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This 15 page Class Notes was uploaded by Sarina Scott on Wednesday September 16, 2015. The Class Notes belongs to Bio 0041-01 at Tufts University taught by Ekaterina Mirkin in Summer 2015. Since its upload, it has received 139 views. For similar materials see General Genetics in Biology at Tufts University.
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Date Created: 09/16/15
General Genetics BIO41 Ekatarina Mirkin Week 1 090815 091415 I Mendel and the History of Genetics a Gregor Mendel s genetic work quotExperiments in Plant Hybridization was rst published in 1866 b Following a failed attempt to replicate his experiment with hawkweed a suggestion from botanist Karl Wilhelm von Nageli Mendel ended his scienti c work c 30 years after Mendel published his work three scientists gave credit to Mendel and his genetic laws in their publication Mendel s failed attempt was disproved when these scientists discovered hawkweed reproduces via parthenogenesis rather than sexual reproduction ll Mendel s Experiment a Mendel grew many generations of pea plants to produce pure breeding strands in which each successive generation was identical for a speci c characteristic b Mendel genetically crossed pea plants via i Self fertilization both female and male gametes are sourced from the same plant ii Cross fertilization female and male gametes are sourced from two different plants 1 Mendel crossed two truebreeding parents via cross fertilization to produce a hybrid progeny which phenotypically resembled only one truebreeding parent c Mendel analyzed each cross using seven characteristics ie seed color each with two alternative traits ie green OR yellow III i P monohybrid crossfertilization between two pure breeding parents with alternate traits for only one characteristic 1 Yellow X green ii F1 rst lial generation of hybrid progeny all progeny phenotypically resemble one parent 1 All yellow progeny yellow trait is dominant green trait is recessive hiding iii F2 second lial generation of progeny resulting from self fertilization of F1 generation 1 Progeny showed 31 yellowgreen phenotypic ratio 2 Recessive green trait reappeared in F2 generation l this information allowed Mendel to conclude that the green trait was present in F1 however it was hiding and thus Each individual carries two copies of a unit of inheritancequot one copy from the maternal parent and the other from the paternal parent Generatien Parental Fl 0 ipilrelireetling r ellew peae it pellen I Green eae lg 99951 Firel filial Fa all game Selffriilizaiien Seeencl filial F21 eeee yellew elem reen IV 31 De nable terms a b C Gene unit of inheritance pea color gene Alleles alternative forms of a single gene Y Yellow y green Homozygote individual with identical alleles of a gene P YY and yy Heterozygote individual with different alleles of a gene F1 Yy e Genotype genetic makeup of an individual the pair of alleles present in an individual f Phenotype an observable characteristic g Dominant allele allele which determines the phenotype of heterozygote Y Yellow h Recessive allele allele that is phenotypically hidden in the heterozygote y green 1 Monohybrids individuals heterozygous for one gene F1 generation j Monohybrid cross cross involving hybrids for a single trait IV Law of Segregation a Mendel s 1St Law The two alleles for each trait segregate during gamete formation each gamete receives only one allele then during fertilization pollen unites at random with an egg thus giving the zygote two copies of the gene for each trait a The tare alletea fer eaeti trait eeparate during gamete termatien 39EEJJT39I EE39S pellen er egga I tr rewe inteelant 7 atnete we t r39 7 terni atien quotquotEm A Wyellew pea team a eLIrelireetling 7 1 eteelt r a 3quot M39Ii l n 39FP L rewe inteelant i Garnete A 39 termatien We 7 is green nee l treln a pLIrelireetling etaelt ti Twe ga metea ene treln eaeti parent unite at ranttem at tertilieatien Gainetee Zygete F1 Hybrid ene pellen grain ene egg i t Eed 1w FEI liliEEL EiDH 5 CIEtJEIDplT39IEI Il 39 a we ra all g ellaw pa ehewing dentinant trait 39r galleriadetermining allele ef pea eeler gene i J Jrentleterrnining aIIIe at pea eelar gene b The Punnett square i In 1906 a British mathematician developed a way to illustrate all possible combinations that could arise from ii iii the segregation and random union of alleles during gamete formation and fertilization Punnett square The Punnett square allows us to visualize Mendel s famous 31 ratio observed in the F2 generation NH P a 11 C ametes l l f REE quoti l or quot Pollen if grain 12 12 FE Each box Eggs quot 2 12 151 mmioJ a 912 ll j 5129quot F1 all identical l 24 Truebreeding P generation plants can both only produce one type of gamete YY I Y yy I y These gametes combine to produce an identical heterozygous F1 progeny Yy Each F1 monohybrid produces an equal ratio of gametes 12 with Y allele 12 with y allele F1 gametes combine to produce F2 progeny with a genotypic ratio of 121 YYYyyy and phenotypic ratio of 31 Yellowgreen Testcross mating method used to determine an unknown genotype in which an individual eXpressing the dominant phenotype genotype AA or Aa is crossed with a homozygous recessive individual aa 1 The phenotypic results of the testcross will determine the genotype of the dominant parental phenotype in question Cross ill Brass 3 o x o a 0 r1 r1 F1 r a F1 5 39 KLquot klquot Va 7 x 3 U 2 D spring all yellow ffspring 11 yellowto green a Progeny all exhibit dominant phenotype I P AA b 12 progeny exhibit dominant 12 exhibit recessive I P Aa V Mendel s 2r101 Law The Law of Independent Assortment a Mendel derived his rst law via the results of monohybrid crosses next he performed dihybrid crosses to derive his second law b Dihybrid cross cross between two truebreeding individuals both homozygous one dominant the other recessive for two genes YYRR x yyrr i Gene for seed color Y yellow y green ii Gene for seed shape R round r wrinkled c All dihybrid F1 progeny expressed both dominant genes and were then allowed to selffertilize to produce the F2 generation i Alleles in the F1 dihybrid cell Y y R r segregate independently to produce the allele combinations YR Yr yR yr present in the gametes Y is equally likely to be found with R or r and the same is true for y thus all four possible types of gametes are produced in equal frequency among a large population d The F2 progeny showed both parental types phenotypically similar to P generation and recombinant types new phenotypic combinations producing four phenotypic variations in a 9331 ratio i Examination of each individual gene shows a 31 ratio the same ratio Mendel s monohybrid cross proving that the alleles for the two alternate genes assort independently of one another 1 axe WHH mm ennetee v I r re 1 F1 gall identiealj 2e if We 11 Hr j r39 e 1 F2 134 1 I 111 111 I m 3 r39 Iquot I i EH H h 1 re are 11 Q3 r o o WEE W r 11111151151 111511quot KPH 1 a a W H W rr W Hr 1131 r em 1311 7 1 I 11 en we were we get394 39 a a a W 151139 W H Jr Fi r Jr 1139 quot Ejaeh hex r 114 H 121 1quot1E Type G enetyne henetype Number P39henetyrnir Fletie Parental r e yellew reLInrJ e15 ene Hecernhineni W e green reLmd 1133 3116 Fleeemninant 39r39 r yellew wrinkled 11311 3116 Parental War green wrinkled 32 1116 Ratie e1 yellew elelnin entj in green rec ee ewe 124 er 31 3 Retina e1 reLIncl rlerninent n te wrinkled ireeeeeiee 124 er 31 VI Rules of probability a Mendel s results and the crosses illustrated in a Punnett square re ect the basic rules of probability i Probability measure of the likeliness that an event will occur of ways an event can occur total of possible outcomes b Product AND rule the probability of two or more independent events occurring together is the product of the probabilities that each event will occur by itself ii iii iv Probability of event 1 and event 2 Probability of event 1 X probability of event 2 EX Two dice are rolled what is the probability of getting a four on two sequential rolls I 16 X 16 136 In genetics the formation of egg and pollen gametes are independent events and thus the probability of a particular genotype is the product of the probabilities that the maternal and paternal alleles will combine into a zygote The Punnett square illustrates the logic of the product rule however it is often not realistic to complete a full Punnett square and thus the product rule is a useful tool c Sum OR rule the probability of either of two such mutually exclusive events occurring is the sum of their individual probabilities i ii Probability of event 1 or event 2 Probability of event 1 probability of event 2 EX One die is rolled what is the probability of getting either a three or a four in one roll I 16 16 13 d Ordering of sequences i ii iii The probability of an event will differ based upon the speci cation of order when the order is speci ed only one possible scenario can occur but when order is not speci ed multiple scenarios can occur and thus the probabilities will differ Speci ed order If a couple has 4 children what is the probability of them having rst a girl and then three boys 1 12 X 12 X 12 X 12 116 NO speci ed order If a couple has 4 children what is the probability of them having a girl and three boys 1 The possible combinations are a G B B B l 116 b B G B B I 116 c B B G B I 116 d B B B G I 116 2 These are mutually exclusive events and thus we must add together the probability of all four scenarios 416 3 A simpli ed way of calculating the probability of a scenario with no speci ed order is to use the equation quYrZ nXyz a quYrZ probability of one scenario i p probability of individual in category 1 ii q probability of individual in category 2 iii r probability of individual in category 3 b nXyz number of scenarios i n total number of individuals ii X number of individuals in category 1 iii y number of individuals in category 2 iv 2 number of individuals in category 3 c For this example probability of one scenario 116 X number of possible scenarios 413 00625 X 4 025 VII Applying probability to Mendel s crosses a Using Mendel s laws of inheritance and the mathematical rules of probability we can predict and calculate the results of compleX genetic crosses without using a Punnett square i EX hybrids that are heterozygous for four traits are allowed to self fertilize Aa Bb Cc Dd what proportion of the progeny will have the genotype AA bb Cc Dd b First analyze the problem by separating the multihybrid cross into four independently assorting monohybrid crosses keep in mind Mendel s genotypic ratios for a monohybrid cross 1AA 2Aa 1aa c NeXt multiple the probability of each independent event AA 14 bb 14 Cc 24 Dd 24 I 14 X 14 X 24 X 24 4256 164 VIII Molecular In uence on phenotype and dominancerecessiveness a Genes are responsible for encoding an organism s proteins and those proteins dictate cellular structure function We now know that the ability of one allele of a particular gene to dominate over its alternative recessive allele is due to its ability to encode a functional protein i Pea shape gene specifies for Sbel starchbranching enzyme 1 which catalyzes the conversion of amylose to amylopectin 1 Dominant R allele encodes normal functioning Sbel enzyme 2 Recessive r allele specifies NO Sbel enzyme causing rr organisms to shrink and wrinkle as they mature 3 Heterozygous Rr plants produce enough normal enzyme to prevent wrinkling ii Pea color gene specifies for Sgr stay green enzyme which leads to the breakdown of chlorophyll 1 Dominant Y allele produces Sgr causing the peas to turn yellow 2 Recessive y allele does NOT produce Sgr and no breakdown of chlorophyll occurs causing the pea to be green in color 3 Heterozygous Yy peas have enough Sgr to break down chlorophyll and thus turn a yellow color Essential Concepts Mendel established purebreeding lines of peas in which a speci c characteristic remained constant from one generation to the next When Mendel crossed purebreeding lines with alternative traits the hybrid progeny always had the characteristics of one parent Discrete units called genes control the appearance of inherited traits genes come in alternative forms called alleles A sexually reproducing organism s body cells contain two alleles for every gene These alleles may be the same homozygote or different heterozygote Genotype refers to the alleles an individual possesses phenotype refers to the trais the individual eXhibits 10 In monohybrid crosses between heterozygotes the dominant and recessive phenotypes will appear in the progeny in a ratio of 31 Alleles segregate during the formation of gametes which thus contain only one allele of each gene Male and female gametes unite at random at fertilization Mendel described the operation of these processes as the law of segregation The segregation of alleles of any one gene is independent of the segregation of the alleles of other genes Menden termed with principle the law of independent assortment According to this law crosses between Aa Bb dihybrids will generate progeny with a phenotypic ratio of 9 A B 3 A 1919 3 aa B 1 aa 1919 The most common eXplanation for why one allele of a particular gene is dominant and an alternative allele is recessive is that the dominant allele encodes a function product a protein while the recessive allele determines either a less functional or nonfunctional version of the protein or no protein at all ChiSquare Test and Pedigree Analysis Ch 23 54 Mendel s rules of inheritance provided mathematical ratios allowing us to predict the outcomes of genetic crosses and thus determines whether two or more genes assort independently or are genetically linked The only drawback to this method of conclusion is that real world genetics are based on chance events and thus will include some amount of deviation from the theoretical predicted values To determine independent assortment vs genetic linkage in realworld eXperiment statisticians devised a method to evaluate the statistically acceptable uctuation from the mean values a ChiSquare quotgoodness of fit test probabilistic test that measures how well the experimentally observed results conform 11 to the predicted values way to quantify the likelihood that an experimentally observed deviation from the predictions of a particular hypothesis have occurred solely by chance i Chisquare values are calculated with numbers NOT percentages this allows the test to account for the sample size b To perform a chisquare test i ii iii iv vi Determine the null hypothesis a statistical hypothesis to be tested and either accepted or rejected in favor of an alternative 1 EX the genes are independently assorted therefore the eXpected ratio is 1 2 1 Calculate the eXpected values based on the null hypothesis Calculate the chisquare value 1 X2 Z OE2E 2 O observed value E eXpected value Calculate df degrees of freedom number of terms n 1 1 df measure of the number of independently varying parameters Calculate pValue from the given table 1 p probability that deviation is due to chance alone 2 Cutoff p 005 p 39Ih39inlus Ea rm at E l i the Hull Hypmhasls 05 o50 01 l f Valuing mm m 059 13115 1101 Fradnm 39 Ill L45 23quot 354 EH I102 021 135 461 59g Ill 053 23 6125 l ll TITLES I130 LEI E ll I th I155 15 435 924 TITLE 1 l l 335 33 l 151119 39ulll Hypnihul FilletIII 4001 4153 HE EEF EA Decide if you reject or fail to reject the null hypothesis 1 If p lt 005 I reject null hypothesis deviation of observed value from eXpected value is statistically II 12 signi cant and due to something other than chance alone 2 If p gt 005 l fail to reject null hypothesis deviation is not statistically signi cant and is due to chance alone a Chisquare test is a quotgoodness of t and determines the probability that a deviation could have occurred due to chance alone however it does not prove linkage or its absence and thus you cannot accept the null hypothesis vii Example Fmgeny lasses l l Experimen l l Exprlmnt l 121 E1 EFIEI El E EllEFiE AB 13 12 35112 3E 141112111 Parentala an 14 12 4112 2 113124 Ali 1quot 12 95112 14 Reenmhi ams s a 12 9112 1 211 11131211 Fatal 1B H112 BE 4 I a1 112 1211 1 til 3 p 121112 pl 1 11111 Mendelian Inheritance in Humans a Most heritable human traits are compleX traits and do not eXpress a simple Mendelian pattern of inheritance many human phenotypes are in uenced by the interaction of multiple genes b Alternately human traits in uenced by a single gene are often characteristic of diseases resulting from a single mutation i The majority of the human disease alleles are recessive due to 1 Molecular logic gene mutation results in the sick phenotype due to the presence of a nonfunctional protein heterozygote produces enough functional protein from one normal allele for healthy phenotype so disease allele is seen as recessive III 13 2 Selection the recessive deleterious allele stays within the population due to its ability to hide in a heterozygote and thus the mutant allele cannot be eliminated from the population ii Example Cystic brosis caused by recessive allele 1 Cystic brosis is caused by a recessive mutation in the CFTR protein which regulates the passage of chloride ions across the cell membrane a CF CF or CF CF I normal phenotype i Heterozygote produces enough functioning protein to express the normal phenotype recessive allele b CF CF I sick phenotype iii Example 2 Huntington s disease caused by dominant allele 1 HD is a late onset dominant disease caused by a mutation in the Htt protein causing abnormal protein aggregates with a new function to form in the brain and cause serious neurological damage a HD HD l normal phenotype b HD HD or HD HD I disease phenotype 2 Due to the late onset of HD affected individuals often reproduce before symptoms of HD appear and thus pass the sick allele to their offspring therefore the mutant allele is not eliminated from the population via selection Pedigrees a Although Mendel s laws apply to humans determining a genetic defect s pattern of transmission in humans is difficult due to 1 long generation time 2 small numbers of progeny 3 absence of controlled mattings and 4 absence of purebreeding lines I instead we can use Mendel s laws to systematically analyze a pedigre an orderly diagram of a family s relevant genetic features extending through as many generations as possible b Interpreting a pedigree 14 D Male a 1i Female Unattenteri Se unapeeified I I Dieeaeeel E Deeeaeeel Multiple pl gEl ly D23 Eenaanguineeue mating Mating line Cteneratien l gimplip We a Line at rieeaent eneratien ll 1 t 2 lndieitlual number within generatien ii From a pedigree with sufficient information we can determine the mode of inheritance of a trait single vs multiple allele and dominant vs recessive allele C Dominant traits i The trait cannot skip a generation every affected child must have at least one affected parent ii Two affected parents can produce unaffected children both parents must be heterozygotes for this to occur iii Trait exhibits a vertical pattern of inheritance appears in every generation d Recessive traits i The trait can skip a generation heterozygous carriers hide the recessive allele ii Two affected parents cannot produce unaffected children e Rare recessive traits i Unaffected parents of an affected child must both be heterozygous carriers ii A horizontal pedigree pattern is a strong indication that the trait in questions in a rare recessive trait trait rst appears among several members of one generation and is not seen in earlier generation iii Can assume for rare recessive traits that individuals who marry into the family are not a carrier of the mutation if 1 they are not related to the family and 2 they are not phenotypically affected I have AA genotype Essential concepts 15 A null hypothesis is a model that leads to a discrete numerical prediction The chisquare test helps determine whether two genes are linked by comparing differences between the numbers of progeny of different classes observed in an eXperiment and the numbers of progeny of these classes eXpected from the null hypothesis that genes are unlinked and thus assort independently The probability value p measures the likelihood that deviations from the predicted values have occurred by chance alone the null hypothesis is rejected with p lt 005 In a vertical pattern of transmission a trait that appears in an affected individual also appears in at least one parent one of the affected parent s parents and so on If a trait is rare a pedigree with a vertical pattern usually indicates that the diseasecausing allele is dominant In a horizontal pattern of transmission a trait that appears in an affected individual may not appear in any ancestors but it may appear in some of the persons s siblings A pedigree with a horizontal pattern usually indicates a rare recessive diseasecausing allele Affected individuals are often products of consanguineous mating Recessive disease alleles like the CF alleles that cause cystic brosis usually specify either no protein or lessfunctional versions of the protein that the normal dominant allele produces Dominant disease alleles may have a number of biochemical eXplanations In the case of Huntington disease the diseasecausing HD allele specifies an abnormal deleterious version of the protein produced by the normal recessive allele
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