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1p DNA Mutations Pocket Hercules OZZIE SKINNER MT(AMT), CLT, MAOM JAMES A. HALEY VA HOSPITALMOLECULAR DIAGNOSTICS03/23/2013
2MUTATIONS What and how do mutations occur? A mutation is a permanent change in the DNA sequence of a geneCan cause problems with growth, development, and function of the body’s systemsMutations in a gene's DNA sequence can alter the amino acid sequence of the protein encoded by the geneThese changes can affect many genes along the chromosome and disrupt the proteins made from those genesThe effects of structural changes depend on their size and location, and whether any genetic material is gained or lostCan affect the DNA sequence of a cell's genome or the DNA or RNA sequence of a virusOne look around THIS room tells you that each person has slight differences in their physical make up — and therefore in their DNA. These subtle variations in DNA are called polymorphisms (literally "many forms"). Many of these gene polymorphisms account for slight differences between people such as hair and eye color. But some gene variations may result in disease or an increased risk for disease. Although all polymorphisms are the result of a mutation in the gene, geneticists only refer to a change as a mutation when it is not part of the normal variations between people.A sudden change in the amount, arrangement or structure of the DNA of an organism.Central Dogma of Molecular Biology
3MUTATIONS What and how do mutations occur? Mutations range in size from a single DNA building block(DNA base) to a large segment of a chromosomeGene mutations occur in two ways: they can be inheritedfrom a parent or acquired during a person’s lifetimeHereditary (or germline) mutations: are passed from parent to childAcquired (or somatic) mutations: occur in the DNA of individual cells at some time during a person’s lifeThese changes can be caused by environmental factors or if a mistake is made as DNA copies itself during cell divisionAcquired mutations in somatic cells (cells other than sperm and egg cells) cannot be passed on to the next generationSome genetic changes are very rare; others are common in the populationGenetic changes that occur in more than 1 percent of the population are called polymorphismsGermline MutationsGermline Mutations are present in the egg and sperm cells, which are also called germ cells).This type of mutation is present throughout a person’s life in virtually every cell in the body.Mutations that occur only in an egg or sperm cell, or those that occur just after fertilization, are called new (de novo) mutations. De novo mutations may explain genetic disorders in which an affected child has a mutation in every cell, but has no family history of the disorder.Acquired/Somatic MutationsAlterations in DNA that occur after conception.Somatic mutations can occur in any of the cells of the body except the germ cells (sperm and egg) and therefore are not passed on to children.
4MUTATIONS Affects on health and development A gene is a recipe for making a proteinEach cell depends on thousands of proteins to do their jobs in the right places at the right timesBy changing a gene’s instructions for making a protein, a mutation can cause the protein to malfunction or to be missing entirelyWhen a mutation alters a protein that plays a critical role in the body, it can disrupt normal development or cause a medical conditionA condition caused by mutations in one or more genes is called a genetic disorderIncompatible with life: changes occur in genes that are essential for development, and often disrupt the development of an embryo in its earliest stagesIt is important to note that genes themselves do not cause disease—genetic disorders are caused by mutations that make a gene function improperly.
5MUTATIONS Affects on health and development Only a small percentage of mutations cause genetic disordersSome mutations alter a gene’s DNA base sequence but do not change the function of the protein made by the geneOften, gene mutations that could cause a genetic disorder are repaired by certain enzymes before the gene is expressed (makes a protein)Although most mutations that change protein sequences are harmful or neutral, some mutations have a positive effect on an organism (e.g. 32 base pair deletion in human CCR5/Delta 32 mutation/HIV resistance)A Few FactsNew genetic diseases are discovered every month; as of 2001, there are estimated to be approximately 1,100 genetic diseases.Genetic diseases are present in 8 percent of live births.Nucleotides are the alphabet of DNA. There are only four "letters" in DNA : adenine (A), thymine (T), guanine (G) and cytosine (C). They always go by pairs, A with T, and G with C. Such pairs are called "base pairs".Almost every cell in our body contains a complete copy of our genome. The exceptions are egg/sperm cells, which only carry half of our genome, as well as red blood cells and some white blood cells, which have no DNA at all (otherwise blood transfusions would often cause an immune reaction, like organ transplants).If unfolded the DNA in each cell's nucleus would be 2 meters long. Humans have an estimated 100 trillion cells. In other words, if the all the DNA from every cell in a person's body were patched up together they would form a strand of 200 billion kilometers, or more than 1,000 times the distance between Earth and the Sun.There are in fact 23 pairs of chromosomes, each person inheriting a maternal and paternal copy of each. Pairs of chromosomes are numbered from the largest (chromosome 1) to the smallest (chromosome 21).“Mutations are often Bad, but,……………………..…..………… some can be Good”
6First, Smallpox, then The Black Death of 1348 MUTATIONSFirst, Smallpox, then The Black Death of 1348Came out of the East, and reached the shores of Italy in the spring of 1348.Unleashed a rampage of death across Europe.Within three years, anywhere between 25% and 50% of Europe's population had fallen victim to the pestilence.The plague presented itself in three interrelated forms:The bubonic variant (the most common)+ swellings or buboes that appeared on a victim's neck, armpits or groin.+ Victims had a life expectancy of up to a week+ Infected fleas that attached themselves to rats and then to humans spread this bubonic type of the plague.Pneumonic plague+ attacked the respiratory system and was spread by merely breathing the exhaled air of a victim.+ life expectancy was measured in one or two days.Black Plague Mutations derived from SmallpoxIn 180 AD, Marcus Aurelius, a conqueror better known as the Stoic Emperor of Rome, succumbed to some sort of disease, which may have been smallpox, brought into Rome by soldiers returning from Seleucia. Many soldiers also died from this, known as Galen's Plague.Ancient history includes vivid descriptions of epidemics that seized their victims suddenly and produced an agonizing death. One such episode occurred in Athens, Greece, in 430 B.C.E., and another occurred in Egypt, Persia, and Rome a century later.Oriental rat flea“Regurgitates”
7MUTATIONS The Black Death, 1348 Septicemic version of the disease attacked the blood systemHaving no defense and no understanding of the cause of the pestilence, the men, women and children caught in its onslaught were bewildered, panicked, and finally devastatedThe plague disease, generally thought to be caused by Yersinia pestis. (Gram negative, bipolar staining coccobacilli)The "black death" again devastated Europe during the 14th century over a 5 year period causing 25 million deathsWho was to blame?
8The Black Death, 1348 - DNA evidence MUTATIONSThe Black Death, DNA evidenceSurvivorsHowever, some were able to survive the devastating Black Plague, such as the residents of Eyam, EnglandThe village had quarantined itself in order to stop the plague from spreading beyond the villageInvestigationIn October 2010 a multinational medical group investigated the role of Yersinia pestis in the Black DeathThey tested DNA and protein signatures specific for Y. pestis in human skeletons from widely distributed mass graves all over Europe that were associated archaeologically with the Black Death.The new research ends the debate about the etiology of the Black Death, and decidedly demonstrates that Y. pestis was the causative agent of the epidemic plague that devastated Europe during the Middle AgesThe obvious question,How did the residents of Eyam survive?.
9MUTATIONSThey developed the Delta 32, CCR5 Mutation in the gene for the human chemokine receptor 5 (CCR5)How HIV Enters the White Cells – The MechanismSome rare strains of HIV infect via the CXCR4 receptor so by no means does a positive result for CCR5 delta 32 allow someone to engage in risky behaviorDelta 32 codes for a protein on the surface of white blood cells which acts as a receptor for other molecules involved in inflammationThe CCR5Δ32 mutation results in a nonfunctional protein that cannot serve as a cell surface co-receptor and, thus, confers some resistance to HIV-1 infectionPeople who have two copies (homozygous) of the Delta 32 mutation were virtually immune to The Black DeathThe Delta 32 mutation is more common in people of Northern European descent.Chromosome 3
10Mutations are caused by: Radiation:Alpha particles, Beta particles, Gamma rays, Cosmic rays, and X-rays, can wreak havoc on the molecules of your DNACytosine and Thymine – are most vulnerable to radiation that can change their propertiesThe effect of the radiation may not be to kill the cell, but to alter its DNA code in a way that leaves the cell alive but with an error in the DNA blueprintVirusesViruses that use RNA as their geneticmaterial have rapid mutation ratesAn advantage since these viruses will evolve constantly and rapidly, and thus evade the defensive responses of e.g. the human immune system.X-Ray tech leaves the room.Up to 10% of invasive cancers are related to radiation exposureX-rays and gamma rays are known human carcinogens (cancer-causing agents). The evidence for this comes from many different sources, including studies of atomic bomb survivors in Japan, people exposed during the Chernobyl nuclear accident, people treated with high doses of radiation for cancer and other conditions, and people exposed to high levels of radiation at work, such as uranium miners.The effects of radiation on the cell include interference with cell division, damage to chromosomes, damage to genes (mutations), neoplastic transformation (a change analogous to the induction of cancer), and cell death.When radiation creates mutation in non-germ cells, it can eventually lead to loss of the affected cell’s ability to control its division. Though the effect may not appear for a number of years, the eventual, uninhibited cell division may cause cancerous growth.
11MUTATIONS Mutations are caused by: Transposons: (jumping genes) Sequences of DNA that can move or transpose themselves to new positions within the genome of a single cellThe mechanism of transposition can be either "copy and paste" or "cut and paste“Oncogenes (genes that cause tumors) may be activated by the random reshuffling of transposons to a position adjacent to the oncogeneBarbara McClintock found that they were responsible for a variety of types of gene mutations: insertions, deletions and translocationsIn developing somatic tissues like corn kernels, a mutation that alters color will be passed on to all the descendant cellsThis produces the variegated patternwhich is so prized in Indian cornTransposable elements (TEs), also known as "jumping genes," are DNA sequences that move from one location on the genome to another.There are 2 different classes of transposable elements found in the genomes of different eukaryotic organisms:Class I Transposons first transcribe the DNA into RNA and then use reverse transcriptase to make a DNA copy of the RNA to insert in a new location.Class II transposons move by a "cut and paste" process: the transposon is cut out of its location and inserted into a new location.
12MUTATIONS Mutations are caused by: During DNA replication: (SNP/Point mutation)The replacement of a single base nucleotide with another nucleotide of the genetic material, DNA or RNASingle-nucleotide polymorphisms may fall within coding sequences of genes, non-coding regions of genes, or in the intergenic regions (regions between genes)Often the term point mutation also includes insertions or deletions of a single base pair
13MUTATIONS Mutations are caused: During DNA replication: (SNP/Point mutation)One can categorize point mutations as follows:Transitions: replacement of a purine base with another purine or replacement of a pyrimidine with another pyrimidinePurines are Pyrimidines areAdenine and Guanine Cytosine , and ThyminePurines are the double ringed nitrogenous basesPyrimidines are the single ringed nitrogenous basesTransversions: replacement of a purine with a pyrimidine or vice versa.Approximately two out of three single nucleotide polymorphisms (SNPs) are transitions.PUGA2
14MUTATIONS Mutations are caused: During DNA replication: (SNP/Point mutation)Point mutations can also be categorized functionally:Nonsense mutations: Premature stop codon in a DNA sequence or in the transcribed mRNANonsense mutations are known to cause Cystic fibrosis, Beta thalassaemia , and Hurler syndromeStart codon (ATG) MethionineDNA stop codons are TAG, TAA, and TGARNA stop codons are UAG, UAA, and UGALack the enzyme to break down long chains of sugar molecules
15MUTATIONS Mutations are caused by: sickle-cell disease During DNA replication: (SNP/Point mutation)Point mutations can also be categorized functionally:Missense mutations: point mutation in which a single nucleotide is changed, resulting in a codon that codes for a different amino acidMissense mutations are known to cause sickle-cell diseasesickle-cell diseaseGlutamineAspartic acid
16MUTATIONS Mutations are caused by: During DNA replication: (SNP/Point mutation)Point mutations can also be categorized functionally:Silent mutations: DNA mutations that do not result in a change to the amino acid sequence of a proteinA point mutation that changes a codon to a synonym (one that codes for the same amino acid) is also known as a synonymous mutationAbout 50 genetic diseases have been linked to synonymous mutationsThis includes silent mutations in CFTR, the gene that is linked with Cystic fibrosis.
17MUTATIONS Mutations are caused by: Deletions: Example A mutation in which a part of a chromosome or a sequence of DNA is missingDeletion is the loss of genetic materialDeletions can be caused by errors in chromosomal crossover during meiosis (process of cell division in sexually reproducing organisms)Small deletions are less likely to be fatal; large deletions are usually fatalDeletions genetic disorders can range from:Male infertility to Duchenne muscular dystrophy to “Cri du chat”ExampleOriginal The fat cat ate the wee rat.Deletion The fat ate the wee rat.
18Notice anything unusual? Cri du chat syndrome / 5p- syndrome
19MUTATIONS Mutations are caused by: Example Duplications Duplications occur when part of a chromosome is copied (duplicated) too many timesThis type of chromosomal change results in extra copies of genetic material from the duplicated segmentDuplications arise from an event termed unequal crossing-over that occurs during meiosis between misaligned homologous chromosomes (corresponding chromosomes from each parent)Duplications of oncogenes are a common cause of many types of cancerExampleOriginal The fat cat ate the wee rat.Duplication The fat cat cat ate the wee rat.
20MUTATIONS Mutations are caused by: Inversions An inversion involves the breakage of a chromosome in two places; the resulting piece of DNA is reversed and re-inserted into the chromosomeGenetic material may or may not be lost as a result of the chromosome breaksAn inversion that involves the chromosome’s constriction point (centromere) is called a pericentric inversionAn inversion that occurs in the long (q) arm or short (p) arm and does not involve the centromere is called a paracentric inversionExampleOriginal: The fat cat ate the wee rat.Insertion: The fat tar eew eht eta tac.If inversion leads to an embryo having too few or too many copies of genes, the embryo can miscarry, fail to grow, or be born alive with substantial medical problems.If chromosome 16 is affected by just one inversion it can cause leukemia
21MUTATIONS Mutations are caused by: Inversions On the left of the diagram is human chromosomenumber 5 (of 23)On the right of the diagram is the matchingchromosome from a chimpanzeeThe region from p14.I to q14.I, the order has beenflippedEvolutionist calls this a inversion mutation betweenMan and ChimpOverall, there are nine inversion mutations betweenman and chimpanzeeChromosome 5
22MUTATIONS Mutations are caused by: Isochromosomes An isochromosome is a chromosome with two identical armsInstead of one long (q) arm and one short (p) arm, an isochromosome has two long arms or two short armsAs a result, these abnormal chromosomes have an extra copy of some genes and are missing copies of other genesAssociated diseasesGirls with Turner syndromePallister-Killian syndromeSome tumors
23MUTATIONS Mutations are caused by: Dicentric chromosomes: human chromosome 2Unlike normal chromosomes, which have a single constriction point (centromere), a dicentric chromosome contains two centromeresDicentric chromosomes result from the abnormal fusion of two chromosome pieces, each of which includes a centromere. These structures are unstable and often involve a loss of some genetic materialAssociated diseasesMyelodysplasia (MDS):A collection of conditions that result whenbone marrow cells produce damagedcells that don't mature properlyAcute Myeloid Leukemia (AML)
24MUTATIONS Mutations are caused by: Ring chromosomes Ring chromosomes usually occur when a chromosome breaks in two places and the ends of the chromosome arms fuse together to form a circular structureThe ring may or may not include the chromosome’s constriction pointIn many cases, genetic material near the ends of the chromosome is lostRing chromosomes may form in cells following genetic damage by mutagens like radiation, they may also arise spontaneously during developmentAssociated diseasesRing chromosome 20 syndrome - epilepsyRing chromosome 14/13-mental retardationRing chromosome 15 - dwarfism
25MUTATIONS Mutations are caused by: Translocation: juxtapositioning When chromosomes break and the fragments rejoin to other chromosomesA gene fusion may be created when the translocation joins two otherwise separated genes, the occurrence of which is common in cancerIt is detected on cytogenetics or a karyotype of affected cellsTranslocations can be balanced or unbalanced
26MUTATIONS Mutations are caused by: Translocation: balanced translocationIn a balanced translocation, pieces of chromosomes are rearranged but no genetic material is gained or lost in the cellWhen a person's cells divide to create egg or sperm cells for reproduction, the egg or sperm cells can end up with extra genetic material or missing genetic materialThis could lead to miscarriage depending on which chromosome and genes are affectedIn about 4.5% of all couples with recurrent miscarriages, one or both parents has a balanced translocation
27MUTATIONS Mutations are caused by: Translocation: unbalanced translocationAn unbalanced translocation occurs when a child inherits a chromosome with extra or missing genetic material from a parent with a balanced translocationThis is usually in the form of a loss of genetic material, called Monosomy and a gain to genetic material, which is TrisomyMonosomy/ TrisomyBoth types of are “aneuploidy” :(having an abnormal number ofchromosomes)
28MUTATIONSMutations are caused by: Trisomy 21/Downs S.
29Mutations are caused by: Monosomy X - genotype 45, X,
31Transgenic Rainbow Trout MUTATIONSMyostatin- is a gene that limits muscle growthThe protein is a member of a superfamily of molecules called transforming growth factors beta (TGF-b) or growth differentiation factor 8Discovered that a mutation in the myostatin gene is responsible for increased muscle mass, also known as 'double muscling‘Scientists hope that myostatin inhibitors may be able to treat diseases such as muscular dystrophyThere is some concern about the possibility of abuse of myostatin inhibitors by athletesIn humans, myostatin is encoded by theMSTN geneAnimals lacking myostatin, have significantlylarger musclesTransgenic Rainbow Trout
32MUTATIONS Myostatin-related muscle hypertrophy Who wants some “rump roast?”“It taste God awful;You said it tasted like chicken”. You lied mama, you lied.If you see me coming at you, don’t run.My muscles are so tight, I couldn’t catch a cold.myostatinmodulatorSiblings