Seminar onMUTATION :Seminar onMUTATION PRESENTED BY , KANCHAN HANMANT MANE . II SEM. MSC MICROBIOLOGY


Index :Index Role of mutation in evolution. Environmental mutagenesis. Toxicity testing. References


ROLE OF MUTATION IN EVOLUTION :ROLE OF MUTATION IN EVOLUTION MUTATION :A mutation is a permanent structural alteration in DNA. In most cases ,DNA changes either have no effect or cause harm but, occasionally a mutation can improve an organism chance of surviving & passing the beneficial change on its descendants. Mutation is either spontaneous or induced.


Slide 4:Mutation commonly seen as something bad often associated with cancer but can also be good or have no effect at all. Mutations are often presented as unfortunate events that happen only occasionally, usually with damaging consequences However, mutations are not at all rare, and the large majority of them are of no concern to us or our offspring. Mutations are the ultimate source of genetic variation, providing the basis for evolution. Without mutations there would be no life! Seen on the time scale of evolution, the short term negative “side effects” of mutations might be diseases as cancer and inborn errors and afflictions. EVOLUTION : Evolution is usually defined as a change in allele frequency over time ,or heritable change or lasting change .


Causes of Mutation: :Causes of Mutation: Induced Mutations exposure to chemical mutagens exposure to ionizing radiation, including ultraviolet rays DNA sequences are altered for no apparent reason, usually due to a DNA replication error. Chromosome replication is 99.999% accurate. Errors in the DNA replication process happen only about once in 100,000 bases. However, the human genome has about 6 billion bases. That means each replication cycle will have 6,000 errors. But DNA repair is also possible. Cells contain several complex systems to fix damage before, during, and after replication. As a result, DNA replication and repair disorders are pretty rare.


Slide 6:Most mutations that occur are quickly lost from the population, often in just one generation. However few Mutations that initially occur at random may end up seeming to be "directed" in highly nonrandom patterns. Within a population, each individual mutation is extremely rare. But at more than six billion of the human species every single base pair of the three billion in the genome in each individual is mutated several times, somewhere in the population, every generation.


Slide 7:However, very small effects on survival and reproduction may greatly affect the long-term rates at which different mutations accumulate in particular genes and at particular sites within genes. Mutations suppose to be random but in fact the result is really nonrandom: some positions in DNA almost never change, some change very few and others change relatively often


Somatic versus germinal mutation :Somatic versus germinal mutation . The first point to consider is where is the mutation occurring? in either somatic or germinal tissue, and these changes are called somatic mutations and germinal mutations respectively. Most of our cells are somatic cells and consequently most mutations are happening in somatic cells. What would be the consequences of a somatic mutation in a cell of a fully developed organism?


Slide 9:If the mutation is in tissue in which the cells are still dividing, then there is the possibility of a mutant clone's arising. If the somatic mutation is in a post mitotic cell—that is, one that is no longer dividing—then the effect on phenotype is likely to be negligible. That is not to say that somatic mutation is unimportant. Cancer occurs as a direct consequence of somatic mutation. Aging may be caused at least in part by the accumulation of somatic mutations with time.


Slide 10:Cancer mutations arise in a special category of genes called proto-oncogenes, many of which regulate cell division. When mutated, such cells enter a state of uncontrolled division, resulting in a cluster of cells called a tumor. The question : May mutation be considered as a BAD THING or a GOOD THING? , One answer is that a change is a good thing because without change life cannot evolve. If it had not been for mutation the world would still be covered in primeval slime! Genetic variability is essential to the process of evolution and the formation of new species. Without mutations in the genetic material of some earlier primate species, we would not be here.


Slide 11:Another answer is : It is a bad thing, because consequence may be a genetic disease. Mutations may be not bad and not good thing because they have no any effect. Mutations in non-coding regions usually do nothing to the phenotype of the individual. Within the coding regions of alleles, some types of mutations have no effect on the resulting proteins.


Slide 12:If a gene is altered in a germ cell, the mutation is termed a germinal mutation. It may affect a single gene or an entire chromosome. Because germ cells give rise to gametes, some gametes will carry the mutation and it will be passed on to the next generation. Germinal mutations may not affect the individuals in which they occur, but may result in genetic disorders in their offspring.


One of variant of germinal mutation is genetic shuffling :One of variant of germinal mutation is genetic shuffling If your mom had genes associated with bushy eyebrows and your dad had genes associated with a big nose. Is this genetic shuffling good, bad, or neutral? Answer: If your spouse is wild about the bushy eyebrows/big nose combination, you were lucky and hit on a winning combination! This shuffling is important for evolution because it can introduce new combinations of genes every generation. However, it can also break up "good" combinations of genes.


The Role of Mutation in Evolution :The Role of Mutation in Evolution If DNA replicated perfectly every time, without errors, the only life-forms existing now would be those that existed about three billion years ago: single-cell organisms. Mutations, therefore, are critical to the development of diverse life-forms. According to the definition of mutations you gave you understand what type of mutation is crucial in evolution? So as the result of mutation changes or abnormality which will appear in the next generations may become so common that it emerges as the norm. Thus Evolution, in fact, is driven by mutation.


The basic mechanisms of evolution: 1. natural selection Darwin's grand idea of evolution by natural selection is relatively simple :The basic mechanisms of evolution: 1. natural selection Darwin's grand idea of evolution by natural selection is relatively simple For example, some beetles are green and some are brown. If birds prefer to eat green beetles then the surviving brown beetles have brown baby beetles because this trait has a genetic basis. Thus brown offspring, becomes more common in the population. If this process continues, eventually, all individuals in the population will be brown. Scientists have worked out many examples of natural selection


NATURAL SELECTION. :NATURAL SELECTION.


Artificial selectionLong before Darwin and Wallace, farmers were using the idea of selection to cause major changes in the features of their plants and animals. :Artificial selectionLong before Darwin and Wallace, farmers were using the idea of selection to cause major changes in the features of their plants and animals. This process is called artificial selection because people (instead of nature) select which organisms get to reproduce. These common vegetables were cultivated from forms of wild mustard. This is evolution through artificial selection.


Misconceptions about natural selection: :Misconceptions about natural selection: First, natural selection does not produce perfection. This should be pretty clear just by looking at the populations around us: people may have genes for genetic diseases, plants may not have the genes to survive a drought, a predator may not be quite fast enough to catch her prey every time she is hungry. No population or organism is perfectly adapted. Second, Natural selection is the simple result of variation, differential reproduction, and heredity — it is mindless and mechanistic. It has no goals; it's not striving to produce "progress" or a balanced ecosystem. Thus Natural selection just selects among whatever variations exist in the population. The result is evolution


Misconceptions about natural selection :Misconceptions about natural selection :Third, natural selection is sometimes interpreted as a random process. Mutations are "random" in the sense that the sort of mutation that occurs cannot generally be predicted based upon the needs of the organism. However, this does not imply that all mutations are equally likely to occur. The genetic variation that occurs in a population because of mutation is random- but selection acts on that variation in a very non-random way: genetic variants that aid survival and reproduction are much more likely to become common than variants that don't. Natural selection is NOT random


About bacteria :About bacteria Bacteria must have evolved on our planet for about 3.8 billion years. The currently found diversity of bacterial life forms is impressive, particularly with regard to their differences in the capacity to live under extreme environmental conditions ,such as chemical composition ,PH, temperature & pressure. In addition many bacterial spe. Have become symbionts or pathogenic & have adapted to living in close community with other organisms.


ENVIRONMENTAL MUTAGENESIS :ENVIRONMENTAL MUTAGENESIS An environmental mutagen, or genotoxin,is a physical or chemical agent that is present in the environment and can induce damage to the genetic material or can cause an alteration in the proper functioning of the genetic material of an organism. The primary function of genetic toxicology isto detect and understand the properties ofagents that induce deleterious effects ingenetic elements at doses below those that induce physiological toxicity. It will publish manuscripts in the six general areas of mechanisms of mutagenesis; genomics; DNA damage; replication, recombination, and repair; public health; and DNA technology.


Slide 22:We are using a variety of chemicals in our industries & to these chemicals millions of works are being exposed regularly. Even our agriculture is being industrialized & also we are using large no. of chemicals in the form of fertilizers , insecticides ,fungicides etc. The present work in industry & agricultural expose themselves to chemicals in other ways For e.g. : medicines ,food dyes, food preservatives, dyes . It will not be on exaggeration to state that chemicals have become an important part of our life. Our technology has greatly increased the amounts of various gases like Co ,Co2 , So2 ,No,No2, H2S ,that can be quiet hazardous for e.g. Sulfurous gases enter the atmosphere through industrial & automobile combustion.


Slide 23:Reaction : SO2 + H2O ? H2SO4?H+ + HSO3 Both so2 & H2so3 have been shown to be mutagenic in a number of organisms. No & No2 are produced during combustion of fossil fuels. NO2 + H2O ? HNO3 HNo2 is a potent mutagen as such . light NO2 ? NO + O2 All these examples are mutagenic combustion produces one another class of hazardous chemicals known as “Hydrocarbons”. Some of these hydrocarbons are directly mutagenic ,while other are metabolically converted in to mutagens.


Toxicity testing :Toxicity testing The means by which the toxicity of a chemical or other test material is determined Genetic Toxicology deals with the study an characterization of physical and chemical agents that affect the hereditary material, and its mechanisms, of living organisms.


Dimensions of the Toxic Chemical Problem :Dimensions of the Toxic Chemical Problem Chemical entities 4-10 million Developed annually ~6000 In commerce ~65,000 In common use ~6,000 Regulated water 129 air 25


SINGLE DOSE ACUTE TOXICITY TESTING FORPHARMACEUTICALS :SINGLE DOSE ACUTE TOXICITY TESTING FORPHARMACEUTICALS INTRODUCTION – Acute toxicity studies in animals are usually necessary for any pharmaceutical intended for human use. The information obtained from these studies is useful in choosing doses for repeat-dose studies, providing preliminary identification of target organs of toxicity, and, occasionally, revealing delayed toxicity. Acute toxicity studies may also aid in the selection of starting doses for Phase 1 human studies, and provide information relevant to acute overdosing in humans. II. DEFINITION – Acute toxicity is the toxicity produced by a pharmaceutical when it is administered in one or more doses during a period not exceeding 24 hrs.


TESTING PROCEDURES :TESTING PROCEDURES The test compound should be administered to animals to identify doses causing no adverse effect & doses causing major (life-threatening) toxicity. The use of vehicle control groups should be considered. For compounds with low toxicity, the maximum feasible dose should be administered .Acute toxicity studies in animals should ordinarily be conducted using two routes of drug administration: (1) The route intended for human administration, and (2) intravenous administration, if feasible. When intravenous dosing is proposed in humans, use of this route alone in animal testing is sufficient. Studies should be conducted in at least two mammalian species, including a non rodent species when reasonable. The objectives of acute studies can usually be achieved in rodents using small groups of animals (for instance, three to five rodents per sex per dose). Where non rodent species are appropriate for investigation, use of fewer animals may be considered. Any data providing dose-range finding data for repeat-dose toxicity studies, may be acceptable.


IV. OBSERVATION :IV. OBSERVATION Animals should be observed for 14 days after pharmaceutical administration. All mortalities ,clinical signs, time of onset, duration, and reversibility of toxicity should be recorded. Gross necropsies should be performed on all animals, including those sacrificed moribund, found dead ,or terminated at 14 days. In addition, if acute toxicity studies in animals are to provide the primary safety data supporting single dose safety/kinetic studies in humans (e.g., a study screening multiple analogs to aid in the selection of a lead compound for clinical development), the toxicity studies should be designed to assess dose-response relationships and pharmacokinetics. Clinical pathology and histopathology should be monitored at an early time and at termination (i.e., ideally, for maximum effect and recovery.


Toxicology – Historical Perspective :Toxicology – Historical Perspective Human (Mammalian) toxicology White Rat Rabbit Dog/Cat Computer simulation?


Referances :Referances www.google.com www.yahoo.com Benjamin Lewin 2002 GENES viii oxford.


Thank you ! :Thank you !