vs. Convergence (eyes) in constructing a phylogenetic tree. – some similarities reflect shared ancestry, other traits similar to convergence; shared adaptations to a shared environment, convergent evolution Lecture Five: Genomic Variation – online, 15.3b, 8.3a BED IS Outcomes meaning of "C-value". – genome:all of the DNA sequences in one copy of an organism's chromosome – nuclear DNA / nuclear chromosome – the amount of DNA in one genome is called C "paradox" or "enigma" associated with C values – C values are variable within a taxonomic range – is distributed over one set of chromosomes – # of chromosomes has nothing to do with complexity or genome sizes meaning of haploid (n) and diploid (2n) relationship between C and n as measures of genome size. – one C value is distributed over one set of chromosomes – karyotype: range of chromosomes – diploid = two sets of chromosomes – C value proportion of the human genome that codes for protein. – 2% of the human genome codes for proteins Lecture Outcomes non-nuclear genomes in typical plant and animal cells. – plant cells have DNA in mitochondria, chloroplasts trend in C value from prokaryotic vs. eukaryotic cells. – plants have more then fungi – genome size increases from prokaryotes to eukaryotea relationship between C value and organismal complexity – C value has no correlation with organismal complexity relationship between C value and ploidy – ploidy refers to the number of sets of chromosomes – 3n = 3c distribution of linear vs. circular chromosomes in the various domains of life. – Linear chromosomes are almost only found in Eukarya – mitochondria and chloroplasts in plants have circular genomes role of nucleosomes in DNA packaging in chromosomes – a chromosome is packaged chromatin: DNA plus protiens – each chromosome is made up of one molecule of dsDNA – each chromosome has two chromatids general trends in costs of DNA sequencing – cost decreasing, almost close to 10,000 to sequence individual genome relative distribution of various component of genome sequence ("junk" vs. essential DNA) – about 25% of genome unknown, likely junk – 55% of genome is composed of lots of transposons (parasites), viruses and “dead genes” (junk) – 10% introns (junk) – 10% essential, 2% coding (genes) Lecture Six: Genomic Replication – 12.2, 12.3a, 12.3g, 8.3b BED IS Outcomes purine and pyrimidine base-pairing in DNA/RNA – base pairing in DNA is usually (A-T, C-G) – base pairing in RNA is usually (A-U, C-G) – pairing is anti-parallel – always 3' to 5' outcome of the classic Meselson and Stahl experiment – created a laboratory simulation of the reducing atmosphere – placed components of a reducing atmosphere: hydrogen, methane, ammonia, water vapour, in a closed apparatus and exposed the gases to an energy source (sparking electodes) – a large assortment of organic compounds formed – including urea, amino acids, lactic, formic and acetic acids – about 15% of the carbon initially in methane ended up in organic molecules – HCN and folmaldehyde added – direction of movement of DNA polymerase on the template strand – DNA polymerase can add deoxyribonuclside triphosphates only to the 3' hydroxyl end – therefore runs 5' to 3' on the synthesized strand – and runs 3' to 5' on the template strand meaning of semi-conservative, semi-discontinuous, leading and lagging strand – semi conservative: one strand of the parent strand acts as a template for two newly synthesized strands – semi-discontinuous: lagging strand synthesized discontinuously, in okazatki fragments away from the replication fork general action of proteins in Fig. 12.15. - DNA replication Lecture Outcomes basic structure of double-stranded DNA – distinct 3' and 5' end confers polarity on DNA backbones – 3' has free OH hydroxyl – 5' has free phosphate – two strands of DNA run anti-parallel Cells programmed to die? – surplus cells – after use has run out – cells know how long there are b/c they know how long their telometers are – once their telometers shorten to a critical length, apoptosis occurs – if telomerase is over expressed, more cancer – expression of telomerase is turned off in somatic tissuse – gene not expressed – more expressed in low degrees in actively cycling cells, early in development and during gametogenesis – babies born young, w long telomerases – upregulated in majority of cancer tumours – expresses telomerase inaapropriately components necessary for DNA synthesis direction of elongation of a given DNA strand – deoxyribonucleoside triphosphates have to extend 3' to 5' structure of a replication bubble – replisomes: all proteins operating at the fork – topoisomerase not included – replication “bubble” arises from two replication forks going in opposite directions – one replisome for both strands – replisomes replicate one strand continuously, one discontinuously – replisomes has two DNA polymerase molecules working simultaneously – lagging strand loops out relationship between replicated DNA and metaphase chromosomes – G1: single chromosomes, one DNA molecule – S phase: DNA replication – G2: chromatid replicated – Mitosis: DNA separated – always only one chromosomes – the number of chromosomes does not change – the amount of DNA and structure changes of chromosomes – C value doubles – n value does not change reason why chromosomes shorten at each replication – primer at end of chromosome of lagging strand cannot be replicated – at every replication chromosomes get shorter mechanism by which telomerase adds telomeres to chromosomes – telomerase adds sequence at the end of the chromosome to 3' end – brings its own RNA template allowing it to extend the 3' end, allowing repair of 3' end – DNA synthesis needs a template – telomerase brings its own RNA template, in order to extend the end of the chromosome – stretch at the end (telometer), repeating, non-coding, repetitive DNA – keeps extending 3'end – therefore can be extended by DNA synthesis – Yes, exact same problem happens at each end, telomerase works at both ends – if telomerase is over expressed, more cancer – expression of telomerase is turned off in somatic tissuse – gene not expressed – more expressed in low degrees in actively cycling cells, early in development and during gametogenesis – babies born young, w long telomerases – upregulated in majority of cancer tumours – expresses telomerase inaapropriately Lecture Seven: Inheritance of Sameness – SimUText sections 1-3 IS Outcomes stages and main characteristics of the stages of mitosis. main features of each stage of mitosis with respect to cytoskeleton and chromatin Interphase: – G2 continues to synthesize RNA and proteins including those required for mitosis – G1 only phase that varies in length for different species – whether a cell divides rapidly or slowly depends on length of G1 – G1 also phase where many cells stop dividing – division arrest is often designated G0 phase – ex. nervous cells normally enter G0 when fully mature Prophase: – chromosomes condense into short rod like structures – nucleolous becomes smaller and disappears – mitotic spindle begins to form b/w the two centromeres: as the centromeres start migrating towards opposite ends of cell to form the spindle poles Prometaphase: – nuclear envelope breaks down – spindle microtubules form centrosomes at opposing spindle poles toward centre of cell – kinetochores form: a complex of several proteins – kinetochore microtubules bind to kinetochore – these connections determine the outcome of mitosis b/c they attach the sister chromatids of each chromosome to microtubules leading to opposite spindle poles Metaphase: – spindle is fully formed – chromosomes moved by spindle microtubules become aligned at metaphase plate Anaphase: – spindle separates the sister chromatids and moves them to opposite spindle poles – at this point chromosome segregation is complete – kinetochores first sections to move toward opposite poles Telophase: – the chromosomes condense and return to the extended state typical of interphase – nucleolus reappears – RNA transcription resumes – a new nuclear envelope forms around the chromosomes at each pole Cytokinesis: – division of the cytoplasm – completes cell division by producing two daughter cells each containing a daughter nucleus produced by mitosis – furrowing: – the layer of microtubules at the former spindle midpoint extends laterally until it stretches entirely across the dividing cell – a band of microfilaments forms just inside the plasma membrane – powered by motor proteins the microfilaments slide together tightening the band and constricting the cell – the constriction forms a groove (the furrow) in the plasma membrane – furrow gradually deepens until daughter cells are completely separate – distributes organelles and other doubled structures approx. equally role and mechanism of the mitotic spindle. – mitotic spindle made up of microtubules and their proteins – mictrotubules disassemble from their interphases arrangement and reorganize into the spindle – animals / protists have a centrosome – a site near the nucleus where microtubules radiate in all directions – centrosome is the MTOC – main microtubule organizing centre – centrosome contains a pair of centrioles (90 degrees to each other) – centrioles replicated during S phase – as prophase begins centrosomes separate into two parts – at the end of prophase after the nuclear envelope breaks down the spindle moves into the region formerly occupied by the nucleus and continues growing until it fills the cytoplasm – asters: centrosomes at the spindle tips which form poles of spindle changes in amount of DNA throughout the cell cycle – see table Lecture Outcomes mechanisms that ensure "inheritance of sameness" location of actively cycling cells in multicellular animals/plants – nails, hair, skin, – roots, tips, outer layers of plants function of rapid cycling cells at various stages of the life cycle examples of situations in which cells would be programmed to die by apoptosis – surplus of cells – after use has run out – cells know how old they are b/c hey know how long their telometers are – once their telometers shorten to a critical length apoptosis occurs interphase G2: organelles and main features of chromosome anatomy composition of microtubules, intermediate filaments and microfilaments interaction between spindle fibres and kinetochores – kinetochore microtubules: – connect the chromosomes to the spindle poles – nonkinetochore microtubules: – extend between the spindle poles, without connecting to chromosomes – at the spindle midpoint the microtubules from one pole overlap with the microtubule from the opposite pole – the entire spindle is lengthened, pushing the poles further apart – pushing movement produced by microtubules sliding over one another in the zone of overlap – powered by proteins acting as microtubule motors – also push apart by growing in length as they slide role of motor proteins in chromosome segregation – chromosomes “walk” themselves to poles along stationary microtubules using motor proteins in their kinetochores – kinetochore microtubules do not move much with respect to poles during the anaphase movement – tubulin subunits of the kinetochore microtubules disassemble as the kinetochore pass along them – the microtubules become shorter as the movement progresses role of cell cycle checkpoints – checkpoints: prevent critical phases form beginning until previous phases complete – ex. CDK's are protein kinases, enzymes that add phosphate groups to target protein – “switched on” only when combined with other protein called a cyclin – concentration of cyclin rises and falls during cell cycle so does enzyme activity of the CDK's – internal controls that regulate the cell cycle are modified by signal molecules that originate from outside the dividing cells – in animals these molecules include the peptide hormones and similar proteins called growth or death factors – external factors bind to receptors on cell surface which respond by triggering reactions inside the cell – these reactions often include steps that add phosphate groups to the cyclin – overall effect is to speed, slow or stop progress of cell division – contact inhibition: stabilizes growth in fully developed organs and tissues – as long as cells of most tissues are in contact with one another or the extra cellular fluid they are shunted into the G0 phase and prevented from dividing implications for cell division if various components malfunction (ie. what if drugs prevent microtubule polymerization?) Lecture Eight: Origins of Variation – 12.4, 9.4 BED IS Outcomes mechanism of proofreading and likely result of proofreading defects – DNA polymerases back up and remove mismatched nucleotides from a DNA strand – if a newly added nucleotide is mismatched the DNA polymerase reverses – using a built in deoxyribonuclease to remove the added incorrect nucleotide – the enzyme resumes working forward – 1 mispair per 1 million nucleotides mechanism of mismatch repair – any base-pair mismatch that remains after proofreading face another round of correction by DNA repair mechanisms – mismatched bases are either too large or too small to maintain the correct separation and cannot form normal hydrogen bonds – bases mismatches distort the structure of the DNA helix – provide recognition sites for the enzymes catalyzing mismatch repair – enzymes encounter distortion, remove portion of the new chain including mismatched nucleotides – gap then filled in by DNAP – also works on dna damaged by chemicals and radiation – the rare replication errors that remain, a primary source of mutations – mutations: differences in DNA sequences that remains in replicated copies of DNA differences among insertion sequences, transposons and retrotransposons mobile elements: – can move from one place to another – cut and paste segments of DNA – “jumping genes” – move from place to place within the genome of a given cell insertion sequences: – the simplest TE's – contain only genes for their transposition – an enzyme that catalyzes recombination reactions for inserting or removing the TE from the DNA – at the two ends, short repeated sequences, same DNA running in opposite directions – therefore transpose enzyme (recombonase) can identify ends of TE when it catalyzes transposition transposon: – inverted repeat sequences at each end enclosing a central region with one or more genes – genes in central region typically codes for antibiotic resistance retrotransposons: – transposition occurs via a RNA intermediate – an enzyme called reverse transcriptase (encoded by one of the genes in retrotransposon) uses RNA as a template to make a DNA copy of the retrotransposon – the DNA copy is then inserted into the DNA at a new location, leaves the original in place implications of insertion of mobile elements into DNA – causes genetic changes – produces mutations by inserting into genes and knocking out their function – increase or decrease gene function by transposing into regulatory sequences of DNA – biological mutagens – TE's become permanent residents in DNA, replicated during cell division – becomes part of genetic material of species reasons why transposons are not actually "jumping" genes – TE's are always integrated into DNA – never “in the air” between one location or another – transposition starts with contact between the TE and the target site basic structure of retrovirus genome – retrovirus infects a host cell – reverse transcriptase is carried in virus particle and is released – copies the single stranded RNA genome into a double stranded DNA copy – viral DNA is then inserted into the host DNA (by genetic recombination) – where it is replicated and passed on to progeny cells during cell division Lecture Outcomes different types of genomic variation among humans – ventor individual genome sequence showed 1.2 million variants – 1/4 variant bases are SNPs (single nucleotide polymorphisms) – 3/4 are CNV, inversions, etc – each person has about 1000 CNV affecting 35% of its genes – each person has about 300 variants in insertion of retro elements (eg LINES & SINES) structure of IS elements, transposons, retrotransposons and retroviruses – transposase: bacterial elements that code for their own mobility – insertion sequence (IS) only job is to reproduce itself – recombonase makes cuts, can send copy of itself, parasite – transposons code for antibiotic resistance, genes moblie – retrotransposons: IS element that moves via RNA – transcription by RNA polymerase produces RNA copy of retrotransposon – retrotransposon encoded reverse transcriptase makes DNA copy – retrotransposon copy integrates into target cell – retroviruses: can move within genomes – ERV's: endogenesis retroviruses – can cause disease, mutations and disrupts function of genes, biological mutagens types of evidence that might be useful in determining how long the human genome has been infected by a given mobile element. – the amount/type of species that also carry the mobile element in their genome – the distribution of the mobile element in the human population – the length it takes for retro transcription mechanism by which tautomeric shifts in DNA bases leads to alternative base pairing – tautomeric shifts causes change in structure to where alternate base pairing can occur – all bases can switch into their enol form, but prefer their ketotautomer mechanism by which alternative base pairing gives rise to mutation during replication – insertions/deletions due to replication slippage – repairing double stranded breaks can create rearrangements (deletion, duplication, inversion, translocation) difference between DNA damage and mutation Lecture Nine: Origins of Variation II – 9.1, 9.3, 15.2b, 15.9 BED IS Outcomes characteristics of STR loci that make them useful for forensic DNA analysis (DNA fingerprinting). – several loci in non coding regions of the genome are used for analysis – each loci is and example of an STR (short tandem repeat) – it is a short sequence of DNA that is repeated every 3-5 bps – each locus has a different repeated sequence – the number of repeats varies among individuals in a population – a given individual is either heterozygous or homozygous for an STR allele – therefore each individual has a unique combination of alleles (minus twins) – analysis of multi STR loci can discriminate the DNA between two people mechanism of DNA recombination – genetic recombination requires two things: DNA molecules that differ from one another – a mechanism for bringing the molecules into close proximity – and a collection of enzymes to “cut” “exchange” and “paste” the DNA back together – occurs between sequences of DNA that are similar but not identical 1. homologous regions of DNA paired 2. enzymes breaks a covalent bond in each of the four sugar-phosphate backbones 3. the free ends of the backbones are then exchanged and reattached to the other DNA molecule – results in two recombined molecules – therefore cutting and pasting four DNA backbones results in one recombination event stage of meiosis when recombination occurs – recombination occurs in prophase I of meiosis Lecture Outcomes reason why incorrect tautomers of bases are not recognized as mismatches and removed by excision repair mutagenic mechanism of – this pairing doesn't distort the helix action of base analogues such as 5 Bromouracil – polymerases cannot tell 5 bromouracil from thymine – gets incorporated into DNA as mutagen – 5 bromouracil tautomerically unstable – increases mutagen frequency – induced mutation by chemical mutagenic mechanism of action of UV radiation – UV radiation causes thymine diamers that distort the helix – ring structure of thymine very susceptible to absorbing energy from UV light – reorganizes electrons in two adjacent thymines and makes bonds between them – base to base distorts helix – very difficult for polymerases to deal with and hard to transcribe / replicate – dimers stall replication and can be lethal – cells relax their polymerases and relax base-pairing rules – creates damage with wrong bases, therefore mutations mechanisms of repair of UV photodamage – dimers can be repaired by photolyase or excision – photlyase breaks bonds (driven by photo of visable light) – UV light only available with sunlight – humans don't have photolyase, no mammals, lost over evolutionary time – bacteria/plants have it – excision repair removes diamers mutagenic mechanism of in/del damage during replication – insertions / deletions usually due to deletions – replication slippage can lead to insertions or deletions mutagenic mechanism of ionizing radiation – radioactivty is a characteristic of unstable isotopes – decays over time, releases dangerous radiation – decay of radioactive iodine an cesium creates ionizing radation that rips e-'s from oxygen in the body – can result in breaks in the DNA backbone – if both sides are broken, pieces of chromosome breaks off various types of chromosomal rearrangement resulting from attempts to repair double strand breaks possible consequences of relocation of DNA sequences within or between chromosomes – deletion, – duplication – inversions – translocations possible advantages of gene duplication – creates gene families general use of gene families to create phylogenetic trees – gene families reflect evoultonary relatedness Lecture Ten: Meiosis – 9.1, 9.3, SimUText sections 1-3 IS Outcomes products of meiosis in animals vs. plants, fungi and algae animals: – diploid phase dominates life cycle – diploid (mitosis) to haploid (meiosis) – gametes are produces by meiosis – males: each of four nuclei produced is enclosed in a separate cell by cytoplasmic divisions – females: one of four nuclei becomes functional as an egg cell plants & some fungi – alternate between haploid and diploid generations 1. fertilization produces diploid sporophytes 2. sporophytes grow by mitosis 3. some of the cells undergo meiosis producing haploid spores 4. spores are not yet gametes, divide by mitosis again to produce haploid gametophytes 5. gameotphytes develop into egg or sperm nuclei – all of the sperm or eggs produced by a gametophyte are genetically identical because they arise by mitosis most fungi – diploid phase is limited to a single cell – because gametes are produced by mitosis, all are genetically identical 1. diploid cell produced by fertilization 2. zygote divides by mitosis to produce haploid cells 3. two haploid cells fuse to form diploid nucleus 4. nucles divides by meiosis forming four haploid cells 5. mitosis into haploid spores timing of meiosis in vertebrate life cycles – males experience prophase I of meiosis after puberty – females experience prophase I of meiosis as a fetus – born with eggs in meiotic arrest – if an eggs gets fertilized then meiosis continues main differences between meiosis and mitosis mitosis: – “sameness” – chromosomes are replicated and partitioned to esure identical daughter cells with the same number of chromosomes, same sequence of DNA meiosis: – “difference” – two kinds of difference: halved chromosome number and recombined chromosomal DNA sequence (genetic recombination) – products of meiosis not intended to add to the body of the organisms that produces them characteristics of homologous chromosomes – the two representations of a chromosome in a diploid cell represents a homologous pair – same genes arranged in the same order in the DNA of the chromosomes – one chromosome paternal – one chromosome maternal – they carry the same arrangement but different versions of each gene (alleles) Lecture Outcomes reason why meiosis I is "reductional" and meiosis II is "equational" meiosis I: – chromosomes line up in homologous pairs, recombine and split into daughter cells – number of chromosomes is half of the original cell – diploid to haploid cells therefore reductional meiosis II: – sister chromatids are separated into different cells – number of 'chromosomes” stays the same, amount of DNA decreases changes in C and n during meiosis – see table mechanism of recombination during prophase – the two chromosomes of each homologous pair line up on top of one another – called pairing or synapsis – fully paired homologues are called tetrads (four chromatids in each pair) – chromosomes physically exchange segments by genetic recombination role of cohesin and synaptonemal complex – during prophase I, as the homologous chromosomes pair they are held tightly together by a protein framework called the synaptonemal complex – towards the end of prophase I the synaptonemal complex disassembles and disappears how homolgues pair in order for all non-sister chromatids to participate in recombination – chromosomes pair one on top of the other so that any two of the four chromatids can undergo recombination mechanism by which recombination creates new combinations of alleles – supported by the framework of the synaptonemal complex regions of homologous chromatids exchange segments producing new combinations of alleles – exchange involves the breaking and rejoining of DNA molecules by enzymes – four resulting nuclei of meiosis I and II receives one of four chromatids in a tetrad – two receive unchanged “parental” chromatids and two receive chromatids that have a new combination of alleles due to recombination – these two are recombinants – note that recombinations does not just “switch” alleles of a given gene – rather all of the DNA sequence stretching from the site of recombination to the end of the chromatid is exchanged – recombination technically a mutagen mechanism by which recombination creates copy number variation (CNV) – if repetitive sequence pairing “slips” unequal crossing over can generate CNV's randomness of alignment of homologous pairs at metaphase I – independent assortment – random segregation of maternal and paternal chromosomes results in very different sets of gametes – during prometaphase I spindle tubules make connections to kinetochores – for each homologous pair chromosomes connect to the spindle poles randomly – therefore the random combinations of paternal and maternal chromosomes during segregation leads to genetic variability – 2^23 different combinations of maternal and paternal chromosomes to be delivered to the poles relationship between distance separating genes and the likelihood of recombination between them – genes that are close together have very little DNA between them, therefore are hard to combine – low between closely linked genes – higher with distal genes – recombination happens rarely for genes at the top, more at the bottom way in which meiosis can be thought of as a kind of DNA "repair". That is, how can you inherit mutations on both homologues of chromosome 6 but give a chromosome 6 with no mutations to your offspring? – during meiosis and fertilization genetic variability arises from four sources: 1. genetic recombination of homologous chromosomes 2. the different combinations of maternal and paternal chromosomes segregated to the poles during anaphase I 3. the different combinations of recombinant chromatids segregated to the poles during anaphase II 4. the particular sets of male and female gametes that unite in fertilization mechanism by which errors in MI or MII give rise to aneuploid products of meiosis non disjunction / failure in chromosome segregation: – occurs during meiosis I – failure to separate the two homologous chromosomes of a tetrad in anaphase I – one pole receives both pairs of chromosomes whereas one pole has no copies of that chromosome – meiosis II will separate the chromatids of the two pairs as usual, but the gametes will have two copies of the extra chromosome misdivision / failure at meiosis II: – chromatids do not separate to opposite poles during anaphase II – gametes with abnormal number of chromosomes result – zygotes that receive and extra chromosome from an abnormal gamete end up having three copies of that one chromosome – in humans, most of these zygotes do not survive – with the exception of 3 copies of the 21 chromosome resulting in Down Syndrome Lecture Eleven: Inheritance of Variation I – chapter 10, mendelian pigs SimUText – recommended questions: Ch. 10 Q 1 - 17; Ch. 11 Q 1, 2, 3 IS Outcomes arrangement of genes and alleles on homologous chromosomes in a dihybrid organism – a dihybrid organism is heterozygous for two pairs of alleles how independent assortment creates 4 different products of meiosis from a dihybrid parent Rr Yy x Rr Yy = ratio 9:3:3:1 1. RR YY, RR Yy, Rr YY, Rr Yy 2. RR yy, Rr yy 3. rr YY, rr Yy 4. rr yy application of the sum and product rule of probability – probability the possibility an outcome will occur – the likelihood of an outcome is predicted on a scale of 0 to 1 – product rule: when two or more events are independent, the probability they will both occur is the product of their individual probabilities – sum rule: applies when several events all give the same outcome, their probabilities are added Lecture Outcomes way in which inheritance of polygenic traits show that inheritance is not "blended" – some characters follow a pattern of inheritance in which there are more or less even graduation of types forming a continuous distribution – typically a continuous distribution is the result of polygenic inheritance – several different genes contribute to the same character – if a plot of the trait produces a bell curve with fewer individuals at the extremes and the greatest numbers at the midpoint its a good indication the trait is polygenetic – therefore children present at intermediate and extremes, not supporting that traits are bended, because they would be phased out characteristics of Mendel's work that set him apart as a genetic researcher – techniques and conclusions were advanced – unable to relate the behaviour of his 'factors' to cell structures because the critical information he required wasn't obtained until later – his work predated the information he was describing components of Mendel's explanatory model – traits are passed from parents to offspring as hereditary factors – predictable ratios and combinations – results with crossing monohybrids could be true if: – the genes govern genetic characters occur in pairs in individuals – if different alleles of a gene are present in a pair in an individual; one allele is dominant over the other – the two alleles of a gene segregate and enter gametes singly parental genotypes & distribution of progeny, given parental genotypes in monohybrid, dihybrid and sex-linked crosses monohybrid – F1 heterozygote produced from a cross that involves a single character – PP x pp = 100% Pp offspring (monohybrids) monohybrid cross – a cross between two individuals that are heterozygous for the same pairs of alleles – F1 x F1 = 25% Dh, 50% DH, 25%rh – Pp x Pp = 25% PP, 50% Pp, 25% pp test cross – used to determine whether an individual with a dominant trait is a heterozygote or a homozygote – PP x pp = 100% Pp offspring therefore homozygote – Pp x pp = 50% Pp and 50% pp therefore heterozygote dihybrid – a zygote produced from a cross that involves two characters – RR YY x rr yy = 100% Rr Yy offspring dihybrid cross: – a cross between two individuals that are heterozygous for two pairs of alleles – Rr Yy x Rr Yy = 9:3:3:1 ratio – 9 = R Y – 3 = r Y – 3 = R y – 1 = r y sex linked: genetics of human ABO blood groups – the four blood types A, B, AB and O are produced by different combinations of three alleles of a single gene I – the three alleles are Ia Ib and i type A = Ia Ia or Ia i type B = Ib Ib or Ib i type AB = Ia Ib type O = ii people with type A have: – antigen A on their red blood cells – antibodies against antigen B – donors (A or O) people with type B have: – antigen B on their red blood cells – antibodies against antigen A – donors (B or O) people with type O – neither antigen A or B – have both antibodies against A and B – donors (O only) people with type AB – both the A and B antigens – neither A or B antibodies – donors (A, B, AB, or O) location of various alleles on homologues segregation of various alleles during meiosis number of different gametes produced, given parental genotype Lecture 12: Inheritance in Populations - chapter 10.2, a,b&f, 15, 16.1, 16.2 BED IS Outcomes strategy to distinguish between a phenotype that results from codominance relative to incomplete dominance – incomplete dominance will produce 1/4, 1/2, 1/4 ratios of allele frequencies when two are crossed – co dominance will produce same inheritance pattern – co dominance is when both traits are shown – incomplete dominance is a blend of both traits characteristics that identify a pleiotropic allele – typically a continuous distribution of phenotypes for a trait indicates polygenetic inheritance – can be detected by defining classes of variation – if the plot of results produces a bell shaped curve (fewer at the extremes and greatest numbers clustered around the midpoint) good indication the trait is polygenetic Lecture Outcomes general pathway of eukaryotic membrane protein production. – proteins are assembled from amino acids by ribosomes attached to the endoplasmic reticulum – vesicles – golgi complex function of various MC1R alleles in general physiology of skin/hair pigmentation. – melanincortin 1 receptor – located on the plasma membrane of melanocytes – produce pigment through the proccess of melan0genesis – black, red, yellow melanin produced by melanges, packed into melansomes – melanosomes get exported to keratinocytes which give skin and hair their colour – black and red = brown – MC1R is embedded in membrane – if cAMP levels are high, makes black melanin, lower red melanomes – brown allele can switch on and off making black and red – cAMP levels are high all the time, not sensitive to hormones – cAMP levels are always high b/c black on characteristics of dominant alleles. – dominance occurs because of interaction of genetic production – never actively inhibits recessive gene – one that's on all the time determines phenotype – R alleles off all the time, cAMP levels always low which allele in a heterozygote is dominant, given the biochemical mechanism of action of allele products. – dominance occurs because of interaction of genetic production – never actively inhibits recessive gene factors that affect how allele frequencies change over time in a population. – no selection = no change in allele frequency – no selection, dominant allele does not exceed – in a large population the starting frequency of allele influence future allele frequencies. – inheritance has nothing to fo with changes in allele frequency allele frequencies (p and q), given genotypic frequencies – HW – p^2 +2pq + q^2 = 1 function of various MC1R alleles. Lecture 13: Selection and Fitness – chapter 13, pg 244-249 EPP IS Outcomes meaning of deme, population, allele frequency, genotype frequency – deme: a local interbreeding population of a species – population: a group of sexually interbreeding individuals – genotype frequency: the frequency or proportion of genotypes in a population allele frequencies in a population, given the genotype frequencies – 3:1 ratio of dominant to recessive phenotypes genotype frequencies in the next generation, given the allele frequencies and assuming Hardy-Weinberg equilibrium – allele frequencies do not depend on dominance or recessiveness – remain unchanged from one generation to the next provided that mating is random and and all genotypes are equally viable – allele and genotype frequencies can be predicted with HWE Lecture Outcomes conditions necessary for Hardy-Weinberg equilibrium – refers to situation in which evolution is not happening – mutation rate low enough to be ignored – most important: no selection at locus being observed – large population – random mating – no immigration – no emigration – no selection whether a population is in HWE, given observed genotype or phenotype – divide frequency by total populations – multiply by number of alleles (recessive and dominant) – calculate total frequency over total population frequencies effect of selection on changes in allele frequency – HW used for expected genotype frequencies – if not evolving then HW should show expected frequencies – compare observed frequencies to determine if population in HWE – if in HWE no selection forces occurring – if one or more of the assumptions of HWE is violated then then pop. may be evolving – evolution = change in allele frequencies relative vs. absolute fitness – for each genotype we can estimate (based on reproductive success, survival...etc) its average absolute fitness (W) and average relative fitness (w) how to calculate relative fitness – fittest genotype has w = 1 – all other genotypes w = W/Wmax – difference in w between genotypes reflects strength of selection how to quantify strength of selection – strength of selection pressure important – for one genotype can differ in relative fitness and absolute fitness – the higher it is, the more fit it is (relative fitness) – the most fit gene always has a relative fitness of 1 – everything else has a lower relative fitness – if difference in w is large selection is strong = faster evolution – smaller difference = smaller selection relationship between dominance/recessiveness of alleles and response to selection. – dominance relationships can constrain selection – heterozygotes carry recessive allele and shield allele from selection – prevents natural selection from complete extinction of an allele – important to know if a allele is dominant or recessiveness – harmful recessive allele is never removed from population – favourable recessive allele will eventually out do the harmful dominant alleles effect of heterozygote advantage on genetic variation – equilibrium between two alleles is impossible without new mutations – not so if heterozygote has superior reproductive fitness to both homozygotes – know as homozygote advantage – usually expressed in genes that affect fitness (longevity, number of offspring produced, resistance to disease) why the amount of genetic variation in a population is important – cheetah threatened because of lack of genetic variation – can't adapt to environmental changes – inbreeding depression: increased expression of deleterious, recessive alleles – most genetic disorders are due to recessive alleles different types of selection (stabilizing, directional) and their effect on genetic variation stabilizing selection: – large and small individuals most likely to die – close to middle of distribution more likely to survive – decrease in genetic variation for the trait under selection – baby body weight – most widespread type of selection directional selection – second most common selection – gradual change in mean value – one end had relatively high selection – one end has high fitness – changes mean value from one population to the next – results in lower genetic variability – all low fitness alleles weeded out disruptive selection – extreme values for a trait are favoured over intermediate values – variance of the trait increases as the population is divided into two groups Lecture 14: Selection Versus Other Evolutionary Forces – chapter 15 EPP – chapter 13, pg. 249 only IS Outcomes difference between Batesian and Mullerian mimicry & how the population frequency of a mimic phenotype may affect its fitness Batesian: – frequency dependent selection – species that mimic distasteful models are protected against predators – the more frequent the mimic and less frequent the model the greater the chance the predator will attack the mimic – conversely, the less frequent the mimic compared to the model, the greater the chance the mimic will be protected Mullerian – mimicry between different species – benefits both species by enabiling predators to learn a single warning pattern that applies to all potentially distasteful prey – when rare, patterns offer little protection b/c predators will have had less negative experiences with the pattern – when common, offer greater protection to unpalatable individuals why the same phenotype may be selected against in one environment but have a selective advantage in a different environment – spatial and temporal organization of an environment may significantly affect the extent to which a population will rely on genetic polymorphism as an adaptive strategy – ex. industrial melanism – environments pose different selection pressures meaning of genetic load and genetic death – genetic load: the extent to which a population departs from an optimal genetic constitution – genetic death: sterility, inability to find a mate, any means that reduces reproductive ability, or death before a reproductive age Lecture Outcomes effect of various types of selection on amount of variation in a population. – stabilizing: decreases variability of trait selected against – directional: shifts mean value, results in lower genetic variability – disruptive: increases variance as population is divided into two distinct groups examples of stabilizing, directional, disruptive. – stabilizing: baby body weight, babies with very high or low weight causes complications – directional: cheetahs, speed, long tailed birds – disruptive: birds in the south, small/large breaks reasons why directional selection does not remove all genetic variation from a population. – environment change, recessive alleles in heterozygotes, not in the same direction all of the time – environment dictates fitness for selection pressures characteristics, and examples, of frequency dependent selection. – depends of frequency of population – negative frequency dependent selection: – advantage to being rare – predators preferentially hunt common forms – rare male mating advantage (females prefer mating with rare males) – positive frequency dependent selection: – predators learn warning coloration – selection goes to whichever is most common – more common = more bad experiences eating – common allele replaces negative allele reasons why all living things are not perfectly adapted to their environment. – limited by available genetic variation availability – limited by dominance relationships – play catch
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