13 - Genetic Variation in Individuals and Populations I.pptx.pdf

Akhobadze Madona M.D., PhD Genetic Variation in Individuals and Populations: Mutation and Polymorphism (I) 2022  Content: Categories Of Human Mutation, The Origin Of Mutations, Types Of Mutations And Their Consequences, Human Genetic Diversity, Inherit...

Akhobadze Madona M.D., PhD Genetic Variation in Individuals and Populations: Mutation and Polymorphism (I) 2022  Content: Categories Of Human Mutation, The Origin Of Mutations, Types Of Mutations And Their Consequences, Human Genetic Diversity, Inherited Variation And Polymorphism In DNA Reading: Ch. 9 - Thompson & Thompson Genetics in Medicine, Robert L. Nussbaum, Roderick R. McInnes, Seventh Edition  MUTATION Mutations—inherited changes in the genetic material— provide new genetic variation that allows organisms to evolve genes that are transmitted from parents to offspring during reproduction genetic information is accurately duplicated during the semiconservative replication of DNA heritable changes in the genetic material are called mutations THE TERM MUTATION REFERS TO (1) the change in the genetic material and (2) the process by which the change occurs An organism that exhibits a novel phenotype resulting from a mutation is called a mutant any sudden, heritable change in the genotype of a cell or an organism Mutational changes in the genotype of an organism include changes in chromosome number and structure, as well as changes in the structures of individual genes MUTATION ultimate source of all genetic variation; it provides the raw material for evolution Without mutation, all genes would exist in only one form. Alleles would not exist, populations of organisms would not be able to evolve and adapt to environmental changes if mutations occurred too frequently, they would disrupt the faithful transfer of genetic information from generation to generation MUTATIONS CAN BE CLASSIFIED INTO THREE CATEGORIES: 1. genome mutations - mutations that affect the number of chromosomes in the cell 2. chromosome mutations - mutations that alter the structure of individual chromosomes 3. gene mutations - mutations that alter individual genes GENOME MUTATIONS alterations in the number of intact chromosomes (called aneuploidy) arising from errors in chromosome segregation during meiosis or mitosis Missegregation of a chromosome pair during meiosis causes genome mutations responsible for conditions such as trisomy 21 Down syndrome GENOME MUTATIONS Genome mutations produce chromosomal aneuploidy and are the most common mutations seen in humans with a rate of one missegregation event per 25 to 50 meiotic cell divisions developmental consequences of many such events may be so severe that the resulting aneuploid fetuses are spontaneously aborted shortly after conception without being detected. Genome mutations are also common in cancer cells CHROMOSOME MUTATIONS changes involving only a part of a chromosome partial duplications or triplications, deletions, inversions, and translocations can occur spontaneously or may result from abnormal segregation of translocated chromosomes during meiosis occurring at a rate of approximately one rearrangement per 1700 cell divisions, less frequently than genome mutations these mutations are rarely perpetuated from one generation to the next because they are usually incompatible with survival or normal reproduction. Chromosome mutations are also frequently seen in cancer cells GENE MUTATIONS changes in DNA sequence of the nuclear or mitochondrial genomes ranging from a change in as little as a single nucleotide to changes that may affect many millions of base pairs errors introduced during the normal process of DNA replication, or mutations arising from a failure to repair DNA Some mutations are spontaneous, whereas others are induced by physical or chemical agents called mutagens  EXAMPLES OF GENE MUTATION The first base of the second codon is mutated by a base substitution, deletion, or insertion. Both the single–base pair deletion and insertion lead to a frameshift mutation in which the translational reading frame is altered DNA Replication Errors DNA repair enzymes first recognize which strand in the newly synthesized double helix contains the incorrect base and then replace it with the proper complementary base, a process termed proofreading The enzyme DNA polymerase faithfully duplicates the double helix, through a combination of strict base pairing rules (A pairs with T, C with G) and molecular proofreading Repair of DNA Damage 10,000 and 1,000,000 nucleotides are damaged per human cell per day by spontaneous chemical processes such as depurination, demethylation, or deamination by reaction with chemical mutagens (natural or otherwise) in the environment; and by exposure to ultraviolet or ionizing radiation Some but not all of this damage is repaired THREE MAJOR FACTORS OF SPONTANEOUSLY OCCURRING MUTATIONS ARE: (1) the accuracy of the DNA replication machinery, (2) the efficiency of the mechanisms that have evolved for the repair of damaged DNA, and (3) the degree of exposure to mutagenic agents present in the environment. Perturbations of the DNA replication apparatus or DNA repair systems, both of which are under genetic control, have been shown to cause large increases in mutation rates MUTATION: BASIC FEATURES OF THE PROCESS Mutations occur in all organisms from viruses to humans. They can occur spontaneously or be induced by mutagenic agents. Mutation is usually a random, nonadaptive process. mutations provide new genetic variability that allows organisms to adapt to environmental changes. mutations have been, and continue to be, essential to the evolutionary process Seth Wright in 1791 on his farm by the Charles River in Dover, Massachusetts Among his flock of sheep, Wright noticed a peculiar male lamb with unusually short legs used the new short-legged ram to breed his ewes in the next season. Two of their lambs had short legs. Short-legged sheep were then bred together, and a line was developed in which the new trait was expressed in all individuals. MUTATION: SPONTANEOUS OR INDUCED Spontaneous mutations are those that occur without a known cause. They may truly be spontaneous, resulting from a low level of inherent metabolic errors, or they may actually be caused by unknown agents present in the environment. Induced mutations are those resulting from exposure of organisms to physical and chemical agents that cause changes in DNA (or RNA in some viruses). Such agents are called mutagens; they include ionizing irradiation, ultraviolet light, and a wide variety of chemicals MUTATION: A REVERSIBLE PROCESS mutation in a wild-type gene can produce a mutant allele thatresults in an abnormal phenotype the mutant allele can also mutate back to a form that restores the wild-type phenotype. That is, mutation is a reversible process The mutation of a wild-type gene to a form that results in a mutant phenotype is referred to as forward mutation When a second mutation restores the original phenotype lost because of an earlier mutation, the process is called reversion or reverse mutation Reversion may occur in two different ways: (1) by back mutation, a second mutation at the same site in the gene as the original mutation, restoring the wild-type nucleotide sequence, or (2) by suppressor mutation, a second mutation at a different location in the genome, which compensates for the effects of the first mutation Back mutation restores the original wild-type nucleotide sequence of the gene, whereas a suppressor mutation does not Suppressor mutations may occur at distinct sites in the same gene as the original mutation or in different genes, even on different chromosomes. TYPES OF MUTATIONS AND THEIR CONSEQUENCES Nucleotide Substitutions Missense Mutations A single nucleotide substitution (or point mutation) in a DNA sequence can alter the code in a triplet of bases and cause the replacement of one amino acid by another in the gene product they alter the “sense” of the coding strand of the gene by specifying a different amino acid hemoglobinopathies Nucleotide Substitutions Chain Termination Mutations replacement of the normal codon for an amino acid by one of the three termination codons are called nonsense mutations Since translation of mRNA ceases when a termination codon is reached a mutation that converts a coding exon into a termination codon the mRNA carrying a premature mutation is often unstable (nonsense-mediated mRNA decay), and no translation is possible Even if the mRNA is stable enough to be translated, the truncated protein is usually so unstable that it is rapidly degraded destroy a termination codon and allow translation to continue until the next termination codon is reached Nucleotide Substitutions RNA Processing Mutations introns to be excised from unprocessed RNA and the exons spliced together to form a mature mRNA requires particular nucleotide sequences located at or near the exon-intron (5′ donor site) or the intron-exon (3′ acceptor site) junctions Mutations that affect these required bases at either the splice donor or acceptor site interfere with (and in some cases abolish) normal RNA splicing at that site Nucleotide Substitutions “Hotspots” of Mutation Nucleotide changes that involve the substitution of one purine for the other (A for G or G for A) or one pyrimidine for the other (C for T or T for C) are called transitions In contrast, the replacement of a purine for a pyrimidine (or vice versa) is called a transversion POINT MUTATIONS Mutations that involve changes at specific sites in a gene include the substitution of one base pair for another or the insertion or deletion of one or a few nucleotide pairs at a specific site in a gene “HOTSPOTS” OF MUTATION Mutations alter the nucleotide sequences of genes in several ways, for example the substitution of one base pair for another or the deletion or addition of one or a few base pairs Watson and Crick pointed out that the structures of the bases in DNA are not static Hydrogen atoms can move from one position in a purine or pyrimidine to another position—for example, from an amino group to a ring nitrogen. Such chemical fluctuations are called tautomeric shifts. TAUTOMERIC SHIFTS rare, but they may be of considerable importance in DNA metabolism because some alter the pairing potential of the bases The more stable keto forms of thymine and guanine and the amino forms of adenine and cytosine may infrequently undergo tautomeric shifts to less stable enol and imino forms The bases would be expected to exist in their less stable tautomeric forms for only short periods of time. if a base existed in the rare form at the moment that it was being replicated or being incorporated into a nascent DNA chain, a mutation would result. When the bases are present in their rare imino or enol states, they can form adenine-cytosine and guanine-thymine base pairs The net effect of such an event, and the subsequent replication required to segregate the mismatched base pair, is an A:T to G:C or a G:C to A:T base-pair substitution Mutations resulting from tautomeric shifts in the bases of DNA involve the replacement of a purine in one strand of DNA with the other purine and the replacement of a pyrimidine in the complementary strand with the other pyrimidine. Such base-pair substitutions are called transitions. Base-pair substitutions involving the replacement of a purine with a pyrimidine and vice versa are called transversions. There are three substitutions—one transition and two transversions—possible for every base pair. A total of four different transitions and eight different transversions are possible  Deletions and Insertions Small Deletions and Insertions When the number of bases involved is not a multiple of three and when it occurs in a coding sequence, the reading frame is altered beginning at the point of the insertion or deletion resulting in frameshift mutations  Deletions and Insertions Large Deletions and Insertions deletions within the large dystrophin gene on the X chromosome in Duchenne muscular dystrophy or the large neurofibromin gene in neurofibromatosis type 1 Many cases of a-thalassemia are due to deletion of one of the two α-globin genes on chromosome 16, β-thalassemia is only rarely due to deletion of the β-globin gene Another type of point mutation involves the addition or deletion of one or a few base pairs. Base-pair additions and deletions within the coding regions of genes are collectively referred to as frameshift mutations because they alter the reading frame of all base-pair triplets in the gene that are distal to the site at which the mutation occurs POINT MUTATIONS All three types of point mutations—transitions, transversions, and frameshift mutations—are present among spontaneously occurring mutations large proportion of the spontaneous mutations that have been studied in prokaryotes are single base-pair additions and deletions rather than base-pair substitutions These frameshift mutations almost always result in the synthesis of nonfunctional protein gene products.  Deletions and Insertions Effects of Recombination recombination between different members of the Alu family class of interspersed repeated DNA located in introns of the low-density lipoprotein receptor gene has been documented as the cause of a duplication of several exons, resulting in familial hypercholesterolemia Recombination occurring between mispaired chromosomes or sister chromatids can lead to gene deletion or duplication The mechanism of unequal crossing over is believed to be responsible for deletion of one of the α-globin genes in α-thalassemia  Dynamic Mutations The mutations in disorders such as Huntington disease and fragile X syndrome involve amplification of trinucleotide repeat sequences may expand during gametogenesis, in what is referred to as a dynamic mutation, and interfere with normal gene expression MUTATION: SOMATIC OR GERMINAL A mutation may occur in any cell and at any stage in the development of a multicellular organism. The immediate effects of the mutation and its ability to produce a phenotypic change are determined by its dominance, the type of cell in which it occurs, and the time at which it takes place during the life cycle of the organism. In higher animals, the germ-line cells that give rise to the gametes separate from other cell lineages early in development All nongerm-line cells are somatic cells. Germinal mutations are those that occur in germ-line cells, whereas somatic mutations occur in somatic cells. If dominant mutations occur in germ-line cells, their effects may be expressed immediately in progeny. If the mutations are recessive, their effects are often obscured in diploids. Germinal mutations may occur at any stage in the reproductive cycle of the organism. If the mutation arises in a gamete, only a single member of the progeny is likely to have the mutant gene. If a mutation occurs in a primordial germ-line cell of the testis or ovary, several gametes may receive the mutant gene, enhancing its potential for perpetuation. the dominance of a mutant allele and the stage in the reproductive cycle at which a mutation occurs are major factors in determining the likelihood that the mutant allele will be manifested in an organism If a mutation occurs in the DNA of cells that will populate the germline, the mutation may be passed on to future generations somatic mutations occur by chance in only a subset of cells in certain tissues and result in somatic mosaicism as seen, for example, in many instances of cancer Somatic mutations cannot be transmitted to the next generation.  HUMAN GENETIC DIVERSITY During the course of evolution, the steady influx of new nucleotide variation has ensured a high degree of genetic diversity and individuality When a variant is so common that it is found in more than 1% of chromosomes in the general population, the variant constitutes what is known as a genetic polymorphism alleles with frequencies of less than 1% are, by convention, called rare variants Genetic Polymorphism There are many types of polymorphism Some polymorphisms are due to variants that consist of deletions, duplications, triplications, and so on, of hundreds to millions of base pairs of DNA and are not associated with any known disease phenotype Other similarly sized alterations are rare variants that clearly cause serious illness INHERITED VARIATION AND POLYMORPHISM IN DNA Single Nucleotide Polymorphisms SNPs usually have only two alleles corresponding to the two different bases occupying a particular location in the genome SNPs are common and occur on average once every 1000 base pairs, which means that there is an average of 3,000,000 differences between any two human genomes The total number of variant positions among all humans is far greater and is estimated to be more than 10,000,000, although this estimate is likely to be too low since we certainly do not yet have a complete catalogue of all variants, particularly the rare ones, in every ethnic group across the globe INHERITED VARIATION AND POLYMORPHISM IN DNA Insertion-Deletion Polymorphisms caused by insertion or deletion (indels) of between 2 and 100 nucleotides Indels number in the hundreds of thousands in the genome indels are referred to as simple because they have only two alleles, that is, the presence or absence of the inserted or deleted segment the other half are multiallelic due to variable numbers of a segment of DNA that is repeated in tandem at a particular location Multiallelic indels are further subdivided into microsatellite and minisatellite polymorphisms  Microsatellites stretches of DNA consisting of units of two, three, or four nucleotides, such as TGTG... TG, CAACAA... CAA, or AAATAAAT... AAAT, repeated between one and a few dozen times The different alleles in a microsatellite polymorphism are the result of differing numbers of repeated nucleotide units contained within any one microsatellite and are therefore often referred to as short tandem repeat polymorphisms or STRPs.  Minisatellites results from the insertion, in tandem, of varying numbers of copies of a DNA sequence 10 to 100 base pairs in length, known as a minisatellite has many alleles due to variation in the number of copies of the minisatellite that are repeated in tandem, referred to as variable number tandem repeats (VNTRs) Simultaneous detection of a number of minisatellite polymorphisms was one of the first methods of DNA fingerprinting to be used for identity testing DNA fingerprinting of twins by means of a probe that detects VNTR polymorphisms at many loci around the genome. Each pair of lanes contains DNA from a set of twins. The twins of the first set (as well as the twins of the third set) have identical DNA fingerprints, indicating that they are identical (monozygotic) twins. The set in the middle have clearly distinguishable DNA fingerprints, indicating that they are fraternal twins.  Copy Number Polymorphisms most recently discovered form of human polymorphism are copy number polymorphisms (CNPs) CNPs consist of variation in the number of copies of larger segments of the genome, ranging from 200 bp to nearly 2 Mb CNPs are most readily discovered by the application of a new technology, array comparative genome hybridization გმადლობთ, ყურადღებისთვის!!!