BIL 250 Exam 3 Notes
BIL 250 Exam 3 Notes BIL 250
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Date Created: 09/28/15
Ch 15 The Dynamic Genome Transposable Elements 04082015 Introduction 0 Gene therapy correction of a genetic de ciency in a cell by the addition of new DNA and its insertion into the genome Retroviruses very similar to retrotransposons in genome Transposable mobile elements can move to new positions within same chromosome or to a different chromosome 0 50 human genome is made up of transposable elements 151 Discovery of Transposable Elements in Maize McClintock s experiments the D5 element Chromosome 9 broke frequently at 1 locus due to presence of 2 genetic factors 0 D5 dissociation element transposable element located at site of break Nonautonomous bc Ds only breaks chromosome jumps in presence of Ac 0 Ac activator element class 2 DNA transposable element required to activate chromosome breakage at Ds autonomous bc can jump without help 0 g 153 new phenotypes in corn produced thru movement of D5 on chromosome 0 a chromosome breaks near Ds l loses DNA fragment with dominant genes l recessive genes expressed l colorless sector on kernel affects all genes C Sh Wx o b Ds inserted in C gene l colorless kernel background Ds excised by AC allows C color expression l spots Affects only 1 gene Unstable phenotype phenotype characterized by frequent reversion either somatically or germinally or both due to the interaction of transposable elements with a host gene Autonomous and nonantonomous elements CmDs cmutableDs allele carrying Ds insert 0 With no Ac l colorless kernels Ds stuck on gene 0 With Ac l spots Ac activates Ds in some cells to leave C gene 0 Unstable only when Ac in genome Transpose To move from one location in the genome to another CmAc allele carrying Ac insert 0 Always unstable l spots 0 Transformation due to spontaneous generation of Ds form inserted Ac Ds is an incomplete mutated version of Ac 0 Ac is autonomous transposable element that encodes the proteins transposase or reverse transcriptase necessary for its transposition and for the transposition of nonautonomous elements in the same family 0 Encode info for their own movement and for movement of unlinked nonautonomous elements in genome Ds is nonautonomous transposable element that relies on the protein products of autonomous elements for its mobility Transposable elements only in maize Transposable elements signi cant component of genome in most if not all organisms Implies that genomes inherently unstable and dynamic 152 Transposable Elements in Prokaryotes 2 types of transposable elements in bacteria 0 IS elements short sequences that can move themselves to new positions but don t carry genes other than those needed for their movement Transposons longer sequences that carry genes needed for their movement and can carry other genes Bacterial insertion sequences Insertion sequence IS elements mobile piece of bacterial DNA capable of inactivating a gene into which it inserts 0 Can also block expression of genes in same operon downstream of insertion site 0 Identi cation of discrete IS elements 0 Crosshybridization in E coli showed that same bit of DNA can insert in different places in bacterial chromosome 0 Structure of IS elements o Transposase enzyme encoded by transposable elements that undergo conservative transposition Required for movement of IS 0 IS elements begin and end with short inverted repeat sequences Required for their mobility Bc IS are regions of identical sequence they are sites where many crossovers may take place 0 Ex recombination bw F factor plasmid and E coli chromosome to form Hfr strains result of single crossover bw IS element located on plasmid and IS on chromosome multiple IS F factor can insert at multiple sites Prokaryotic transposons R factors plasmids carrying genes that encode resistance to several antibiotics o Transferred rapidly on cell conjugation like F factor in E coli Transposon Tn mobile piece of DNA that is anked by terminal repeat sequences and typically bears genes encoding transposition funcUons 2 types of bacterial transposons 0 Composite transposons contain variety of genes that reside bw 2 nearly identical IS elements that are oriented in opposite directions inverted repeat sequence found in identical but inverted form n ex at the opposite ends of a DNA transposon Don t encode transposase l mobility NOT due to association with IS 0 Simple transposons contain variety of genes that reside bw short inverted repeat sequences Encode their own transposase in region bw inverted repeat sequences AND carry bacterial genes 0 IS elements are short mobile sequences that encode ONLY proteins needed for their mobility 0 Composite and simple transposons contain additional genes that confer new functions to bacterial cells Mechanism of transposition Transposition process by which mobile genetic elements move from one location in the genome to another 0 Depends on action of transposase o Occurs in 2 stages 0 1 Excision from the original location 0 Replicative copy and paste mechanism of transposition that generates a new insertion element integrated elsewhere in the genome while leaving the original element at its original site of insertion Transposase catalyzes formation of intermediate cointegrate product of the fusion of two circular transposable elements donor and recipient plasmids to form a single larger circle Cointegrate resolves into 2 smaller circles n 1 copy remains at original location of element a other copy integrated at new genomic position 0 Conservative cut and paste mechanism of transposition that moves a mobile element to a new location in the genome as it removes it from its previous location Transposases cuts ends of transposon like replicative BUT cuts element out of donor site and makes staggered cut at target site and inserts element 0 2 Insertion into a new location 0 transposase makes 5bp staggered cut in target site 0 transposable element inserts bw staggered ends 0 host DNA repair machinery lls gap opposite each single strand overhang by using bases in overhang as template 0 targetsite duplication short directrepeat DNA sequence adjacent to ends of a transposable element that was generated during the element s integration into the host chromosome all elements anked by targetsite duplication what differs is the length of duplication transposable elements have inverted repeats at their ends the inverted repeats anked by targetsite duplication direct repeat 153 Transposable Elements in Eukaryotes 2 classes of eukaryotic transposable elements 0 class 1 retrotransposons class 2 DNA transposons Class 1 retrotransposons Retrovirus RNA virus that replicates by rst being converted into doublestranded DNA uses an RNA intermediate 0 RNA copied into DNA by reverse transcriptase o Provirus chromosomally inserted DNA copy of retroviral genome 0 Long terminal repeat LTR direct repeat of DNA sequence at the 5 and 3 ends of retroviruses and retrotransposons Retroviruses encode 3 proteins that take part in viral replication 0 Gag gene encodes proteins for maturation of RNA genome o Pol gene encodes reverse transcriptase o Env gene encodes structural protein that surrounds the virus Ty element A yeast LTR retrotransposon 0 Has gag and pol genes but not env can t leave cell 0 Transcribed into RNA transcripts that are reverse transcribed into DNA No env gene Ty can t leave cell l DNA copies inserted back into genome of same cell To prove RNA intermediate 0 Ty element altered by adding an intron and promoter activated by addition of galactose 0 Found that introns spliced out in RNA processing before reverse transcription Retrotransposon transposable element that uses reverse transcriptase to transpose through an RNA intermediate LTRretrotransposons type of class 1 transposable element that terminates in long terminal repeats and encodes several proteins including reverse transcriptase 0 Use copy and paste transposition Class 2 DNA transposons DNA transposons transposable element that moves directly from one site in the genome to another P elements DNA transposable element in Drosophia Hybrid dysgenesis syndrome of effects including sterility mutation chromosome breakage and male recombination in the hybrid progeny of crosses between certain laboratory and natural isolates of Drosophia o M cytotype Laboratory stocks of Drosophia melanogasterthat completely lack the Pelement transposon o P cytotype Natural stocks of Drosophia melanogasterthat contain 20 to 50 copies of the Pelement O O Mfemae x Pmae l dysgenic hybrid progeny Pfemale x Mmale normal offspring Hypothesis dysgenic mutations caused by insertion of transposable elements into speci c genes render them inactive O Reversion from excision of these inserted sequences 0 P element found in P strains wild but absent from M strains lab 0 Transposase genes in P elements silenced in P strains 0 O M strain has no P element l silencing mechanism inactive Mfemale no P elements x Pmale P elements l P element in zygote in silencingfree environment P elements from male can transpose throughout diploid genome l inserts cause dysgenic offspring Maize transposable elements revisited O O O 0 D5 and Ac are DNA transposons Like the P element Ac encodes a single protein transposase Nonautonomous Ds doesn t encode transpoase thus cannot transpose on its own When Ac in genome its transposase can bind to both ends of Ac or Ds elements and promote their transposition Utility of DNA transposons for gene discovery 0 DNA transposons have been modi ed and used in 2 important ways 0 1 to make mutants that can be identi ed by presence of a transposon tag method used to identify and isolate a host gene through the insertion of a cloned transposable element in the gene 0 O O Pelements can be used to create mutations by insertion to mark the position of genes and to facilitate the cloning of genes P elements inserted into genes in vivo disrupt genes at random creating mutants with different phenotypes Interesting mutant phenotypes cloned 2 as vectors that can introduce foreign genes into a chromosome 0 O O 0 goal to transfer allele ry eye color into y genome recipient genotype is homozygous for rosy ry mutation inject plasmid with defective P element and a helper plasmid encoding transposase new ry gene in progeny can be inherited in stable Mendelian fashion 0 like P element Ac engineering for use in gene isolation by transposon tagging 154 More Transposable Elements Than Ever Imagined Cvalue DNA content of a haploid genome Cvalue paradox discrepancy or lack of correlation between the DNA content of an organism and its biological complexity Genome size frequently correlated with amount of DNA in genome that s derived from transposable elements Transposable elements in the human genome 50 human genome made up of transposable elements LlNEs long interspersed elements type of class 1 transposable element that encodes a reverse transcriptase 0 Move like retrotransposon with help of element encoded reverse transcriptase but lack LTRs SlNEs short interspersed elements type of class 1 transposable element that does not encode reverse transcriptase but is thought to use the reverse transcriptase encoded by LlNEs o Nonautonomous LlNEs have structural features of LINES but don t encode their own reverse transcriptase Get transcriptase from genes encoded by LlNEs in genome o Alu most abundant SINE in humans 0 How do organisms survive with so many insertions in genes and so much mobile DNA in genome 0 Many elements inserted into introns l spliced out no effect 0 Insertions into exon subjected to negative selection elimination of a deleterious trait from a population by natural selection 0 Most mobile DNA inactive and cannot move or increase in copy number Other still capable of movement rendered inactive by regulatory mechanisms Few active LlNEs and Alus cause diseases The grasses LTR retrotransposons thrive in large genomes Differences in genome sizes of grasses correlate primarily with the number of LTR retrotransposons Synteny situation in which genes are arranged in similar blocks in different species Safe havens site in the genome where the insertion of a transposable element is unlikely to cause a mutation thus preventing harm to the host 0 Safe havens in small genomes targeted insertions o Smaller genome l higher probability insertion will disrupt a coding sequence 0 Targeting feature of certain transposable elements that facilitates their insertion into regions of the genome where they are not likely to insert into a gene causing a mutation 155 Epigenetic Regulation of Transposable Elements by the Host Eukaryotic hosts use RNAi to repress the expression of active transposable elements in their genomes In this way a single element that inserts near a gene can be transcribed to produce dsRNA that will trigger the silencing of all copies of the element in the genome MlTEs are nonautonomous DNA transposons that can attain high copy numbers While MlTEs can utilize the transposase of autonomous elements they probably evade host repression because their ampli cation does not lead to the silencing of the transposase gene 156 Summary transposable elements discovered in maize as cuase of unstable mutations o Ds is nonautonomous bc transposition requires presence of Ac autonomous lnsertion sequence IS elements found in bacteria 0 Composite transposons contain lS anking 1 genes 0 Simple transposons 2 major transposable elements in eukaryotes 0 class 1 retrotransposons RNA intermediate 0 class 2 DNA transposons intermediate is the DNA itself Ac Ds and P elements Introduction 0 Genetic variants phenotypic differences in one or more particular characters 0 2 processes responsible for genetic variation 0 mutation change in DNA sequence of a gene ultimate source of evolutionary change produce new alleles that become raw material for 2nOI level of variation recombination o recombination outcome of cellular processes that cause alleles of different genes to become grouped in new combos DNA not absolutely stable each base pair capable of mutating 0 Gene mutations mutational events within individual genes 0 Cells have systems to identify and repair damaged DNA preventing most mutations o BUT mutations needed for evolution low level must be tolerated Similarities bw mutation and recombination 0 Both are major sources of variation 0 Mechanisms of DNA repair and recombination have some similar features 161 The Phenotypic Consequences of DNA Mutations point mutations a small lesion usually insertiondeletion of a single base pair Types of point mutations Base substitutions 1 base pair is replaced by another Baseinsertionsdeletions 0 Transition replacement of a base by the other base of the same chemical category Purine replaced by purine Alle or Gle Pyrimidine replaced by pyrimidine Cle or TDC o Transversion replacement of a base of 1 chemical category by a base of the other Pyrimidine replaced by purine CA CIZIG TIZIA TIZIG Purine replaced by pyrimidine AC AlT GC GET 0 Insertionsdeletion are of nucleotide pairs convention to call them basepair insertionsdeletions lndel mutations insertionaldeletion collective term for all insertionaldeletion mutations o Simplest additiondeletion of single base pair 0 Can have simultaneous addition or deletion of multiple base pairs at once The molecular consequences of point mutation in a coding region Synonymous silent mutations changes 1 codon for an amino acid into another codon for that same amino acid 0 Doesn t alter AA sequence get same protein Missense nonsynomous mutations codon for 1 AA changed into a codon for another AA 0 Alters AA sequence l can affect protein structurefunction o Conservative substitution 1 AA replaced by a chemically similar AA Less likely to affect protein 0 Nonconservative substitution 1 AA replaced by a chemically different AA Likely to cause severe protein change Nonsense mutations codon for 1 AA changed into a stop codon o Considerable effect on protein 0 Single base pair changes that inactive proteins often due to splice site mutations 0 Lead to large insertionsdeletions l dramatic change in coding region Frameshift mutations insertiondeletion of a nucleotide pair or pairs causing a disruption of the translational reading frame 0 lndel mutations can effect more of polypeptide sequence than just the mutation site 0 Cause entire AA sequence downstream of mutation site to bear no relation to original AA sequence 0 Typically result in complete loss of normal protein structurefunction The molecular consequences of point mutations in a noncoding region 0 DNA level 0 binding sites for RNA pol and its factors 0 Binding sites for transcription regulating proteins 0 RNA level o Ribosomebinding sites of bacterial mRNAs o 5 and 3 splice sites for exon joining in eukaryotes 0 sites that regulate translation and localize mRNA to particular areas 0 functional consequences of point mutation in noncoding regions depends on if it creates or disrupts a binding site 0 binding site mutation changes expression pattern of a gene by altering amount of protein product expresses at certain times or in a certain tissue gene expression pattern of alters response to certain environmental cues 0 regulatory mutations alter amount of protein product produced NOT protein structure 0 some binding site mutations can obliterate a required step in normal gene expression l inactivates gene product or blocks its formation 0 g 164 consequences of point mutations on gene products 0 point mutations in coding regions alter protein structure with or wo altering mRNA size 0 point mutations in regulatory regions can prevent synthesis of mRNA and protein 162 The Molecular Basis of Spontaneous Mutations mutagens agent capable of increasing the mutation rate spontaneous mutations mutation occurring in the absence of exposure to mutagens induced mutations mutation that arises through the action of a mutagen Luria and Delbruck uctuation test 0 do spontaneous mutations occur in response to selecting agent induced or are variants present in most populations 0 E coli spread on plate with a phage phage infects and kills bacteria 0 Rarely colonies were resistant to phage attack mutants o Con rms mutants produced spontaneously lf mutations are spontaneous then they could occur at different times in different cultures 0 Fluctuation variation in resistant colonies per culture Fluctuation test test used in microbes to establish the random nature of mutation or to measure mutation rates o If phage induced mutation uctuation should be same on individual cultures bc all exposed to phage similarly o Explanation mutations occurring randomly in time Early mutations gave higher resistant cells bc mutants had time to produce many resistant descendants Paradigm of mutation mutations can occur in any cell at any time and their occurrence is random Suggests that resistant cells selected by environmental agents phage rather than produced by it 0 Replica plating way of screening colonies arrayed on a master plate to see if they are mutant under other environments Master plate grown on nonselective medium no phage Velvet used to imprint master plate and create identical replica plates containing selective medium T1 phage 0 Replica plates showed identical patterns of resistant mutant colonies If mutation occurred after exposure to phage patterns on each plate would be different Mutation event must have occurred before exposure 0 Con rms that mutations occur randomly all the time not in response to selective agent Mechanisms of spontaneous mutations Spontaneous mutations can be caused by 0 Insertion of transposable elements from elsewhere in genome 0 DNA replication errors 0 Spontaneous lesions from damage done by environment 0 Errors in DNA replication 0 Transition mismatches Bases in DNA have several tautomeric forms that can pair to wrong base If base becomes ionized can mismatch more frequent than mismatches caused by tautomerization Usually corrected by proofreading function of bacterial DNA pol lll Other repair systems correct many mismatches that DNA pol lll misses o Transversion mismatches Mispairing purinepurine or pyrimidinepyrimidine energetically unfavorable bc of DNA structure 0 lndel mutations insertiondeletion of 1 base pairs l frameshift mutations when alter bases not divisible by 3 size of codon in proteincoding regions Replication slippage lndels arise when loops in single stranded regions are stabilized by the slipped mispairing of repeated sequences during replication Spontaneous lesions DNA damage occurring in the absence of exposure to mutagens due primarily to the mutagenic action of the byproducts of cellular metabolism naturally occurring DNA damage 0 Depurination loss of a purine base Interrupts glycosidic bond bw base an deoxyribose ln replication apurinic sites DNA site that has lost a purine residue cant specify a base complementary to original purine l genetic damage Repair systems remove apurinic sites lf base inserted across from apurinic site mutation o Deamination cytosine yields uracil Unrepaired U residues pair with A in replication results in a GCAT transition 0 Oxidative damage Active oxygen species produced as byproducts of aerobic metabolism Ex 8oxo dG is a product formed after DNA attacked by oxygen radicals n Frequently mispaired with A results in high level of Gle transversions Spontaneous mutations in humans trinucleotiderepeat diseases Trinucleotiderepeat triplet expansion expansion of a 3bp repeat from a relatively low number of copies to a high number of copies 0 Responsible for many genetic diseases Fragile X syndrome a trinucleotiderepeat disease 0 Fragile site in X chromosome breaks in vitro change in the a of C66 repeat ina region of FMRl gene transcribed but not translated normal variation in CGG repeats in FMR1 gene bw 654 permutation alleles have increased number of the repeat 50200 0 individual unaffected bc not suf cient to cause disease phenotype o BUT they are more unstable readily expanded than normal More expanded repeat l greater instability o Leads to greater expansion in offspring Full mutation high frequency of repeats gt200 0 After 50 repeats replication machinery cannot faithfully replicate correct sequence large variation in repeat 5 0 Disease cause by ampli cation of a 3bp repeat CAG 0 Huntington disease WT HD gene has a repeated seq often win proteincoding region mutation correlated with expansion of this repeat region 0 Kennedy disease expansion of trinucleotide repeat in gene encoding the androgen receptor Trinucleotiderepeat disease similarities suggest common mechanism 0 Many diseases include neurodegeneration cell death win nervous system 0 Trinucleotide repeats fall win open reading frames of transcripts of mutated genes l expansion of contractions of repeats of a single AA 0 Not true for all trinucrepeat diseases 0 ln fragile X syndrome trinucleotide expansion near 5 end of FMRl mRNA before translation start site phenotypic abnormalities of FMRl mutations have no effect on protein structure 0 mutant FMRl genes are hypermethylated associated with transcriptionally silenced genes hypoth repeat expansion leads to changes in chromatin structure that silence transcription of mutant gene FMRl gene deleted in some patients with fragile X syndrome supports lossof function mutation 163 The Molecular Basis of Induced Mutations mutagenesis experiment in which experimental organisms are treated with a mutagen and their progeny are examined for speci c mutant phenotypes Mechanisms of mutagenesis mutagens induce mutations by different mechanisms 0 can replace a base in the DNA 0 alter a base so that it speci cally mispairs with another base 0 damage a base so it can no longer pair with any base under normal conditions incorporation of base analogs 0 base analogs chemical whose molecular structure mimics that of a DNA base because of the mimicry the analog may act as a mutagen incorporate into DNA in place of normal bases pairing properties of analogs unlike normal bases l cause incorrect nucleotides to be inserted opposite them in replication l produce mutations 0 ex base analog 2aminopurine 2AP analog of adenine that pairs with thymine but if protonated mispairs with cytosine speci c mispairing 0 some mutagens alter a base in such a ways that it will form a speci c mispair o Alkylating agents add alkyl groups to many positions on all 4 bases 0 ex addition of oxygen at position 6 of guanine l creates 06 alkylguanine l direct mispairing with T results in GCAT transitions lntercalating agents mutagen that can insert itself bw the stacked bases at the center of the DNA double helix causing an elevated rate of indel mutations o Planar molecules that mimic base pairs and are able to slip in between intercalate stacked nitrogen bases at core of DNA double helix 0 In this intercalated position agent can cause insertiondeletion of a SNP Base damage 0 Mutagen damages 1 bases l replication block DNA synthesis will not proceed past a base that cannot specify its complementary partner Replication blocks can cause further mutation 0 UV light l generates photoproducts distinct types of alteration in DNA Photoproducts unite adjacent pryimidines in DNA 0 Ionizing radiation l formation of ionized and excited molecules that can damage DNA Most damaging reactive oxygen species are OH 02 H202 n Leads to formation of different adducts and degradation products Can also damage DNA directly a Cause breakage of Nglycosydic bond l formation of apurinic or apyrimidinic sites that can cause strand breaks A atoxin Bl carcinogen attaches to guanine l breaks bond bw base and sugar l liberated base and generates an apurinic site The Ames Test evaluating mutagens in our environment 0 Many compound are potential cancercausing agents carcinogens 0 Must test newly synthesized compounds 0 Mice model too slow and expensive 0 Strong correlation bw ability of compounds to cause cancer and their ability to cause mutations o Mutation rates in bacterial systems effective model to evaluate mutagenicity of compounds BUT not all carcinogens mutagenic some produced in body mutagenic agents these are produced in liver enzymatic rxns that convert carcinogens into bioactive metabolites did not take place in bacteria 0 Solution treat special strains of bacterium with extracts of rats livers containing metabolic enzymes 0 Special strain has 1 of several mutant alleles of gene responsible for histidine synthesis known to revert only by certain additional mutational events Treated bacteria exposed to test compound then grown in medium lacking histidine 0 Only revertant individuals would grow l measure freq of reversion 0 Compounds that induced elevated reversion l mutagenic and possible carcinogens Ames test way to test whether a chemical compound is mutagenic by exposing special mutant bacterial strains to the product formed by that compound s digestion by liver extract and then counting the number of colonies 0 Only new mutations presumably produced by the compound can produce revertants to wild type able to form colonies 164 Biological Repair Mechanisms Most important repair mechanism ch 7 Proofreading function of DNA pol o replicate DNA as part of the replisome 0 DNA pol and pol I able to excise mismatched bases Direct reversal of damaged DNA 0 To repair a lesion l directly reverse it regenerates normal base 0 Possible in a few cases o Mutagenic photodimer caused by UV light Photoreactivation requires light to function u Cyclobutane pyrimidine dimer CPD repaired by CPD photolyase n Enzyme binds to CPD and splits it to regenerate original bases Other repair pathways required to remove UV damage in absence of light of appropriate wavelength gt300nm o Alkyltransferases remove certain alkyl groups that have been added to position 06 of guanine by mutagens nitrosoguanidine or ethylmethanesulfonate Baseexcision repair Homologydependent repair systems mechanism of DNA repair that depends on the complementarity or homology of the template strand to the strand being repaired 0 Unlike reversal of damage these pathways include removal and replacement of 1 or more bases Baseexcision repair subtle basepair distortions are repaired by the creation of apurinic sites followed by repair synthesis 0 Occurs after DNA proofreading o Targets nonbulky damage to bases results from methylation deamination oxidation spontaneous loss of DNA base 0 Carried out by DNA glycosylases that cleave basesugar bonds l liberated altered bases generating apurinic or apyrimidic AP sites AP endonuclease nicks damaged strand upstream of AP site 0 Deoxyribophosphodiesterase cleans up backbone by removing stretch of neighboring sugarphos residues so DNA pol can ll gap with complementary nucleotides 0 DNA ligase seals new nucleotides into backbone Numerous DNA glysosylases exist 0 UracilDNA glycosylase removes uracil from DNA U residues cause spontaneous deamination of C lead to CZT transition if unrepaired Adcantage to having T rather than U as neutral partner of A spontaneous C deamination can be recognized as abnormal and then excisedrepaired ln bacteria mutational hotspots corresponed to deaminations at certain C residues 0 GCAT transition hot spots in lacl gene showed methylcytosine residues 0 Why are 5methylcyotosine hot spots for mutations T not recognized by enzyme uracilDNA glycosylase not repaired l CZT transitions generated by deamination more frequent at 5methylcytosine sites 0 0 Over evolutionary time these sites converted to ATOrich regions In contrast codingregulatory regions less methylated remain GC rich Nucleotideexcision repair excisionrepair pathway that breaks the phosphodiester bonds on either side of a damaged base removing that base and several on either side followed by repair replication Able to relieve replication and transcription blocks and repair the damage 2 autosomal recessive diseases in humans caused by defects in nucleotideexcision repair 0 xeroderma pigmentosum XP early development of cancers esp skin 0 Cockayne syndrome premature aging Nucleotide excision repair process 0 1 recognition of damaged bases o 2 assembly of multiprotien complex at the site 0 3 cutting of damaged strand several nucleotides upstream and downstream of the damage site and removal of the nucleotides 30 bw the cuts 0 4 use of undamaged strand as template for DNA pol followed by strand of ligation 2 types of nucleotideexcision repair that differ in damage recognition step 1 o transcriptioncoupled nucleotideexcision repair TCNER activated by stalled transcription complexes and corrects DNA damage in transcribed regions of the genome 0 Global genomic repair GGR activated by stalled replication fork and correct lesions anywhere in genome takes place at nontranscribed sequences heterogenous genetic disorders caused by mutations in any one of several genes encoding a particular process 0 XP and Csyndrome have mutation in nucleotideexcision repair Csyndrome 0 Repair system cannot recognize stalled transcription complexes l cell more likely to activate apoptosis suicide pathway l premature aging symptoms XP 0 Cannot repair original damage bc of mutations in 1 of their XP proteins 0 Mutations accumulate l incr risk of cancer Postreplication repair mismatch repair Mismatch repair system for repairing damage to DNA that has already been replicated o Recognizesrepairs mismatched bases and small loops caused by insertiondeletion of nucleotides indel during replication Mismatch repair systems must do 3 things 0 1 recognize mismatched base pairs 0 2 determine which base in mismatch is the incorrect one o 3 excise incorrect base and carry out repair synthesis 0 1 recognize damage of newly replicated DNA by MutS protein 0 MutS binds to distortions in double helix caused by mismatched bases 0 Binding initiates pathway by attracting 3 other proteins MutL MutH Uer MutH cuts strand with incorrect base 0 2 determine which base in mismatch incorrect o Replication errors product mismatches on newly synthesized strand l replaces base on that strand 0 How to distinguish newly synthesized strand from old one ln eukaryotes Cytosine bases often methylated n In E coli methyl groups relevant to mismatch repair added to adenine bases Adenine methylase takes a few mins to modify new DNA strand n In this interval MutH nicks methylation site on strand with unmethylated A o 3 excise incorrect base 0 Uer binds at nick uses its helicase activity to unwind DNA Protective singlestrandbinding protein coats unwound parental strand while part of new strand bw mismatch and nick excised Errorprone repair translesion DNA synthesis 0 Some repair pathways are themselves signi cant sources of mutation 0 But they have evolved to prevent potentially more serious outcomes cell deathcancer Stalled replication form can initiate celldeath pathway o Replication blocks can be bypassed by insertion of nonspeci c bases 0 ln e coli SOS system errorprone process whereby a bypass polymerase replicates past DNA damage at a stalled replicating fork by inserting nonspeci c bases Last resort form of damage tolerance that allows cell to trade death for certain level of mutagenesis Unusual class of e coli mutants survived UV exposure wo sustaining additional mutations o Suggests that some e coli genes function to generate mutations when exposed to UV light 0 UVinduced mutation will not occur if DibB UmuC or UmuD genes mutated SOS mechanism 0 1 UV light induces synthesis of RecA protein when DNA pol lll replicative pol stalls at DNA damage site DNA ahead of pol continues to unwind exposing regions of singlestranded DNA that becomes bound by singlestrandbinding proteins RecA joings singlestrandedbinding proteins l forms proteinDNA lament o 2 RecA signal induction of several genes that encode members of new family of DNA pols that can bypass replication block Translesion DNA synthesis damagetolerance mechanism in eukaryotes that uses bypass polymerases to replicate DNA past a site of damage Translesions bypass polymerases family of DNA polymerases that can continue to replicate DNA past a site of damage that would halt replication by the normal replicative polymerase n Differ from replicative pol Can tolerate ususually large adducts on bases Bypass pol have much higher error rates 0 Lack 3 5 proofreading activity 0 Can only add a few nucleotides before falling off Main function of errorprone pol to unblock replication fork not synthesize long stretches of DNA that could contain many mismatches 0 Several bypass pol always present in eukaryotic cells bc always present their access to DNA must be regulated integral part of replisome is the PCNA proliferating cell nuclear antigen protein that functions as sliding clamp to orchestrate myriad events at replication fork Rad6 protein enzyme that adds ubiquitin to proteins present at stalled replication fork Addition of ubiquitin to PCNA changes its conformation so it can now bind to bypass pol l translesion synthesis Enzymative removal of ubiquitin tag on PCNA l dissociation of bypass pol l restoration of normal replication Any base mismatch due to translesion synthesis still has change of detectioncorrection by mismatch repair pathway Repair of doublestranded breaks 0 Correction systems exploit DNA complementarity to make errorfree repairs characterized by 2 stages 0 1 removal of damaged bases from 1 strand of double helix 0 2 use of other strand as template for DNA synthesis need to ll in singlestrand gap doublestranded break DNA break cleaving the sugarphosphate backbones of both strands of the DNA double helix 0 can cause variety of chromosomal aberrations resulting in cell death or precancerous state 0 integral feature of some normal cellular processes that require DNA rearrangements meiotic recombination o arise spontaneously from reactive 0 species produced as by product of cell metabolism or induced by ionizing radiation 0 2 distinct mechanisms Nonhomologous end joining NHEJ mechanism used by eukaryotes to repair doublestrand breaks 0 When doublestranded breaks occur in cells where undamaged strands or sister chromatids not present ends must be repaired perfectly or imperfectly bc broken ends can initiate harmful chromosomal rearrangements o NHEJ pathway proteins KU7O and KU80 bind to broken ends l form heterodimer that prevents further damage to ends and recruits other proteins to trim strand ends to generate 5 P and 3 OH ends required for ligation DNA ligase IV joins the 2 ends Homologous recombination o Synthesisdependent strand annealing SDSA errorfree mechanism for correcting doublestrand breaks that occur after replication of a chromosomal region in a dividing cell Uses sister chromatids available in mitosis as templates o SDSA pathway Proteins bind to broken ends l endonucleoase trim 5 ends to expose singlestranded regions a Proteins coating of these regions include RecA homolog Rad51 Rad51 forms long laments as it associated with single stranded region Rad51DNA lament searches undamaged sister chromatid for complementary sequence that will by used as template strand invasion 3 end of invading strand displaced 1 of undamaged sister chromatids l forms Dloop and primes DNA synthesis from its free 3 end new DNA synthesis continues from both 3 ends until both strands unwind from their templates and anneal ligation seals nicks o replicated by conservative process both strands are newly synthesized The involvement of DSB repair in meiotic recombination Doublestranded breaks naturally initiate crossover events 0 But just as dangerous if not processed correctly Crossing over takes place bw 2 homologous chromosomes 0 Recombination takes places after replication fork passed thru chromosomal region forming 2 chromatids from each homologous chromosome 0 1 chromatid from 1 homologou chromosome will recombine with a nonsister chromatid from other homologous chromosome 0 every pair of homologs must have at least 1 crossover recombination initiated by Spoll enzymes makes DNA double strand cuts in 1 of chromatids that will recombine o Spoll remains attached to now free 5 ends Protects ends from further damage Attracts other proteins needed for next step of recombination o 5 ends trimmed protein complex binds to singlestranded 3 ends complex includes Rad51 searches for complementarity o meiotic recombination different path from doublestrand break repair in meiosis Rad51 searches for complementarity in sister chromatid in DSB repair Rad51 searches a nonsister chromatid 0 search culminates in strand invasion and Dloop formation 0 homologs become connected as result of recombination 165 Cancer An Important Phenotypic Consequence of Mutation all cancers of somatic cells arise from series of special mutations that accumulate in a cell Cancerpromoting mutations fall into categories 0 Those that incr ability of cell to proliferate Decre susceptibility of cell to suicide pathway apoptosis 0 Those that incr general mutation rate of cell or its longevity so that all mutations are more likely to occur How cancer cells differ from normal cells 0 Cancer class of disease characterized by the rapid and uncontrolled proliferation of cells within a tissue of a multitissue eukaryote o Cancers are generally thought to be genetic diseases of somatic cells arising through sequential mutations that create oncogenes and inactivate tumorsuppressor genes Malignant tumor cancer aggregate of cells all descended from an initial aberrant founder cell 0 Malignant cells all members of a single clone 0 Cancer cells differ from normal cells by phenotypic characters 0 Rapid division rate 0 Ability to invade new cellular territories 0 High metabolic rate 0 Abnormal shape Mutations in cancer cells 0 Evidence of genetic origin for transformation of cells from benign into cancerous state 0 Many mutagenic agents cause cancer suggests they produce cancer by introducing mutations into genes 0 Mutations frequently associated with particular kinds of cancers have been identi ed Oncogene gainof function mutation that contributes to the production of a cancer 0 Proteins encoded by oncogenes usually activated in tumor cells 0 Mutation need be present in only 1 allele to contribute o Protooncogene normal cellular counterpart of a gene that can be mutated to become a dominant oncogene Tumorsuppressor genes encode protein that suppresses tumor formation 0 WT alleles of tumorsuppressor genes are thought to function as negative regulators of cell proliferation o Mutations in tumorsuppressor genes that promote tumor formation are lossoffunction recessive mutations Mutation must be present in both alleles of the gene 0 Classes of oncogenes o Protooncogenes generally encode class of proteins that are active only when proper regulatory signal activate them Some protein products have positive control on cell cycle Others have negative control of apoptotic pathway 0 Mutant protein uncoupled from its normal regulatory pathway l continuous unregulated expression Oncoprotein protein product of an oncogene mutation 0 Ex ras oncogene Single basepair substitution l oncoprotein found in human bladder cancer Normally functions by cycling bw active GTPbound state and inactive GDPbound state Oncoprotein always binds GTP even in absence of normal signals l continuously propagates signal that promotes cell proliferation Tumorsuppressor genes 0 Some encode negative regulators who normally inhibit cell cycle 0 Others encode positive regulators that normally activate apoptosis 0 Others indirect player normal role to repair damaged DNA or control cellular longevity 0 Ex p53 gene mutations p53 protein found in 50 tumors P53 protein transcriptional regulator that s activated in response to DNA damage WT p53 prevents progression of cell cycle until DNA damage repaired and in some instances induces apoptosis No p53 gene l cell cycle progresses even if damaged DNA not repaired l progression into mitosis elevates overall frequency of mutations chromosomal rearrangements and aneuploidy l incr chance other mutations that promote cell proliferationblock apoptosis will arise 166 Summary Introduction 0 Downs syndrome set of physical and mental disorders by presence of an extra chromosome 21 0 Gene mutations are charges win a gene chromosome mutations are changes in a chromosome region encompassing multiple genes Chromosome mutations largescale variations Any type of change in chromosome structure or number 0 Changes in chromosome number number of DNA molecules changes 0 Changes in chromosome structure result in novel sequence arrangements win 1 DNA double helices 171 Changes in Chromosome Number 0 2 basic types 0 aberrant euploidy changes in whole chromosome sets 0 aneuploidy changes in parts of chromosome sets Aberrant euploidy Euploid organisms with multiples of the basic chromosome set genome 0 Normal euploids Haploids n 1 chromosome set Diploids 2n 2 chromosome sets Aberrant euploids Organisms with morefewer than normal sets 0 Higher ploidy level larger size of organism Monoploid individual with 1 chromosome set that is normally diploid missing 1 chromosome set 0 Common in insects Males develop by parthogenesis development of specialized type of unfertilized egg into embryo Wo need for fertilization o In most other species monoploid zygotes fail to develop Bc individuals of diploid species carry genetic load total set of deleterious recessive alleles in an individual genotype Deleterious recessive alleles masked by WT alleles in diploids but automatically express in monoploid o Monoploids are sterile Polyploids individuals with more than 2 chromosome sets additional chromosome sets o Triploid 3n tetraploid 4n 0 Common in pants rare in animals 0 Even numbers of chromosomes more common than odd bc polyploids originate from doubling and redoubling Autopolyploids polyploid formed from the doubling of a single genome 0 have multiple chromosome sets originating from win 1 species diff chromosome sets are homologous o triploids 3n usually autopolyploids cross 4n X 2n 2n and n gametes unite to form 3n triploid sterile bc unpaired chromosome at meiosis pairing can only take place bw 2 of the 3 chromosomes l gamete could get 1 or 2 chromosomes n bivalents 2 homologous chromosomes paired at meiosis paired homologs segregate to opposite poles n univalent single unpaired meiotic chromosome unpaired homologs pass to either pole randomly n trivalent paired group of 3 paired centromeres segregate as bivalent and unpaired one as a univalent aneuploidy genome w a chromosome that differs from the normal chromosome number for the species by a small of chromosomes 1 or 2 u give ride to sterile offspring aneuploids also polyploids with odd 5 of chromosome sets are sterile bc their gametes and offspring are aneuploid o Autotetraploids 4n arise by doubling of a 2n complement to 4n spontaneous or induced by chemical agents that disrupt microtubule polymerization a chromosome segregation powered by spindle bers l disruption of microtubule polymerization blocks chromosome segregation Colchicine common antitubulin agent treat diploid 2n for 1 cell cycle l tetreaploids 4n n Colchicine treated cells S phase takes place but chromosome segregationcell division does not n Entering telophase nuclear membrane forms around entire doubled set of chromosomes Not all alleles in genotype doubled u If diploid cell of genotype AaBb double l autotetraploid genotype AAaaBBbb 4 even l can have regular meiosis n Chromosomes pair as bivalents and quadrivalents normal segregation l diploid gametes l tetraploid offspring u If trivalent forms segregation leads to nonfunctional aneuploidy gametes l sterile Phenotypic ratio 351 expected Allopolyploids polyploid formed from the union of 2 separate chromosome sets and their subsequent doubling 0 have sets from 2 or more diff but closely related species 0 diff chromosome sets are homeologous partly homologous o Georgi Karpechenko wanted to make fertile hybrid with leaves of cabbage and roots of radish Each species has 18 chromosomes n1n29 Fusions of n1n2 gametes l progeny 18n but sterile bc 9 chromosomes from cabbage parent too different pairs did not synapse and segregate normally at meiosis Accidental chromosome doubling to 2n12n2 l sterile hybrid allopolyploids I Give fertile progeny n Amphidiploid doubled diploid Cross either parental species with sterile offspring 2n1n2 l n1n2 gametes a N2 chromosome had no pairing partners sterile n Created new species with no possibility of gene exchange with other cabbageradish o Allopolyploidy major force in evolution of new plant species 50 all angiosperm plants are polyploids resulting from autoor allopolyploidy 0 bread wheat natural allopolyploid 6n42 composed of 2 sets each of 3 ancestral genomes at meiosis pairing always bw homologs from same ancestral genome always 21 bivalents o allopolyploids can be produced arti cially by fusing diploid cells from diff species Agriculturalapplications o Monoploids Diploidy a nuisance bc I want to induceselect new favorable recessive mutations but new mutations can only be detected if homozygous u want to nd favorable new combos of alleles at diff loci but allele combo in heterozygotes will be broken up by recombination at meiosis monoploids arti cially derived from products of meiosis in plant s anthers l grown into embryoid small dividing mass of monoploid cells l monoploid plant monoploids exploited in several ways a look for favorable allelic combo from recombination of alleles already present in heterozygous diploid parent monoploid subject to chromosome doubling l produces homozygous diploid cells fertile a treat with mutagen l plate on medium that selects for desired trait l select for resistance resistant plants doubled l resistant homozygous diploid fertile o Autotriploids sterile absence of seeds 0 Autotetraploids increased size gives large fruits owers o Allopolyploids synthesized arti cially to combine useful features of parental species into 1 type Polyploid animals 0 Rare in animals but are cases in nature 0 Triploidtetraploid Drosophila synthesized experimentally 172 Changes in Chromosome Structure Rearrangements changes in chromosome structure 0 production of abnormal chromosomes by the breakage and incorrect rejoining of chromosomal segments deletion loss of a chromosome segment duplication doubling of a chromosome segment inversion segment win the chromosome reversed o removal of segment rotates 180 reinserted in same location translocation segment moved to a different chromosome DNA breakage major cause of rearrangements Both DNA strands must break at 2 diff location then broken ends rejoined to produces a new chromosomal arrangement How chromosomal rearrangement produced by breakage keep in mind 1 each chromosome a single doublestranded DNA molecule 2 1St event in rearrangement is the generation of 2 double stranded breaks in chromosomes 3 doublestranded breaks potentially lethal if left unrepaired 4 repair systems in cell correct doublestranded breaks by joining broken ends back together 5 if 2 ends of same break rejoined l original DNA order 0 if ends of 2 diff breaks joined l rearrangement 6 chromosomal rearrangements that survive meiosis produce DNA molecules with 1 centromere and 2 telomeres o if rearrangement produces chromosome wo a centromere ancentric chromosome lacks a centromere chromosome wont be dragged to either pole at anaphase of mitosismeiosis not incorporated into either progeny not inherited o if rearrangement produces chromosome w 2 centromeres dicentric chromosome has 2 centromeres pulled simultaneously to opposite poles l forms anaphase bridge l anaphasebridge chromosome typically not incorporated into either progeny not inherted o if rearrangement produces chromosome wo a telomere chromosome cant replicate properly bc telomeres needed to prime DNA replication at ends 0 7 if rearrangement duplicatesdeletes a segment l gene balance affected 0 larger segment lostduplicated l more likely gene imbalance will cause phenotypic abnormalities Nonallelic homologous recombination NAHR crossing over bw repetitive duplicated DNA segments from diff loci lf sequences pair up that aren t in same positions on homologs l crossing over can produce aberrant chromosomes Deletions duplication inversions translocations all possible 2 types of rearrangements Unbalanced rearrangements changes gene dosage of a chromosome segment chromosomal material gainedlost in 1 chromosome set 0 Deletion loss of a segment win 1 chromosome arm and the connecting of the 2 segments on either side of deleted segment 0 Duplication repetition of a segment of a chromosome arm Simplest 2 segments adjacent tandem duplication Duplicated segment can end up at diff position on same or diff chromosome Balanced rearrangements changes chromosomal gene order but doesn t removeduplicate any DNA 0 lnversions internal segment broken twice ipped 180 rejoined o Reciprocal translocation 2 nonhomologous chromosomes each broken once creates acentric fragments that trade places Sometimes DNA breaks that precede formation of a rearrangement occur Within genes Disrupts gene function bc part of gene moves to new location and no complete transcript can be made 0 In addition sequences on either side of rejoined ends form sequences that are not normal 0 Sometimes fusion produces a nonfunctional hybrid gene composed of parts of 2 other genes Deletions loss of a part of 1 chromosome arm 0 Process 2 chromosomal breaks cut out intervening segment 0 Deleted fragment has no centromere l cant be pulled to pole in cell division l segment lost lntragenic deletion small deletion win a gene 0 lnactivates gene effect of a null mutation of gene o If homozygous null phenotype viable l homozygous deletion viable o Distinguished from single nucleotide mutations bc genes w deletions never revert to WT Multigenic deletions deletion of several adjacent genes 0 If both homologs have same deletion combo lethal Complete elimination of any segment from genome is deleterious Even if heterozygous 1 normal homolog and 1 w deletion may not survive Lethal outcome due to disruption of normal gene balance 0 Deletion can also uncover deleterious recessive alleles allow single copies to be expressed 0 Small deletions with normal homolog sometimes viable Deletions identi ed by examining meiotic chromosomes under microscope o Deletion loop loop formed at meiosis by the pairing of a normal chromosome and a deletioncontaining chromosome 0 Drosophila deletion loops visible in polytene chromosome Homologs pair and replicate many times each chromosome represented by thick bundle of replicates Each has set of bands of xed position and number act as chromosomal landmarks used to assign location of deletion on chromosome 0 Identify deletion Deletion of segment on 1 homolog sometimes unmasks recessive alleles on other homolog l unexpected expression 0 Pseudodominance sudden appearance of a recessive phenotype in a pedigree due to the deletion of a masking dominant gene the recessive alleles show dominance Deletion mapping use of a set of known deletions to map new recessive mutations by pseudodominance 0 Pairs mutations against set of de ned overlapping deletions 0 Each deletion paired w each mutation phenotype observed to see if mutation pseudodominant Cri du chat syndrome caused by heterozygous deletion 0 Characteristic phenotype cat like mewing by affecting infants Includes mental retardation Fatality rates low 0 Williams syndrome autosomal dominant 0 Unusual development of nervous system 0 Patient have pronounced musical ability O Caused by deletion on 1 homolog o Abnormal phenotype caused by haploinsuf ciency of 1 or more of the genes in lost segment 0 Sequence analysis reveals origin of deletion bc normal sequence bounded by repeated copies of PMS gene 0 Crossover bw anking copies of PMS gene on opposite ends of lost segment leads to duplication and Williams syndrome deletion Most human deletions arise spontaneously in gonads of normal pa rent of affected person 0 Ex cri du chat can result from parent heterozygous for reciprocal transocation bc segregation produces deletions o Deletion can result form recombination win heterozygotes with perventric inversion inversion spanning the centromere on 1 chromosome Animalsplants show diff survival of gametesoffspring with deletions 0 Animal sperm function regardless of genetic content 0 Heterozygous diploid plant pollen with deletion of 2 types Functional pollen w normal chromosome Nonfunctional pollen with de cient homolog Analogous to sensitivity of pollen to wholechromosome aneuploidy Duplications produce extra copy of some chromosome region Tandem duplication duplicate regions adjacent to each other lnsertional duplication extra copy located elsewhere in genome Diploid cell with duplication has 3 copies of that region 0 Simple sequence repeats used as molecular markers Segmental duplications has 2 or more large nontandem repeats 0 Larger than simple sequence repeats encompasses whole genes and regions bw o Dispersion of duplicated units mostly win same chromosome 0 Important role as substrates for nonallelic homologous recombination Crossing over bw segmental duplications l rearrangements l are key differences bw human and apes o Ancestral wholegenome duplication l polyploids Every gene doubled doubled genes are source of some segmental duplications Ex baker s yeast after doubling many gene copies lost and remaing sets rearranged resulting in new species Inversions segment cut out ipped and reinserted Paracentric centromere outside of inversion Pericentric centromere inside of inversion Inversions are balanced rearrangements no change in amount of genetic material no gene imbalance 0 Individuals normal if no breaks win genes Analyses usually on inversion heterozygote diploid cell w 1 normal chromosome and 1 inverted homolog o Detect location of inverted segment microscopically paired homologs form visible inversion loop 0 Inversion loop formed by meiotic pairing of homologs in inversion heterozygote Paracentric inversion crossing over win inversion loop connects homologous centromeres in a dicentric bridge 2 centromeres drawn to opposite poles and produces an acentric fragment no centromere o Anaphase I chromosomes separate Bridge breaks l 2 chromosomes with terminal deletions Acentric fragement lost 0 lnviable l crossover event lethal Very low frequency of viable recombinants close to O 0 RF reduced in proportion to size of inversion for gene anking inversion longer inversion l greater prob crossover Heterozygous pericentric inversion has same genetic effect as paracentric inversion but for diff reasons 0 Centromeres win inverted region crossing over normal no bridge l BUT produces chromatids w duplication and a deletion for diff parts of chromosome 0 If gamete with crossover chromosome fertilized zygote dies gene imbalance 0 RF 0 for genes win pericentric inversion Detection o Inversion heterozygotes inversion loop causes pairing problems in inversion region reduces opportunity for crossing over in neighboring regions 0 WT Drosophila x natural population F1 generation WT F1 female x recessive parent very low RF close to O Reduced crossing over in that region caused by inversion spanning the region 0 Pericentric inversions detected microscopically via arm ratios longshort Normal 41 Inversion 11 Balancer chromosome has multiple inversions 0 Used to retain favorable allele combo in uninverted homolog 0 Want to keep stock with all alleles on 1 chromosome together Combine this genome with balancer l eliminates crossovers only parental combos appear in progeny Reciprocal translocations simplest type of translocation 2 chromosomes trade acentric fragments created by 2 simultaneous chromosome breaks Meiosis in individual heterozygous for reciprocal translocation l 2 common patterns of segregation o N normal chromosomes 0 T translocated chromosomes Adjacent1 segregation passage of a translocated and a normal chromosome to poles T1N2 and T2N1 0 Both meiotic product de cient for a diff arm and has duplicate of other inviable Alternate segregation passage of both normal chromosomes to one pole and both translocated chromosomes to the other pole N1N2 and T1T2 0 Products balanced and viable Detection o Semisterality 50 reduction in viable gameteszygotes l diagnostic for translocation Segregation types equal in number half population of gametes nonfunctional semisterality o Pseudolinkage appearance of linkage of 2 genes on translocated chromosomes Robertsonian translocation produces progeny carrying an almost complete extra copy of chromosome 21 0 Small proportion of Downs syndrome cases result from translocation in 1 of the parents Translocations can produce progeny with extra material from part of genome l translocation on chromosome 21 can cause Downs Applications of inversions and translocations Gene mapping Synthesizing speci c duplicationsdeletions o Pericentric inversions and translocations generate meiotic products with a duplication and a deletion Positioneffect variegation variegation caused by the inactivation of a gene in some cells through its abnormal juxtaposition with heterochromatin Rearrangements and cancer 0 Cancer disease of abnormal cell proliferation Protooncogenes genes whose function is to regulate cell division 0 Mutation in coding or regulatory region cancer 0 Chromosomal rearrangements esp translocations can interfere with normal function of protooncogenes o Translocation can relocate a protooncogene next to a new regulatory element 0 Translocation can form a hybrid gene Identifying chromosome mutations by genomics Comparative genomic hybridization DNA microarrays used to detect and quantify duplicationsdeletions of given DNA segment MutanttoWT ratios larger than 1 ampli ed regions 0 Ratio 2 l duplication 0 Ratio less than 1 l deletion Overall incidence of human chromosome mutations Chromosome mutations frequent in human sexual reproduction 15 conceptions abort spontaneously half show chromosomal abnormalities 0 live births 06 have chromosomal abnormalities 0 resulting from both aneuploidy and chromosomal rearrangements 174 Summary Introduction Population group of individuals of same species Population genetics analyzes the amount and distribution of genetic variation in populations changes over time in amount or patterning of that variation and the forces that control this variation Mendel s laws explain how genes are passed from parent to offspring in controlled cases with known pedigrees 0 But insuf cient in understanding transmission of genes in natural populations not all individuals produce offspring not all offspiring live Development of DNA technologies ability to observe directly differences bw DNA sequences of individuals throughout their genomes can measure differences in large samples of individuals to understand the population 181 Detection Genetic Variation population genetics used to analyze any variable or polymorphic locus in DNA sequences of a population locus location in genome can be single nucleotide site or stretch of many nucleotides single nucleotide polymorphisms SNPs nucleotidepair difference at a given location in the genomes of two or more naturally occurring individuals 0 most widely studied variants in human population genetics microsatellite loci locus composed of several copies repeats of a short 2 to 6 bp sequence motif 0 Difference alleles have different numbers of repeats Single nucleotide polymorphisms SNPs SNPs most prevalent types of polymorphisms in most genomes 0 Have just 2 alleles Common SNPs the less common allele occurs at a frequency of 5 or greater Rare SNPs less common allele occurs at a frequency below 5 SNPs occur win genes 0 SNPs win proteincoding regions Synonymous diff alleles encode same AA Nonsynonymous 2 alleles encode diff AAs Nonsense 1 allele encodes a stop codon and he other an AA 0 Silent SNPs occur outside coding regions can be genetic markers 0 To study SNP variation in population rst need to determine which nucleotides sites are variable constitute a SNP o SNP discovery sequence genomes of a small sample of individuals of a species then compare these sequences 0 Determine genotype allelic composition of individuals at each SNP Microarrays Microsatellites locus composed of several copies repeats of a short 2 to 6 bp sequence motif difference alleles have different numbers of repeats Powerful loci for population genetic analysis 0 alleles at microsatellite very large 20 0 high mutation rate variation level higher 0 abundant in most genomes microsat with trinucleotide repeats found in coding sequences of some genes encode strings of a single AA 0 but most found outside exon l variation of repeats not associated with diff phenotypes 2 methods to discover microsat loci in genome o if complete genome sequence available use computer to search 0 species wo genome sequences make genomic library screen with probe for motif of interest ie AG repeats determine DNA sequence of selected clones to identify microsat and sequences anking them 0 after microsat and anking seq identi ed DNA samples from set of individuals analyzed to determine repeats in each individual 0 oligonucleotide primers desgined to match aning seq for PCR 0 size of PCR products reveal repeats in a microsat allele Haplotypes combos of alleles at multiple loci on same chromosome homolog 2 homologous chromosomes that share the same allele at each loci have same haplotype used for physically close loci or larger regions when little to no recombination over the region and possible to apply to entire chromosome haplotype network shows relationships among haplotypes and the positions of the mutations de ning the haplotypes on the branches insights from haplotype analysis Genghis Khan o starcluster haplotype prevalent in Y chromosome of Asian men 0 use mutation rate to estimate when in history haplotype arose o haplotype most common in Mongolia arose there 0 men with this haplotype are all descendants of Genghis Khan Other sources and forms of variation Inversions translocations deletionsduplications presenseabsence of a transposable element at particular locus in genome Insertiondeletion polymorphism indel presenceabsence of 1 nucleotides at a locus in 1 allele relative to another 0 Genetic variation found in mitochondrial mtDNA and chloroplast chNA genomes of eukaryotes 0 Have both SNP and microsat in organelle genome o mtDNA and chNA maternally inherited analysis used to follow history of female lineages 0 study of mtDNA rst genetic analysis to show that all modern humans came from Africa The HapMap Project HapMap genomewide haplotype map 0 Genotype lots of people get highly detailed picture of variation in our species 182 The GenePool Concept and HardyWeinberg Law Gene pool sum total of all alleles in the breeding members of a population at a given time 0 population size N 16 0 total of alleles in diploid population 2N 32 Genotype frequency proportion of individuals in a population having a particular genotype Freq of NA genotype AA individualsN Allele frequency measure of the commonness of an allele in a population proportion of all alleles of that gene in the population that are of this speci c type 0 p A allele freq o q a allele freq pq 1 HardyWeinberg law equation used to describe the relationship between allelic and genotypic frequencies in a randommating population p22pqq210 expected genotype frequencies under HW law 0 fAA 02 prob that individual in next generation will be NA 0 fiaa C72 0 fAa sampling process of reaching into gene pool to pick an allele 0 use HW law to calculate o genotype frequencies in next generation from allele frequencies in current generation 0 allele frequencies from the genotypes frequencies Win a single generation HW law assumes 0 random mating in the population Tendency for individuals who are phenotypically similar to mate violates HW law 0 All genotypes equally viable Estimate of gene freq inaccurate if 1 genotype has reduced viability die before genotype counted 0 Population cant have subpopulations genotype counts from overall population may not give accurate estimate of overall allele freq 0 in nitely large populations HardyWeinberg equilibrium stable frequency distribution of genotypes o consequence of random mating in the absence of mutation migration natural selection or random drift 0 For very low freq allele homozygotes very rarely found 0 Consequence recessive alleles for genetic disorder can occur in many more heterozygotes than individuals expressing the disorder HW law still applies where there are more than 2 alleles per locus 0 Sum of all individual freq 1 HW law applies to Xlinked loci O O O Males are hemizygous for Xlinked genes a male has a single copy of these genes For X linked genes in males genotype freq equal to allele freq For X linked genes in females genotype freq follows normal H W expectations Xquot2 test use to test whether observed genotype freq at a locus ts HW predictions 0 Use genotype freq to calculate allele freq fA I0 fa q calculate expected genotype freq under HW law DAZ 2m qAZ calculate expected number of individuals for each genotype expected genotype freq x sample size N calculate Xquot2 probability under the null hypothesis that the observed data t HardyWeinberg predictions is Plt 0005 with df 1 183 Mating Systems assumption of random mating is met if all individuals in the population are equally likely as a choice when a mate is chosen Populations that are not random mating will not exhibit exact HW proportions for the genotypes at some or all genes 0 3 types of bias in mate choice that violate the assumption of random mating are assortative mating isolation by distance and inbreeding Assortative mating occur if individuals choose mates based on resemblance to themselves 0 Positive assortative mating similar phenotypes mate more commonly than expected by chance 0 Expect excess homozygote alleles 0 Negative assortative mating dissortative mating preferential mating between phenotypically unlike partners 0 More heterozygotes than expected Isolation by distance bias in mate choice that arises from the amount of geographic distance between individuals causing individuals to be more apt to mate with a neighbor than another member of their species farther away Consequence 0 Population structure division of a species or population into multiple genetically distinct subpopulations If species has population structure proportion of homozygotes more than expected under HW Inbreeding mating bw relatives Progeny of inbreeding more likely to be homozygous at any locus than progeny of noninbred matings l more likely to be homozygous for deleterious recessive alleles Inbreeding depression reduction in vigor and reproductive success from inbreeding The inbreeding coef cient F degree of inbreeding probability that the 2 alleles at a locus in an individual are identical by descent IBD Amount of risk from inbreeding depend on 2 factors 0 1 freq of the deleterious allele in the population 0 2 degree of inbreeding presence of a closed loop in pedigrees indicates that individual is inbred I 0 identical by descent IBD When two copies of a gene in an individual trace back to the same copy in an ancestor prob that z and y alleles are IBD is the prob that they are the same copy 12 plus the prob that they are different copies that are IBD 12Fa o Pzy 12 12Fa 0 Fl Pxy X Pwz X Pzy Inbreeding coef cient Fi for offspring of mating bw halfsibs 0 Fl 12quot3 x 1Fa 0 Fa inbreeding coef cient of the ancestor o quot3 bc are 3 individuals in inbreeding loop not counting I 0 general formula for computing inbreeding coef cients from pedigrees 0 Fl 12quotn x 1Fa o n individuals in inbreeding loop not counting l o if not given info assume no inbreeding Fx 0 random mating assumption of HW violated in inbreeding o modify to correct predicted genotypic proportions for diff degrees of inbreeding using F mean inbreeding coef cient for the population fAA p2 qu fAa 2m 2qu 726 672 qu 0 shows how inbreeding reduces freq of heterozygotes by 2qu and adds half this amount to each homozygous class degree of risks jumps dramatically for rare alleles o brothersister and parentoffspring matings the riskiest Population size and inbreeding In small populations individuals more likely to mate with a relative than in large populations Formula for the increase in inbreeding bw generations in nite populations L iii l ll iii g II II It III 184 Genetic Variation and Its Measurement how to quantify variation ex G6PD Xlinked gene that encodes an enzyme that catalyzes a step in gycoysis 0 allele A leads to reduced enzymatic activity individuals with this allele develop hemolytic anemia o A allele also confers 50 reduction in risk of malaria in carriers 0 In Africa malaria endemic here A allele reaches freq 20 even though A rare elsewhere 0 Sampled males observed just 1 allele and 1 haplotype for each individual bc gene Xlinked WT allele B has full enzymatic acitivity o Allele A has modestly reduced enzymatic activity 0 0 Individuals with A or B don t develop hemolytic anemia How to quantify variation at G6PD locus o Segregation sites S of variable or polymorphic nucleotide sites in a set of homologous DNA sequences 0 Number of haplotypes NH count of the of haplotypes at a locus in a population 0 Show that Africa sample has greater variation 0 Con both depend heavily on sample size Calculate allele freq in place of S and NH not sample size biased 0 Use to calculate GD Gene diversity GD probability that 2 alleles drawn at random from the gene pool will be different GD 2 1 Egg 0 1 i i 1 1 a 0 pi freq of the ith allele 0 GD varies from 01 Near 1 large alleles of roughly equal frequencies 0 when there s a single allele near 0 there s a single very common allele with freq of 099 or higher 0 gene diversity high in Africans 059 compared to non africans who only have B allele 00 GD heterozygosity H expected proportion of heterozygotes under HW equilibrium 0 H measure of the genetic variation in a population with respect to one locus stated as the freq of heterozygotes for thatlocus Only applies to diploids doesn t apply to Xlinked loci in males Nucleotide diversity Heterozygosity or gene diversity averaged over all the nucleotide sites in a gene or any other stretch of DNA 0 GD for a single nucleotide site averaged over all nucleotide sites in a gene 0 Africans have 4x as much nucleotide diversity at G6PD as nonafricans o Unicellular eukaryotes most diverse plant inverts verts 185 The Modulation of Genetic Variation New alleles enter the population mutation and migration Mutation is the ultimate source of all genetic variation Mutation rate probability that a copy of an allele changes to some other allelic form in one generation 0 Know mutation reate and nucleotide differences sbw 2 sequences l can estimate how long ago the 2 seq diverged To estimate mutation rate start with single homozygous individual and follow pedigree back for several generations compare DNA seq of founding individual to DNA seq of descendants and record any mutations o observed mutations per genome per generation estimate of mutation rate microsatellite mutation rate gt SNP mutation rate 0 higher mutation rate greater variation l microsat more useful in population geneticsDNA forensics migration gene ow movement of individuals or gametes between populations 0 species divided into subpopulations by physical barriers l reduce gene ow bw subpopulations but some still occurs 0 individuals from diff subpopulations cant mate unless there is migration isolated subpopulations diverge as each accumulates its own unique mutations 0 gene ow limits genetic divergence bw subpopulations genetic admixture mix of genes that results when individuals have ancestry from more than one subpopulation Recombination and linkage disequilibrium Linkage disequilibrium is the outcome of the fact that new mutations arise on a single haplotype 0 LD will decay over time because of recombination Recombination can create variation in form of new haplotypes Observed and expected frequencies of the 4 possible haplotypes for 2 loci each with 2 alleles o Linked loci A and B have alleles A and a and B and b with frequencies pA pa pB pb o 4 possible haplotypes are AB Ab aB ab with observed frequencies PAB PAb PaB and Fab 0 If a random relationship bw the alleles at the 2 loci then the frequency of any haplotype will be the product of the frequencies of the 2 alleles that compose that haplotype Ex pab pa x pb Linkage equilibrium association bw alleles at 2 loci is random 0 Observed and expected frequencies the same Linkage disequilibrium association bw alleles at 2 loci is nonrandom 0 speci c allele at the rst locus is associated with a speci c allele at the second locus more often than expected by chance 0 A alleles always with B allele while a always with b no chromosomes with haplotypes Ab or a8 0 observed and expected frequencies will not be the same how does LD arise 0 When new mutation occurs at a locus it appears on a single speci c chromosome so is instantly linked to speci c alleles at any neighboring loci on that chromosome 0 Migrants bw subpopulations give rise to LD in subpopulation receiving the migrants LD bw 2 loci will decline over time as crossovers bw them randomize the relationship bw their alleles 0 rate this happens depends on the frequency of recombinants RF bw the 2 loci among the gametes that form the next generation can use the level of LD bw a mutation and the loci surrounding it to estimate the time in generations since the mutation rst arose in the population 0 Older mutations have little LD with neighboring loci while recent mutations show high level of LD with neighboring loci Ex A arose by random mutation but was maintained in population bc it provided protection against malaria Genetic drift and population size In in nitely large populations HW law says allele freq remain same from 1 generation to next But actual populations are nite allele freq may change from 1 generation to next due to chance sampling error when gametes drawn from gene pool to form next generation 0 Random genetic drift change in allele freq bw generations due to sampling error Changes in allele frequency that result bc the genes appearing in offspring are not a perfectly representative sampling of the parental genes Drift weaker in large populations At any locus drift can continue from 1 generation to next until 1 allele has become xed 0 Drift doesn t proceed in speci c direction toward loss or xation of an allele Drift a random process 0 When population size small N10 population became xed 0 When population size large N500 populations retained both alleles in all 6 trials Fate of an allele determined by its freq in the population 0 Prob that an allele will drift to xation in future generation that allele s freq in the present generation Allele freq 05 l 5050 chance of xation or loss from the population in a future generation 0 Newly arising mutation will ultimately be lost from a population bc of drift bc if N each modestly large 10000 prob that new mutation will reach xation extremely small 0 average time required for a lucky mutation to become xed is 4N generations 0 in smaller population 12 the size 4N generations is 12 as long new mutations xed more rapidly consequence of drift slightly deleterious alleles can be brought to xation or advantageous alleles lost by this random process 0 individual with advantageous allele dies from random event before passing allele on o if heterozygotes carrying favorable allele may pass only less favorable allele to offspring by chance 0 neutral alleles variants an allele that has no effect on the tness of individuals that possess it 0 neutral evolution nonadaptive evolutionary changes due to random genetic drift 0 change in freq of neutral alleles over time due to drift 0 foundation for molecular clock constant rate of substitution of amino acids in proteins or nucleotides in nucleic acids over long evolutionary time 0 distinct from Darwinian evolution favorable alleles rise in freq bc carriers leave more offspring populations often contractexpand in size over time 0 can be caused by migration of small number of members of a population founders to a new location establish new population 0 founder effect random difference in the freq of an allele or genotype in a new colony as compared to the parental population that results from a small number of founders drift cause by random sampling of original population to create the new population ex genetic diversity among native american lower than people from other regions 0 population size can change win a single location 0 bottleneck period of one or several consecutive generations of contraction in population size 0 reduction of population size increases level of drift in a population 0 level of inbreeding also increases 0 Population size is a key factor affecting genetic variation in populations 0 Genetic drift is a stronger force in small populations than in large ones 0 The probability that an allele will become xed in or lost from a population by drift is a function of its frequency in the population and population size 0 Most new neutral mutations are lost from populations by drift Selection Adaptations some heritable feature of an individual s phenotype that improves its chances of survival and reproduction in the existing environment 0 Natural selection differential rate of reproduction of different types in a population as the result of different physiological anatomical or behavioral characteristics of the types Darwinian theory of evolution 0 Individuals w features that enhance their ability to survive and reproduce adaptations will transmit these features to their offspring 0 Over time these features will rise in frequency in the population l populations will change over time evolve as the environment nature favors selects features that enhance the ability to survive and reproduce Darwinian tness relative probability of survival and reproduction for a genotype 0 Considers viability and fecundity 0 Measures of Darwinian tness Absolute tness W of offspring an individual has Relative tness w tness of an individual relative to some other individual usually the most t individual in the population 0 Applied to genotypes absolute tness for AA genotype WAA average of offspring left by individuals with that genotype 0 how allele frequencies can change over time when different genotypes have different tnesses natural selection relative contribution of each genotype to gene pool tness x frequency don t sum to 1 rescale by dividing by sum of all 3 l expected freq of genotype that contribute to gene pool 0 freq of alleles in next generation difference bw p and p o plot p by time measured in of generations t l tempo allele freq change inder natural selection dom allele rises rapidly then plateau slowly approach xa on once dom allele at high freq unfavored recessive allele occurs mostly in heterozygotes selection ineffective at purging it from population favored recessive rises slowly in freq the rapidly approaches xation Forms of selection Directional selection changes the frequency of an allele in a constant direction either toward or away from xation for that allele 0 Positive selection favorable allele is brought to a higher frequency in a population bc individuals carrying that allele have more viable offspring than other individuals 0 Purifying selection removes deleterious variants of a DNA or protein sequence thus reducing genetic diversity Balancing selection Natural selection that results in an equilibrium with intermediate allele frequencies o If the heterozygous class has a higher tness than either of the homozygous classes then natural selection will favor the maintenance of both alleles in the population Diff forms of selection leave distinct signature on DNA seq near target locus in a population 0 Positive selection detected in DNA aeq by its effects on genetic diversity and LD lower diversity and higher LD near the target 0 Directional selection causes a loss of genetic variation in the region surrounding the target locus balancing selection can prevent the loss of diversity by random genetic drift leading to regions of unusually high genetic diversity in the genome Arti cial selection Breeding of successive generations by the deliberate human selection of certain phenotypes or genotypes as the parents of each generation Balance bw mutations and selection The amount of genetic variation in populations represents a balance between opposing forces mutation and migration which add new variation versus drift and selection which remove variation Balancing selection also serves to maintain variation in populations As a result of these processes allele frequencies can reach equilibrium values explaining why populations often maintain high levels of genetic variation Genetics a study of genes at all levels from molecules to populations 0 key to genetic analysis to examine the effects of mutations UNIT 1 Transmission genetics identifying and discovering genes specifying developments 1 how are genes identi ed Finding mutants and controlled mating key to genetic analysis to examine effects of mutations diff bw mutant and WT 0 mutant less popular WT more popular 2 principles of gene inheritance chromosomal bias 0 genes distributed thru inheritance of chromosomes 0 a 1 case of single gene inheritance including sex linked trait and pedigree analysis 0 b 2 or more single gene inheritances dihybrid trihybrid etc 0 giving up chi square table and formula given on test know how to use it nd out p value gtlt 5 o c organelle genes maternal inheritance o distinguish on pedigree analysis 0 maternal inheritance only females have a mutation 0 could be mitochondria or chloroplasts be clear on 9331 l dihybrid cross 0 what testing when performing dihybrid cross 0 test cross 3 locating eukaryotic genes by recombination mapping 0 a crossing over produces recombinants 0 further apart 2 genes are on chromosome l more recombinants recombinants always less than nonrecombinants 0 frequency map unit 3point test cross chi square test 0 b mapping with molecular markers 0 SNP 0 Molecular marker can be used to predict disease if conservatively linked to mutation 0 Use molecular marker as starting point to map genes esp if linked 4 genetic transmission in bacteria and their virus 0 a conjugation b transformation via a bacteria phage c transduction F factor can have regional diploidy 5 gene interactions bW 2 alleles of the same gene 0 a aeic o dominant recessive codominance incomplete dominance dominant negative haplosuf cient haploinsuf cient bc genes 0 b interactions of genes in biological pathways 0 1gene1polypeptide hypothesis 0 complementation test 0 heterokaryon c epistasis OOOOOO UNIT 2 From DNA to phenotypes 6 DNA structure and replication RS strain fatality in mice experiment con rms DNA genetic material Wilkinson 0 Copying mechanism complementary base pairing important bc allows DNA to be heritable with very little mistake Be able to distinguish picture of DNA and RNA 0 Identify C2 attached to OH group or 0 Diff bc have diff sugar backbone 7 RNA transcription and processing 0 how does ce know where to start promoter sequence speci c 0 10 35bps need to know the reading frame UAG stop codon Will give table of genetic code 0 Only eukaryotes have processing 0 How distinguish bw intron and exon 8 Proteins and their synthesis 9 regulation of gene expression in prokaryotes bacteria ac operon cAMP positivenegative regulation 10 regulation of gene expression in eukaryotes yeast GAL4 UASs chromatin remodeling histone code GAL4 transcription factors that interacts with many GAL genes that are in pathway of breaking down galactose for energy 0 How does it interactcontrol other genes By binding to upstream activating sequence enhancer l turn on gene 11 genetic control of development Drosophila Hox genes toolkit genes Hox genes determine body segments Bicoid gene gap gene 12 Genomes and genomics physical mapping sequence map bioinformatics comparative and functional genetics shotgun method contig sequencing analysis 0 indentify coding regions then which are promoters etc codon bias reading frame depends on which nucleotide you start on UNIT 3 Mutation Variation and Evolution 13 transposable elements makes up most of the eukaryotic genome and responsible for mutation prokaryotics transposons R plasmid eukaryotic transposons o classl retrotransposons 0 class 2 DNA transposons Ac and Ds elements in maize In Which autonomis p element in Drosophila how still read human DNA with 50 transposable elements 14 gene mutation mutation spontaneous induced repair recombination mutagens UV light Mutation causes change in DNA sequence 15 chromosome mutation largescale chromosomal changes number and structure euploidy polyploidy monoploid 16 genetic composition allele of populations and how they change over time HardyWeinberg equilibrium FST measure of genetics structure similaritiesdissimilarities bw populations how used to characterize differences 0 He used 1 example questions on it done in class 0 Linkage 17 Quantitative traits inheritance environmental factors 0 continuous variation heritability broad and narrow sense 18 evolution 0 a sorting process 0 natural selection Dawinian Evolution 0 Origin of new genes Speciation DON T worry about Ch 19 math problems 0 Just look at what was done in class QUIZ 5 1 Gene or trait said to be poly morphic if 0 More thn 1 form exists in population 2 Population genetics concerned with o How genes confer relative reproductive success on the individuals Whtehr allele freq are changing over time 3 Inbreeding in populations that are normally outbreeding leads to which 0 More individuals affects by rare diseases 4 If mating occurs solely bw relatives eventually what will happen to the population o It will become completely homozygous o Directional selection 5 What is the ultimate source of all genetic variation Mutation 6 In a randomly mating lab population of drosophila 4 of ies have black bodies encoded by autosomal recessive b and 96 have brown bodies WT encoded by B If this population is assumed to be in HW equilibrium then what are the genotypic freq of BB and Bb Freq BBO64 and BbO32 7 SNPs can have a max of 4 alleles at any 1 locus DNA sequences with SNP at 1 locus o AAGGCCAT o AGGGCCAT 0 ACGGCCAT 0 ATGGCCAT 8 polyploidy that occurs in nature is thought to be a driving force behind evolution and is basis for many examples of speciation 9 a likely explanation for abnormal human phenotypes associated with trisomies is altered gene dosage 10 trisomy is an example of aneuploidy 11 1 of the primary reasons some allopolyploid organisms are fertile and able to propagate is chromos set from each parent species present in allopolyploids able to synthesize Ch 20 questions will be similar questions on test explains quantitative variation by proposing that traits are controlled by a large number of genes each with a small effect on the trait When the trait value for the heterozygous class at a QTL is exactly intermediate between the trait values for the two homozygous classes when the trait value for the heterozygous class at a QTL is equal to the trait value for one of the two homozygous classes Gene action under which the phenotype of heterozygotes is intermediate between the two homozygotes but more similar to that of one homozygote than the other Quantitative trait locus QTL mapping is a procedure for identifying the genomic locations of the genes QTL that control variation for quantitative or complex traits QTL mapping evaluates the progeny of controlled crosses for their genotypes at molecular markers and for their trait values If the different genotypes at a marker locus have different mean values for the trait then there is evidence for a QTL near the marker Once a region of the genome containing a QTL has been identi ed QTL can be mapped to single genes using congenic lines Geneinactivating mutations may occur and rise to high frequency when habitat or lifestyle changes relax natural selection on traits and underlying gene functions circumvent the pleiotropic effects of mutations in the coding sequences of genes that have multiple roles in development
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