BIO 101 Module 13 DNA Mutation and Its Impact on Evolution PDF

BIO 101 MODULE 13 DNA MUTATION AND ITS IMPACT ON EVOLUTION We often popularly associate mutation with superhero movies like X-Men and Spiderman, with Hulk being exposed to high amounts of gamma radiation, Cyclops as an inborn mutant, and Spiderman being bitten by a genetica...

BIO 101 MODULE 13 DNA MUTATION AND ITS IMPACT ON EVOLUTION We often popularly associate mutation with superhero movies like X-Men and Spiderman, with Hulk being exposed to high amounts of gamma radiation, Cyclops as an inborn mutant, and Spiderman being bitten by a genetically engineered spider. These show how different factors can cause mutation, and in effect alters one’s ability or trait. Though fictional, mutation in the natural world has the same significant impacts. Mutation is the ultimate source of genetic variations. By understanding the science of mutation, it can provide us with explanations on the diversity of life, a normal versus disease state cell, and how organisms transformed and evolved, among others. Specific Topic Outcomes: At the end of the module, you should be able to: describe DNA mutations and their causes enumerate specific types of DNA mutations evaluate the significance of mutation on genome changes, genetic variations, and evolution Learning Resource: Alberts B, Johnson A, Lewis J, Morgan D, Raff M, Roberts K, Walter P. 2015. Molecular Biology of the Cell. 6th Edition. New York: Garland Science. 1465 pp. o Chapter 4 DNA, Chromosomes, and Genome pp. 216-236 only o Chapter 5 DNA Replication, Repair, and Recombination pp. 266-298 only Links to Open Educational Resources: Alberts et al. 2002. The Maintenance of DNA Sequences: https://www.ncbi.nlm.nih.gov/books/NBK26881/. How Genomes Evolve: https://www.ncbi.nlm.nih.gov/books/NBK26836/ Khan Academy. Genetic Mutations. https://www.khanacademy.org/test- prep/mcat/biomolecules#genetic-mutations. Khan Academy. Impact of mutation on translation into amino acids. https://www.khanacademy.org/science/high-school-biology/hs-molecular-genetics/hs-rna-and- protein-synthesis/v/impact-of-mutations-on-translation-into-amino-acids. Nature Education Scitable. Genetic Mutation. https://www.nature.com/scitable/topicpage/genetic- mutation-1127/. University of Houston's College of Engineering. Lesson: All Sorts of Mutations: Changes in the Genetic Code. https://www.oercommons.org/courses/mutations/view. MODULE CONTENT How Genome Evolved? 1. Evolution depends on mistakes and accidents followed by nonrandom survival. 2. DNA sequences are inherited with fidelity, only one nucleotide pair in a thousand is changed every million years. Mutation - any heritable change in the DNA that may have deleterious or (rarely) advantageous consequences to an organism or its descendants. These are errors in DNA replication, recombination, or repair which causes change in local DNA sequences or large-scale genome rearrangements. Genetics and Molecular Biology Division, Institute of Biological Sciences College of Arts and Sciences, University of the Philippines Los Baños College, Laguna 4031  BIO 101. Introductory Molecular Biology MODULE 13 How does mutation become fixed in the population and become a characteristic of the species? a. If the mutation has deleterious effect, it is eliminated by purifying selection and will not become fixed. b. If the species has a major reproductive advantage, it can spread rapidly in the population. Types of Mutation (Recall BIO 30 Genetics topics on Mutations) 1. Base substitution Simply called as point mutation One base pair is substituted for another Most common type of mutation A popular example is the mutation of Glu to Val which causes sickle cell anemia There are two types: Transition and Transversion a. Transition § Occurs when a purine (A-G) is substituted with other purine (A-G) and when a pyrimidine (T-C) is substituted by another pyrimidine (T-C) b. Transversion § This occurs when a purine is substituted by a pyrimidine and vice versa c. Point mutations that occur in DNA sequences; silent, missense or nonsense. c.1. Silent point mutation If the substitution results to a synonymous codon The amino acid is not changed c.2. Missense When the substitution of a single pair causes the substitution of a different amino acid in the resulting protein. May be categorized as conservative if the properties and functionality of the amino acid was not changed, and otherwise, if non-conservative c.3. Nonsense Nonsense mutation happens when the substitution results to a stop codon. Figure 13.1. Types of Point Mutations. (Image from: Wikimedia Commons. 2010. https://upload.wikimedia.org/wikipedia/co mmons/6/69/Point_mutations-en.png) 2. Deletions Deletion results in frameshift mutations Happens when one or more base pairs are lost from the DNA This mutation results in a protein missing one or two amino acids As the bases adjust, the coded amino acids are different from the normal amino acid sequence Genetics and Molecular Biology Division, Institute of Biological Sciences College of Arts and Sciences, University of the Philippines Los Baños College, Laguna 4031  BIO 101. Introductory Molecular Biology MODULE 13 Figure 13.2. Deletion leading to Frameshift. (Image from: Wikimedia Commons. NHS National Genetics and Genomics Education Centre. 2014. https://upload.wikimedia.org/wikipedia/commons/e/e0/Frameshift_deletion_%2813062713935%29.jpg) 3. Insertion The insertion of additional base pairs results to a frameshift This may result to a different amino acid being coded Figure 13.3. Insertion leading to Frameshift. (Image from: Wikimedia Commons. NHS National Genetics and Genomics Education Centre. 2014. https://upload.wikimedia.org/wikipedia/commons/2/2f/Frameshift_duplication_%2813062836963%29.jpg) Genetics and Molecular Biology Division, Institute of Biological Sciences College of Arts and Sciences, University of the Philippines Los Baños College, Laguna 4031  BIO 101. Introductory Molecular Biology MODULE 13 4. Inversions of chromosomal segments leading to inversion loops 5. Translocations of DNA from one chromosome to another (A) Inversion (B) Translocation Figure 13.4. Inversion (A) and Translocations (B) of chromosomal segments. (Image from: Wikimedia Commons. (A) Ensembl Genome Browser. 2011. https://upload.wikimedia.org/wikipedia/commons/e/ec/Inversion_pericentrique.JPG (B) National Human Genome Research (USA). 2009. https://upload.wikimedia.org/wikipedia/commons/3/30/Translocation.gif) 6. Duplications followed by Divergence a. Genes are duplicated repeatedly and the copies diverged to take on new functions which vary from one species to another. Figure 13.5. The three evolutionary fates of duplicate genes. (Image from: Wikimedia Commons. 2017. https://upload.wikimedia.org/wikipedia/commons/b/b9/Evolution_fate_duplicate_genes_-_vector.svg) b. Gene duplication occurs at high rates in all evolutionary lineages. c. In yeast, the duplications are the result of DNA replication errors from the inexact repair of double-strand chromosome breaks. d. Compared to single-nucleotide substitution, duplications have created more differences between two species. Genetics and Molecular Biology Division, Institute of Biological Sciences College of Arts and Sciences, University of the Philippines Los Baños College, Laguna 4031  BIO 101. Introductory Molecular Biology MODULE 13 e. The fate of Duplicated Genes e.1. Loss-of-function mutations (Degenerative/Gene Loss) e.2. Both copies to remain functional while diverging in their sequence and pattern of expression a. Subfunctionalization b. Neofunctionalization f. Act on a smaller scale to create single genes by stringing together short duplicated segments of DNA Proteins encoded can be recognized by the presence of repeating similar protein domains. Mutagenesis – this is the process of creating mutations or changes in the genetic material. It can be categorized as either spontaneous or induced. Types: (1) Spontaneous Natural processes inside the cell that could be prone to errors or mistakes a) Spontaneous Replication Errors DNA replication though with high fidelity is naturally with errors DNA Polymerase enzymes sometimes insert the wrong nucleotide or too many or too few nucleotides into a sequence Figure 13.6. Spontaneous replication errors which are passed on from one generation to the next. (Image from: Griffiths AJF, Miller JH, Suzuki DT, et al. 2000. An Introduction to Genetic Analysis. 7th edition. New York: W. H. Freeman; 2000. https://www.ncbi.nlm.nih.gov/books/NBK21897/figure/A2711/?report=objectonly) b) Tautomerization Purine and pyrimidine bases in DNA exist in different chemical forms, or tautomers, in which the protons occupy different positions in the molecule Nucleotide base shifting into its rarer tautomeric form (the "imino" or "enol" form) results to base-pair mismatching Genetics and Molecular Biology Division, Institute of Biological Sciences College of Arts and Sciences, University of the Philippines Los Baños College, Laguna 4031  BIO 101. Introductory Molecular Biology MODULE 13 Rare base-pairing arrangements result when one nucleotide in a base pair is the rare form instead of the common form Base In Normal In Tautomeric State Pairs State Pairs with with A T C T A G G C T C G A Figure 13.7. Tautomeric shifts in nucleotide bases. (Image from: 2014 Nature Education Adapted from Pierce, Benjamin. Genetics: A Conceptual Approach, 2nd ed. https://www.nature.com/scitable/topicpage/dna-replication- and-causes-of-mutation-409/) c) Replication Slippage commonly observed replication error occurs at the repetitive sequences when the new strand mispairs with the template strand could cause several repeats to become unpaired can be backward or forward slippage i.e. newly synthesized strand loops out a bit, resulting in the addition of an extra nucleotide base, or when the template strand loops out a bit, resulting in the omission, or deletion, of a nucleotide base in the newly synthesized, or primer, strand, respectively. Usually the cause of microsatellite or simple sequence repeat polymorphism Genetics and Molecular Biology Division, Institute of Biological Sciences College of Arts and Sciences, University of the Philippines Los Baños College, Laguna 4031  BIO 101. Introductory Molecular Biology MODULE 13 Figure 13.8. Replication slippage. (Image from: Molecular Biology Web Book. 2017. https://www.web- books.com/MoBio/Free/Ch7F3.htm) d) Spontaneous Depurination / Deamination or Spontaneous Lesions caused by normal chemical reactions two types of errors: i. depurination, bond connecting a purine to its deoxyribose sugar is broken by a molecule of water, resulting in a purine-free nucleotide that cannot act as a template during DNA replication ii. deamination, loss of an amino group from a nucleotide, again by reaction with water Most of these spontaneous errors are corrected by DNA repair processes If repair does not occur, a nucleotide that is added to the newly synthesized strand can become a permanent mutation Figure 13.9. Depurination and Deamination. Griffiths AJF, Miller JH, Suzuki DT, et al. 2000. An Introduction to Genetic Analysis. 7th edition. New York: W. H. Freeman; 2000. https://www.ncbi.nlm.nih.gov/books/NBK21897/figure/A2721/?report=objectonly) Genetics and Molecular Biology Division, Institute of Biological Sciences College of Arts and Sciences, University of the Philippines Los Baños College, Laguna 4031  BIO 101. Introductory Molecular Biology MODULE 13 (2) Induced Mechanisms of outside agents or mutagens as a result of its interaction with the DNA Mutagens are any chemical or physical agents that can induce mutations a) Chemical Mutagens 1. Base Analogues Incorporation of some chemical compounds that are sufficiently similar to the normal nitrogenous bases of DNA Can produce mutations by causing incorrect nucleotides to be inserted opposite them in replication Example: o 5-bromouracil (5-BU) is an analog of thymine that has bromine at the C-5 position in place of the CH3 group found in thymine o 2-aminpurine analog of adenine that can pair with thymine but can also mispair with cytosine when protonated Figure 13. 10. Mutagenic effect of 5-bromouracil (5-BU) and 2-aminopurine (2-AP). (Image from: Griffiths AJF, Miller JH, Suzuki DT, et al. 2000. An Introduction to Genetic Analysis. 7th edition. New York: W. H. Freeman; 2000. https://www.ncbi.nlm.nih.gov/books/NBK21936/figure/A2734/?report=objectonly) 2. Base Modifying agents Alkylating agents (adds Me or Et groups) Epoxides and tetraethyl lead Ethylmethane sulfonate (EMS) and methylmethane sulfonate (MMS) o Alkylates G Figure 13.11. Examples of Base Modifying Agents. (Image from: Griffiths AJF, Miller JH, Suzuki DT, et al. 2000. An Introduction to Genetic Analysis. 7th edition. New York: W. H. Freeman; 2000. https://www.ncbi.nlm.nih.gov/books/NBK21936/figure/A2736/?report=objectonly) Genetics and Molecular Biology Division, Institute of Biological Sciences College of Arts and Sciences, University of the Philippines Los Baños College, Laguna 4031  BIO 101. Introductory Molecular Biology MODULE 13 3. Intercalating Agents another important class of DNA modifiers flat molecules that insert themselves between adjacent bases in the double helix, causing distortion at the point of insertion includes proflavin, acridine orange, and a class of chemicals termed ICR compounds oxidation of benzo[a]pyrene and covalent binding to DNA Aflatoxin B1 generates apurinic sites following the formation of an addition product at the N-7 position of guanine Figure 13.12. Intercalating Agents. (Image from: Griffiths AJF, Miller JH, Suzuki DT, et al. 2000. An Introduction to Genetic Analysis. 7th edition. New York: W. H. Freeman; 2000. https://www.ncbi.nlm.nih.gov/books/NBK21936/figure/A2737/?report=objectonly) b) Physical Mutagens 1. UV Radiation generates a number of photoproducts in DNA Two different lesions that occur at adjacent pyrimidine residues o cyclobutane pyrimidine photodimer o 6-4 photoproduct Figure 13.13. Structure of cyclobutane pyrimidine dimer and 6-4 photoproduct. Griffiths AJF, Miller JH, Suzuki DT, et al. 2000. An Introduction to Genetic Analysis. 7th edition. New York: W. H. Freeman; 2000. https://www.ncbi.nlm.nih.gov/books/NBK21936/figure/A2740/?r ) eport=objectonly UV Radiation at 260 nm Genetics and Molecular Biology Division, Institute of Biological Sciences College of Arts and Sciences, University of the Philippines Los Baños College, Laguna 4031  BIO 101. Introductory Molecular Biology MODULE 13 dimerization of adjacent pyrimidine bases o cyclobutyl dimer / thymine dimer (6-4) lesion o (6-4) photoproduct distorts helix as DNA bases are pulled closer extensive cleavage of H-bonds inhibits advance of replication fork Other UV UV-A: nearly visible range (320nm) causes pyrimidine dimers. UV-B: (290-320nm) emitted by the sunlight. These UV rays are highly lethal to our DNA. UV-C: (180-290nm) one of the most energy-consuming forms of the UV which is extremely lethal 2. Ionizing Radiation X-rays, gamma rays, high speed e-s or alpha particles; fast-moving neutrons More potent than UV Effects: o formation of rare tautomeric enols o removal of C from the DNA o favored formation of the imine tautomer of C o production of ss/ds breaks on the DNA backbone 3. Heat stimulates water-induced cleavage of the β-N-glycosidic bond results in an AP / baseless site not normally mutagenic because cells have effective systems for repairing nicks Figure 13.14. Baseless site formation. (Image from: Griffiths AJF, Miller JH, Suzuki DT, et al. 2000. An Introduction to Genetic Analysis. 7th edition. New York: W. H. Freeman; 2000.) Genetics and Molecular Biology Division, Institute of Biological Sciences College of Arts and Sciences, University of the Philippines Los Baños College, Laguna 4031 BIO 101. Introductory Molecular Biology MODULE 13 c) Biological Agents 1. Transposable Elements mobile pieces of DNA that can move from one location in a genome to another presence of a transposon in a wild type gene disrupts the normal function of that gene Figure 13.15. Transposons in corn. (Image from: Wikimedia Commons. 2017. https://upload.wikimedia.org/wikipedia/commons/9/99 /Transposons.jpg) 2. Viruses can insert viral DNA into the genome and disrupt genetic function 3. Bacteria some bacteria are also dangerous provokes DNA damage and DNA breakage e.g. Helicobacter pylori o cause inflammation during which oxidative species are produced that can damage DNA or reduce efficiency of DNA repair systems o H. pylori also produces nitroso-derivatives which can modify bases Mutator Genes o Genes which, in their mutant state, increases frequency of mutations in other genes o Eg. § DNA polymerase I and Dam methylase DNA repair enzymes Keeps mutation frequency low When mutated, mutation frequency of the gene increases Mutational Hotspots o Regions in the DNA that are mutated more frequently than other genes o Eg. Genetics and Molecular Biology Division, Institute of Biological Sciences College of Arts and Sciences, University of the Philippines Los Baños College, Laguna 4031  BIO 101. Introductory Molecular Biology MODULE 13 § Kataegis Mutation hot spots used as positive marker in breast cancer (UC San Diego, 2016) Found in chromosome 17 and 22 Associated with low tumor invasiveness and better prognoses Figure 13.16. Kataegis. (Image from: Medical Xpress. 2017. https://scx2.b-cdn.net/gfx/news/hires/2016/3-genemutation.jpg) DNA, Chromosomes, and genomes Genome Comparisons o Reveal functional DNA Sequences by their conservation throughout evolution o Exons § regions of the genome that code for the amino acid sequences of proteins § found in short segments (average size about 145 nucleotide pairs) conserved regions § closely similar pieces of DNA sequence nonconserved regions § reflect DNA whose sequence is much less likely to be critical for function approach to deciphering genome § search for DNA sequences that are closely similar between different species § principle that DNA sequences that have a function are much more likely to be conserved than those without a function DNA sequencing studies have highlighted the most interesting regions in our genome § 5% of the human genome consists of “multispecies conserved sequences.” § one-third of these sequences code for proteins § consist of DNA containing clusters of protein-binding sites that are involved in gene regulation Genome Alterations are caused by failures of the normal mechanisms for copying and maintaining DNA also caused by transposable DNA elements parasitic DNA sequences that can spread within the genomes they colonize disrupt the function or alter the regulation of existing genes create novel genes through fusions between transposon sequences and segments of existing genes point mutations substitution of one base pair for another large-scale genome rearrangements deletions, duplications, inversions, and translocations of DNA from one chromosome to another mobile DNA elements are important source of genomic change Genome Sequences of Two Species differ in proportion to the length of time since they have separately evolved phylogenetic tree (Fig 13.1) basic organizing framework for comparative genomics Genetics and Molecular Biology Division, Institute of Biological Sciences College of Arts and Sciences, University of the Philippines Los Baños College, Laguna 4031  BIO 101. Introductory Molecular Biology MODULE 13 comparisons of gene or protein sequences trace the relationships of all organisms purifying selection selection that eliminates individuals carrying mutations that interfere with important genetic functions Figure 13.17. A phylogenetic Tree showing the relationship between humans and the great apes based on nucleotide sequence data (Chen and Li, 2001). molecular clock for evolution o set of molecular clocks corresponding to different categories of DNA sequence o runs most rapidly and regularly in sequences that are not subject to purifying selection o runs most slowly for sequences that are subject to strong functional constraints o determined not only by the degree of purifying selection, but also by the mutation rate o in animals, clocks are based on functionally unconstrained mitochondrial DNA sequences § run faster than clocks based on functionally unconstrained nuclear sequences § mutation rate in animal mitochondria is exceptionally high categories of DNA for which the clock runs fast are most informative for recent evolutionary events more reliable guide to the detailed structure of phylogenetic trees than classical methods of tree construction A comparison of Human and Mouse Chromosomes shows how the structures of genomes diverge rodent lineages have unusually fast molecular clocks, and have diverged from the human lineage more rapidly than otherwise expected small blocks of DNA sequence are being deleted from and added to genomes at a surprisingly rapid rate § small chromosome duplications and from the multiplication of transposons have compensated for these deletions loss of DNA sequences in small blocks during evolution can be obtained from a detailed comparison of regions of synteny in the human and mouse genomes DNA is added to genomes both by the spontaneous duplication of chromosomal segments and by insertion of new copies of active transposons The Size of a Vertebrate Genome reflects the relative rates of DNA Addition and DNA loss in a lineage all vertebrates experience a continuous process of DNA loss and DNA addition For example § suppose that in the lineage leading to Fugu rubripes (puffer fish) the rate of DNA addition happened to slow greatly Genetics and Molecular Biology Division, Institute of Biological Sciences College of Arts and Sciences, University of the Philippines Los Baños College, Laguna 4031  BIO 101. Introductory Molecular Biology MODULE 13 § this would result in a major “cleansing” from this fish genome of those DNA sequences whose loss could be tolerated § result is an unusually compact genome but retaining through purifying selection the vertebrate DNA sequences that are functionally important Changes in Previously Conserved Sequences Can Help Decipher Critical Steps in Evolution chromosome sites that have experienced deletions in the 6 million years since human lineage diverged from that of chimpanzees more than 500 such sequences—conserved among other species but deleted in humans— have been discovered Each deletion removes an average of 95 nucleotides of DNA sequence § one of these deletions affects a protein-coding region § the rest are thought to alter regions that affect how nearby genes are expressed Gene Duplication Provides an Important Source of genetic Novelty During Evolution To create such families, genes have been repeatedly duplicated, and the copies have then diverged to take on new functions that often vary from one species to another occurs at high rates in all evolutionary lineages, contributing to the vigorous process of DNA addition Duplicate Genes Diverge Pseudogene - contemporary genomes where one copy of a duplicated gene can be seen to have become irreversibly inactivated by multiple mutations. § “duplication and divergence” almost certainly explains the presence of large families of genes with related functions in biologically complex organisms, and it is thought to play a critical role in the evolution of increased biological complexity. The Evolution of the Globin Gene Family Shows How DNA Duplications Contribute to the Evolution of Organisms The globin gene family provides an especially good example of how DNA duplication generates new proteins, because its evolutionary history has been worked out particularly well. Mutation plays an important role in evolution. The ultimate source of all genetic variation is mutation. Mutation is important as the first step of evolution because it creates a new DNA sequence for a particular gene. Mutation acting as an evolutionary force by itself has the potential to cause significant changes over very long periods of time. If mutation were the only force acting on pathogen populations, then evolution would occur at a rate that we could not observe. Genes Encoding New Proteins Can be Created by the Recombination of Exons Each separate exon often encodes an individual protein folding unit, or domain. It is believed that the organization of DNA coding sequences as a series of such exons separated by long introns has greatly facilitated the evolution of new proteins. The duplications necessary to form a single gene coding for a protein with repeating domains. Neutral Mutations Often Spread to become Fixed in a Population, with a Probability That Depends on Population Size When a new neutral mutation occurs in a population of constant size N that is undergoing random mating, the probability that it will ultimately become fixed is approximately 1/(2N). Genetics and Molecular Biology Division, Institute of Biological Sciences College of Arts and Sciences, University of the Philippines Los Baños College, Laguna 4031  BIO 101. Introductory Molecular Biology MODULE 13 This is because there are 2N copies of the gene in the diploid population, and each of them has an equal chance of becoming the predominant version in the long run. For those mutations that do become fixed, the average time to fixation is approximately 4N generations. A Great Deal can be Learned from Analyses of the variation Among Humans Single-nucleotide polymorphisms (SNPs) § These are simply points in the genome sequence where one large fraction of the human population has one nucleotide, while another substantial fraction has another § ordinary SNPs inherited from our prehistoric ancestors, certain sequences with exceptionally high mutation rates stand out. References: Alberts B, Johnson A, Lewis J, Morgan D, Raff M, Roberts K, Walter P. 2015. Molecular Biology of the Cell. 6th ed. New York: Garland Science. 1465 pp. LINK: https://drive.google.com/file/d/0B2yBwK59Xx0kYjVYZUlGSkpBYWM/view. Chen FC, Li WH. 2001. Genomic divergences between humans and other hominoids and the effective population size of the common ancestor of humans and chimpanzees. Am J Hum Genet. 68(2):444-456. doi:10.1086/318206. Lodish H, Berk A, Kaiser CA, Krieger M, Scott MP, Bretscher A, Ploegh H. 2007. Molecular Cell Biology. 6th Ed. New York: W.H. Freeman and Co. 973 p. (Fifth edition: https://www.dropbox.com/s/jj4act69qqnons6/Molecular%20Cell%20Biology%205th%20Ed%20by %20Lodish%20et%20al.pdf?dl=0). Genetics and Molecular Biology Division, Institute of Biological Sciences College of Arts and Sciences, University of the Philippines Los Baños College, Laguna 4031