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Genetics Exam II Notes

by: Simrat Kaur

Genetics Exam II Notes Biol 3301

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Simrat Kaur

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These are the notes that will cover exam II
Chin-Yo Lin/Timothy F Cooper
Study Guide
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This 52 page Study Guide was uploaded by Simrat Kaur on Sunday October 9, 2016. The Study Guide belongs to Biol 3301 at University of Houston taught by Chin-Yo Lin/Timothy F Cooper in Fall 2016. Since its upload, it has received 241 views. For similar materials see Genetics in Biology at University of Houston.


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Date Created: 10/09/16
Chapter 22: Population Genetics and Evolution Part 1 ● Quantitative Trait Loci (QTL) ○ Quantitative trait loci​: genes that contribute to quantitative traits. ○ QTL are not fundamentally different to the genes that control discrete phenotypes, but they are more difficult to detect. There will be several genes that contribute to the same phenotype and the phenotype is more variable, so the analysis of genotypes is more difficult than saying if a genotype does/does not have a specific phenotype. ○ Mapping of a discontinuous trait relies on our ability to determine the genotype of a particular phenotype. ○ QTL mapping is a method that detects linkage between a trait of interest and markers at known locations throughout the genome. ■ Step 1: Interbreed two divergent parental lines to generate an F​ gener1​ion (all heterozygous) ■ Step 2: Backcross the F​ off1​ring to either of the two parental lines and genotype the offspring for the markers. ● GWAS -QTL mapping in humans ○ QTL mapping requires controlled crosses → not possible in humans ○ Genome wide association studies (GWAS)​ is a method used to identify the vast majority of human disease genes. ○ GWAS​: analyze associations between a trait and genetic variation present in a population. Variants associated with a trait are near genes that contribute to that trait. ■ Considers each marker that has a different version in the two parents as an allele, and tests for linkage between the marker and the phenotype of interest. ■ The closer a marker is to the gene affecting fruit size that differs in effect between the two parents, the more tightly linked the marker and the gene will be. They will tend to inherit together the backcross offspring. ○ Distinct distributions for genotypic classes at a marker locus signal the location of a QTL near the marker. Odds =​ Prob(Data|QTL) Prob(Data|no QTL) ■ “LOD” = Log (10) of the Odds Part 2 ● How does genetic/phenotypic variation arise and get maintained? ○ Natural selection ○ Mutation ○ Migration ○ Genetic drift ● Population genetics ○ Population: ​ ​ a group of interbreeding individuals ○ Gene Pool​:​ the collection of alleles found in a population → this is the source of genetic information from which the next generation is produced. There will almost always be more alleles in a population than in any one individual ​ ○ Hardy-Weinberg (H-W)​ equilibrium hypothesis​ predicts the frequency of alleles and genotypes in the next generation of an idealized population with a known gene pool. ■ The population is infinite. ■ Mating is random. ■ No difference in fitness of different genotypes. *In practice, these assumptions ​are not met​: ​H-W serves as a NULL model to assess the influence of deviations from assumptions* ● H-W equilibrium predicts genotype frequencies from allele frequencies ○ Prediction 1:​ if a population has a known frequency of two alleles, the frequency of genotypes in the next generation can be calculated using: ​ ​ ​ p + 2p ​ q + q​ 2​= 1 ​ ​ ​ ​ ​ ​ p + 2​pq + ​q + 2p​ ​ r + ​r + 2q ○ Prediction 2:​ H-W equilibrium predicts that the genotype frequencies will not change between generations. Even if a population starts away from H-W equilibrium, a single round of mating is sufficient for equilibrium to be reached. Expected Example: A​1​​1 A​1​​2​ A​2​​2​ Chi-Square Test (X​ ): X​ = ∑​(observed-expected)​ = 1 + 0.08 + 1 P = 0.15 (df = 1) ● H-W is used as a null hypothesis. If we follow genotype frequencies in a population and find ● How can we determine if genotype frequencies are changing? ● How do allele frequencies change? ​ ​ ​​ ​​ ○ Over successive generations you can see that B​ will 1​ continue to increase, causing B​ to de2​ease – eventually B​ w2​l ​fix​, or reach a frequency of 1, in the population. ○ The speed with which B​ increas1​ depends on its fitness relative to B​ 2​The larger the difference, the more quickly B​ will fix. 1​ ○ Called directional selection because selection drives the frequency of B​ in a consistent direction → up. 1​ ○ Mutation is the ultimate source of genetic variation, but by itself, it changes allele frequencies slowly. Variation acted on by natural selection can cause rapid changes. ● Random sampling causes a deviation from expected allele frequencies. ○ An assumption of H-W with important, but not intuitive, consequences is that the population has infinite size. ○ This assumption cannot be met, since all populations are finite. Violating the assumption of infinite population size can lead to big deviations from H-W predictions. The random sampling of events in finite populations will cause genotype, and therefore, allele, frequencies to change each generation. This is known as ​genetic drift. Infinite population size Finite population size Over successive generations, genetic drift continually alters allele frequencies. Eventually, an allele will go extinct. Here, 4 replicate populations each started with two alleles at equal frequency. ○ In small populations, a sampling effect can cause allele frequencies to differ substantially from expectations. ■ Founder effect:​ where a small sample of large population establishes a new population. ■ Genetic bottleneck:​ describes a dramatic decrease in population size (can be due to migration or ecological event) ● Bottlenecks are one reason why some alleles are common in some groups. ● Inbreeding ○ Inbreeding​, also known as ​consanguineous mating​, is mating between individuals that share a greater proportion of alleles than would two random members of a population. ○ An effect of inbreeding is an increase in the frequency of homozygous genotypes. ○ Related individuals are more likely to share alleles, so they are more likely to produce homozygotes. ○ Sewall Wright investigated the consequences of inbreeding and devised the ​coefficient of inbreeding (F)​ as an arithmetic measure of the probability of homozygosity for an allele obtained in identical copies from an ancestor. ○ The coefficient quantifies the probability that two alleles in the homozygous individual are ​identical by descent (IBD), having descended from the same copy of the allele carried by a common ancestor. ● Non-random mating reduces variation ○ Non-random mating tends to reduce the amount​ ​of variation in a population. ○ Example: if there were two alleles in a population and three genotypes, ​A/A; ​ ​​​ ​; a/a​, each only mating with other individuals of the same genotype. The frequency of the A​/​a​ genotype would quickly decline. ○ The reason for this is that offspring of ​A/A​ x ​A/A​ and ​a/a​ x ​a/a​ parents have the parental genotype whereas only half the offspring of ​A​/​a​ x ​A​/​a​ parents have the parental genotype. The fraction of this genotype declines by half each generation. Chapter 7: DNA Structure and Replication ● 7.1:​ DNA is the hereditary molecule of life ○ Before DNA was known to be the hereditary molecule, there were five characteristics of hereditary molecules identified: ■ Localized to the nucleus, component of chromosomes. ■ Present in stable form in cells. ​ ■ Avery, MacLeod, and McCarty used heat-skilled SIII bacteria, live RII bacteria and infected mice. ■ The extract of heat-killed SIII bacteria was divided into aliquots and treated to destroy either DNA, RNA, proteins, or lipids and polysaccharides. ■ All aliquots killed the mice except the one with the DNA destroyed. ● Bacteriophage: Viruses which infect Bacteria ○ Alfred Hershey and Martha Chase decided to study viruses that infect bacteria ○ They conducted experiments with the Waring Blender. ○ Proteins​ contain large amounts of ​sulfur​ but almost no phosphorus. ○ DNA​ contains large amounts of ​phosphorus​ but no sulfur. ○ Hershey and Chase35​parately labeled32​ther phage proteins (with ​ S) or DNA (with ​ P) and then traced each radioactive label in the course of infection. ○ After infection, in both experiments, agitation by a blender separated the empty phage particles from the infected bacteria. ○ In the protein labeling experiment, the radioactivity was detected in the empty phage particles (ghosts). ○ In the DNA labeling experiment, the radioactivity was detected inside the infected bacteria. RESULTS: ● 7.2: ​The DNA double helix consists of two complementary and antiparallel strands ○ DNA is a polymer composed of four kinds of nucleotides joined by covalent phosphodiester bonds with two polynucleotide chains that join to form a double helix. *KNOW THE IMPORTANCE OF EACH CARBON POSITION IN THE SUGAR GROUP* ○ Each polymer/strand is made of nucleotides connected by phosphodiester bonds. ○ Strands have directionality. ○ Two strands are antiparallel. ○ Complementation of bases and hydrogen bonds hold strands together. ● Chargaff’s Rule ● Rosalind Franklin ○ X-ray diffraction pattern of DNA crystals. ● Watson and Crick ○ DNA model ​ ​ ​ ​ *GET COMFORTABLE WITH THE TERMINOLOGY* ● Initiation of replication ○ DnaA first binds the 9-mer sequences, bends the DNA, and breaks hydrogen bonds in the A-T rich sequences of the 13-mer region. ○ DnaB is a ​helicase​ that uses ATP energy to break hydrogen bonds of complementary bases to separate the strands and unwind the helix. ○ DnaB is carried to the DNA helix to DnaC. ○ The unwound DNA strands are kept from reannealing by single-stranded binding protein (SSB). ○ Unwinding of circular chromosomes will create torsional stress, potentially leadi​ upercoiled DNA. ○ Enzymes called t ​ opoisomerases​ catalyze controlled cleavage and rejoining of DNA that prevents overwinding. ​ ​ PUTTING IT ALL TOGETHER → → → → → → → →→ → → → ​ ○ Replication errors produce a DNA mismatch and inability of the mismatched bases to form the appropriate H-bonds. ○ This leads to displacement of the 3’-OH into the 3’ to 5’ exonuclease “site” of the enzyme. ○ Several nucleotides (including the incorrect one) are removed and new nucleotides are incorporated. ● Telomeres ○ The leading strand of linear chromosomes can be replicated to the end. ○ The lagging strand requirement for a primer means 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​. ○ The RNA in telomerase is complementary to the telomere repeat sequence and acts as a template for addition of DNA. ○ The template RNA of telomerase allows new DNA replication to lengthen the telomere sequences. ○ Once telomeres are sufficiently elongated, the ​α polymerase synthesizes additional RNA primers. ○ New DNA replication then fills out the chromosome ends. ○ Telomere sequences in most organisms are quite similar. ● Importance of telomerase activity ○ Mice that are homozygous for loss-of-function mutations of the TERT (telomerase reverse transcriptase) gene give rise to developmental defects. ○ These defects are first observed in the fourth and fifth generations, due to loss of telomere length with each generation. ○ By the fourth and fifth generations, shortening of the chromosomes is critical and apoptosis is induced. ​ ​ ​ ​ ■ The PCR primers define the 5’ to 3’ boundaries of the replication products. ■ PCR is composed of three steps that result in exponential amplification of large numbers of the target DNA. ○ Steps of PCR: ■ Denaturation:​ the reaction is heated to ~95°C to denature the DNA into single strands. ■ Primer annealing:​ the reaction temperature is reduced to ~45-68°C to allow primers to hybridize to their complementary sequences in the target DNA. ■ Primer extension:​ the reaction’s temperature is raised to 72°C to allow ​Taq polymerase to synthesize DNA. ○ Limitations of PCR: ■ Some knowledge of the target DNA sequences is required in order to determine primer sequences. ■ Amplification products longer than 10 to 15 kb are difficult to produce. ○ Despite these limitations, PCR is a practical way to obtain large quantities of DNA from a particular gene for molecular analysis. ○ Separation of PCR products: ■ Amplified DNA fragments are separated from the rest of the reaction mixture by gel electrophoresis and visualized by ethidium bromide staining. ■ PCR product sizes are measured in base pairs (bp) ■ Differences in the size of DNA amplified by a pair of primers are related to the amount of DNA between the primers. ● Dideoxynucleotide DNA sequencing (dideoxy sequencing) ○ The ultimate description of a DNA molecule is its precise sequence of bases. ○ The Sanger (dideoxynucleotide) method was the most open to automation and is the method of choice today. ○ This method uses DNA polymerase to replicate new DNA from a single-stranded template. ○ The four standard deoxynucleotide bases (dNTPs) are present in large amounts. ○ Each reaction contains a small amount of dideoxynucleotide (ddNTP)​, which lacks a 3’-OH group. ○ The principal of Sanger sequencing ■ Whenever a ddNTP is incorporated into the product DNA molecule, replication ceases. ■ A separate reaction is carried out for A, T, G, and C using a corresponding amount of ddNTP. ■ Each reaction tube produced a series of partial DNA molecules, each of which ends with that nucleotide. ■ All four reactions must run side by side on a gel in order to determine complete sequence. ○ Visualization of DNA sequence ■ After the reactions are complete, the reactions are run side by side on a gel. ■ The bands shown in the autoradiograph are visible because the primers that begin each fragment were labeled with radioactive isotopes (end-labeling). ■ The shortest bands are the DNA products closest to the primer and these travel fastest on the gel. The gel is read from the bottom up, all four lanes together. ○ Automated DNA sequencing ■ Automated DNA sequencers use a single reaction for each DNA sequence, in which all four ddNTPs are included. ■ Each ddNTP is labeled with a unique fluorescent marker. ■ The DNA is synthesized and a mixture of fragments is produced and run on a DNA gel. ■ The fluorescent label on each ddNTP has a different wavelength, and a laser light excites the fluorescent tag on each fragment as it passes. ■ The wavelength of the fluorescence is read as the fragment passes, and the information is recorded by computer. ■ The fluorescence pattern produced shows the sequence of the DNA. Chapter 8: Molecular Biology of Transcription and RNA Processing ● RNA transcripts carry the messages of genes ○ RNA ribonucleotides​ are composed of a sugar, nucleotide base, and one or more phosphate groups, with two critical differences compared to DNA nucleotides: ■ Thymine is replaced by ​uracil. ■ The sugar ​ribose​ is used instead of deoxyribose. ● RNA synthesis ○ RNA polymerase​ catalyzes the addition of each ribonucleotide to the 3’ end of the growing strand. ○ Two phosphates are eliminated in the process, as in DNA synthesis. ● RNA classification ○ Messenger RNA (mRNA)​: produced by protein-encoding genes and is a short-lived intermediary between DNA and protein. ■ The only type of RNA that undergoes translation. ■ Transcription of mRNA is often followed by post-transcriptional processing. ○ Transfer RNA (tRNA)​: encoded in dozens of forms and is responsible for binding an amino acid and depositing it for inclusion into a growing protein chain. ○ Ribosomal RNA (rRNA)​: combines with numerous proteins to form ribosomes. ○ Small nuclear RNA (snRNA)​: found in the nucleus of eukaryotes and plays a role in mRNA processing. ○ Micro RNA (miRNA)​: active in plant and animal cells and is involved with post-transcriptional regulation of mRNA. ○ Long non-coding RNA (lncRNA)​: belongs to a class of genes that is nearly as numerous as protein coding genes. ● Gene structure ○ The gene contains several segments with distinct functions. ○ The ​promoter​ is immediately ​upstream​ (5’) to the start of the transcription, referred to as the +1 nucleotide. ○ The promoter controls the access of RNA polymerase to the gene. ○ The ​coding region​ of the gene is the portion that contains the information needed to synthesize the protein product. ○ The ​termination region​ of the gene regulates the end of transcription. ​ ● Transcription Initiation ○ RNA polymerase initiates through a two-step process ■ First, the holoenzyme makes a loose attachment to the promoter sequence to form the closed promoter complex. ■ The holoenzyme next unwinds about 18 bp of DNA around the -10 position to form the ​ pen promoter complex​. ● Transcription termination mechanisms ○ Termination of transcription in bacteria is signaled by a DNA termination sequence that usually has a repeating sequence. ○ In ​intrinsic termination​, a mechanism dependent only on the presence of the repeat, induces secondary structure needed for termination. ○ Rho-dependent termination​ requires a different termination sequence and the ​rho protein​. ● Intrinsic termination ○ Most bacterial termination occurs via intrinsic termination. ○ Termination sequences include an inverted repeat followed by a string of adenines. ○ mRNA containing the inverted repeats form into a short ​stem-loop structure,​ called a hairpin. ○ The hairpin followed by a series of “U”s in the mRNA causes the RNA polymerase to slow down and destabilize. ○ The instability caused by the slowing polymerase and the U-A base pairs induces the polymerase to release the transcript and separate from the DNA. ● Rho-dependent termination ○ Certain bacterial genes require the action of rho protein for termination. ○ Rho-dependent termination sequences do not have a string of uracils. Instead, they have a ​ ho utilization (rut) site​, a stretch of about 50 nucleotides rich in cytosines. ○ Rho-dependent termination also uses a terminator site which forms a hairpin structure when transcribed. ● Eukaryotic transcription uses multiple RNA polymerases ○ Eukaryotic promoters and consensus sequences are more diverse than those of bacteria. ○ Eukaryotes have three different RNA polymerases that recognize different types of RNAs. ○ The complex that assembles to initiate and elongate transcription is more complex in eukaryotes than in bacteria. ○ Eukaryotic genes carry introns and exons, and require processing to remove introns. ○ Eukaryotic DNA is associated with proteins to form chromatin; the chromatin composition of a gene affects its transcription. ○ Chromatin thus plays an important role in gene regulation of eukaryotes. ● Eukaryotic polymerases ○ RNA polymerase I (RNA pol I)​: transcribes three ribosomal RNA genes. ○ RNA polymerase II (RNA pol II)​: transcribes protein coding genes and most small nuclear RNA genes. ○ RNA polymerase III (RNA pol III)​: transcribes tRNA, one small nuclear RNA, and one ribosomal RNA. ● Promoter elements ○ The most common eukaryotic promoter consensus sequence is the ​TATA box​, or the Goldberg-Hogness box​, located at about position -25. ○ The consensus sequence is 5’-TATAAA-3’ ○ A C​ AAT box​ is often found near the -80 position. ○ A ​GC-rich box​ (consensus 5’-GGGCGG-3’) is located at -90, or further upstream. ● Promoter recognition ○ RNA pol II recognizes and binds to promoter sequences with the aid of proteins called transcription factors (TFs)​. ○ TFs bind to regulatory sequences and interact directly, or indirectly, with RNA polymerase; those interacting with pol II are called TFII factors. ○ The TATA box is the principal binding site during promoter recognition. ● Detecting promoter consensus elements ○ Research to verify that a segment of DNA is functionally important component of a promoter has two components: ■ Discovering the presence and location of DNA sequences that transcription factors will bind to. ■ Mutational analysis to confirm that functionality of each sequence. ● Mutational analysis of promoters ○ Researchers produce many different point mutations and compare the level of transcription generated by the mutant sequence relative to wild type. ○ Mutations inside the consensus region significantly reduce levels of transcription. ○ Mutations outside the consensus region have nonsignificant effects on transcription. ● Enhancer sequences ○ Enhancer sequences​: increase the level of transcription of specific genes. ○ They bind proteins that interact with the proteins that are bound to gene promoters, and together the promoters and enhancers drive gene expression. ○ Enhancers may be variable distances from the gene they affect and may be upstream or downstream of the gene. ● Silencer sequences ○ Silencer sequences​: DNA elements that act at a distance to repress transcription of their target genes. ○ Silencers bind transcription factors called ​repressor proteins​ that induce bends in DNA. ○ These bends reduce transcription of the target gene. ○ Silencers may be located variable distances from their target genes, either upstream or downstream. ● Post-transcriptional processing modifies RNA molecules ○ Eukaryotic transcripts are more stable than bacterial transcripts. ○ In eukaryotes, transcription and translation are separated in time and location. ○ Eukaryotic transcripts have ​introns​, which are not found in bacterial transcripts. ○ These features are all related to post-transcriptional modification of eukaryotic transcripts. ○ The initial eukaryotic gene mRNA is called ​pre-mRNA​ whereas the fully processed mRNA is called the m​ ature mRNA​. Modifications include: ■ 5’ capping ■ 3’ polyadenylation ■ Intron splicing ● Functions of 5’ Capping ○ Protection of mRNA from rapid degradation. ○ Facilitating transport of mRNA out of the nucleus. ○ Facilitating subsequent intron splicing. ○ Enhancing translation efficiently by orientation the ribosome on the mRNA. ● Functions of 3’ polyadenylation ○ Facilitating transport of mature mRNA across the nuclear membrane to the cytoplasm. ○ Protecting the mRNA from degradation. ○ Enhancing translation by enabling the ribosomal recognition of mRNA. **Some eukaryotic transcripts (e.g. histone genes) do not undergo polyadenylation** ● Pre-mRNA intron splicing ○ Intron splicing requires great precision to remove intron nucleotides accurately. ○ Errors in intron removal would lead to incorrect protein sequences. ● Splicing signal sequences ○ Specific short sequences define the junctions between introns and exons. ○ The ​5’ splice site​ is at the 5’ intron end and contains a consensus sequence with an invariant GU dinucleotide at the 5’- most end of the intron. ○ The ​3’ splice site​ at the opposite end of the intron has an 11 nucleotide consensus with a pyrimidine rich region and a nearly invariant AG at the 3’- most end. ○ A third consensus region, called the ​branch site​, is 20 to 40 nucleotides upstream of the 3’ end of the intron. ○ It is pyrimidine-rich and contains an invariant adenine called the ​branch point adenine near the 3’ end of the consensus. ○ Mutation analysis shows that all three consensus sequences are required for accurate splicing. ● Splicing ○ Introns are removed from the pre-mRNA by an snRNA-protein complex called ​spliceosome​. ○ The 5’ splice site is cleaved first and a ​lariat intron structure​ is formed when the 5’ intron end binds to the branch point adenine. ○ Then the 3’ splice site is cleaved and the exon ends are ligated together. ● Spliceosome composition ○ The spliceosome is a large complex made up of many snRNPs (U1 through U6). ○ The composition is dynamic, changing through the steps of splicing. ○ Spliceosome components are recruited to 5’ to 3’ splice sites by SR proteins; these bind to sequences in exon called ​exonic splicing enhancers (ESEs)​ and ensure accurate splicing. ● Intron self-splicing ○ RNAs can contain introns that catalyze their own removal. ○ There are three categories: group I, group II, and group III. ○ Group I​ introns are large, self-splicing ribozymes that catalyze their own excision from mRNAs, and from tRNA and rRNA precursors of bacteria, simple eukaryotes, and plants. ○ Intron self-splicing​ takes place via two transesterification reactions that excise the intron and ligate the exon ends. PUTTING IT ALL TOGETHER ← ← ← ← ← ← ← ← ← ← ← ● Alternative transcripts of single genes ○ It is common for large eukaryotic genomes to express more proteins than there are genes in the genome. ■ Example: human cells can produce over 100,000 distinct polypeptides but contain ~22,000 genes. ○ Three transcription-associated mechanisms can explain this. ​ ​ ​ ○ Though there are 61 codons that specify amino acids, most genomes have 30-50 different tRNA genes. ○ A relaxation of the strict complementary base-pairing rules at the third base of the codon is called ​third-base wobble. ○ tRNA molecules with different anticodons for the same amino acids are called iso-accepting tRNAs​. ● How third-base wobble works ○ Most synonymous codons can be grouped into pairs that differ only in the third base; the pairs either both carry a purine (A or G) or both carry a pyrimidine (C or U). ○ Third-base wobble occurs through flexible pairing at the 3’-most nucleotide of the codon and the 5’-most nucleotide of the anticodon. ○ However, a pyrimidine must still base-pair with a purine. ● Charging tRNA Molecules ○ tRNA molecules are transcribed from tRNA genes. ○ Correct charging of each tRNA molecule is crucial for the integrity of the genetic code. ○ Enzymes called ​aminoacyl-tRNA synthetases​ or ​tRNA synthetases​ catalyze the addition of the correct amino acid to tRNAs. ○ Recognition of the iso-accepting tRNAs by the enzyme is complex with no single set of rules. ● Experiments Deciphered the Genetic Code ○ A remarkable set of experiments in the 1960s deciphered the genetic code and answered the following questions: ■ Do neighboring codons overlap one another? ■ How many nucleotides make up an mRNA codon? ■ Is the polypeptide-coding information of mRNA continuous or does it contain gaps? ● No Overlap in the Genetic Code ● Conclusive Evidence of Nonoverlap ○ In 1960, a study of single nucleotide substitutions by Fraenkel-Conrat and colleagues showed that single nucleotide changes led to single amino acid changes. ○ An overlapping code would have led to multiple amino acid changes as a result of altering one nucleotide. ○ The results of the study are consistent with a nonoverlapping genetic code. ● A Triplet Genetic Code ○ Proof of a triplet genetic code came in 1961 when researchers (Crick, Barnett, Brenner, and Watts-Tobin) created mutations by insertion or deletion of single nucleotides. ○ This leads to a change in reading frame of the mRNA. ○ Reading frame​ refers to the specific codon sequence as determined by the start codon ● Frameshift Mutations ○ Mutations that alter reading frame are called ​frameshift mutations​ and garble the sense of the translated message. ■ Wild type: YOU/MAY/NOW/SIP/THE/TEA ■ Mutant addition: YOU/MAC/YNO/WSI/PTH/ETE/A ■ Mutant deletion: YOU/MAY/NOS/IPT/HET/EA ○ All the codons after the addition or deletion will specify the wrong amino acids ● Reversion of Frameshift Mutations ○ Frameshift mutations may be restored if a second mutation in a different location in the gene restores part of the reading frame. ■ Mutant addition: YOU/MAC/YNO/WSI/PTH/ETE/A ■ Reversion mutant deletion: YOU/MAC/YNO/SIP/THE/TEA ○ The frameshift is now confined to just a small area between the original mutation and the reversion mutation – the rest of the protein (sentence) is normal. ● Interpretations of the Experiments Confirm That the Genetic Code Is a Triplet Code ○ Single additions or deletions of nucleotides into the rII gene of T4 bacteriophage caused frameshift mutations. ○ Addition of two nucleotides or deletion of two nucleotides produced frameshifts as well. ○ Addition of three nucleotides or deletion of three nucleotides produced a “mutant” region between the first and last of the added or deleted nucleotides but a non-frameshifted protein outside of the altered region. ● No Gaps in the Genetic Code ○ Crick and colleagues suggested that the genetic code is read continuously, with no gaps, spaces, or pauses between codons. ○ For example, if a spacer were present a transcript might read: YOUxMAYxNOWxSIPxTHExTEAx; if the spacer existed, an inserted or deleted nucleotide would affect only one codon. ○ YOUxMATYxNOWxSIPxTHExTEA ● Deciphering the Genetic Code ○ The genetic code was deciphered between 1961 and 1965. ○ It was a milestone in establishing the central dogma of biology: DNA → RNA → protein. ● First Steps in Deciphering the Genetic Code ○ Nirenberg and Matthai performed an experiment in 1961 that laid the groundwork for later work. ○ Strings of repeating nucleotides were translated in vitro and the resulting polypeptide identified. ○ For example, an artificial mRNA containing only uracils, poly(U), resulted in polypeptides containing only phenylalanine, so the codon UUU corresponds to the amino acid Phe. ● Khorana Extended the Analysis of the Genetic Code ○ Khorana synthesized mRNA molecules with repeating di-, tri- and tetranucleotides, and translated them in vitro to define more codons. ○ For example, a dinucleotide repeat (UC)n produces an mRNA with the sequence 5-UCUCUCUCUCUCUCUC-3 and two possible codons, UCU and CUC. ○ The resulting polypeptides had alternating amino acids, serine (Ser) and leucine (Leu). ● Nirenberg and Leder’s Results ○ Nirenberg and Leder tested all 64 possible codons. ○ They identified all 61 of the codon-amino acid associations. ○ They also identified the three stop codons, UAA, UAG, and UGA. ● The (Almost) Universal Genetic Code ○ In all organisms, the processes of transcription and translation are similar. ○ Because the genetic code is universal, bacteria can be used to produce important proteins from plants and animals. ○ However, there are a few exceptions to the universality of the genetic code, found principally in mitochondria, though there are two exceptions in living organisms. ● Ribosomes Are Translation Machines ○ The main function of ribosomes is to read the message in the mRNA and catalyze the formation of peptide bonds between appropriate amino acids. ● Ribosome Composition ● Important Regions of Ribosomes ○ The ​peptidyl site (P-site)​ holds the tRNA to which the polypeptide is attached. ○ The ​aminoacyl site (A-site)​ binds a new tRNA molecule containing an amino acid to be added to the growing polypeptide chain. ○ The ​exit site (E-site) ​provides an avenue for exit of the tRNA after its amino acid has been added to the chain. ○ Ribosomes also form a channel from which the polypeptide chain emerges. ● Translation Occurs in Three Phases ○ Translation can be divided into three phases: initiation, elongation, and termination. ○ The phases are similar in bacteria and eukaryotes, though there are several differences. ● Bacterial Translational Initiation ○ rRNA aligns with the consensus sequence in mRNA and positions A site over the start codon. ● The Shine-Dalgarno Sequence ○ The preinitiation complex forms when the 16S rRNA and the Shine-Dalgarno sequence on the mRNA base pair. ○ The Shine-Dalgarno sequence is a purine-rich sequence of about six nucleotides three to nine nucleotides upstream of the start codon. ○ A complementary pyrimidine-rich sequence is found near the 3 end of the 16S rRNA. ● The Second Step of Initiation ○ The initiator tRNA binds to the start codon where the P-site will be once the ribosome is fully assembled. ○ The amino acid on the initiator tRNA is a modified amino acid, ​N-formylmethionine fMet​ (fMet);​ the charged initiator tRNA is called ​tRNA​. ○ Initiation factor, IF-2, and a GTP molecule are bound to the tRNAfMet and IF-1 joins the complex; together these form the 30S initiation complex. ● The Final Step of Initiation ○ The 50S subunit joins the 30S subunit to form the intact ribosome. ○ The union of the two subunits is driven by hydrolysis of GTP to GDP. ○ The dissociation of IF1, IF2, and IF3 accompanies the joining of the subunits to create the 70S initiation complex. ● Polypeptide Elongation ○ Elongation begins with recruitment of elongation factor (EF) proteins that use energy of GTP hydrolysis to: ■ Recruit charged tRNAs to the A-site. ■ Form peptide bonds between sequential amino acids. ■ Translocate the ribosome in the 3 direction along the mRNA. ● Polypeptide Elongation in Bacteria ● Translation Termination → → → → → → → → → → → → ● Translation and Transcription ○ In bacteria, the coupling of transcription and translation allows ribosomes to begin translating mRNAs that have not yet been completed. ○ In eukaryotes, mRNAs are produced in the nucleus. ○ They are processed to form mature mRNAs, then sent to the cytoplasm for translation. ● Translation of Bacterial Polycistronic mRNA ● Transfer RNAs and Genetic Code Specificity ○ Chaperville and others determined that the specificity of the codon-amino acid correspondence was due to the mRNA-tRNA interactions. Cys​ ○ They prepared normal Cys-tRNA​ , then converted the attached cysteine to alanine to produce a tRNA that recognizes the codon for Cys but carried Ala. ○ In in vitro translation, the resulting polypeptide had Ala instead of Cys. ● Two Important Conclusions: ○ The genetic code derives specificity from the interaction between tRNA & mRNA. ○ The fidelity of the aminoacyl-tRNA synthetases in recognizing each of their tRNAs and correctly charging them, is extremely important. ● Translation Is Followed by Polypeptide Processing and Protein Sorting ○ Posttranslational Processing​: modifies polypeptides into functional protein by removal or chemical alteration of amino acids. ■ Example: fMet is not found in functional bacterial proteins, and methionine is not always the first amino acid in eukaryotic proteins. ■ The absence of these from the N-terminus of proteins is due to their removal after translation. ○ Protein sorting​ uses ​signal sequences​, also called ​leader sequences​, to direct proteins to their cellular destinations. ● Modification of Amino Acids ○ Phosphorylation​, carried out by kinases, can activate or inactivate a protein. ○ Other enzymes may add methyl, hydroxyl, or acetyl groups to amino acids. ○ Carbohydrate side chains are added to some proteins. ● Cleavage of Polypeptides ○ Polypeptides may be cleaved into multiple segments that have separate functions or that aggregate to form a functional protein. ○ The hormone insulin is first produced as p ​ reproinsulin​, from which the “pre-amino” segment at the N-terminus is cleaved to produce proinsulin. ○ Proinsulin forms disulfide bonds and is cleaved again to produce insulin, a functional protein consisting of two separate chains held together by the disulfide bonds. ● Protein Sorting ○ The signal hypothesis suggests a mechanism by which proteins are transported to their correct locations. ○ It proposes that the first 15-20 amino acids of many polypeptides contain an “address label” that directs proteins to their correct locations. ○ Blobel suggested that the signal sequence directs proteins to the ER, where they are sorted for their specific destinations. ● Destruction of Incorrectly Folded Proteins ○ Mutations cause protein defects by changing the amino acid sequence, usually by altering protein folding and stability. ○ Incorrectly folded proteins will not function normally. ○ Within the ER, proteins that are incorrectly folded are bound by molecules called chaperones​ that help proteins fold correctly. ● Chaperones and Protein Folding ○ Once a chaperone has assisted a protein to fold correctly, it releases the protein. ○ Proteins that cannot fold properly are irreversibly bound to chaperones. ○ These chaperone-protein complexes are sequestered and then destroyed. ○ There are some diseases that result from a failure of this process. Chapter 11: Chromosome Structure ● Bacterial Chromosomes Are Simple in Organization ○ Bacteria have single chromosomes that are almost always circular. ○ Some species have linear chromosomes. ○ A few carry more than one chromosome. ● Bacterial and Archaeal Chromosomes ○ Most bacterial and archaeal species contain a single closed circular chromosome. ○ These are variable in size. ○ The single or largest (if more than one) chromosome carries essential genes required for survival and reproduction. ● Plasmids ○ Bacteria also carry multiple copies of one or more plasmids. ○ These are extrachromosomal DNA molecules. ○ They carry nonessential genes, unless the bacteria are exposed to certain antibiotics. ● Chromosome Organization ○ Bacterial and archaeal chromosomes are densely packed to form the ​nucleoid​. ○ The chromosome is organized into a series of tight loops. ○ These allow for efficient packaging of relatively long DNA molecules into small spaces. ● Bacterial Chromosome Compaction ○ Bacterial chromosomes are compacted in two ways: ■ Proteins help put DNA into loops that pack the chromosome into the ​nucleoid. ■ The circular DNA undergoes s ​ upercoiling. ● Proteins Associated with Chromosomes ○ Small nucleoid-associated proteins​ participate in the DNA bending that contributes to folding and condensation of chromosomes. ○ Structural maintenance of chromosome (SMC) proteins attach directly to the DNA, holding it in coils or V-shapes to form large nucleoprotein complexes. ● Supercoiling ○ Covalently closed circular chromosomes exist in several forms. ○ The relaxed circle is the least twisted. ○ The highly supercoiled form is the most tightly twisted; the chromosome is compacted so that it occupies less space in the nucleoid. ● Eukaryotic Chromosomes Are Organized as Chromatin ○ A eukaryotic chromosome has one DNA double helix, with a diverse array of proteins. ○ The DNA and associated proteins of a chromosome are called ​chromatin​. ○ Proteins that organize chromosomes are essential and provide a mechanism for condensation, segregation, and organization of chromosomes. ● Chromatin Composition ○ Each chromosome is approximately half DNA and half protein. ○ About half of the proteins are ​histone proteins​, small proteins that tightly bind DNA. ○ The remaining proteins, the ​nonhistone proteins​, are very diverse and perform a variety of tasks in the nucleus. ● Histones ○ There are five types of histone proteins: H1, H2A, H2B, H3, and H4; they are highly conserved among eukaryotes. ○ Two molecules each of histones H2A, H2B, H3, and H4 form an ​octamer. ○ A span of DNA ~ 146 bp long wraps around each octamer to form a ​nucleosome. ● Nucleosome Assembly ○ Histones H2A and H2B assemble into d ​ imers​; H3 and H4 also form dimers. ○ Two H3-H4 dimers form a ​tetramer​, after which two H2A-H2B dimers associate with it to form the octamer. ○ The wrapping of DNA around the nucleosome is the first level of DNA condensation, and compacts the DNA about sevenfold. ● Higher Levels of Chromatin Compaction ● Higher-Order Chromatin Structure ● Higher-Order Chromatin Condensation ○ Chromatin loops of 20 to 100 kb are anchored to the chromosome scaffold by nonhistone proteins at sites called ​MARs (matrix attachment regions)​. ○ The ​radial loop-scaffold model​ suggests that the loops gather into “rosettes” and are further compressed by nonhistone proteins. ○ Metaphase chromatin is compacted 250-fold compared to the 300-nm fiber. ● Roles of Higher-Order Chromatin Condensation ○ Chromosome compaction allows for efficient separation of chromosomes at anaphase. ○ The chromatin loops formed during condensation play a role in the regulation of gene expression. ○ Active transcription takes place in segments of loops distant from MARs; thus larger loops have more active transcription than small loops. ● Nucleosome Distribution and Synthesis During Replication ○ The presence of nucleosomes on chromosomes raises several questions about DNA replication. ○ Experimental evidence suggests that old histones are retained as single molecules, dimers, or tetramers. ○ Most nucleosomes present after replication are assembled partially from old nucleosome components and partially from new histones. *This is the basis for epigenetic inheritance.* ● Nucleosomes and Replication ○ As the replication fork passes, nucleosomes break down into component parts. ○ H3-H4 tetramers immediately reassociate randomly with one of the sister chromatids. ○ H2A-H2B dimers disassemble and are reassembled from both old and new histones. ● Chromosome Regions Are Differentiated by Banding ○ Chromosome condensation reaches a maximum at metaphase. ○ Cytogeneticists can distinguish such chromosomes microscopically based on size, shape, and banding pattern. ○ Chromosome bands appear light or dark when chromosomes are treated with specific dyes and stains. ● Chromosome Structures and Banding Patterns ○ Centromeres divide chromosomes into chromosome arms, segments of unequal length. ○ The ​short arm​ is called the ​p arm​ and the l​ ong arm​​ arm​. q ○ Chromosome shapes are named based on centromere position, which determines the relative sizes of the arms. ● Chromosome Shapes ○ Metacentric​: the centromere is near the middle of the chromosome. ○ Submetacentric​: the centromere is between the center and the tip. ○ Acrocentric​: the centromere is close to one end. ○ Telocentric​: the centromere is at the tip of the chromosome and there is no p arm. ● Karyotypes ○ A ​karyotype​ is an ordered photographic display of a complete set of chromosomes for a species. ○ The chromosomes are grouped into homologous pairs in descending order of size. ○ The sex chromosomes are identified separately. ○ Chromosomes may be stained with dyes to show distinctive banding patterns for each chromosome. ● Chromosome Banding Techniques ○ Chromosome banding​ allows cytogeneticists to identify each chromosome in a karyotype. ○ Different stains and dyes are used to produce banding patterns. ○ The standard for human chromosome banding is ​G (Giemsa) banding​; the patterns are distinct and reproducible. ● Uses of Karyotypes ○ Karyotypes allow for recognition of abnormalities in chromosome number or structure. ○ Extra or missing chromosomes can be easily identified, as can chromosome rearrangements such as insertions, deletions, or others. ○ Comparison between species allows for tracing of evolutionary history of related species. ● In Situ Hybridization ○ In situ hybridization uses molecular probes, labeled with fluorescence or radioactivity, to detect their target sequences. ○ First-generation methods used nucleotide probes labeled with ​ P.32​ ○ New generation methods utilize fluorescent labels with a greatly improved resolution, so that each labeled chromosome can be identified. ● Fluorescent In Situ Hybridization ○ Currently, fluorescent in situ hybridization uses molecular probes labeled with compounds that emit fluorescent light when excited by UV or visible light. ○ Various labels that emit light of different wavelengths can be used simultaneously. ○ For human chromosomes, there are 24 different fluorophores available, unique to each chromosome. ● Chromosome Territory During Interphase ○ Chromosomes are not uniformly distributed within a nucleus. ○ Boveri, who first observed this, suggested that the variation in position might be related to gene activity. ○ Cremer and Cremer showed that chromosomes are partitioned into specific regions, chromosome territories, during interphase. ● Dynamic Chromosomes ○ Chromosomes do not occupy the same territory in each nucleus, but once confined to a territory, a chromosome does not leave until the M phase is initiated. ○ However, chromosomes are active within their territories and move, twist, and turn during transcription and DNA replication. ○ Chromosomes appear to be anchored in their territories by their centromeres. ○ Interchromosomal domains​ are regions between territories. ○ These are channels for movement of proteins, enzymes, and RNA molecules. ○ Early replicating parts of chromosomes are generally near the center of the nucleus and late replicating parts are near the periphery. ● Chromosome Position and Transcriptional Activity ○ Transcriptionally active portions of chromosomes are found nearer to interchromosomal domains, probably due to: ■ Greater access to needed proteins and enzymes. ■ Faster dispersal of RNA transcripts, once they are completed. ● Dynamic Chromatin Structure ○ Changes in level of compaction regulate access to DNA by proteins for replication, transcription, recombination, and repair. ○ Position effect variegation (PEV)​ in Drosophila illustrates the effect of chromatin compaction on gene expression. ○ Muller identified x-ray-induced mutations in fruit flies that resulted in variegated eye color. ● Analysis of Position Effect Variegation ○ Muller noticed that the X chromosomes of flies with variegated eye color had undergone inversion. ○ The white gene had been moved from its normal position near the telomere to a region near the centromeric heterochromatin. ○ The extent to which heterochromatin spreads from the centromere outward varies from one chromosome to the next. ● Heterochromatin and PEV ○ The stopping point of heterochromatic​ spread determines whether or not the relocated white gene will be expressed. ○ If the w gene remains euchromatic, ​ it is expressed; if the gene is compacted into heterochromatin, it is not expressed. ○ Some eye cells will have an active white gene, others an inactive one, giving a speckled appearance. ● The Occurrence of PEV Shows ○ Gene expression can be silenced by the gene’s chromosomal position. ○ Silencing is a feature of chromatin structure that can be transmitted from one cell generation to the next. ● PEV Mutations ○ Genetic analysis of eukaryotic genomes shows that PEV is widespread. ○ Mutations modifying PEV led to identification of proteins that play a role in establishing and maintaining chromatin structures. ○ Two types of mutations have been identified: ■ E(var) Mutations ● E(var) mutations, enhancers of position-effect variegation, increase or enhance the appearance of the mutant white phenotype in flies with a variegating allele of the white gene. ● E(var)s encourage the spread of heterochromatin beyond its normal boundaries. ● These mutations produce a greater number of eye cells lacking pigment. ■ Su(var) Mutations ● Su(var) mutations, suppressors of position-effect variegation, increase or enhance the appearance of the mutant white phenotype in flies with a variegating allele of the white gene. ● Su(var)s restrict the spread of heterochromatin or interfere with its function. ● These mutations produce a greater number of pigmented eye cells. ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ ● Reduced Fertility in Aneuploidy ○ In trisomics, chromosome segregation during meiosis is disturbed because of failure to properly pair and segregate. ○ Two patterns of synapsis are possible: a trivalent synapsis or a bivalent and univalent arrangement. ○ Neither mechanism can segregate three chromosomes equally at anaphase I. ○ In trisomics, meiosis results in two chromosomes moving to one pole and one chromosome moving to the other. ○ Thus half the gametes contain two copies of the chromosome; these will produce trisomic offspring that are unlikely to survive. ○ This results in a form of semisterility, in which only some of the offspring produced are viable. ● Mosaicism ○ Mosaicism can develop as a result of mitotic nondisjunction early in embryogenesis. ○ For example, 25-30% of Turner syndrome cases occur in females that are mosaic, with some 45, XO cells and some 46, XX. ○ Some Turner syndrome individuals carry 47, XXX cells too. ● Gynandromorphs ○ In some insects such as butterflies and fruit flies, sex-chromosome mosaicism produces gynandromorphs. ○ These are individuals with some female and some male cells. ○ These occur due to sex-chromosome nondisjunction in early development. ● Changes in Euploidy Result in Various Kinds of Polyploidy ○ Polyploidy is the presence of three or more sets of chromosomes in the nucleus of an organism. ○ It can result from duplication of chromosome sets within a species (autopolyploidy). ○ It can also occur from combining the chromosome sets of different species (allopolyploidy). ○ Many types of polyploidy are possible. ● Autopolyploidy ○ Three mechanisms lead to autopolyploidy: ■ Multiple fertilizations of one egg by multiple pollen grains. ■ Mitotic nondisjunctions in sex stem cells. ■ Meiotic nondisjunction lead


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