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GPP Lecture handouts
Introduction to Genetics (BLGY1232)
University of Leeds
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Genetics Pedagogies Project, School of Philosophy, Religion and History of Science Lecture 1: What is genetics? Inheritance as we observe it Offspring resemble parents in broad terms i. same species Offspring often share more similarities with their parents than with individuals But they are not identical to either parent or to their siblings (except in the case of identical twins) What is the mechanism that ensures both this continuity of inheritance and this variation? Genetics aims to answer this question Inheritance and development Organisms are not born whatever is inherited has to go through a process of development to get from to mature individual The inherited material i. genes, guide development but do not entirely determine it There are other factors acting throughout the lifetime Organism and environment What is the environment? Internal vs external Complex interaction between genes and environment Examples of traits affected inheritance and environment a) Organisms with the same inheritance can develop in very different ways depending on the environment In social insects like bees and ants queens and workers are genetically identical but morphologically very different due to different feeding as larvae All larvae are fed on royal jelly for three days, but are then moved onto pollen and nectar, while continue on royal jelly b) Organisms in the same environment can develop differently under the influence of different genes Leptin is a hormone that is involved in appetite regulation and metabolism ob mutation affects function of leptin and causes mice to be abnormally obese they both overeat and metabolise food less efficiently Internal environment In the womb: congenital anomalies affect approx. 1 in 33 babies (WHO) 1 Genetics Pedagogies Project, School of Philosophy, Religion and History of Science cases due to factors, including: o Infections: rubella o Chemicals: pesticides, heavy metals (lead, mercury etc) o Radiation o Medicines: retinoic acid (acne medications) o Recreational drugs o Alcohol o Smoking o Maternal nutrition: folic iodine cases have no identified specific cause In the egg: provides the environment for the very first cell divisions in development e. proteins laid down during the production of the Drosophila egg (before fertilization) determine body axis formation in the embryo Terminology: Phenotype An observable character or characters in an may refer to structural or functional characters e. blood group, hair colour Genotype The genetic of an individual with respect to a given characteristic(s) e. an individual with the phenotype blood group O has the genotype OO. Remember that genes interact with one another and with the environment so that individuals with the same genotype do not necessarily have the same phenotype e. honey bee queen vs worker, and Haploid Describes a cell or individual with a single copy of each chromosome e. an egg or sperm cell Diploid Describes a cell or individual with two copies of each chromosome e. a normal human somatic cell Gene A sequence of DNA that affects a given characteristic of an organism producing a protein or RNA molecule e. a sequence on human chromosome 9 produces the ABO antigens. Genome The complete genetic of an individual or species (for all characteristics) Locus The position of a gene on a chromosome: for ABO blood group the locus is chromosome 9, 9q34.1q34 Allele One or more alternative variations of a particular gene that can exist at that gene locus e. A, B, and O alleles for blood groups Homozygote A diploid individual with two identical alleles at a given locus e. (in ABO blood groups) AA or BB Heterozygote 2 Genetics Pedagogies Project, School of Philosophy, Religion and History of Science Lecture 2: Basic Development Development one cell to many cells As discussed in the last lecture, organisms do not appear in the world complete and fully formed The organism has to undergo a process of development from a single cell to a organism In humans: from 1 cell trillion cells Around 200 different cell types: nerve, bone, skin, liver, retina etc. etc. etc. Development begins at fertilization Haploid GAMETES (also known as GERM CELLS) i egg and sperm each have a single copy of each chromosome 23 in humans (all other cells in the body are diploid and are called SOMATIC CELLS) Gametes fuse to form a diploid ZYGOTE or fertilized egg Note that the sperm cell is much smaller than the egg and contains little cytoplasm, so the cytoplasm of the zygote is largely from the egg i. maternally derived Genomic equivalence Because all of the cells of the organism derive from the zygote cell division, they all contain the same set of genetic material or genome Each cell (or expresses a certain of this genome Cells do not lose the genes they do not express but retain the potential (in the right circumstances) to express any or all of the genes in the genome genes are expressed in most or all cells as they are necessary for basic processes of metabolism, cell division etc. Other genes are expressed only in certain cell types e. ABO blood antigens (see Lecture 1) Some genes have multiple functions depending on the cell type, location in the organism and time e. sonic hedgehog Evidence for genomic equivalence Genomic equivalence was demonstrated cloning o Removing the haploid nucleus from an unfertilized egg cell and replacing it with a diploid nucleus from a somatic cell of another individual o Given the right conditions the egg will develop into a genetic of the original organism, showing that all of the original genome has been retained 4 Genetics Pedagogies Project, School of Philosophy, Religion and History of Science Cell potentials TOTIPOTENT cells can develop into any embryonic structure and into structures (chorion i. embryonic part of the placenta) PLEURIPOTENT cells can become any embryonic cell type which is why ICMs are favoured for stem cell research but not structures UNIPOTENT cells can only replicate themselves (in normal circumstances) Cell differentiation depends on communication Cell differentiation depends on cells receiving and responding to signals ( turning genes on and off) o from the maternal cytoplasm o from the own genes o from other cells around them o from the environment Maternal gene effects to zygotic gene effects products of maternal genes in the cytoplasm of the egg guide the early stages of development e. axis formation in Drosophila. This is known as maternal effect at the TRANSITION the zygotic genome begins to be expressed the maternal gene products activate the first zygotic genes, which in turn signal other zygotic genes to turn on etc. e. segmentation in Drosophila Environmental effects on development developmental effects can be perturbed environmental effects o e. in sea urchins, water condition salinity, temperature, pH levels etc. can alter embryonic development o in vertebrates, neural tube closure (essential for proper development of the brain and spinal cord) is highly dependent on dietary factors 1 in live human births are affected spina bifida failure of the neural tube to close fully This incidence can be cut supplementation with folic acid Chance in development White spotting o Melanocyte migration in black and white cats The pigment cells originate in the neural crest on the dorsal side of the embryo and migrate around the developing body to the ventral side Certain genes interfere with this migration so that the pigment cells do not make it all the way around the body hence black cats with white feet and white bellies The specific gene has not been identified in cats (though there is a known gene in mice that has similar effects) 5 Genetics Pedagogies Project, School of Philosophy, Religion and History of Science Other resources: Developmental biologist Scott Gilbert with more on the evidence for genomic equivalence: A chance to explore the debate about the ethics of stem cell research in more depth: Gap genes and pair rule genes in Drosophila at the Interactive Fly: The genetics of calico cats: For more on cloning and (and check out the additional resources) Lecture 3: How does it all work? Genes are necessary but not sufficient to create an organism The search for the genetic material The genetic must be capable of accurate reproduction to explain the continuity we observe in inheritance must be capable of change to explain the variation we see in inheritance (and evolution) must be able to encode a great deal of information because living organisms are extremely complex Chromosomes behave consistently with hereditary factors germ cells have half the number of chromosomes that somatic cells do Chromosomes are made largely of protein and nucleic acids (deoxyribonucleic acid or DNA and ribonucleic acid or RNA) protein was a better candidate for the genetic material, because it has a more complex chemical composition than nucleic acids 7 Genetics Pedagogies Project, School of Philosophy, Religion and History of Science transforming principle (1928) genetic material from a lethal smooth strain of bacteria somehow transforms the rough strain, making it lethal Avery et al. (1944): DNA is the transforming principle If you destroy the RNA in the bacterial preparation, it can still transform rough cells into smooth cells, but if the DNA is destroyed, the transformation no longer happens therefore the DNA must be the transforming principle Further support for DNA as the genetic material DNA is localised in the nucleus (and we know that the nucleus is crucial in reproduction) Germ cells contain half the amount of DNA that somatic cells do (and we know that the germ cells contain half of the hereditary material) DNA is highly stable, where RNA and protein are not (we know that the hereditary material must be stable, in order to ensure continuity in inheritance) Structure of DNA Any proposed model for the structure of DNA has to fulfil certain requirements: Must explain how DNA can be accurately replicated Must explain how DNA can encode a huge amount of information Must be made of sugar nitrogenous bases (adenine, cytosine, guanine, thymine) phosphate group, all in equal quantities Must obey rules Quantity of adenine (A) quantity of thymine (T) Quantity of cytosine (C) quantity of guanine (G) In humans: o A o T o C o G Ratios differ in different organisms but always A T and C G From diffraction studies o Must have a helical structure with 10 nitrogenous bases for each turn of the helix 8 Genetics Pedagogies Project, School of Philosophy, Religion and History of Science There are different types of RNA: Messenger RNA (mRNA): translated into amino acid sequence of proteins Some RNAs are not translated into proteins they are functional in themselves Ribosomal RNA (rRNA): makes up the ribosome on which mRNA is translated to produce proteins Transfer RNA (tRNA): brings amino acids to the ribosome during translation Small nuclear RNA (snRNA): involved in RNA processing (splicing) Translation: mRNA protein Amino acids are the building blocks of protein molecules In translation, the mRNA acts as a template for a chain of amino acids See above for the function of rRNAs and tRNAs in translation The genetic code With 4 bases (A, U, C, G) there are 64 possible triplets, known as codons 61 of these combinations encode the 20 amino acids found in living organisms (these are known as sense codons) a particular triplet of bases encodes each amino acid e. lysine the code is degenerate with 2 exceptions (AUG for methionine and UGG for tryptophan) there is more than one triplet encoding each amino acid the code is continuous no nucleotides are missed the code is the mRNA is read in successive, discrete groups of three nucleotides the code is (almost) universal with a very few exceptions, the code is the same in all organisms there are 3 stop codons to indicate the end of translation (known as nonsense codons) and one to initiate the start (AUG, which also encodes the amino acid methionine) The amino acid string goes through several levels of folding to create the final, functional protein molecule (see PowerPoint slide) Required readings: On the role that small RNAs play in gene expression: 10 Genetics Pedagogies Project, School of Philosophy, Religion and History of Science On the role of the environment in regulating gene expression: On epigenetics: Nessa Carey, The Epigenetics Revolution, Icon Books, 2011, Introduction and Chapter 4 (paper copies provided). Other resources: A fantastic Lego animation of DNA replication: For more information on transcription factors: James idiosyncratic but entertaining account of the discovery of the structure of DNA, The Double Helix, is available in the library (bear in mind that this is personal perspective and not everyone agrees with his portrayal of other people involved). Watson and 1953 paper is available in the Nature archive at together with several other relevant papers from the time. An animated guide to protein folding: Lecture 4: How does it all work 2 Mutations (changes in the DNA sequence) Spontaneous mutations Chemical changes in bases o Minor chemical changes in bases can lead to e. C changing to U or T, or loss of bases leaving a gap in the DNA sequence, which is then filled randomly any of the 4 bases Replication errors o Replication is balanced between speed and accuracy 11 Genetics Pedagogies Project, School of Philosophy, Religion and History of Science a) agents Make chemical changes to a single base in the DNA sequence o e. nitrous acid changes cytosine to uracil leading to a change from pair chemical mutagens are often used to induce mutations in model organisms for experimental purposes o e. ENU is known as a because it induces point mutations at a very high rate throughout the genome used in the Nobel Prize winning zebra fish screening programme in the mid1990s 49 male fish were treated with ENU, causing random DNA point mutations in their sperm cells over different mutant strains were identified in their descendants b) Base analogs chemically similar to normal bases and replace them during DNA replication base analogs can spontaneously change chemical state o e. (5BU) In one state, 5BU pairs with A in place of T When 5BU changes its chemical state it pairs with G instead Result (after subsequent DNA replication) is that an pair is replaced with a pair And the reverse can happen if the 5BU is in its G binding state when it is incorporated c) Intercalating agents e. acridine insert themselves between bases in the strand, creating a gap that is complemented at random during DNA replication, with any one of the 4 bases results in an insertion and therefore a frameshift Mutations can also be induced radiation High energy radiation gamma radiation) causes breaks in the DNA strand Subsequent of missing bases can lead to mutations UV exposure causes formation of thymine dimers Adjacent T bases on the DNA strand develop a chemical bond which distorts the DNA helix, interfering with normal DNA replication transcription This can happen up to times per second in a cell exposed to UV 13 Genetics Pedagogies Project, School of Philosophy, Religion and History of Science Normally the repair mechanisms can deal with these However, if you are over exposed the number of dimers that form is too much for the repair processes to deal with and the cell is damaged and will die leads to symptoms of sunburn Thymine dimers form at random in the genome If they occur in genes involved in regulating cell division (e. p53 tumour suppressor), and are not repaired, they can interfere with gene expression and this can lead to uncontrolled, abnormal cell division i. cancer Note that this is a statistical phenomenon UV exposure entail the development of cancer, but the more exposure, the more thymine dimers will form, the less chance they will be repaired, and the greater chance they will occur in a crucial gene Consequences of mutations A stable mutation leads to a variant allele Haplophenotype is the phenotype associated with a single allele o If the mutation is silent, or conservative, the phenotype will be normal o or frameshift mutations can lead to malfunctioning or differently functioning proteins So an individual heterozygous for the mutant allele could have one of a number of phenotypes o If the product of a single copy of the allele is sufficient for normal function (i. haplosufficient) the mutation will have no effect on the individual i. phenotype will be normal o If the normal allele is not haplosufficient, the phenotype will be mutant e. individual may suffer a disorder Severity depends on how much the function of the mutant protein is affected An individual homozygous for the mutant allele will suffer more severe symptoms than a heterozygote Epigenetics Molecular mechanisms that alter the way genes are expressed, therefore alter the phenotype (without changing the DNA sequence) Can be mediated environmental factors (but not always) Can be passed on to offspring (but not always) 14 Genetics Pedagogies Project, School of Philosophy, Religion and History of Science Methylation or acetylation (addition of an acetyl group COCH3) of these tails can modulate gene expression either increasing or decreasing it In the example on the slide, acetylation of the amino acid tail of the histones reduces the affinity of the histones for DNA the loosening the structure and making the DNA more accessible for transcription. This process is generally reversible allows gene expression to be altered in response to circumstances Kabuki Syndrome o Affects 1 in live births. Symptoms include: Developmental delay Intellectual impairments Small stature Seizures Characteristic facial features cases due to mutations in the MLL2 gene on chromosome 12 o Mainly de novo mutations MLL2 failure to activate certain genes via histone modification is an epigenetic process The inactive X chromosome (Xi) produces Xist RNA o This ncRNA binds to Xi, wrapping it up This in turn leads to histone changes and repressor recruitment Xi becomes tightly so that no transcription (other than Xist) can take place These modifications are passed on to daughter cells at cell division Inherited epigenetic effects In the Dutch Hunger Winter (Nov 1944 May 1945), due to a combination of blockades preventing food supplies getting through and very severe weather conditions, reducing local supplies, widespread malnutrition in Netherlands. 20K people died of starvation Good medical record keeping means that we can study the effects. Looking at women who were pregnant during the Hunger Winter: o If they were malnourished in the 1st trimester, and then ate normally for the rest of the pregnancy, their babies were normal weight at birth 16 Genetics Pedagogies Project, School of Philosophy, Religion and History of Science o If they ate normally in the first stages of the pregnancy, but were malnourished in the last trimester, their babies were born small (this is to be expected because most growth takes place in the last trimester). But the effects seem to pass on to the next generation o the children of the normal babies (whose mothers had been malnourished in the 1st trimester) were likely to be heavier than average, even though their mothers ate normally during their pregnancies. Related effects have been observed in male lineages: o In an isolated region of northern Sweden in the late 19th and early 20th centuries, there were periodic serious food shortages, interspersed with periods of plentiful food supply so you would eat a lot when you got the chance! Men who went through a period of food shortage in their slow growth period (the years just before puberty, around had sons with a decreased risk of CVD Men who had plentiful food during SGP had grandsons with an increased risk of diabetic diseases Evidence for inherited epigenetic effects We yet fully understand the mechanisms of these phenomena in humans but there is some evidence from studies of animal models For example, (in a particular inbred strain of mice) o When males are fed a low protein, high sugar diet, and females are fed normally, the offspring show abnormal patterns of expression in genes involved in metabolism, and changes in epigenetic modifications in the liver o When pregnant female rats are exposed to high doses of a fungicide called vinclozolin (used in wine making) at a certain point in pregnancy, their male offspring are born with defects in development of the testicles and reduced fertility AND of males are affected for the next 3 generations A later study showed that exposure to vinclozolin leads to unusual patterns of DNA methylation (suggesting an epigenetic effect) 17 Genetics Pedagogies Project, School of Philosophy, Religion and History of Science An excellent BBC documentary on the discovery of epigenetics: Horizon: The Ghost in your Genes Royal Society Lecture on Genetics, Epigenetics and Disease: Professor Steve Jones on nurture or neither? What we do not know about Lecture 5: Chromosomes, linkage and genetic maps Human Karyotypes and Chromosome Structure Karyotype diploid chromosome profile as seen in somatic cells all the pairs are matched up and arranged in order Remember from Lecture 1: Haploid Describes a cell or individual with a single copy of each chromosome e. a human egg or sperm cell contains 23 chromosomes Diploid Describes a cell or individual with two copies of each chromosome e. a normal human somatic cell contains 46 chromosomes (22 pairs of autosomes and 1 pair of sex chromosomes: XX or XY) Each pair of chromosomes (e. the copy of chromosome 1 inherited from the father and the copy of chromosome 1 inherited from the mother) is called a homologous pair Within the chromosome: the strand of DNA is wrapped around groups of histone proteins the complex formed the DNA together with the proteins is called chromatin (meaning because of the way it takes up certain chemical stains and shows up under the microscope) the packaging process continues, winding the chromatin tighter and tighter in the chromosome, in preparation for cell division Each chromosome has: 19 Genetics Pedagogies Project, School of Philosophy, Religion and History of Science o A short arm p arm o A long arm q arm o A centromere a specialized region of the chromosome, important in the movement of the chromosome within the cell during cell division Prior to cell division, the chromosome duplicates to form sister chromatids (e. 2 copies of the chromosome 1 inherited from the father) which remain connected at the centromere NOTE: it is essential that you do not confuse homologous pairs of chromosomes with pairs of sister chromatids, so make sure you are clear on the definitions above Cell cycle M phase both nuclear division and cell division (cytokinesis) take place in M phase chromosomes are visible only during this period I (interphase) chromatin is unravelled to allow transcription and replication take place so the chromosomes not visible during this phase of interphase: G1 gap (growth) cells that are transcribing and producing proteins necessary for their function but not dividing S synthesis of DNA DNA is replicated G2 gap (growth) cells that do not divide (e. neurons) usually arrest in G1 Proteins necessary for cell division are produced G0 resting phase e. stem cells become quiescent or dormant and divide until needed aging or damaged cells can be pushed into G0 to prevent them dividing and hence propagating errors in DNA replication etc. Mitosis occurs in somatic cells during growth and development e. in embryos, and in cell types with a quick turnover e. skin cells, lining of intestine 1 diploid cell 2 diploid cells identical to the original 20
GPP Lecture handouts
Module: Introduction to Genetics (BLGY1232)
University: University of Leeds
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