General Genetics (BIO 340) PDF

Selective Breeding Thursday, October 17, 2024 9:24 PM - Humans have been aware of genetics via selective breeding for over 10,000 years - Selective breeding examples ○ The change of corn (small to large ears of corn) ○ Australian sheep ○ The evolution of dogs (from wolves to dogs) - The backfires of selective breeding ○ The small toy dogs having physical issues (Chiari Malformation) Intoduction Page 1 Experiments and Main Outcomes Thursday, October 17, 2024 10:02 PM Gregor Mendel - Amateur botanist - published and explanation of hereditary transmission in plants, 1866 - His work was independently rediscovered by 3 botanists in 1900 ○ Correns ○ De Vries ○ Von Tschermak Mendel's Analysis - Garrod describes and inheritance of a disorder in humans (alkaptonuria) ○ Baston said trait must be a rare recessive character ○ Sutton and Boveri independently observed chromosome movement during cell division DNA is hereditary Material - The Bacterial Transforming principle by Griffith (1930's) ○ One bacteria take up information/material from another bacteria, changing the original bacteria's properties - Avery, McLeod, and McCarty Experiment ○ Outcome: DNA is the 'transforming factor' - Hershey-Chase Experiment ○ Outcome; DNA is the genetic Material Progress in Understanding DNA Function - 1960s: Mechanisms of transcription and translation were laid out - The genetic code was deciphered - 1970s: cloning and development of recombinant DNA technology progressed rapidly Genomes - 1980s: the beginning of studying and comparing genomes - Genome: the complete set of genetic information carried out by a species - 2001: the first published draft of the human genome Intoduction Page 2 DNA Structure Thursday, October 17, 2024 10:29 PM DNA: Deoxyribonucleic Acid - Genetic material - Double stranded structure (double helix or duplex ○ Triple helix Structure proposed by Pauling and Corey (1953) ○ Double helix structure found by Watson and Crick (1953) - DNA replication: duplicates the DNA prior to cell division - Transcription: one DNA strand is used to direct RNA synthesis DNA Nucleotides - Made of deoxyribose (5-carbon sugar), a phosphate group and a nitrogenous base, either ○ Adenine (A) ○ Guanine (G) ○ Thymine (T) ○ Cytosine (C) - Molecule held together by hydrogen bonds between the nitrogenous bases - They are linked by a phosphodiester bond between the 5' phosphate group of one nucleotide and the 3' hydroxyl of another ○ Helps distinguish polarity via the 3' hydroxyl group ○ Phosphate group outside = 5'  DNA’s charge is negative due to the phosphate group - Chargaff's rule: complementary base pairing ○ A with T (2 hydrogen bonds between) ○ C with G (3 hydrogen bonds between) Molecular Basis of Hereditary Variation Page 3 DNA Replication Friday, October 18, 2024 2:35 AM 3 Postulated methods 1. Semi-conservative Watson and Crick (1953) One strand of DNA separates into two strands where half is the parental strand and the other is the daughter (new) strand 2. Conservative Bloch (1955) The whole DNA structure acts as a template 3. Dispersive Dellbruck (1954) Every 10 bases in the DNA is cut and a new DNA is inserted between them The Meselson-Stahl Experiment - Figured out how to differentiate between the original DNA and the daughter DNA - Outcome: Semi-conservative method was correct DNA replication happens in the synthesis (S) phase of the cell cycle, before mitosis or meiosis the two strands of the double helix separate during replication, and each strand serves as a template from which the new complementary strand is copied. Molecular Basis of Hereditary Variation Page 4 RNA Friday, October 18, 2024 2:44 AM RNA: Ribonucleic Acid - Used as genetic material by some viruses - Messenger RNA (mRNA): undergoes translation to produce proteins at nucleoprotein structures (ribosomes) - RNA is single stranded - Nitrogenous Bases ○ Guanine ○ Adenine ○ Cytosine ○ Uracil - Pairing ○ A with U ○ G with C - Nucleotides made of ribose (5-carbon sugar), a nitrogenous base, and a phosphate group Molecular Basis of Hereditary Variation Page 5 Genes and Chromosomes Friday, October 18, 2024 11:16 PM Genes: the physical units of heredity, defined DNA sequences Chromosomes: long molecules of double-stranded DNA and protein, that contain genes DNA is wrapped around histones, creating a nucleosome; all inside the chromosome and the chromosomes are inside the nucleus Molecular Basis of Hereditary Variation Page 6 Early Genetic Concepts Sunday, October 20, 2024 1:18 PM Phenotype: the observable traits of an organism Genotype: the genetic constitution on an organism Alleles: variant forms of a gene The study of gene transmission was a foundation of genetics Molecular Basis of Hereditary Variation Page 7 The Central Dogma by Francis Crick (1970) Sunday, October 20, 2024 1:23 PM DNA is replicated and then transcribed into RNA and the RNA is translated into Protein - DNA replication happens in the nucleus - DNA to RNA transcription happens in the nucleus  In prokaryotes, translation happens in the cytoplasm - RNA to Protein translation happens in the cytoplasm ○ RNA can leave the nucleus through the nuclear pores Updated Central Dogma RNA Transcription - RNA polymerase uses the non-coding/template strand to make RNA - The mRNA product is complementary to the template strand and is almost identical to the other DNA strand, called the non-template strand, with the exception that RNA contains a uracil (U) in place of the thymine (T) found in DNA - Happens in 3 stages 1. Initiation Molecular Basis of Hereditary Variation Page 8 1. Initiation ▪ When the DNA is unwound, forming a transcription bubble 2. Elongation ▪ RNA polymerase tracks along the DNA template and synthesizes mRMA in the 5' to 3' direction, unwinding and rewinding DNA as it reads ▪ RNA polymerase add nucleotides by base pairing with the DNA template 3. Termination RNA Translation - In the cytoplasm and endoplasmic reticulum (eukaryotes). Cytoplasm only (prokaryotes) - Key players ○ Ribosomes ○ tRNA w/ an anticodon ○ After translation we end up with a sequence of amino acids that gives us a polypeptide chain - Protein Synthesis ○ one of a cell’s most energy-consuming metabolic processes ○ proteins account for more mass than any other component of living organisms (with the exception of water) ○ The small subunit ribosomes bind the mRNA template ○ The large subunit ribosomes bind tRNAs  An alpha helix and a beta sheet in a protein are a type of secondary structure Molecular Basis of Hereditary Variation Page 9 The Genetic Code Sunday, October 20, 2024 1:32 PM The genetic code: The relationship between a nucleotide codon and its corresponding amino acid  It is UNIVERSAL - Protein sequences consist of 20 commonly occurring amino acids. - Triplet codon: a three-nucleotide sequence that each amino acid is defined by - There are 64 possible nucleotide triplet combinations - Stop codons: terminate protein synthesis and release the polypeptide ○ There are 3 (UAA, UAG, UGA)  AUG codon is special: it also serves as a start codon to initiate translation Molecular Basis of Hereditary Variation Page 10 Darwin's Theory of Evolution Saturday, October 19, 2024 10:08 PM Evolution: The theory that all organisms are related by a common ancestry and have diversified over time primarily via natural selection - Natural selection works at the phenotypic level but based on underlying genetic variation Darwin's Theory of evolution was independently proposed in the late 1850s by Charles Darwin and Alfred Wallace 3 Main Principles 1. Variation exists among members of populations regarding the expression of traits 2. Variation of traits is passed from one generation to the next 3. Certain variant forms of traits give individuals that possesses then a higher rate of survival and reproduction, these traits are passes to the next generation with higher frequency Forces of Evolution Page 11 Five Fundamental Forces of Evolution Monday, October 21, 2024 1:01 AM 1. Mutation 2. Selection 3. Genetic Drift 4. Migration 5. Nonrandom Mating Mutation  The ultimate source of genetic variation - The addition of genetic variation increases the hereditary diversity of a population (generates new alleles) - The slow addition of allelic variants serve as "raw material" of evolutionary change - Types of Mutations ○ Point Mutation: change of a single base ▪ Silent mutation: has no effect on the protein sequence ▪ Missense mutation: results in an amino acid change ▪ Nonsense mutation: changes an amino acid to a stop codon ○ Frameshift mutation: insertion/deletion of 1+ bases ▪ Insertion/deletion mutation: results in a shift in reading the frame Natural Selection - The differential reproductive success of members of a species due to possession of different forms of adaptive characters - Best adapted forms will increase in a population Genetic Drift - The random change in allele frequencies due to chance in randomly mating populations - Occurs in all populations - Stronger in small populations that in large ones - Because of drift, even favored alleles can be lost from a population - Fixation: an allele frequency of 1.0 ○ All other alleles have been eliminated from the population Migration (Gene Flow) - The movement of alleles from one population to another - If allele frequencies are different between locations, then the movement of alleles can change allele frequencies - The lack of movement between populations can lead to the differentiation of populations Nonrandom Mating - Occurs when the probability that two individuals in a population will mate is not the same for all possible pairs of individuals Forces of Evolution Page 12 the same for all possible pairs of individuals - Affects genotype frequencies, not allele frequencies - Homozygotes increase in frequency and heterozygotes decrease - Assortative Mating: an individual's preference to mate with partners who are phenotypically have equal - Disassortative mating: individual's prefer a different phenotype Forces of Evolution Page 13 Genetic Variance Monday, October 21, 2024 4:04 AM - The diversity of alleles and genotypes within a population Heritability: the fraction of phenotype variation that can be attributed to genetic differences (genetic variance) among individuals in a population - The greater the hereditability of a population's phenotypic variation, the more susceptible it is to the evolutionary forces that act on heritable variation Inbreeding: the mating of closely related individuals - can have the undesirable effect of bringing together deleterious recessive mutations that can cause abnormalities and susceptibility to disease - Inbreeding depression: the dramatic increase of the likelihood of two carriers mating and eventually producing diseased offspring Forces of Evolution Page 14 Tracing Evolutionary Relationships Monday, October 21, 2024 9:14 PM Evolutionary relationships among organisms can be depicted in a diagram called a phylogenetic tree Cladistic Approach - The most common approach - Sorts evolutionary relationships in to groups called clades/monophyletic groups ○ Members of a clade have shared derived characteristics, either morphological of molecular - Ancestral characters: those inherited attributes that resemble those of an ancestor to the group - Derived characters: those features that are different from features found in the ancestor Tree Components in a Rooted Tree - Rooted trees reflect the most basal ancestor - Terminal nodes: organisms that we have data on - Internal nodes: point in evolution there organisms at the terminal nodes diverged - MRCA: most recent common ancestor - Branches ○ The length of each branch is proportional to the time elapsed since the split Number of Possible Trees - Formula: Tree Morphology and Anatomy - First consider the common morphological features shared by groups of organisms under consideration Evolutionary Relationships Page 15 under consideration - Find an outgroup; an organism lacking a feature shared by all the others (the ingroup) Analogy or Homoplasy: When similar characteristics occur because of environmental constraints and not due to a close evolutionary relationship - Homologous structures share a similar embryonic origin - Analogous organs have a similar function Evolutionary Relationships Page 16 Concepts of Monophyly, Polyphyly, and Paraphyly Monday, October 21, 2024 9:40 PM Monophyly: includes a group of organisms descended from a single ancestor Polyphyly: Composed of unrelated organisms descended from more than one ancestor Paraphyly: includes the most recent common ancestor, but not all of its descendants Evolutionary Relationships Page 17 Constructing Phylogenetic Trees using Molecules Monday, October 21, 2024 9:45 PM These trees using molecules are constructed based on share features that are DNA or protein sequences Phylogenetic Trees can be inferred using maximum parsimony (the simplest scientific explanation that fits the evidence) Steps 1) Compare DNA nucleotide sequences and record the numbering the amount of differences between then ordering the organism with their number of differences from smallest to largest, top to bottom 2) Form clades using the identical and closely related sequences 3) Sequence the organisms beginning with the closest at the top and the more distance going down Evolutionary Relationships Page 18 History Tuesday, October 22, 2024 12:35 AM - Discovery of DNA structure in 1953 - Photo 51 is famous for the double helix structure (B-DNA) - Watson and Crick discovered that the DNA strands were held together by individual base units ○ Bases along one strand matched bases (complementary) on the other strand ○ The two strands are held togehter by hydrogen bonds Recitation 1 Lesson (Cental Dogma) Page 19 DNA Structure Wednesday, October 23, 2024 12:22 AM - Deoxyribonucleic Acid - Made up of nucleotide that link of form strands - The bonding between the two strands causes the formation of a double helix - Has a 5-carbon sugar and a nucleotide (Adenine, Guanine, Cytosine, Tyrosine) - DNA is a polymer with two polynucleotide chains that form a double helix ○ Polymer: poly/multiple of smaller monomer units (nucleotides) ▪ Comprise living organisms RNA - Ribonucleic Acid ○ Single-stranded ○ Ribose only ○ Uses uracil instead of thymine ○ Has a hydroxyl group (OH) in the 2' position - Chargaff's Rule: equal ratios of C:G and A:T (DNA) and equal ratios of C:G and A:U (RNA) ○ C+G+A+T=100% Recitation 1 Lesson (Cental Dogma) Page 20 Central Dogma Wednesday, October 23, 2024 11:01 PM Replication ->DNA -> transcription ->RNA -> translation -> Protein DNA Replication - Semiconservative ○ Found by Meselson and Stahl experiment ▪ Radioactive tag on nitrogenous bases cause density differences ○ Each double helix in a new generation will have both an old (parental) and a new (daughter) strand coiled around each other - Leading strand is continually synthesized - Lagging strand is synthesized in fragments - New strands always built from 5'-3' Transcription - Making mRNA from DNA - Copying a segment of DNA and the RNA polymerase transcribing it into RNA in order to synthesize mRNA - Process 1. DNA is unwound 2. Noncoding strand is used as the template to create a strand of mRNA 3. mRNA leaves the nucleus Translation - Happens in the cytoplasm by ribosomes - Ribosomes use tRNA carrying amino acids and attach them together to for the primary structure of a protein - Each amino acid is coded for by a codon (set of 3 nucleotides) - mRNA is translated to make the polypeptide chain  ALL polypeptide chains start with AUG (Methionine) - The tRNA is charged with amino acids that match their anticodon ○ It binds to the corresponding mRNA strand ○ The amino acids from the tRNA will attach to each other in a chain ○ The used tRNA exits the ribosome, leaving the amino acid and the chain will continue to grow until a stop codon in reached Recitation 1 Lesson (Cental Dogma) Page 21 Amino Acids Thursday, October 24, 2024 12:05 AM - 20 amino acids encoded by 61 codons - Many codons will code for the same amino acid (redundancy) - The start codon will ALWAYS BE Methionine Recitation 1 Lesson (Cental Dogma) Page 22 Probability Monday, October 28, 2024 4:50 PM - Probability: the frequency of an event among all possible ones ○ When summed over all possible events, probabilities add up to 1 Additive Rule of Probability - If two events, A and B, are mutually exclusive, then the probability that either one occurs is the sum of their individual probabilities ○ Independent Events - Two events are independent is the probability that one occurs does not affect the probability of the other occurring Multiplicative Rule of Probability - If two events, A and B, are independent, then he probability that they both occur in given by: ○ Conditional Probability - The probability that an event (A) will occur, when another event (B) is known to occur (probability of A given B) ○ Binomial Distrbution - Many types of probability problems have two outcomes or can be reduced to two: success and failure ○ ▪ p = numerical probability of success ▪ q = numerical probability of faliure ▪ p+q = 1 ▪ n = number of trials ▪ x = number of successes Proability Page 23 Gregor Mendel Tuesday, October 29, 2024 2:34 PM He demonstrated that traits are transmitted from parents to offspring in specific patterns His 5 Critical Innovations 1. Controlled crosses between plants 2. Use of pure-breeding strains 3. Selection of dichotomous traits a. Dominant or recessive 4. Quantification of results 5. Use of replicate, reciprocal, and test crosses ○ Replicate crosses: repeated crosses and produced hundreds of F1 plants and several thousand F2 plants ○ Reciprocal crosses: the same genotypes are crossed but the sexes of the donating parents are switched, allowing Mended t0 control how many traits he studied t once ○ Test crosses: specific crosses between one pure breeding strain and one with unknown genotypes ▪ Two-point test cross produces 4 phenotypes Test Cross: the dominant-expressing organism is crossed with an organism that is homozygous recessive for the same characteristic True-breeding strain: a group of identical individuals that always produce offspring of the same phenotype when mated with each other Monohybrid: combination of two parental strains that differ for only one trait Dichotomous Trait: A trait that is physically expressed by one of two distinct possible outcomes Gene: discrete inherited factor Allele: form of a gene Phenotype: the observable characteristic of an organism Genotype: the specific allelic composition of an individual - Phenotypic ratios are different from genotypic ratios Law of Segregation - Paired genes must segregate equally into gametes such that offspring have an equal likelihood of inheriting either factor - The alleles of a particular gene segregate independently into individual gametes during meiosis Mendel Page 24 during meiosis - This is why we can apply the Punnett square to accurately predict the offspring of parents with known genotypes - The physical basis of the law is the first division of meiosis in which the homologous chromosomes with their different versions of each gene are segregated into daughter nuclei Law of Independent Assortment - genes do not influence each other with regard to the sorting of alleles into gametes, and every possible combination of alleles for every gene is equally likely to occur - Pairs of alleles segregate independently of other pairs of alleles during gamete formation in meiosis - Can be illustrated by the dihybrid cross, which is a cross between two true- breeding parents that express different traits for two characteristics Mendel Page 25 Autosomal Inheritance Tuesday, October 29, 2024 5:31 PM - The reansmission of traits carried on autosomes - Two copies of each autosome Dominant Inheritance - 6 characteristics 1. Each individual who has the disease has at least one affected parent 2. Males and females are affected in equal numbers 3. Either sex can transmit the disease allele 4. In crosses where one parent is affected and the other is not, about half the offspring express the disease 5. 2 unaffected parents will not have any children with the disease 6. 2 affected parents may produce unaffected children Recessive Inheritance - 6 characteristics 1. Individuals who have the diseases are often born to parents who do not 2. If only one parent has the disorder, the risk that a child will have it depends on the genotype of the other parent 3. If both parents have the disorder, all children will have it 4. The sex ratio of affected offspring is expected to be equal 5. The disease is no usually seen in each generation, but if an affected child is produced by unaffected parents, the risk to subsequent children is 1/4 6. If the disease is rare in the population, unaffected parents of affected children are likely to be related to one another Autosomal Inheritance Page 26 Pedigrees Tuesday, October 29, 2024 6:24 PM - Family trees that are a way of tracing the inheritance of traits in humans and some animals - A standard notation is used to indicate males and females, their relationships, and the individuals who show the trait and those who do not - Generations are indicated by roman numerals Solving pedigree TIPS - Presence of skipping a generation ○ Dominant = No skipping ○ Recessive = Skipping - Autosomal vs Sex-linked ○ Autosomal = Male to male transmission, trait goes to both males and females ○ x-linked: males are more affected than females - Y-linked = only males are affected - Mitochondrial Inheritance = trait inherited from mother only by ALL childen Autosomal Inheritance Page 27 Chromosomes Tuesday, October 29, 2024 7:01 PM - Genes are located on chromosomes - Diploid (2n): two homologous copies of each chromosome ○ One from mum and one from dad - Homologous chromosomes have the same genes in the same locations but not always the same alleles - Each parent contributes one set of homologs ○ During meiosis, an egg and a sperm is made (haploid) ▪ Haploid (n): one copy of a chromosome ○ The chromosomes fuse together during fertilization making a zygote (diploid) Human Chromosomes - Autosomes: chromosomes 1-22 - Sex chromosomes: Chromosome 23 (XX or XY) Homologous chromosomes vs. sister chromatids - Homo chrom: the maternal and paternal full chromosomes - Sis chrom: identical and connected at centromeres Cell Division and Chromosome Heredity Page 28 Cell Division Friday, November 1, 2024 9:24 PM Mitosis produces 2 identical daughter cells, exact replica of parent cell - Non-reproductive (somatic) cells are diploid Reproductive cells - Gametes are produced from germ-line (reproductive) cells - Meiosis produces gametes that have 1/2 the number of chromosomes that the original cell - Gametes are not identical to each other Cell Division and Chromosome Heredity Page 29 Cell Cycle Friday, November 1, 2024 9:33 PM 1. G1 ○ Active gene expression and cell activity ○ Prep for DNA synthesis 2. S phase (synthesis) ○ DNA replication ▪ After this, chromosomes exist as dyads (2 identical sister chromatids) □ Joined at the centromeres ○ Chromosome duplication 3. G2 ○ Prep for cell division 4. M phase ○ Mitosis (somatic cells only) ▪ Mitosis and cytokinesis Sub stages ▪ Prophase ▪ Prometaphase Kinetochores appear at the centrosome ▪ Metaphase ▪ Anaphase ▪ Telophase ▪ cytokinesis or ○ Meiosis (germ-line cells only) Sub stages □ Prophase □ Prometaphase □ Metaphase □ Anaphase □ Telophase ▪ Accomplishes karyokinesis (partitioning of DNA into daughter cell nuclei and cytokinesis (partitioning of the cytoplasm) Cell Division and Chromosome Heredity Page 30 Mitosis vs. Meiosis Friday, November 1, 2024 10:04 PM Mitosis - One diploid splits into two diploid cells - Only one cell division - Somatic cells undergo mitosis Meiosis - One diploid splits into 4 haploid cells - Two cel divisions ○ Meiosis 1 ▪ In prophase, synapsis (homologous chromosome dyads paired) and crossing over exchange of material between homologous chromosomes happens ○ Meiosis 2 ▪ Sister chromatids actually separate - Only germ-line cells undergo meiosis Cell Division and Chromosome Heredity Page 31 Gene Interaction Monday, November 4, 2024 4:45 PM - Dominance relationships between alleles have a molecular basis - Gene expression can be affected by interactions with other genes, causing characteristic changes in Mendelian ratios - Mutations to different types of genes can produce the same phenotype - Complementation tests can determine the number of genes causing a mutant phenotype Patterns of Inheritance Page 32 Molecular Basis of Dominance Monday, November 4, 2024 5:03 PM - The terms dominant and recessive have a phenotypic basis - The dominance of one allele over another is determined by the protein product of that allele - The overall phenotype in the consequence of the activities of the protein products of the alleles of the gene Patterns of Inheritance Page 33 Recessive Mutations Monday, November 4, 2024 5:07 PM - The phenotype of a recessive mutation is seen only in homozygous individuals - The disease phenylketonuria (PKU) is caused by a mutation in the PAH gene - Loss of function mutation ○ Causes a gene to lose some or all of its normal function ○ When a mutation eliminates functional protein, toxins are produced ○ Hypomorphic mutations: those that have lost only some of their function ○ Null mutations: those that have lost all of their function ○ These are recessive is the normal allele is haplosufficient ▪ Haplosufficient: one (haplo) copy is sufficient to produce the wild type phenotype in the heterozygous genotype ▪ Patterns of Inheritance Page 34 Fully Dominant Mutations Monday, November 4, 2024 5:26 PM - The phenotype is fully dominant mutation is seen in both heterozygous and homozygous individuals - - Loss of function mutations are dominant if the normal allele is haplosufficient - Patterns of Inheritance Page 35 Effects of Mutation Monday, November 4, 2024 5:32 PM - A wild type phenotype is produced when an organism has two copies of the wild type allele - Mutant alleles can be: ○ Gain-of -function: the gene product acquires a new function or express increased wild type activity ○ Loss-of-function: there is a significant decrease or complete loss of functional gene product Patterns of Inheritance Page 36 Incomplete Dominance vs. Codominance Wednesday, November 6, 2024 1:16 AM Incomplete Dominance - the phenotype of the heterozygote is intermediate between those of the two homozygotes, on one quantitative scale (eg. Color or size) - Often the dominance of one allele over the other is not complete, in this case designations such as are used instead of A, a or B, b - When heterozygous individuals display intermediate phenotypes between either homozygous type - Typically the heterozygote is more similar to one of the homozygous types than the other - Examples: snapdragons and Andalusian chickens Codominance - the phenotype of both alleles is fully expressed in the heterozygote - Leads to heterozygotes with a different phenotype than that of either homozygote - There is detectable expression of both alleles in the heterozygotes - More than one pattern of dominance may exist between different alleles of a gene - Examples: ABO blood type (multiple alleles), sickle cell anemia, shorthorn cattle Patterns of Inheritance Page 37 The C Gene System of Mammalian Coat Color Wednesday, November 6, 2024 1:34 AM - The C gene is responsible for coat color for mammals like cats, rabbits and mice - It produces and enzyme active in the production of melanin - There are dozens of alleles of the gene, but 4 that form an allelic series (order of dominance among alleles) The Allelic Series of the C Gene - The wild type allele, C, produces a functional enzyme and full coat color - Produces a 'dilute' phenotype called chinchilla - Produces a phenotype called Himalayan with little pigment on the body but full color on the extremities - c is a fully recessive null allele and produces and albino phenotype - There is an order of dominance among the alleles ○ ○ ○ ○ cc = albino The Molecular Basis of the C Gene Allelic Series - The C allele produces a tyrosinase enzyme that is 100% active, whereas that of the allele is less sensitive that 20% active - The allele enzyme is Temperature-sensitive; functional at lower temps (like the paws, ears and tail), and nonfunctional at highe temps (the trunk) ○ Happens commonly in rabbits and cats - The c allele produces no functional enzyme Patterns of Inheritance Page 38 Complementation Tests determine if Mutations are in the Same Gene Wednesday, November 6, 2024 1:54 AM - Complementation = the mutations are alleles of different genes (wildtype phenotype is observed) - No Complementation = the mutations are alleles for the same gene (mutation is observed) Gene Interaction Page 39 Gene Interaction Wednesday, November 6, 2024 6:07 PM - Gene interaction occurs where 2+ genes affect the same phenotype, by influencing a common pathway = Epistatic Interactions - If two genes interact, there are fewer phenotypes that in the offspring of the dihybrid cross (usually 9:7 ratio) 9:7 ratio indicates 2 genes interacting in the same pathway Mutations in either gene disrupt the pathway, causing the mutant phenotype  You MUST have both genes producing the necessary enzymes in the pathway in order to have the wildtype phenotype Lethal: inheriting one recessive embryonic lethal from each parent = death for the offspring ○ Example: the agouti locus (Ay) in mice Pleiotropy: one allele = many phenotypes Gene Interaction Page 40 Epistatic Interactions Wednesday, November 6, 2024 6:21 PM Gene Interaction Page 41 Other Types of Gene Interactions Wednesday, November 6, 2024 6:22 PM Duplicate - Genes in a redundant system - They encode the same product, or they encode products that have the same effect in a pathway/compensatory pathways - The genes will lead to the same phenotype - 15:1 ratio Dominant - Having just one or two allele for just one of either genes - 9:6:1 ratio Recessive Epistasis - Homozygosity for the recessive alleles at one locus will mask the phenotypic expression of the alleles at a second locus - 9:3:4 ratio Dominant Epistasis - A dominant allele of one gene masks/reduces the expression of either of the other gene - 12:3:1 ratio Dominant Suppression - Occurs when the dominant allele of one gene suppresses the expression of a dominant allele of a second gene - 13:3 ratio Gene Interaction Page 42 Studying Gene Interactions Wednesday, November 6, 2024 9:24 PM Strategy 1. Find two mutants affecting the same phenotype 2. Do a complementation test to find out if two genes are involved 3. If yes, perform a dihybrid cross and examine the offspring ratios to infer the pathways governed by the two genes Gene Interaction Page 43 Genetic Linkage and Mapping Wednesday, November 6, 2024 9:35 PM - Thomas Hunt established the chromosome theory of inheritance and applied his explanation of genetic linkage ad recombination to genetic mapping Synteny and Genetic Linkage Page 44 Linked Genes Do Not Assort Independent Wednesday, November 6, 2024 9:38 PM - Syntenic Genes: genes located on the same chromosome ○ They are so close together that their alleles cannot assort independently, these are linked genes ○ Genetic linkage produces progeny with 'parental' phenotypes more often than expected ○ Genetic linkage can be quantified to map the positions of genes on chromosomes Recombination and Syntenic Genes - Alleles of syntenic genes can be reshuffled when crossing over occurs between homologs to produce recombinant chromosomes - Nonrecombinant chromosomes (or parental chromosomes): homologs that do not reshuffle alleles under study Synteny and Genetic Linkage Page 45 Independent Assortment of Syntenic Genes Wednesday, November 6, 2024 9:46 PM - Can occur is they are far apart on a chromosome so that recombination occurs very frequently - Syntenic genes that are closer together will tend to segregate together - Crossing over that prevents linked genes from segregating together occurs during prophase l of meiosis Synteny and Genetic Linkage Page 46 Observations About Genetic Linkage Wednesday, November 6, 2024 9:49 PM - Linked genes are always syntenic and always located near one another - Genetic linkage leads to the production of significantly more gametes with parental allele combinations than nonparental combinations - Crossing over is less likely to occur between closely linked genes that between those farther apart on a chromosome Synteny and Genetic Linkage Page 47 Conserved vs. Disrupted Synteny Wednesday, November 6, 2024 9:51 PM - Conserved synteny: genes are located on the homologous chromosome in comparison species - Disrupted synteny: genes that are on the same chromosome in one species are on a different chromosome in another species Synteny and Genetic Linkage Page 48 Conserved vs. Disrupted Linkage Wednesday, November 6, 2024 9:54 PM - Conserved Linkage: conservation of both synteny and gene order of homologous genes between species - Disrupted Linkage: a difference of gene order between the species Synteny and Genetic Linkage Page 49 Types of Chromosome Fragments Wednesday, November 6, 2024 9:57 PM - Chromosomal Inversion: small blocks of genes get flipped around - Reciprocal Translocation: novel chromosomes are created Chromosome fusion: chromosomes fuse together Chromosome fission: chromosomes separate from one another Synteny and Genetic Linkage Page 50 Indications of Genetic Linkage Wednesday, November 6, 2024 10:05 PM - Can be recognized by comparing observed frequencies of gametes or progeny phenotypes with those expected under independent assortment - If genes are linked, parental allele combinations will be observed at higher frequency than predicted by chance - Independent assortment created new combinations of alleles not seen in the parental strains - Linkage: the tendency for genes on the same chromosome to be inherited together Genetic Linkage Analysis Page 51 Wednesday, November 6, 2024 10:16 PM - In independent assortment, a dihybrid, involving unlinked genes, will undergo and produce 4 different gamete combinations with equal frequency - Genes close together on the same chromosomes do not assort independently Genetic Linkage Analysis Page 52 Genetic Recombination Wednesday, November 6, 2024 10:17 PM Recombination: the natural process of breaking and rejoining DNA strands to produce new combinations of genetic material, generating genetic variation Homologous recombination: the exchange of a segment of DNA between two homologous chromosomes during meiosis leading to a novel combination of alleles in the offspring - Genes on the same chromosome can recombine during crossing over - Crossing over: Breakage and re-union leads to the exchange of chromosome parts between homologs - - Each crossing-over event creates two recombinant chromosomes - Complete genetic linkage: observed when no crossing over occurs between linked genes; only parental gametes are formed Incomplete genetic linkage: a mixture of parental and nonparental gametes are produced. ○ The two parental types are approximately equal in frequency, as are the two recombinant types. ○ Recombination frequency varies ○ More common Genetic Linkage Analysis Page 53 Linkage Analysis Wednesday, November 6, 2024 10:35 PM - Linkage Analysis tests if two genes are linked or independently assorting - If genes are linked, we know that they are on the same chromosome - The strength of linkage tells us the distance between two genes - Distance information helps us to draw a map of the genes on each chromosome How to Test - Perform a dihybrid cross to determine if the offspring has a 1:1:1:1 phenotypic ration ○ 1:1:1:1 phenotypic ratio = independent assortment ○ NOT 1:1:1:1 phenotypic ratio = Linked genes Crossover frequency measures the distance between two genes on a chromosome - The greater the distance between two genes, the higher the frequency of crossovers between them (two genes which are close together are rarely separated by a cross) - At very great distances they act completely independent Genetic distance can be estimated by measuring recombination frequency - Genetic Linkage Analysis Page 54 Distance Between Genes Thursday, November 7, 2024 2:29 PM - Can be used to draw a map of the chromosome - Measured in centiMorgans (cM) - 1 cM = a crossover frequency of 0.01 - Genetic map distances are additive Steps to measure the recombination distance between two genes 1. Cross and individual that is heterozygous for both genes with one show is homozygous recessive (testcross) 2. Classify the offspring according to phenotype 3. Determine which offspring are recombinants and non-recombinants 4. Calculate the recombination frequency to estimate the genetic distance between the genes 5. Genetic distance = recombination frequency * 100 - Example: - - Types of crossover outcomes - No crossovers = o% recombinants - Single crossover = 50% recombinants - Two-strand double crossover = 0% recombinants - Three-strand double crossover = 50% recombinants - Four-strand double crossover = 100% recombinants Mapping in Eukaryotes Page 55 - Mapping in Eukaryotes Page 56 Determining Gene Order Thursday, November 7, 2024 2:55 PM Three-point testcross - Useful for mapping three genes - Cross a trihybrid with a individual that is homozygous recessive for all three genes (tester) - Can tell both the order of the genes and the distance between them - Slash notation ○ - Steps 1. Is the data consistent with the proposal of genetic linkage? 2. What are the alleles on parental chromosomes? 3. What is the gene order on the chromosome? i. Compare the parental with the double recombinant genotypes ii. The allele pair for the middle gene will appear 'flipped' in the double recombinants 4. What are the recombination frequencies of the gene pairs? 5. Is the frequency of double crossovers consistent with independence of the single crossovers? - Results ○ He two largest numbers are going to be the parentals ○ The lower numbers are going to be the recombinants ○ The two lowest numbers are going to be double recombinants Example - Answers per each step Mapping in Eukaryotes Page 57 - Answers per each step 1. Yes, because the result are not uniform 2. ABC and abc 3. CAB/cab --> CaB/cAb 4. How often do double crossovers occur? - If crossovers between C and A are independent of crossovers between A and B, then the proportion of offspring with both kinds of crossover is given by: ○ P(crossover between C and A) * P(crossover between A and B) Interference: the presence of one crossover preventing other crossovers from reoccurring nearby Coefficient of interference - I = 1 - (observed frequency/expected frequency of double crossovers) - The higher the strength of interference, the higher I will be Mapping in Eukaryotes Page 58 Null hypothesis Saturday, November 9, 2024 12:06 AM - It is the default position is statistical analysis ( ) ○ There is no association between two phenomena ○ There is no effect by a drug on a disease ○ There is no linkage between two genes ○ There is no evolution occurring in the gene pool Determining a null hypothesis examples Example 1: Example 2: Chi-Squre Analysis Page 59 Alternative Hypothesis Tuesday, November 12, 2024 10:16 AM - It is the rival of the null and defines the rejection region ( ) - One-tailed: the rejection region is in one tail of the sample ○ Example: our company's new drug wok better than the competitor's - Two-tailed: the rejection region is in both tails of the sample ○ Example: our company's new drug works differently than the competitor's - If we can reject the null hypothesis, we say there is evidence for the alternative hypothesis Determining the alternative hypothesis example Chi-Squre Analysis Page 60 Pearson's Chi-Squared Test Tuesday, November 12, 2024 10:27 AM - Pearson's X^2 allows you to summarize… ○ your observed data into a single value ○ How well your observed offspring numbers fit the expected numbers ▪  The sum uses counts NOT ratios AND takes over all offspring types Finding the Text statistic example - If the test statistic is too far away from the general curve, then you reject the null hypothesis Chi-Squre Analysis Page 61 Goodness of Fit Tuesday, November 12, 2024 10:37 AM - The test statistic follows a chi-squared distribution with k degrees of freedom is the null hypothesis is true - Chi-Squre Analysis Page 62 Degrees of Freedom (k) Tuesday, November 12, 2024 10:41 AM For simple null hypothesis - ○ You lose a degree of freedom because the total number of observations is fixed For more complex null hypotheses - ○ Some null hypotheses require expectations to be estimate from the data ○ Each time you estimate a parameter you lose a degree of freedom Chi-Squre Analysis Page 63 Chi-square analysis of Mendel's Data Tuesday, November 12, 2024 10:45 AM - Interpretation of the chi-square results is based on the corresponding P value - To determine the P value 1. Determine the degrees of freedom ▪ Degrees of freedom must be taken into account because the greater the # of categories, the more deviation is expected due to chance 2. Locate the chi-square value on the line according to the degrees of freedom in the table Chi-Squre Analysis Page 64 Chi-square ( ) test Steps Tuesday, November 12, 2024 10:52 AM 1. State the null and alternative hypotheses 2. Count observed offspring #'s 3. Calculate expected #'s under null hypothesis 4. Calculate text statistic 5. Calculate the # of degrees of freedom 6. Compare statistic with appropriate P value to determine whether the null hypothesis should be rejected Chi-Squre Analysis Page 65 Genetic polymorphism Tuesday, November 12, 2024 10:56 AM - Within a population, a single gene has more than one allele - Example: the MN blood group in humans ○ It is caused by a single gene with two alleles, M and N ○ Within a species, different populations can have different allele frequencies ▪ - A population's gene pool consists of the set of alleles carried by it members ○ Population size is N ○ Number of alleles is 2N - The genotype frequencies give the relative # of each genotype in the population ○ - The allele frequencies (p and q) give the relative # of each allele in the population ○ P = frequency of dominant allele ○ Q = fequency of recessive allele ○ ○ Example: ▪ ▪ The wet vs. dry ear wax population ▪ Video explanation of another example in video 2; timestamps 09:35 - 12:30 Hardy-Weinberg Equilibrium Page 66 12:30 Hardy-Weinberg Equilibrium Page 67 Hardy-Weinberg Equilibirium Tuesday, November 12, 2024 12:12 PM What determines how much polymorphism a population has? - Evolutionary forces (mutation and migration) create diversity - Evolutionary forces (natural selection and drift) destroy diversity If allele frequencies are known, can genotype frequencies be estimated? - YES, if certain assumptions can be made: 1. All genotypes have equal survival and reproduction (no natural selection) 2. Mating is random with respect to genotype 3. Effectively infinite (large) population size 4. Mendelian segregation 5. No mutation, migration, or population subdivision - If all these assumptions hold, the population will reach Hardy-Weinberg Equilibrium ○ Typically after 1 generation ○ Regardless of the starting genotype frequencies ○ Genotype frequencies remain the same generation after generation ○ Genotype frequencies can be easily predicted from allele frequencies ○ ○ If Hardy-Weinberg assumptions hold, each offspring can be viewed as the combination of a random egg and a random sperm drawn from the gene pool ○ Graphic representation Hardy-Weinberg Equilibrium Page 68 ▪ ▪ For low frequency alleles, heterozygotes are far more common that homozygotes Example: - Solution and explanation is in video 2; timestamps 15:55 - 17:58 ○ Remember that the denominator for condition probability is addition NOT multiplication Hardy-Weinberg Equilibrium Page 69 Testing Hardy-Weinberg Tuesday, November 12, 2024 12:42 PM Testing Hardy-Weinberg - Hardy-Weinberg Equilibrium is the standard null hypothesis of population genetics - Rejecting the null suggests that some evolutionary force in action on the gene pool - Use a chi-squared goodness of fit test to determine if the null in rejected Example: - - Solution Explanation in video 2 timestamps 21:30-26:23 Why are most populations not at Hardy-Weinberg Equilibrium? - Most do not meet the assumptions ○ Population has structure ○ Mating ins often non-random ○ Many populations are quite small ○ Not all genotypes are equally viable Hardy-Weinberg Equilibrium Page 70 The Wahlund Effect Thursday, November 14, 2024 11:11 PM - An inevitable consequence of genetic variance among subpopulations is deviation from the Hardy-Weinberg expected heterozygosity for the population as a whole - The more different the gene frequencies among subpopulations, the greater the overall reduction of heterozygotes - This "consequence" of variance is known as the Wahlund Effect - Each subpopulation can be in Hardy-Weinberg equilibrium while the entire species is not - Let and represent the allele frequencies of allele A in Population 1 and Population 2 respectively ( and likewise represent allele a) - Let the allele frequency in each population be different ( ). Suppose each population is in an internal Hardy-Weinberg equilibrium, so that the genotype frequencies AA, Aa, and aa are respectively for each population respectively for each populaition - The heterozygosity (H) in the overall population is given by the mean of the two ○ - The departure for Hardy-Weinberg equilibrium due to subdivision can be measured by the index which is the Fixation Index in the Subpopulation reltive to the Total Population ○ ○ The Expected frequency (2pq) is based on mendalian frequencies (usually 0.5) - Example: - Hardy-Weinberg Equilibrium Page 71 Actual Steps 1. Find the average of each genotype 2. Find the allele frequencies - AA + Aa/2 = A freq. (p) - Aa+ Aa/2 = a freq. (q) 3. Find H (expected heterozygosity) - 2pq 4. Calculate observed heterozygosity - 5. Calculate (Fixation Index) - Hardy-Weinberg Equilibrium Page 72 Non-random Mating Friday, November 15, 2024 1:14 AM - Positive assortative mating: bias toward phenotypically similar mates ○ Reduces the frequency of heterozygotes ○ Each successive generation of mating reduces heterozygote frequency by half ○ - Negative assortative mating: bias toward phenotypically different mates - Inbreeding: bias toward mating with relatives ○ Causes an increase in homozygosity - Outbreeding: bias against mating with relatives - Affects genotype frequencies, NOT allele frequencies - Can affect genotype frequencies because… ○ Mates can be limited by geography ○ Mates can be chosen by their traits ○ Mates can be closer related to one another Hardy-Weinberg Equilibrium Page 73 Identity by descent (IBD) Friday, November 15, 2024 1:30 AM - Two homologous genes are IBD if and only if they are derived from the same ancestral gene (without mutation) - An individual is autozygous at a locus if and only if its two genes at that locus are IBD - The coefficient of inbreeding (F) of an individual is the prior probability that it is autozygous based on its pedigree Coefficient of Inbreeding (F) - : the coefficient of inbreeding of individuals I and J is the probability that a randomly chosen pair of homologous genes from I and J are identical by descent - If O is the offspring of I and J, then , the inbreeding coefficient O - Kinship coefficients are determined both by the structure of the pedigree and whether any of the founders of the pedigree are consanguineous Parent-child Kinship - Since there in no inbreeding in the population, the child only shared one allele with its parent - The coefficient of inbreeding between a parent and a child is 0.25 Hardy-Weinberg Equilibrium Page 74 Calculating IBD Pedigrees Friday, November 15, 2024 1:41 AM Example #1 Now also calculating F Example #2 Hardy-Weinberg Equilibrium Page 75 Hardy-Weinberg Equilibrium Page 76 Selection and Fitness Thursday, November 14, 2024 12:33 AM Selection: variation in average reproductive success among phenotypes Evolution by natural Selection: change the heritable characteristics f a population Fitness: the average # of offspring produced by a phenotype Hardy-Weinberg assumes that all genotypes have the same fitness Selection and Fitness Page 77 Natural Selection Thursday, November 14, 2024 12:35 AM - If genotypes have unequal fitness, then allele frequencies will change over time - Selection against a deleterious dominant allele eventually eliminates it from the population - Different types of selection act at each life cycle stage of a sexually reproducing organism ○ Selection Coefficient - Fitness differences are measured by the selection coefficient (s) ○ s show much difference Why doesn't selection eliminate all deleterious alleles? - Deleterious recessive alleles end up at a frequency where gain by mutation balances loss by selection Selection and Fitness Page 78 Directional Selection Thursday, November 14, 2024 12:44 AM - It is a mode of natural selection in which an extreme phenotype is favored over other phenotypes - Eliminates genetic diversity - The advantageous allele increases as a consequence of differences in survival an reproduction among different phenotypes ○ The increases are independent of the dominance of the allele, and even if the allele is recessive, I will eventually become fixed Allele frequencies can respond to natural selection Selection and Fitness Page 79 Heterozygote Advantage Thursday, November 14, 2024 12:48 AM - Also known as overdominance - In some cases, selection can maintain polymorphism rather than reduce it (balancing selection) - Example: sickle cell hemoglobin with Malaria ○ If you are in a place where malaria is high, HbAS has the highest chance of survival ○ In place where Malaria is low, HbAA has the highest chance of survival - Example: the sheep of Soay Island (Scotland) ○ Horn variation in males ○ Bigger horn = higher reproductive success ○ Smaller horns = higher chance of survival ○ Heterozygotes = highest overall fitness Selection and Fitness Page 80 Differential Reproduction and relative fitness Thursday, November 14, 2024 12:11 PM Differential reproduction - Natural selection favors members of a population over others as a result of differences in the traits they possess - The favored individuals reach reproductive age at higher rates than other population members, they reproduce and higher rates, or both - The result leads individuals with the most favored genotype to have higher success at producing offspring (differential reproduction) Relative Fitness - In order to measure the impact of differential reproduction in the next generation, we use the relative fitness (w) - W quantifies the reproductive success of the other genotypes relative to the genotype that is most favored - Organisms that have the greatest reproductive success have a relative fitness of w = 1.0 and the less successful ones have w < 1.0 - Fitness differences are measured by the selection coefficient (s) - The relative fitness (w) of an organism is expressed as - Relative fitness = Absolute fitness of a genotype / the highest absolute fitness in the population Modeling Selection Page 81 Modeling selection Thursday, November 14, 2024 12:22 PM - In order to model how selection affects a gene pool, we will make the following assumptions: ○ HW assumptions ○ One locus, two alleles ○ Discrete generations ○ Variation in genotype fitness, relative fitness (w) ▪ Fitness: a measurement of the relative ability of individuals to reproduce successfully Modeling Selection Page 82 Allele Fitness Thursday, November 14, 2024 12:26 PM Explained via example - Let p be the allele frequency of A and - The fitness of the alleles are: ○ ○ - The average fitness of the population is: ○ - Frequency of allele a in gametes is: ○ Modeling Selection Page 83 Modeling directional selection Thursday, November 14, 2024 12:37 PM Example: ○ The and ○ # of alleles is twice the total population (2N) ○ Make sure to multiply by to is using two alleles ○ Modeling Selection Page 84 Overtime the frequency of one allele increases due to directional selection Modeling Selection Page 85 Modeling heterozygote advantage Thursday, November 14, 2024 12:51 PM - The consequences of natural selection favoring the heterozygote is balances polymorphism - - Only a few homozygotes will reach reproductive age Example: ○ ○ Modeling Selection Page 86 Modeling Selection Page 87 Stable Equilibrium Thursday, November 14, 2024 1:11 PM - The stable equilibrium or p and q, designated and , are calculated as ratios of selection coefficients operating against the homozygous genotypes Modeling Selection Page 88 Genetic Drift Thursday, November 14, 2024 11:10 PM - Result of reproduction; all offspring contain a sample of the parent's genes - It is statistically unlikely that offspring will have the same allele frequencies as their parents - Drift occurs in every finite population (every real population) - Drift is stronger in small populations than in large populations - Because of drift, even favored alleles can be lost from a population Mutations are the ultimate source of polymorphism - Mutation rate (μ): the probability that one copy of an allele changes to another allelic form in one generation Neutrality - Despite the high mutation rates, most mutations are neutral - When calculating the probability of different outcomes under genetic drift, we assume that the A and a alleles do not confer differences in fitness Examples of mutations causing neutral polymorphism Fixation: genetic drift will eventually lead to the loss of all but one allele of a gene Probability that a new mutation will reach fixation - The fact that the frequency of an allele is equal to its probability of fixation means that new mutations will ultimately be lost from a population due to genetic drift - The initial frequency of a new mutation in the gene pool is: Genetic Drift Page 89 ○ - Examples: ○ ○ Genetic Drift Page 90 The founder effect Friday, November 15, 2024 10:44 AM - Populations can contract of expand in size over the years - A smaller population that branches off from a larger one will provide the conditions under which sampling errors can produce significant genetic drift on allele frequency - The migrant (founders), may not carry all the alleles from the original population or they may carry them all but at different frequencies Genetic Drift Page 91 Genetic Bottlenecks Friday, November 15, 2024 10:50 AM - Increases the level of genetic drift in small populations - A relatively large population is reduced due to a catastrophic event independent of natural selection - The survivors of the bottleneck are likely to have low levels of genetic diversity - Allele frequencies are different from those of the original population and an increase in the level of inbreeding could be observed Genetic Drift Page 92 Genetic drift and population size Friday, November 15, 2024 11:02 AM - At any locus of a population one allele can become fixed due to genetic drift - Also in another population, the frequency of A may increase from generation to generation but then decrease from generation to - Genetic drift does not proceed in a specific direction toward loss or fixation of an allele - The fate of an allele depends on the population size and its frequency in the population - Over time, genetic drift reduces the amount of allelic variation in population Genetic Drift Page 93 Balance between mutation and drift Friday, November 15, 2024 12:37 PM - When mutation and drift are in balance, a population can reach an equilibrium at which the loss and gain of variation are equal - We will use heterozygosity (H) as a measure of variation - H will be near 0 when a population is near fixation for a single allele (low variation), and approaches 1 when there are many alleles that have equal frequency (high variation) Finding - represents the equilibrium value of - To find we will need 2 equations ○ One relates the change in H to population size (drift) ○ Another related change in H to the mutation rate - Step 1: use an equation for the decline in variation (H) between generations as a function of population size (drift) ○ - Step 2: from the previous equation, the change in between generations due to drift is: ○ - The change in H between generations due to mutation is: ○ - When the population reaches equilibrium, the loss of heterozygosity by drift will be equal to the gain from mutation, meaning: ○ Genetic Drift Page 94 Balance between mutation and selection Friday, November 15, 2024 12:52 PM - Allelic frequencies may reach equilibrium is the introduction of new alleles by continuous mutation is balance by their removal via natural selection - New deleterious mutations, which could be completely recessive of partly dominant, are constantly arising spontaneously - Natural selection removes them from the population, but there is an equilibrium between their appearance and removal - Example: - Deleterious recessive allele - The equation for equilibrium frequency this is ○ ▪ μ = mutation rate ▪ s = selection coefficient - The equation above shows that the frequency at equilibrium depends on the ratio μ/s - When the mutation rate for A towards a gets larger and the selective disadvantage smaller, then the equilibrium frequency ( ) of a recessive deleterious allele will arise - Example Genetic Drift Page 95 - ○ A lethal allele is s=1 Partial dominant deleterious allele - An allele with some deleterious effect in heterozygotes as well as in homozygotes - - Where a is a partially dominant deleterious allele and its equilibrium frequency is determined as: ○ ▪ h is describing the degree of dominance of the deleterious allele - Example: - Genetic Drift Page 96 Friday, November 15, 2024 1:20 PM - Mendelian Genetics was developed using discrete traits (certain fixed values) - Most phenotypic traits are continuous (can take any conceivable value within an observed range) ○ Example: height - Continuous traits can also be explained by Mendel's rules ○ Example: ○ ○ Mendelian Explanation for above example: ○ Measuring Quantitative Variation Page 97 ○ ○ Mendelian Model explains 1:4:6:4:1 ratio in ○ Measuring Quantitative Variation Page 98 Continuous phenotypic variation from multiple additive genes Friday, November 15, 2024 1:55 PM - The # of distinct phenotypic categories for a polygenic train produced by the segregation of additive alleles of a given # of genes (n) is calculated as: ○ - Example: ○ For 4 additive genes contributing to a polygenic trait, n = 4, and the # of distinct phenotypic categories is: ▪ - As the # of genes increases, the phenotypic diferences between categries become very subtle Measuring Quantitative Variation Page 99 Complex Traits Friday, November 15, 2024 2:00 PM - If a large number of genes affect a trait, it becomes hard to distinguish phenotypic categories - Traits are also affected by the environmental effects, further blurring the distinction among categories - Variation of a complex trait can be portrayed by a frequency distribution - Distribution of height in a population follows a normal (bell) curve - Distributions can have the same mean but have different variance and thus standard deviations Measuring Quantitative Variation Page 100 Allele segregation in quantitative trait production Friday, November 15, 2024 2:04 PM - In 1916, Edward East, used the multiple gene hypothesis to investigate the patterns of inheritance produced in the length of the corolla in Nicotiana longiflora (tobacco plant) - East designed his experiment using true-breeding parental lines (short and long) - There is a small amount of variation in corolla length in each true-breeding strain, which suggests that gene-gene interactions or multifactorial effects produce some variability - The F1s ended up being intermediate, but not significantly more variable than the parental lines - The F2s were also intermediate, but more variable - He then decided to do selective breeding in order to get a population of short corollas and long ones ○ he was able to reconstitute lines nearly as different and uniform as his original parental lines - East's conclusions 1. Corolla length in the tobacco plant results from segregation of alleles of multiple genes 2. The phenotypic expression of each genotype is influenced with genes interaction with environmental factors Measuring Quantitative Variation Page 101 Genetic and environmental deviations Friday, November 15, 2024 2:18 PM - A simple mathematical model that can be applied to any quantitative trait (X) can be expressed in terms of the population mean ( ) and deviations from the mean due to genetic (g) and environmental (e) factors ○ - The equation above can be simplified to get ○ - n Partitioning Phenotypic Variance Page 102 Genetic and environmental variances Friday, November 15, 2024 3:23 PM - The trait variance can be partitioned into the genetic and the environmental variances: ○ - In the equation above, we can assume that the genotype and environment are nor correlated (they are independent) - Variance: measures how far a set of random #'s are spread out from their mean - Example: - Partitioning Phenotypic Variance Page 103 Partitioning Phenotypic Variance Page 104 Broad-sense Heritability ( ) Friday, November 15, 2024 4:11 PM - Measures the proportion of total phenotypic variation that is due to genetic variation ○ - If all the variation in a particular population is due to environmental sources and no genetic variation is present, the - If all of the variation in the population is due to genetic sources, then and Example: Partitioning Phenotypic Variance Page 105 Partitioning genetic variance Friday, November 15, 2024 4:19 PM Additive variance (a): due to the effects of individual alleles Dominance variance (d): due to dominance relationships among alleles Interactive variance (i): due to epistatic interactions between alleles Genetic variation formula: Example #1: all genetic variance is additive variance Example #2: all genetic variance is dominance variance Example #3 : genetic variance is additive and dominance variance Partitioning Phenotypic Variance Page 106 Narrow-sense Heritability ( ) Friday, November 15, 2024 4:34 PM - Measures the proportion of total phenotypic variation that is due to additive genetic variation ○ Fisher's fundamental theorem of natural selection - The rate of evolution via natural selection in a population is proportional to the additive genetic variance in the population - Thus narrow-sense heritability ( ) measures how well a population will respond to selection Response to selection - Selection differential (S): measures the difference between the population mean and the individuals selected for mating - Response to selection (R): measure how well the selection differential can be passed on to progeny - The higher , the stronger the response to selection Partitioning Phenotypic Variance Page 107 - Example: Partitioning Phenotypic Variance Page 108 Features of Hereditary Material Tuesday, November 19, 2024 1:37 PM - For a molecule to serve as the genetic material, it must be… ○ Localized to the nucleus and a component of chromosomes ○ Able to accurately replicate itself ○ Store information ○ Express information - DNA… ○ Is a double helix consisting of 2 complementary and antiparallel strands ○ is composed of 4 types of nucleotides, joined by a covalent phosphodiester bonds with 2 polynucleotide chains that come together to form a double helix - DNA Nucleotides ○ Composed of a deoxyribose (5-carbon) sugar, a phosphate group and 1 of 4 nitrogenous bases ▪ Adenine (A) ▪ Guanine (G) ▪ Thymine (T) ▪ Cytosine (C) - Nitrogenous bases ○ There are 2 types ○ Pyrimidines (have only 1 ring) ▪ Cytosine ▪ Thymine ▪ Uracil ○ Purines (have 2 rings put together) ○ Adenine ○ Guanine Complementary DNA nucleotide pairing - The 2 polynucleotide chains of a double helix form a stable structure that follows 2 rules… a. The bases of one strand are complementary to the bases in the corresponding strand (A with T, and C with G) b. The 2 stands are antiparallel with respect to their 5' and 3' ends Basis of complementary pairing - Combines 1 purine with 1 pyrimidine - The chemical basis of the pairing is the formation of stable hydrogen (H) bonds between the bases on the antiparallel strands - 2 H bonds form between A and T; 3 H bonds between C and G - Hydrogen bond donor: hydrogen on nitrogen or oxygen - Hydrogen bond acceptor: a free pair of electrons on nitrogen or oxygen - Origins of DNA replication and promoters, regions that need to be melted, are often AT rich DNA Structure Page 109 often AT rich ○ AT rich DNA melts at a lower temperature point than GC rich DNA due to the 2 hydrogen bonds rather than 3 Standard Base-pairing arrangements Tautomeric Shifts - Hydrogen potential changes - DNA Structure Page 110 - DNA Structure Page 111 Antiparallel Orientation Tuesday, November 19, 2024 1:41 PM - This orientation of the two strands of the double helix is essential for forming stable H bonds - It bring together the partial charges of complementary nucleotides into alignment - If 2 strands were to align in parallel, the charges on complementary nucleotides would repel each other - The phosphate (P) group is ALWAYS the 5' group - The hydroxyl (OH) group is ALWAYS the 3' group DNA Structure Page 112 The twisting double helix Friday, November 22, 2024 1:20 PM - The DNA helix has an axis of helical symmetry, an imaginary line that passes lengthwise through the core of the helix - 1Å = 0.1 nm (0.0000000001 m) - Each base pair is separated from the other base pair by a distance of 3.4 Å (0.00000000034 m, 3.4e-10) - Each turn of the helix measures 34 Å (0.0000000034, 3.4e-9) ○ This span is occupied by approximately 10.5 base pairs - The diameter of the molecule is 20Å (o.oooooooo2, 2e-9) ○ The diameter results from the fact that each complementary base pair is 20Å wide DNA Forms - A-DNA ○ Can be formed under conditions of dehydration - B-DNA ○ Normal double helix DNA - Z-DNA ○ Helps in binding in vaccinia virus pathogenesis - DNA Structure Page 113 Chargaff's Rule Friday, November 22, 2024 1:40 PM - States that DNA from any cell of all organisms should have a 1:1 ratio (base-pair rule) of pyrimidine and purine bases, and that the amount of guanine = cytosine and the amount of adenine = thymine DNA Structure Page 114 DNA Replicaton Friday, November 22, 2024 1:44 PM 3 postulated methods of DNA Replication - Meselson-Stahl experiment concluded that semi-conservative is correct Origins and directionality of replication in bacterial (prokaryotic) DNA - DNA replication in most often bidirectional, preceding in both directions from a single origin of replication in bacterial chromosomes - Eukaryotic chromosomes have multiple origins of replication - John Cairns reported the first evidence of bacterial origins or replication in 1963 ○ Showed the expansion around the origin of replication, forming a replication bubble, once replication starts in bacteria ○ At each end of each bubble is a replication fork ○ Replication is complete when the replication forks meet Multiple replication origins in eukaryotes - Autoradiograph analysis shows multiple origins of replication on eukaryotic chromosomes - Large eukaryotic genomes contain thousands of origins of replication, separated by 40,000 to 50,000 base pairs - The human genome contains more than 10,000 origins DNA replication precisely duplicates the genetic material - Best studied in bacteria - Though replication is very similar among Bacteria, Archaea, and Eukarya, the processes are not identical DNA Replication Page 115 - The enzymes and proteins involved are parts of large complex aggregations of proteins and enzymes called replisomes ○ They assemble at each replication fork Replication initiation in bacteria - Replication of E. coli requires that replication-initiating enzymes locate and bind to oriC consensus sequences (mer) - Enzymes DnaA, DnaB, and DnaC bind at oriC and initiate DNA replication - Replication origins have sequences that attract replication enzymes - DnaA binds first, bends the DNA, and breaks H bonds, forming and open complex - DnaC delivers DnaB protein to the open complex to initiate helicase activity DNA Replication Page 116 DNA Replication Rules Friday, November 22, 2024 2:49 PM 1. DNA synthesis only occurs in one direction, from 5' to the 3' end 2. DNA unwinding and synthesis have to be coordinated DNA Replication Page 117 DNA replication Steps Friday, November 22, 2024 2:51 PM 1. Helicase breaks hydrogen bonds, topoisomerase relaxes super-coiling a. Topoisomerases catalyze controlled cleavage and rejoining of DNA that prevents overwinding 2. DnaB is a helicase that uses ATP energy to break H bonds to separate the strands and unwind the helix a. Single-stranded binding (SSB) protein prevents reannealing 3. DnaG synthesizes RNA primers a. Primase, an RNA polymerase, synthesizes RNA primers  DNA polymerase CANNOT initiate DNA strand synthesis on their own (de novo) 4. DNA polymerase III synthesizes daughter strand a. DNA polymerase elongates DNA strands by adding nucleotides to the 3' end of RNA primer b. 5. DNA polymerase III elongates the leading strand continuously and the lagging strand discontinuously a. 1 copy of DNA polymerase III (pol III) synthesizes 1 daughter strand continuously in the same direction as fork progression b. The other copy of pol III elongates the daughter strand discontinuously, in the opposing direction to fork progression via short segments (Okazaki fragments) 6. DNA polymerase I removes and replaces nucleotides of the RNA primer a. DNA polymerase I (pol I) binds to a single stranded gap (DNA-RNA) and uses two activities to complete replication b. Its 5'-3' exonuclease activity removes the ribonucleotides from the RNA Primer one at a time starting from the 5' end of the primer c. Its 5'-3' polymerase activity adds DNA nucleotides DNA Replication Page 118 c. Its 5'-3' polymerase activity adds DNA nucleotides to the 3' end of the DNA segment preceding the primer 7. DNA ligase joins the Okazaki fragments a. When RNA primer removal is complete, DNA ligase replaces pol I at DNA-RNA single-stranded gaps and catalyzes the formation for a phosphodiester bond to join Okazaki fragments sealing het gap between the segments DNA Replication Page 119 Simultaneous synthesis of leading and lagging strands Friday, November 22, 2024 8:57 PM - In E. coli, daughter DNA strands are synthesized by the DNA pol III holoenzyme - Holoenzyme refers to multiprotein complex in which a core enzyme is associated with the additional component needed for full function - The replisome is found at each replication fork and contains 2 copies of pol III carrying out replication of the leading and lagging strand simultaneously - The DNA pol III core - The tau proteins are joined to a protein complex called the clamp loader, 2 additional proteins form the sliding clamp DNA Replication Page 120 Eukaryotic DNA Polymerases Friday, November 22, 2024 9:20 PM - Eukaryotes have many more DNA polymerases than bacteria - DNA polymerase α carries out synthesis of RNA primers - Polymerase ε and δ carry out lagging and leading strand synthesis, respectively - Each interacts with proliferating cell nuclear antigen (PCNA), which functions as the sliding clamp DNA Replication Page 121 DNA Proofreading Friday, November 22, 2024 9:24 PM - DNA replication in very accurate because the DNA polymerases undertake DNA proofreading to correct occasional errors - Errors in replication occur once about every billion nucleotides in E. coli - Proofreading ability of DNA polymerase enzymes is due to a 3' to 5' exonuclease activity - once - Several nucleotides (including the incorrect one) are removed and new nucleotides are incorporated from 5' to 3' DNA Replication Page 122 Finishing replication Friday, November 22, 2024 9:28 PM - The leading strand of linear chromosomes can be replicated to the end - The lagging strand requirement for a primer mean that lagging strands cannot be completely replicated - This problem is resolved by repetitive sequences at the ends of chromosomes, called telomeres - These repeats ensure that incomplete chromosome replication does not affect vital genes - Telomeres are synthesized by the ribonucleoprotein telomerase Telomerase synthesis of repeating telomeric sequence - The template RNA of telomerase allows new DNA replication, to lengthen the telomere sequences - Once telomere are sufficiently elongated, DNA replication fills out the chromosome ends - Telomere sequences in most organisms are quite similar Telomeres, aging, and cancer - Telomerase is active in germ-line cels and some stem cells in eukaryotes - Differentiated somatic cells and cells in culture have virtually no telomerase activity, such cels have limited life spans (30-50 cell division) - Reactivation of telomerase can lead to aging cells that continue to proliferate, a feature of many types of cancer - TERT reactivation is one of the most common mutations in cancers of all types - Werner syndrome ○ Telomerase activity is associated with normal aging of cells ○ This condition causes early onset of some features of aging ○ The mutation in RECQL2, a gene encoding helicase required for telomerase activity, is the cause of this syndrome DNA Replication Page 123 Mutations are rare and occur at random Saturday, November 23, 2024 5:27 PM - Mutations are random and usually deleterious, impairing function of the gene or gene product - Mutations generate inherited genetic diversity that fuels evolutionary change - Gene mutations substitute, add, or delete 1+DNA base pairs - Point mutations: occur at a specific identifiable position - Consequences depending on the type of sequence change and the location of the affected part of the gene - Mutation rates vary among organisms and among different genes in a single species Mutation^J Proofreading and Repair Page 124 Base-pair substitution mutations Saturday, November 23, 2024 8:21 PM - The replacement of 1 nucleotide base pair by another - Types ○ Transition mutations ▪ Purine to purine ▪ Pyrimidine to pyrimidine ○ Transversion mutations ▪ Purine to pyrimidine ▪ Pyrimidine to purine - Tautomeric shift induced mismatches ○ Due to this, DNA inherently can be no more accurate than mutations/base pair Types - Silent mutation: a base pair change that does not alter the resulting amino acid due to the redundance of the genetic code - Missense mutation: a base pair change that results in an amino acid change in the protein - Nonsense mutation: a base pair change that created a stop codon in place of a codon specifying an amino acid - Frameshift mutation: insertion/deletion of 1+ base pairs leads to addition/deletion of mRNA nucleotides, altering the reading frame ○ The wrong amino acid sequence is produced starting at the point of mutation; premature stop codons may also be produced Mutation^J Proofreading and Repair Page 125 Regulatory mutations Saturday, November 23, 2024 8:34 PM - Some point mutations alter the amount (not the amino acid sequence) of protein product produced by a gene - These affect regions like promoters, introns, and regions coding for 5'-UTR and 3'- UTR - Splicing mutations: reduce/eliminate normal pre-mRNA splicing ○ - Cryptic splice sites: production of new splice sites ○ Mutation^J Proofreading and Repair Page 126 DNA proofreading Saturday, November 23, 2024 8:41 PM - Pauses and re-assesses the nucleotide added - If there is a mismatch, the DNA polymerase moves the end of the newly synthesized strand to the 3' to 5' exonuclease site, which cleaves off the mismatched nucleotide Mutation^J Proofreading and Repair Page 127 Mutations may be induced by chemicals/ionizing radiation Saturday, November 23, 2024 9:13 PM - Induce mutations: produced by interactions between DNA and physical, chemical, or biological agents that generate mutations - Mutagens: agents that cause DNA damage leading to mutations - Chemical mutagens ○ Mutation^J Proofreading and Repair Page 128 Radiation-induced DNA damage Saturday, November 23, 2024 9:17 PM - Photoproducts: aberrant structures with additional bonds involving nucleotides; caused by UV irradiation ○ Byproducts ▪ Pyrimidine dimers: produced by the formation of 1 or2 additional covalent bonds between adjacent pyrimidine nucleotides ▪ Thymine dimer: formed between the 5 and 6 carbons of adjacent thymines - 6-4 photoproduct: formed by a bond between carbon 6 on 1 thymine and carbon 4 on the other - Mutation^J Proofreading and Repair Page 129 The Ames Test Saturday, November 23, 2024 9:17 PM - Mimics what happens when animals are exposed to chemicals, and tests the chemicals and their breakdown products for mutagenic potential - Bacteria are exposed to experimental compounds in the presence of mammalian live enzymes - In animals, instead chemicals are transported to the liver, where they are broken down by enzymes - Mutation^J Proofreading and Repair Page 130 Direct repair of DNA damage Saturday, November 23, 2024 9:30 PM Repair of thymine dimers - Nucleotide excision repair - Photoreactivation repair - Mismatch Repair - Repair enzymes distinguish between the original, correct nucleotide and the new, mismatched nucleotide using the presence of methylation on the original strand - In E. coli, methylation is common on the adenine of 5'- GATC-3' sequences - The C in CG dinucleotides in human DNA is methylated 70-80% of the tie. Involved in regulation of gene expression Mutation^J Proofreading and Repair Page 131 Other types of radiation Saturday, November 23, 2024 9:53 PM - Irradiation that has higher energy than UV lights includes x-rays and radioactive materials - These cause damage in multiple ways, the most serious are single-stranded or double-stranded breaks in DNA - If both strands of DNA are broke, neither strand can act as a template for repair - These breaks can block DNA replication and are dealt with by specializes repair systems Mutation^J Proofreading and Repair Page 132 Prokaryotes Friday, November 22, 2024 10:41 PM - DNA template Strand - Promoter : control element - Basic process ○ Initiation: RNA polymerase recognizes and binds to the genes promoter ○ Elongation: RNA polymerase moves down the gene unwinding the double helix, building the mRNA, and rewinding the double helix behind it ○ Termination: RNA polymerase recognizes special nucleotide sequences that cause it to stop - There are difference between prokaryotes and eukaryotes - Transcription begins only when RNA polymerase binds to a promoter - In the transcribed part of a gene one strand is the template strand and the other is the coding strand - RNA polymerase makes an mRNA strand that is complementary to the template strand - The template strand is always the one with its 3' end toward the promoter - The coding strand has the same sequence as the mRNA except that mRNA uses uracil (U) instead of thymine (T) - - RNA polymerase unwinds the DNA double helix and uses the template strand to build a complementary RNA strand (happens in initiation) - A genes sequence is written as the coding strand of the DNA - Transcription begins a few bases from the promoter to leave space for the RNA polymerase - Nucleotide positions downstream of the initiation site (toward the 3' end) are indicated with positive #s Transcription Page 133 - Nucleotide positions upstream of the initiation site (toward the '5' end) are indicated with negative #s Transcription Page 134 Structure of E. coli promoters Friday, November 22, 2024 11:10 PM Transcription Page 135 Initiation Friday, November 22, 2024 11:12 PM 1. The RNA polymerase core enzyme and sigma subunit bind to -10 and -35 promoter consensus sequences 2. DNA unwinds near the start of transcription to form the open promoter complex 3. RNA polymerase holoenzyme initiates transcription and begins RNA synthesis. The sigma subunit disassociates shortly after transcription initiation, and the core enzyme continues transcription 4. The core enzyme synthesizes until it encounters the termination sequence. As RNA synthesis progresses, the DNA duplex unwinds to allow the template strand to direct RNA assembly. The duplex closes following synthesis Transcription Page 136 Elongation Saturday, November 23, 2024 10:04 PM - RNA polymerase moves along the DNA, synthesizing an RNA strand complementary to the template strand - Multiple mRNAs can be made simultaneously form the same gene Transcription Page 137 Termination Saturday, November 23, 2024 10:05 PM - RNA polymerase stops at a specializes termination sequence (Inverted repeat) ○ There be a high A-T content signaling to transcribe the last base - The terminator region of the mRNA folds into a hairpin structure ○ The string of uracils are right after the hairpin - Transcription Page 138 Eukaryotes Saturday, November 23, 2024 10:19 PM - Different RNA polymerases for making different types of RNA - Happens in Nuclei - Initiation, elongation, and termination - RNA processing Types of RNA polymerase - RNA polymerase I: transcribes ribosomal RNA genes - RNA polymerase II: transcribes all protein-coding genes into mRNA - RNA polymerase III: transcribes tRNAs and other small functional RNAs Transcription Page 139 Initiation Saturday, November 23, 2024 10:21 PM - Promoters are upstream (5') of the transcription initiation site - Most promoters have a distinctive conserved site called the TATA box, 30 base pairs (bp) upstream of the initiation site ○ Promoter consensus sequence elements - GC-rich box - CAAT box - TATA box The first step in transcription is binding of TATA-binding protein (TBP), a general transcription factor (GTF) to TATA box - Once TBP has bound, other GTFs ad RNA polymerase II join in to form the preinitiation complex Transcription Page 140 Elongation Saturday, November 23, 2024 10:32 PM - RNA polymerase II separates from the GFTs and moves down the gene, making RNA - The GTFs become available to initiate transcription by another RNA polymerase II complex - RNA polymerase II makes the primary transcript (pre-mRNA) ○ The primary transcript undergoes cotranscriptional modification before leaving the nucleus ▪ Addition of a 5' cap ▪ Addition of a 3' poly(A) tail (80-250 As) ▪ Splicing to remove introns and joins exons ○ Pre-mRNA processing - The pre-mRNA undergoes extensive processing before it is ready to be translated - The additional steps involved in eukaryotic mRNA maturation create a molecule with a much longer half-life that a prokaryotic mRNA - The 3 most important steps of pre-mRNA processing are… 1. The addition of stabilizing factors at the 5' and 3' ends of the molecule ▪ Protects the mRNA form being degraded ▪ Important for transcribing the mRNA out of the nucleus Transcription Page 141 ▪ Important for transcribing the mRNA out of the nucleus ▪ Needed to initiate translation of mRNA into protein 2. The addition of signaling factors at the 5' and 3' ends of the molecule 3. The removal of intervening sequences that do not specify the appropriate amino acids Transcription Page 142 Termination Saturday, November 23, 2024 10:53 PM - Transcription ends when a special termination is reached - Signal sequence triggering termination (polyadenylation) is AAUAAA - An endonuclease recognizes this sequence and cuts the RNA about 20 bp downstream Polyadenylation of 3' pre-RNA - The 3' end of the pre-mRNA is created by an enzyme action that removes the section of the 3'message and replaces it with a string of adenines - The pre-mRNA is cleaved about 20 nucleotides downstream of the polyadenylation signal sequence - This is thought to be associated with the subsequent termination of transcription - Polyadenylation… ○ Protects the RNA from being degraded ○ Is important for transporting the mRNA out of the nucleus ○ Is important for maintaining translation of mRNA into protein - The introns (intervening sequences, not coding for proteins) are removed before protein synthesis - Only exons are eventually translated into polypeptides Transcription Page 143 Amino Acids Monday, November 25, 2024 11:23 AM Proteins are polymers composed of units called amino acids - 20 amino acids are known to exist in proteins - They differ in the structure and chemical properties of their side groups - - Polypeptides are chain of amino acids linked together by peptide bonds ○ - The genetic code is a non-overlapping triplet code ○ A 3-letter code can represent up to 64 codons but there are only 20 amino acids, therefore the genetic code is degenerate ▪ Degeneracy means that nearly 2/3 of mutations, even in coding regions of a genome, will be silent mutations - Structure of a gene Translation Page 144 - Structure of a gene ○ ○ The coding sequence consists of an open reading frame (ORF) that gets translated into a polypeptide ▪ Begins with a start codon, usually AUG (Methionine) ▪ Ends with a stop codon □ UAA, UAG, or UGA □ They do not encode for any amino acid, only used to stop translation Translation Page 145 Translation Machinery Monday, November 25, 2024 11:39 AM - mRNA (codons) - Ribosomes ○ Ribosomal RNA (rRNA) ○ Ribosome proteins - tRNA and tRNA charging enzymes (aminoacyl tRNA synthetases) Translation Page 146 tRNA Monday, November 25, 2024 11:50 AM Transfer RNA (tRNA) - These molecules are adaptors - They match each codon with the correct amino acid - 74-95 bp long - Folds into distinctive cloverleaf shape - Each tRNA binds to only 1 of the 20 aa's - Each anticodon is complementary to the codon for its aa - A tRNA is attached to its amino acid by an aminoacyl-tRNA synthetase - Degeneracy of tRNA ?

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