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Download Unit 5: Gene Expression and Mutation Genetics 2013
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Unit 5: Gene Expression and Mutation Genetics 2013 - 2014 Gene Expression through Time and Tissue Changes in gene expression may occur _____________________________ and in different cell types This may occur at the ____________________________________________/gland level _________________________ changes - Changes to the chemical groups that __________________________________________ DNA that are transmitted to daughter cells after cell division Hemoglobin Adult hemoglobin has _____________ globular polypeptide chains - Two alpha (α) chains = ____________ amino acids - Encoded on chromosome _________ - Two beta (β) chains = ____________ amino acids - Encoded on chromosome ___________ Each globin surrounds an iron-containing ______________ group Globin Chain Switching Subunits change in response to ____________________ levels Subunit makeup ______________ over lifetime - ______________________ = Two epsilon () + two zeta () - ______________________ = Two gamma () + two alpha () - ______________________ = Two beta (β) + two alpha () - The adult type is about 99% of hemoglobins by _______________ years of age Changing Gene Expression in Blood Plasma Blood plasma contains about __________________________ different types of proteins 1|Page Changing conditions cause a change in the ____________________________________________ of the plasma ____________________________________ biology is shedding light on how genes are turned on and off Pancreas The pancreas is a ______________ gland - _______________________ part releases digestive enzymes into ducts - _______________________ part secretes polypeptide hormones directly into the bloodstream ___________________________________________________________________________ produces either endocrine or exocrine cells If transcription factor pdx-1 is activated, some ___________________________________________ follow the exocrine pathway Other progenitor cells respond to different ________________________ and yield daughter cells that follow the endocrine pathway Proteomics Proteomics tracks _____________________________________ made in a cell, tissue, gland, organ or entire body Proteins can be charted based on the relative abundance of each class at different _____________ of development There are _________________________________ categories of proteins - Including the __________________________________________________, which are activated after birth Figure 11.4: My summary____________________________________________________________________________________________ ______________________________________________________________________________________________________________________ Control of Gene Expression A protein-encoding gene contains some controls over its ___________________ expression level - _________________________________ sequence (mutations) - _________________________________ of gene Much of the control of gene expression occurs in two general processes 1) Chromatin __________________________________ = “On/off” switch 2) microRNAs = ___________________________” switch Chromatin Remodeling _______________________________ play major role in gene expression - ______________________ DNA when and where it is to be transcribed and ___________________ it when it is to be silenced The three major types of small molecules that bind to histones are: - ____________________________ group - ____________________________ groups - ____________________________ groups 2|Page ______________________________________ can subtly shift histone interactions in a way that eases transcription Chromatin Remodeling Table Summary: ________________________________________________________________________________________ _________________________________________________________________________________________________________________________________ MicroRNAs MicroRNAs belong to a class of molecules called _________________________________ They are ______________________ bases long The human genome has about 1,000 distinct microRNAs that ____________________ at least 1/3rd of the protein-encoding genes When a microRNA binds to a “target” mRNA, it ________________________________________ ____________________________________ provides a practical application of microRNAs because certain microRNAs are more or less abundant in cancer cells than in healthy ones 3|Page A related technology is called _____________________________________________________ - Small synthetic, double-stranded RNA molecules are introduced into selected cells to ______________gene expression Animation Summary: __________________________________________________________________________________________________________ ________________________________________________________________________________________________________________________________ Maximizing Genetic Information The human genome contains about ________________________________ genes - However, these encode about ____________________________ mRNAs, which in turn specify more than a _____________________ proteins Several events account for the fact that __________________________ outnumber genes The “genes in pieces” pattern of exons and introns and ______________________________ help to greatly expand the gene number An ___________________________ in one gene’s template strand may encode a protein on the coding strand Information is also maximized when a protein undergoes _________________________________________ modifications - Addition of sugars and lipids to create __________________________________ and lipoproteins Another way that one gene can encode more than one protein is if the protein is _____________ to yield two products This happens in ______________________________________ imperfect (Yep, fairly gross) - Caused by a deficiency in the _________________________________ DPP and DSP - Both are cut from the ________________________ DSPP protein 4|Page Most of the Human Genome Does Not Encode Protein Only _____________ of human DNA encodes protein Rest of genome includes: - ______________ DNA - Noncoding ____________ - ____________________ - Promoters and other ______________________ sequences - _________________________________ sequences Viral DNA About _____________ of our genome is derived from RNA viruses called _______________________________ - This is evidence of ____________________________________________ - Sequences tend to ____________________ over time Noncoding RNAs Nearly all of the human genome can be ______________________________, and much of it is in the form of noncoding RNAs (ncRNAs) This includes ________________ and _____________________ However, there are hundreds of thousands of other ncRNAs - These are transcribed from ____________________________ - But are not _____________________________into protein Repeats ___________________________ are the most abundant type of repeat - Sequences that ________________ about the genome - ____________ repeats can copy themselves - Comprise about _____________ of the genome Rarer classes of repeats include those that comprise _________________________________________, and rRNA gene clusters Transposon Animation Summary: ______________________________________________________________________________________________ ________________________________________________________________________________________________________________________________ Be sure to pay attention to types of noncoding regions and their characteristics in Table 11.2 The Nature of Mutations A mutation is change in a DNA sequence that is present in ___________________ of a population May occur at the __________________________________________________ level A _____________________________________ is a genetic change that is present in > 1% of a population The effect of mutations vary 5|Page o “Loss-of-function” mutations – ________________________ o “Gain-of-function” mutations – _______________________ The term mutant refers to ___________________ - Usually connotes an abnormal or unusual, or even uncommon variant that is nevertheless ________________________ Mutations are important to __________________________ Our evolutionary _____________________________ to other species allows us to study many mutations in non-human species Germline mutations - Originate in ____________________________ - Affect ______________________ of an individual Somatic mutations - Originate in ______________________ - Affect only cells that __________________________ from changed cell Mutations Alter Proteins Identifying how a mutation _____________________________________ has clinical applications Examples of mutations that cause disease: - _____________________________ gene - _____________________________ genes Sickle Cell Anemia Results from a __________________________________________________ -globin gene, which replaces glutamic acid (6th position) with valine Phenotype associated with _______________________________ Altered surface of hemoglobin allows molecules to link in ___________________________ conditions Creates __________________________________ of RBC Sickling causes ______________________________________________________________________________________ when RBC become lodged in small blood vessels Thalassemia Caused by another _________________________________________ mutation Too _______________ beta globin chains Excess of alpha globin __________________________ formation of hemoglobin molecules So RBCs die Liberated _______________ slowly damages heart, liver, and endocrine glands Two forms o Thalassemia ______________ (heterozygous) o Thalassemia ______________ (homozygous for mutation and more severe) Collagen A major component of _________________________________________ - Bone, _________________________, skin, ligament, tendon, and tooth dentin More than ____________ collagen genes encode more than ___________ types of collagen molecules Mutations in these genes lead to a variety of ___________________________ problems Collagen has a _____________________ structure - Triple helix of two _________________________ polypeptides 6|Page - Longer ________________________________, procollagen is trimmed to form collagen Collagen Disorders Be familiar with what these are; you will not be asked details Ehler-Danos Syndrome A mutation prevents _________________________ chains from being cut Collagen molecules cannot assemble, and so _________________ becomes stretchy How Mutations Cause Disease Mutations in a gene may cause either ____________________________________ of the same disease or distinct illnesses Table 12.2 lists several examples of mutations and the diseases they produce o You should be able to describe and explain two of these o You should be familiar with the name and ____________________________of the remainder Causes of Mutations Mutations may occur ______________________________ or by exposure to a chemical or radiation An agent that causes a mutation is called a __________________________________________ Spontaneous Mutation ________________________ or new mutations Not caused by _____________________________ to known mutagen Result from errors in __________________________________________ DNA bases have slight _______________________________________ Exist in alternating forms called ________________________________ As replication fork encounters unstable tautomers, ________________________ can occur Tautomer Mispairing Animation Summary: _____________________________________________________________________________________ _________________________________________________________________________________________________________________________________ Spontaneous Mutation Rate Rate ______________________ between genes - _____________________________ usually have higher mutation rates Each human gene has about ____________________________ chance of mutating Each individual has ___________________________________ mutations Mitochondrial genes mutate at a _______________________ than nuclear genes because they cannot ________________their DNA Mutation Rates Do not memorize rates! MIM means: _________________________________________________________________________________________________________ Determining Mutation Rate Estimates of spontaneous mutation rate can be derived from _______________________________, dominant traits For _________________________ genes, mutation rate = # of ____________ cases/2X where X = # of individuals examined 7|Page Types of Mutations Table 12.4 Recognize each of these mutation types Mutational Hot Spots In some genes, mutations are more likely to occur in regions called _____________________ Short ______________________________ sequences o Pairing of repeats may interfere with _____________________________________ enzymes _____________________________________________ o Often associated with _____________________________________________________ DNA symmetry increases the likelihood of mutation: Figure 12.6 Repeated genes are prone to mutation by mispairing during meiosis Induced Mutations Caused by mutagens, many are also ____________________________________ and cause cancer Examples: - ____________________________ agents: remove a base - ______________________________ dyes: add or remove base - ___________________________________: break chromosomes - ___________________________________: creates thymine dimers Site-directed mutagenesis: Changes a gene in a __________________________ way Ames Test An ___________________________ test of the mutagenicity of a substance One version uses Salmonella bacteria with mutation in gene for ____________________________ - ____________________________ are exposed to test substance - Growth on media ________________________________ is recorded - Bacteria ____________________ grow if mutations have occurred - Substance can be mixed with _______________________________________________________________ prior to testing to mimic toxin processing in humans Exposure to Mutagens Some mutagen exposure is __________________________________ - Workplace - Industrial accidents - ______________________________ - Medical _____________________________ - Weapons - ____________________ sources - Cosmic rays, sunlight, earth’s crust Types of Mutations Mutations can be classified in several ways - By whether they ___________________________________________________ a function - By exactly how they ________________________________ DNA 8|Page Point Mutations A change of a ____________________ nucleotide _________________ = Purine replaces purine or pyrimidine replaces pyrimidine A to G or G to A or C to T or T to C _________________ = Purine replaces pyrimidine or pyrimidine replaces purine A or G to T or C T or C to A or G Consequences of Point Mutations ______________________________ mutation = Replaces one amino acid with another ______________________________ mutation = Changes a codon for an amino acid into a stop codon - Creates _______________________________ proteins that are often non-functional A stop codon that is changed to a coding codon ___________________________ the protein Splice Site Mutations Alters a site where an intron is normally ________________________ from mRNA Can affect the phenotype if: 1) Intron is __________________ or exon skipped - Example: _____________________________________ 2) Exon is __________________________ - Example: Familial dysautonomia (FD) Deletions and Insertions The genetic code is read in _______________________ Nucleotides changes __________________ in multiples of 3 lead to disruptions of the reading frame Cause a __________________________________________ and alter amino acids after mutation Nucleotide changes in multiples of 3 will _________________ cause a frame-shift - But they can still __________________________ the phenotype A _____________________________ removes genetic material - __________________infertility: Tiny deletions in the Y An ___________________________ adds genetic material - Gaucher disease: Insertion of one base A __________________________________________ is an insertion of identical sequences side by side - Charcot-Marie-Tooth disease: Tandem duplication of _____________________________ bases Deletion/Insertion Animation Summary: _____________________________________________________________________________________ _________________________________________________________________________________________________________________________________ Note: ______________________________________ of mutations can cause the ___________________ single-gene disorder - Example: Familial ________________________________________________ 9|Page Pseudogenes A DNA sequence similar to a gene but which is _________________________________________ May not even be __________________________ into RNA May have evolved from original gene by _________________________________________________________ mutation __________________________________ between a pseudogene and functional gene can disrupt gene expression Expanding Repeats Insertion of ____________________________________ leads to extra amino acids - The longer proteins ________________________ the cells Some genes are particularly prone to _____________________________ of repeats Number of repeats correlates with _____________________________________________ and more severe phenotype ___________________________________ is the expansion of the triplet repeat with an increase in severity of phenotype with subsequent generations Myotonic Dystrophy: A Triplet Repeat Disease Copy Number Variants (CNV) Are sequences that ______________________________________________ from person to person Range in size from a __________________________________ to millions Account for about _____________ of our genome CNVs may have _________________________________ on the phenotype or they can _____________________ a gene’s function and harm health Indeed, CNVs correlated to _______________________________________ might be used to give medical advice Importance of Position The degree that a mutation _____________________ phenotype depends on: - _____________________ in the gene the change occurs - How it affects ____________________________ or expression of encoded protein Examples – ______________________ and prions - Certain mutations exert effects while others _____________________ Globin Mutations Understand that many different mutations in the same gene can occur, each with different effects Prion Disorders A prion disease can be ___________________________________________________ The prion protein exists in both _______________________________________________________ conformations - The normal form has a ________________________________ made up of helices - In a disease-causing form, the helices open into a _________________________ The amino acid in ____________________ position is key to developing prion disease Individuals ____________________________ with valine (VV) or methionine (MM) develop disease Heterozygotes have ______________________ function Position 178 is also important due to the _______________________ of the protein Not All Mutations Impact Protein Function _________________________________mutations are mutations that do not alter the encoded amino acid Example: - A mutation from CAA to CAG alters the DNA, but the protein sequence __________________________________ - CAA and CAG both code for ___________________________________________ 10 | P a g e - These are called _________________________________________________ A ______________________________________ alters the encoded amino acid to another amino acid - Creates a __________________________________ codon Some nonsynonymous mutations are _________________________________________; Encode a chemically similar amino acid and may not alter function The impact of a missense mutation is not _______________________ from protein sequence alone A __________________________________mutation produces a phenotype under particular conditions or environments Glucose 6-phosphate dehydrogenase enzyme responds to ___________________________________, chemicals that strip electrons from other molecules High levels of oxidants occur when eating _____________________________ or taking certain antimalarial drugs Conditions Individuals with G6PD mutations Low oxidants _______________ phenotype High oxidants RBCs __________________; Hemolytic anemia DNA Repair Errors in ___________________________________ or damage to DNA create mutations - May result in _______________________ Fortunately, most errors and damage are ____________________________ Type of repair depends upon the type of _________________________ or error Organisms vary in their ability to ______________________ DNA Types of DNA Repair In many modern species, _____________________________ of DNA repair peruse the genetic material 1) _____________________________ repair 2) _____________________________ repair 3) _____________________________ repair Photoreactivation Repair Enzymes called _________________________________ use light energy to break the extra bonds in a pyrimidine dimer Enables UV-damaged _____________________to recover from exposure to sunlight _____________________________ do not have this type of repair Excision Repair Pyrimidine dimers and surrounding bases are ______________________________________________________ Humans have _______________________________ of excision repair ____________________________________ repair - Replaces up to ______________ bases - Corrects mutations caused by different insults _____________________________________ repair - Replaces _______________ bases - Specific to _________________________ damage Excision Repair 11 | P a g e DNA Repair Animation Summary: _____________________________________________________________________________________ ________________________________________________________________________________________________________________________ Mismatch Repair Enzymes detect nucleotides that do not base pair in newly replicated DNA The incorrect base is excised and replaced Proofreading is the detection of mismatches Failure of DNA Repair If both copies of a repair gene are mutant, a disorder can result The protein p53 monitors repair of DNA If damage is too severe, the p53 protein promotes programmed cell death or apoptosis Mutations may occur in genes encoding DNA repair proteins Lead to overall increase in mutations Repair Disorders: Trichothiodystrophy At least five genes are involved Symptoms reflect accumulating oxidative damage Faulty nucleotide excision repair or base excision repair or both Repair Disorders: Inherited Colon Cancer Hereditary nonpolyposis colon cancer Affects 1/200 individuals Defect in mismatch repair HNPCC gene is on chromosome 2 Repair Disorders: Xeroderma Pigmentosum Autosomal recessive; Seven genes involved Malfunction of excision repair Thymine dimers remain and block replication Must avoid sunlight Only 250 cases worldwide Repair Disorders: Ataxia Telangiectasis Autosomal recessive disorder Defect in cell cycle checkpoint kinase Cells continue through cell cycle without pausing to inspect DNA Individuals with AT have 50X the risk of developing over general population Heterozygotes have a two- to sixfold increase in cancer risk 12 | P a g e