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Joseph Merritt Ramsey
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This 22 page Class Notes was uploaded by Joseph Merritt Ramsey on Tuesday February 9, 2016. The Class Notes belongs to CELL 2050 at Tulane University taught by Dr. Meenakshi Vijayaraghavan in Winter 2016. Since its upload, it has received 32 views. For similar materials see Genetics in Science at Tulane University.
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Date Created: 02/09/16
February 1, 2016 Chapter 5: Non-Mendelian Inheritance (Cont.) Overview: o What Exactly is Mendelian Inheritance? o What is Non-Mendelian Genetics? The Three Categories of Non-Mendelian Inheritance o 1) Nuclear Genes 1. Maternal Effect o 2) Epigenetic Inheritance 1. Dosage Compensation Mechanism – How Do They Form? o The X-Chromosome has a cell inactivation center (Xic) Having an extra Xic (Extra X Chromosome) causes one to be activated This is done randomly o On this activation center are two genes Xist (X Inactive Specific Transcript) – transcribes RNA coating around the Chromosome all the way to the telomere (it’s not considered mRNA because there is no possibility of it being transcribed Tsix – counteracts the Xist o Xist coats the Chromosomes in RNA and recruited compaction proteins Similar to histone compaction process The chromosome is coated, and the coating recruits protein that induces compaction This is in response to the Xic marking o Tsix is the reversal of Xist This prevents Chromosome compaction Creates a complementary RNA strand to Xist (essentially an RNAi actor) The created resulting double strand is degraded very quickly, removing Xist transcript o Interesting finds have occurred, however, with the Xce Region (this is downstream of the Xic region) This is the X-Chromosome Controlling Element Has an impact on which chromosome becomes Barr body When a gain of function mutation occurs on the Xce location, the result is a Tsix expression (which counteracts Xist and leaves the Chromosome open) Gain of function on Xce in a a Chromosome causes Tsix expression Xce causes Tsix expression So the one that lacks Xce activation (from mutation) leads to the preferential creation of Barr body So it can keep activated (and by doing so inactivate the other) a given maternal/paternal chromosome But the normal Xce has no effect Barr Body Process o 1. Initiation Occurs in early stages, up to the Blastula stage Very early on o 2. Spreading Mechanism of the Chosen X Chromosome (The Barr Body) being coated by RNA This is done by the Xist RNA and proteins o 3. Maintenance Every cell that arises afterward shows the same X-Chromosome compaction So Why Barr Bodies? o Amazon Women considerations (Triple X females) There is a masculinization effect because of the slight increase in proteins and hormones during early development So the presence of the Chromosome still makes a difference even though to will be Barr Bodies o They are compacted in very specialized manner to allow some gene transcription 1. Facultative – can switch between heterochromatic and Euchromatic regions 2. Psuedoautosomal Genes that are present on X and Y Chromosomes need to be expressed Otherwise, the Barr Body would defeat the purpose of balancing out protein presence So Dosage Compensation would be reversed Mic2 is a gene present in both So Barr Body regions with Pseudoautosomal can switch between Hetero and Euchomatin 3. Xist Xist has to unwind to make an RNA to coat the Chromosome Has to be allowed to be transcribed so Maintenance of Barr Body can occur 2. Genomic Imprinting Also known as monoallelic imprinting o Phenomena in which expression of a gene depends on whether it’s inherited from the male or female parent o The inheritance is dependent entirely on how the genes are marked o So only one gene is leading to expression (monoallelic) But Haploinsufficiency is dealing with defects Early in process o Occurs in Spermogenesis or Oogensis o Marking memory (chick knowing its mother) Example of IGF2 (Insulin Growth Factor 2) o What were the findings? Normal Father + Mutant Female = NORMAL Mutant Father + Normal Female = ALL MUTANT o The General Rule of Imprinting: Imprinting is silencing o So it is seen with Igf-2 that it is paternal expression Process of Imprinting o Overall 1. Establishment During gametogenesis Which is going to be silenced? 2. Maintenance Development of embryos as well as all somatic cells afterwards Somatic cells of adult 3. Erasure The imprint is removed Occur only in germ cells during Meiosis Then reimprinted as well o Makes it so the presence of imprinting markers only exists during life So imprinting is only present in lifespan Reestablishment is gender specific and occurs during Gametogenesis Examples o House Fly Methodology Male has three X-Chromosomes (2 paternal, 1 maternal) And always the 2 Paternal Chromosomes are silenced They are imprinted (so maternal X is functioning) Father’s are marked for silencing 2X/2Somatic = 1 (Female), 1X/2 Somatic = .5 (Male) o Marsupial Mammals The paternal X is chosen for inactivation Imprinting is a process of silencing o Differential methlylation Methylation occurs on the Chromosome to differentiate function o Involves the presence of an ICR (Imprinting Control Region) A portion is called the Differentially Methylated Domain (DMD) In the specific region with [Cytosine – Thymine – Cytosine] rich region (added to Cytosine) Done either in sperm or oocyte, not both So methylation occurs on Cytosine Addition of Methyl Group causing silencing ICR has 2 sites for binding: 1. Proteins that can enhance transcription (inducing production) 2. Proteins that can inhibit transcription (preventing production) So when you Methylate the region, those binding sites (specifically the enhancement sites) cannot be accessed 1. Causes bending in the Chromosome 2. Sterically hiders access o Methylation prevents enhancer protein binding through: 1. Genomic bending 2. Stereochemical Hindrance o Let’s go back to IGF2 – why is it encoded? The ICR region is large and inclusive of a few genes, three of particular interest: Igf-2 H19 ICR o So a review: Methylation (Imprinting) does not occur in gametogenesis – erasure occurs Adding methylation does not occur during germ production Only later does the imprinting occur based on the given sex o It is erased and then reestablished based on the sex So, if a maternal gene is Expressed, the Paternal gene is silenced In this instance the paternal gene is imprinted (inactivated) So, on the same idea, Maternally Imprinted = Paternal Expression So, in A Paternally Imprinted Chromosome, a maternal mutation results in the disease of interest o Prader Willie is Maternally Imprinted (so mutation in paternal gene results in disease) o Angelman is Paternally Imprinted (so Maternal Deletion results in Disease) So in the table, Expression is the Opposite of Imprinting Gene Allele Expressed Function WT1 Maternal Wilms tumor-suppresor gene; controls excessive growth INS Paternal Insulin production; cell growth hormone Produces Insulin-Like Igf-2 Paternal Growth Factor II; cell growth Igf-2R Maternal Receptor for Igf-2 H19 Maternal Unknown SNRPN Paternal Splicing Factor on genes Gabrb Maternal Neurotransmitter Receptor February 3, 2016 Chapter 5: Non-Mendelian Inheritance (Cont.) Overview: o What Exactly is Mendelian Inheritance? o What is Non-Mendelian Genetics? The Three Categories of Non-Mendelian Inheritance o 1) Nuclear Genes 1. Maternal Effect o 2) Epigenetic Inheritance 1. Dosage Compensation 2. Genomic Imprinting Example of IGF2 Process of Imprinting Imprinting is a process of silencing o Differential methlylation Examples: Angelman Syndrome and Prader-Willie o Angelman – hyperactivity and unusual seizures Paternally Imprinted (so a functional maternal chromosome is adequate) o Prader Willie – reduced motor function, obesity Maternally Imprinted (needs proper Pternal DNA) o The concept of Isodisomy is Important Meiosis provides copies of each (paternal and maternal) Isodisomy results in unequal distribution (so two copies of a chromosome exist from one parent) o A Look at Chromosome 15 PW an AS genes are very close SNRPN (Small Nuclear Ribonucleoprotein) Lack of proper SNRPN expression from the Paternal Chromosome results in Prader-Willie Involved in the removal of introns and splicing exons; creates splicesomes (so issues lead to problems transcribing) UBE3A (Ubiquitin Protein Ligase 3A) Lack of proper UBE3A expression from the Maternal Chromosome results in Angelman Syndrome Ubiquitin tagging of malfunctioning proteins in insufficient o 3) Extranuclear Inheritance Overview – involves DNA and inheritance patterns outside of the nucleus (also known as cytoplasmic inheritance) Extranuclear DNA is congregated and found inside a region called the Nucleoid o A single, circular chromosome of DNA o A Nucleoid can have more than one copy of a chromosome and a chromosome can code for more than one gene o But they also have ORF’s (Open Reading Frames) which encode for polypeptides with unknown functions Mitochondrial DNA (mtDNA) o Have only about 1-5 nucleoids o Chromosomes are about 17,000 base pairs o 13 Genes Most of the genes code for ETC proteins (oxidative phosphorylation proteins) Most genes used in Mitochondria are shipped in Chloroplast DNA (cpDNA) o 150,000-160,000 base pairs (nucleotides) o 110-120 Genes Many still shipped in from outside o 15-20 Nucleoids Examples 1. Maternal Inheritance (seen in the 4 O’clock Flower) o The pigmentation depends solely on the maternal plant And this pigments is present in an Extranuclear location (plant chloroplasts) These are passed through the Eggs’ Cytoplasm A mix of the two is known as heteroplasmy o 4 Test Crosses (all looking at THE LEAF) 1. White Female with Green Male White Offspring 2. Green Female with White Male Green Offspring 3. Variegated Female with Green Male Any of the Three Offspring 4. Green Female with Variegated Male Green Offspring o Leaf Color Similar to the Blastula question with Mouse Coat Color, the somatic cell can contain all mutant chloroplasts, which case it becomes white But if both are present, Green dominates o Heteroplasmy and its Phenotypic Effect 2. Petite Trait (Seen in Yeast) o Mitochondrial Determination of Growth Patterns More mitochondria leads to more growth o Yeast gametes are Isogamous This means there is no real difference between the male and female gametes) o Two Types of Genetic Inheritance Seen 1. Segregational Mutations This is the normal Mendelian expectation for the inheritance patterns In this case, two and two 2. Vegetative Mutations In Vegetative Mutations, one form completely dominates the other, so the two extremes occur Came in to variations: o A. Neutral – the mutant has no effect o B. Suppressive – the mutant form dominates They reproduce rapidly and outpace the wild types o So with the mutants, the mitochondria don’t promote growth as they should 3. Organelles o The effect on inheritance varies among species Gamete production plays a huge role but can be very different But let’s consider most studied species o Heterogamous Organisms (the two produced gametes are different) Female Gamete – the egg is large and full of all the nutrients and machinery to sustain life for a period of time Provides cytoplasm and organelle machinery Male Gamete – much smaller and motile, not constructed to survive for long on its own Has a small package of proteins it uses to fertilize, so no real contribution other than DNA Process considered Oogamous – the female gamete (oocyte) is highly specialized and developed So the offspring inherit all of their organelles from the mother, male or female A rare exception is called paternal leakage, when the sperm contain a few mitochondria o But even with a sever case, 1- 5 paternal exist for every 100,000 maternal o Mitochondrial diseases can arise So because the mother provides all the mitochondria, mitochondrial related disease can be spread more easily Some examples: 1. Liver, Kidney, Brain tissue (higher concentration of mitochondria) 2. Leber’s Heredity Optic Neuropathy (affects retinal ganglion cells) Endosymbiotic Theory o Primordial Eukaryotic cell engulfed smaller Bacterial cells Purple Bacteria – Mitochondria Cyanobacteria – Chloroplasts o There are two aspects to this theory Endocytosis – the cell wall is broken down and the membranes of the two move together Hence the development of the double membraned nature of Chloroplasts and Mitochondria Symbiosis There was some sort of mutual benefit present While it’s not entirely clear, it is thought the Eukaryote gained the ability to Photosynthesize and Produce ATP while the bacteria where now in a nutrient rich environment o This theory is supported by further research: 1. Organelles have circular chromosomes 2. Organelle genes have striking similarities to bacterial genes rather than nuclear genes Chapter 3: Cell Division Genetic Material o Eukaryotes Double stranded, Linear DNA Well defined organelles are present Chromosomes are made of the Chromatin complex (60% protein (histones), 40% DNA o Prokaryotes Double Stranded, Circular DNA Naked DNA (no protein) o Somatic Cells vs. Germ Cells Somatic Cells are Diploid (have two sets of chromosomes) These sets are comprised of pairs, called Homologous Pairs These pairs are identical in many ways Germ Cells are Haploid (have one set of chromosomes) Cytogenetics o Definition – examination of the chromosomal compaction and composition of an organism o Process for Examination 1. Addition of Division Inducing Agent (condenses and duplicates Chromosomes) 2. Allowance of Replication 3. Centrifuge to Stop Replication and Collect Sample (forms sample pellet) 4. Addition of Hypotonic Solution (swells up cells) 5. Drop Cells on a Slide and Fix Them (no more changes can occur) 6. Stain Cells With Geimsa (stains different components differently) 7. Addition of Trypsin (breaks down histones, reveals DNA bands) 8. Photo Imaging (computer or camera) 9. Karyotype Arrangement o Karyotype Arrangement – the entire chromosome complement of an organism arranged from tallest to shortest Homologue Identification 1. Size o While size can help identify Homologues, it is no suggestive of overall genomic complexity of an organism 2. Centromere Position o 1. Meta-Centric – in the middle o 2. Sub-Met-Centric – closer to the middle o 3. Acro-Centric – closer to one end; ‘p’ is short, ‘q’ is long o 4. Telo-Centric – only one arm 3. Banding Patterns o Banding is induced by the addition of the Trypsin o This can identify and differentiate based on Loci, not based on Alleles February 5, 2016 Chapter 3: Cell Division Genetic Material Cytogenetics o Definition o Process for Examination o Karyotype Arrangement – the entire chromosome complement of an organism arranged from tallest to shortest Homologue Identification Why are Karyotypes important? 1. They Allow for Evolutionary Comparisons o Chimps have 48 Chromosomes, with Chromosome 2A and 2B each adding up to the total of Human Chromosome 2 o Banding with Chimps is also seen to have high similarities to that of humans So the Chromosomes are Similar, but not identicial 2. They Can Identify Abnormalities in an Organism Eukaryotic Chromosomes o Homologues form the Diploid number o Cell Division Why do Cells Divide? 1. Asexual Reproduction o Bacteria reproduce through Binary Fission o DNA is replicated, the Septum if formed, and the cell splits into two new identical cells FTSZ: Filamentous Temperature Sensitive Mutant Z responds to trigger Forms a ring and vibrates and recruits eight other proteins to form on the ring around the membrane The new nine protein complex forms the Septum 2. Multicellularity o In complex organisms, multicellularity is achieved through Mitosis When do Cells Divide? Density determines and initiates cellular They accumulate nutrients and proteins (increasing density) o Mitosis Overview Mitosis is a highly complex process occurring in all Eukaryotic cell types Its goal is Replication and Distribution The cells maintain genetic consistency through generations Equal distribution must occur As a random side note, ferns have a Chromosome number over 1000 Displays how sheer volume does not directly translate into complexity All Cells go Through Stages (Common to all dividing cells, whether actively dividing or not) 1. Interphase (G1, S, G2) 2. Prophase 3. Prometaphase 4. Metaphase 5. Anaphase 6. Telophase 7. Cytokinesis Cells also differ in the time for these stages, depending on their purpose and function Bone Marrow: constant replication Elementary Canal Cells: twice a day replication Liver: once a year Neural Cells: terminally differentiated o Interphase G1 Phase (Gap) – Key Words: Density Restriction point is reached, it must progress So progressed into the S Phase S Phase (Synthesis) – Key Words: Replication, Centromere Chromosomes are duplicated (DNA, Histones) Sister Chromatids form around the Centromere o Part of Chromosome (DNA locus) that forms binding site Monad is a single Chromosome, Dyad is the Sister Chromatids G2 Phase (Gap 2)– Key Words: Kinetochore, Organelles Organelles now begin to divide Kinetochore now deposits itself on the Centromere (will eventually connect with Centrosome) o It then moves into the Mitotic stage (M) Now the cell has enough contents for two separate cells, so it needs to split (92 Chromosomes and Numerous Organelles) Mitosis is the splitting process o Cytokinesis is triggered during Anaphase, which starts cytoplasmic division Mitotic Stages o 1. Interphase – o 2. Prophase – Condensation of Chromosome; Plasma membrane Breaks Down; Physical Assembly of Spindle Apparatus All Euchromatic regions (less compacted) now become Heterochromatic Nuclear membrane breaks down into fragments The Nucleolus (area that creates rRNA) disappears Spindle Apparatus forms Physical Assembly from Centrosome and Centriole, the microtubule forming complex) They are assembled, but that’s it: only assembly o 1. Polar Microtubules – deviating the poles o 2. Astin Microtubules – branching to the outside, holding it in position on the Membrane o 3. Kinetochore Microtubules – go on to connect with Kinetochore proteins on the Centromere o 3. Prometaphase – Kinetochore Microtubule Connects to Centromere; Complete Nuclear Membrane Breakdown The spindle apparatus exists to separate sister chromatin Kinetochore begins polymerizing (growing) from the Centrosome to ‘randomly’ attach to the Centromere Any that fails to attach depolymerizes In this manner, the Spindle Apparatus becomes functional It binds so that each sister chromatid is bound to each pole (giving functionality) The Nuclear Membrane also completely disappears now o 4. Metaphase – Arrangement on the Metaplate Sister Chromatids are arranged on the Metaplate of the cell and are connected to each pole The equatorial plane This arrangement is random (paternal and maternal can line up on either side) and in a single file row o 5. Anaphase – Polymerization of Polar Microtubules and Depolymerization of Kinetochore The Chromosome number must be maintained, so the sisters attached at each pole are now separated I. Kinetochore Microtubules Shorten (depolymerizes) o This pulls the chromatids II. Polar Microtubules Lengthen (polymerizes) o This pushes the cell poles The pulling/tugging This separates the Sisters o If not, nondisjunction occurs Each pair of Sister Chromatids becomes single Chromosomes Cytokinesis is initiated by these steps (when the chromosomes are on either end) o 6. Telophase – “Reverse Prophase” Everything in prophase is reversed now: I. Chromosomes – begin to decondense II. Nuclear Membrane – begins to reform III. Nucleolus – begins to become evident again IV. Microtubules Disappear – spindle apparatus breaks down At this point, the cell is binucleate (two nuclei) o 7. Cytokinesis Plant Cells Occur on the Cell Plate Cell plate is formed from Golgi Vesicles carrying plate proteins o The vesicles merge and extend to the side o Once they reach the side Plasma Membrane, maturation of the Cell Wall occurs Contains very large polysaccharides Animal Cells Occurs through Actin movement (done through Myosin) o Actin is already present at the Cell Membrane Cleavage furrow forms from actin overlapping o Ring diameter shrinks Mitosis + Cytokinesis gives you a Genetically Consistent Cell, Mitosis on its own merely gives a Binucleate Cell Sexual Reproduction o Gametes Types I. Isogamy – identical gametes II. Heterogamy – male and female are different and specialized Reduction Division Occurs – division that reduces to haploid Occurs before fertilization They are not daughter cells – genetically inconsistent o Meiosis precedes by Syngamy (germ cell fusion, fertilization) This: 1. Keeps Consistent Chromosome Number 2. Brings About Variation to Increase Survival
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