06BIS1012012DomRecLect6

06BIS1012012DomRecLect6 - BIS101-001: Genes and Gene...

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Unformatted text preview: BIS101-001: Genes and Gene Expression Dominance and One Gene/One Enzyme Hypothesis Lecture #6 Chapter 4 03/19/12 BIS101001, Spring 2012--Genes and Gene Expression, R.L. Rodriguez 2012 1 Last Lecture Two genes close together on the same chromosome do not assort independently. New combinations of parental alleles can results from either inter- or intrachromosomal recombination. Pairs of homologous chromosomes can exchange segments of non-sister chromatids by crossing over. Gene loci on chromosomes can be mapped by measuring the frequency of recombination in meiosis Genetic map distances based on RF are roughly additive. The occurrence of a crossover can be influenced by a second cross nearby (interference). March 19, 2012 BIS101001, Spring 2012--Genes and Gene Expression, R.L. Rodriguez 2012 2 This Lecture One Gene-One Enzyme Hypothesis Inborn Errors of Metabolism. Molecular Basis of Dominant and Recessive Traits. Complete, Incomplete and Co-Dominance ABO Blood Groups Rh Disease 03/19/12 BIS101001, Spring 2012--Genes and Gene Expression, R.L. Rodriguez 2012 3 One Gene:One Enzyme Hypothesis Once it had been established that genes where located on chromosomes, a mechanism for how genes produce the phenotype needed to be established. The link between genotype and phenotype was first formally proposed by George Beadle and Ed Tatum in 1941 as the "One Gene -- One Enzyme Hypothesis. Beadle and Tatum used auxotrophs and prototrophs of the bread mold Neurospora crassa. 03/19/12 BIS101001, Spring 2012--Genes and Gene Expression, R.L. Rodriguez 2012 4 One Gene -- One Enzyme Hypothesis Gene 1 Gene 2 Gene 3 Enzyme 1 Enzyme 2 Enzyme 3 Precursor P Intermediate Q Intermediate R Product S (S can be any compound that produces a discernible phenotype such as eye or skin color, flower color or black urine) "The synthesis or degradation of any substrate proceeds as a stepwise sequence of reactions catalyzed at each point by a specific enzyme whose structure and activity is determined by a corresponding gene. Accordingly, the genotype determines the particular complement of enzymes available to an organism and thus determines the biochemical phenotype and through it, the morphological phenotype." Beadle & Tatum 03/19/12 BIS101001, Spring 2012--Genes and Gene Expression, R.L. Rodriguez 2012 5 One Gene -- One Enzyme Hypothesis http://www.fgsc.net/Neurospora/sectionB2.htm Fig. 4.1, p.1253 03/19/12 BIS101001, Spring 2012--Genes and Gene Expression, R.L. Rodriguez 2012 6 One Gene One Enzyme Hypothesis The molecular basis for Mendel's round (R) and wrinkled (r) peas was discovered in 1991 when researchers identified a defective allele of the "starch branching enzyme 1" (SBE1). The rr genotype results in the accumulation of sucrose in early seed development which causes these seeds to wrinkle when they mature. 03/19/12 BIS101001, Spring 2012--Genes and Gene Expression, R.L. Rodriguez 2012 7 In Born Errors of Metabolism and Beadle Tatum Hypothesis In 1902, the English physician, Archibald Garrod discovered akaptonuria (AKU), the first human genetic disorder. After studying patients whose urine turned black after exposure to air, Garrod developed the concept of "inborn errors of metabolism". Garrod believed that AKU was due to a defect in a specific step in tyrosine metabolism, causing a buildup of homogentisic acid or homgentisate (also called alkaptone) in the urine of diseased patients. Garrod rightly concluded that this disease behaved as a recessive Mendelian trait. Garrod's observation anticipated Beadle and Tatum's One Enzyme/One Gene Hypothesis of by 40 years. 03/19/12 BIS101001, Spring 2012--Genes and Gene Expression, R.L. Rodriguez 2012 8 Alkaptonuria Pedigree In the pedigree on the right, alkaptonuria looks like an autosomal dominant defect. q it does does not skip a generation q one parent is affected and about half of the progeny are affected q the sexes are equally affected However, like most enzyme deficiency disorders, it is well documented that alkaptonuria is an autosomal recessive trait. This paradox can be resolved by collecting more data on the family. As can be seen on the right, there are two consanguineous matings in the pedigree making the pattern of inheritance consistent with an autosomal recessive trait. For rare, recessive traits, affected parents must be related in some way if they are to produce affected offspring. 03/19/12 BIS101001, Spring 2012--Genes and Gene Expression, R.L. Rodriguez 2012 9 Homogentisic Acid Pathway Ttr Gene Ppo Gene Hgo Gene Try transaminase p-OH-phenylpyruvate oxidase homogentisate 1,2 dioxygenase tyrosine p-OH-phenylpyruvate homogentisic acid maleylacetoacetate AKU is an excellent example of Beadle and Tatum's notion that our morphological phenotype is the result of our biochemical phenotype (page 124 in the text). In normal patients, homogentisic acid is converted to maleylacetoacetate (which does not turn black in air) by the pathway shown above. Noting that normal (homozygous wild type; AA) and carriers of the disease (heterozygotes; Aa) had the same phenotype, (i.e., normal urine), Garrod proposed that the AKU was due to the complete absence of Hgo gene in homozygous recessive individuals (aa). Heterozygous individuals expressed enough of the enzyme from the one normal allele to convert homogentisic acid to maleylacetoacetate. 03/19/12 BIS101001, Spring 2012--Genes and Gene Expression, R.L. Rodriguez 2012 10 The alkaptonuria gene (HGO) and its mutations In 1996, researchers cloned a human gene encoding the enzyme homogentisate 1,2 dioxygenase (HGO). They showed this this gene located on chromosome3 (3q21-23), corresponded to the AKU gene and that individuals with alkaptonuria had mutations in HGO . exons 03/19/12 BIS101001, Spring 2012--Genes and Gene Expression, R.L. Rodriguez 2012 11 Typical Genetic Counseling Problem A couple suspects they are carriers for Late Onset TaySachs, an autosomal recessive disease that appears between 20 and 30 years of age. The couple have 4 young children and want to know the following: What is the chance that their children will have the disease? What is the chance that their children will be unaffected or asymptomatic? What is the chance that an unaffected child will be a carrier? http://en.wikipedia.org/wiki/TaySachs_disease 03/19/12 BIS101001, Spring 2012--Genes and Gene Expression, R.L. Rodriguez 2012 12 Typical Genetic Counseling (Solution) A a Aa aa Parents Gametes Aa Aa 1/2 (a) 1/2 (A) A AA aA 1/2 (A) 1/2 (a) a Siblings Aa AA 1/2 (A) X 1/2 (A) = 1/4 or 25% aa 1/2 (a) X 1/2 (a) = 1/4 or 25% aa 1/2 (A) X 1/2 (a) = 1/4 or 25% + 1/2 (a) X 1/2 (A) = 1/4 or 25% 50% Unaffected sibs; 2/3 will be carriers 03/19/12 BIS101001, Spring 2012--Genes and Gene Expression, R.L. Rodriguez 2012 13 Inborn Errors of Metabolism (IBEMs) 188 "genetic diseases" (inborn errors of metabolism -- IBEM) have been identified. Since 1962, millions of infants have been screened for IBEMs Last year, 7 million US newborns were screened for from 4 to 46 IBEMs. 3000 infants were diagnosed with serious disorders Every state screens for PKU, galactosemia Dietary intervention is the preferred treatment for PKU and galactosemia. http://en.wikipedia.org/wiki/Newborn_screening http://www.aafp.org/afp/2006/0601/p1981.html 03/19/12 BIS101001, Spring 2012--Genes and Gene Expression, R.L. Rodriguez 2012 14 Defects in the Tyrosinase Gene on X Chromosome p OC Albinism q 03/19/12 BIS101001, Spring 2012--Genes and Gene Expression, R.L. Rodriguez 2012 15 Phenylalanine Pathway and Human Disease Phenylalanine phenylalanine hydroxylase phenylalanine transaminase Phenylpyruvic acid PKU tyrosinase Tyrosine tyrosine transaminlase 3,4-Dihydroxyphenylalanine OCA Melanin pigments p-Hydroxyphenylpyruvic acid p-hydroxyphenylpyruvic acid oxidase AKU Maleylacetoacetic acid homogentisate 1,2-dioxygenase 16 Homogentisic acid 03/19/12 BIS101001, Spring 2012--Genes and Gene Expression, R.L. Rodriguez 2012 One Gene-One Enzyme Hypothesis and Genetic Variation) Gene 1 Gene 2 Gene 3 Enzyme 1 Enzyme 2 Enzyme 3 Precursor P [Metabolite Q] [Metabolite R] [Product S] 03/19/12 BIS101001, Spring 2012--Genes and Gene Expression, R.L. Rodriguez 2012 17 Dominance/Recessive Molecular Basis of Dominance and Recessive 03/19/12 BIS101001, Spring 2012--Genes and Gene Expression, R.L. Rodriguez 2012 18 Molecular Basis of Dominance/Recessive 03/19/12 BIS101001, Spring 2012--Genes and Gene Expression, R.L. Rodriguez 2012 19 "R" Homozygous Dominant 03/19/12 BIS101001, Spring 2012--Genes and Gene Expression, R.L. Rodriguez 2012 20 "R" is dominant over "r" 03/19/12 BIS101001, Spring 2012--Genes and Gene Expression, R.L. Rodriguez 2012 21 Homozygous Recessive "r" allele 03/19/12 BIS101001, Spring 2012--Genes and Gene Expression, R.L. Rodriguez 2012 22 Molecular Basis of Dominance Garrod's conclusion that heterozygous individuals expressed enough HGO from the one normal allele to convert homogentisic acid to maleylacetoacetate was the first hint about how dominant and recessive genotypes are expressed. Shown below are the enyzme levels for two Drosophilia eye mutations (1 and 2) relative to wild type (wt). Notice that there is a threshold of enzyme (xanthine dehydrogenase) needed to produce red eyes (wt). Since heterozygotes of the two mutation exceed the threshold, they are recessive to the dominant wild type allele. 03/19/12 BIS101001, Spring 2012--Genes and Gene Expression, R.L. Rodriguez 2012 23 Molecular Basis of Dominance The amount of product made by an enzyme is generally proportional to the amount of enzyme present. Normal function is indicated by a hypothetical threshold for the level of product needed to produce a normal phenotype. When there is an excess of the enzyme, however, the amount of product made follows the law of diminishing return. As show in the next figure, some genetic diseases can be recessive (e.g., alkaptonuria) while others can be dominant. 03/19/12 BIS101001, Spring 2012--Genes and Gene Expression, R.L. Rodriguez 2012 24 Effects of Gene Dosage on Enzyme/Product Conc. Hypothetical Threshold for Normal Phenotype Phenotype proportional to conc. of enzyme product 0 A- AB- B03/19/12 Enzyme Concentration A- A+ B- B+ B+B+ 25 A+A+ BIS101001, Spring 2012--Genes and Gene Expression, R.L. Rodriguez 2012 Molecular Basis of Dominance When the amount of enzyme produced by the heterozygote (A+A-) is sufficient enough to generate adequate levels of enzyme product for normal function or the normal phenotype (i.e., haplosufficient), A+ is considered dominant over A- and Ais considered recessive to A+. When the amount of product made by the B-B+ heterozygote is not sufficient to achieve the threshold level (i.e., haploinsufficient), the defect B- is dominant to B+ and B+ is considered recessive to B-. In the case of A-A+, the wild type allele (A+) is dominant over the defective allele (A-) and A- is only observed in the homozygous recessive (A-A- or aa) condition. 03/19/12 BIS101001, Spring 2012--Genes and Gene Expression, R.L. Rodriguez 2012 26 Incomplete and Co-Dominance In some instances, there may be no threshold for a particular phenotype. Instead, phenotype can be directly proportional to the amount of enzyme product . This is known as incomplete dominance. Alternatively, both alleles of a gene may be active and reveal themselves in the heterozygote. This is called "codominance". 03/19/12 BIS101001, Spring 2012--Genes and Gene Expression, R.L. Rodriguez 2012 27 Incomplete and Co-Dominance 03/19/12 BIS101001, Spring 2012--Genes and Gene Expression, R.L. Rodriguez 2012 28 Codominance and PCR DNA Markers DNA parentage testing polymerase chain reaction and microsatellite fluorescently-labeled DNA markers M = Mother, C1-2 = Two Children, F1-2 = Two Alleged Fathers 03/19/12 BIS101001, Spring 2012--Genes and Gene Expression, R.L. Rodriguez 2012 29 Codominance A,B andO Blood Group Antigens The A,B,O blood group system is a classic example of co-dominance. O Rh-positive O Rh-negative A Rh-positive A Rh-negative B Rh-positive B Rh-negative AB Rh-positive AB Rh-negative ----------------38 percent 7 percent 34 percent 6 percent 9 percent 2 percent 3 percent 1 percent 03/19/12 BIS101001, Spring 2012--Genes and Gene Expression, R.L. Rodriguez 2012 30 ABO blood groups 03/19/12 BIS101001, Spring 2012--Genes and Gene Expression, R.L. Rodriguez 2012 31 Blood Donations and Transfusion Typically, each donated unit of blood, referred to as "whole A drop of whole blood blood" is separated into multiple components, such as red blood cells, plasma, platelets, and cryoprecipitated AHF (antihemophilic factors). Each component is transfused to individuals, depending on their needs. Serum is the clear, thin and sticky fluid portion of the blood that remains after coagulation. Serum contains no blood cells, platelets or fibrinogen. http://www.aabb.org/Content/About_Blood/Facts_About_Blood_and_Blood_Banking/aabb_faqs.htm#3 03/19/12 BIS101001, Spring 2012--Genes and Gene Expression, R.L. Rodriguez 2012 32 Codominance of ABO Blood Groups The A and B blood group antigens are sugar molecules (fucose and N-acetylgalactosamine) that are connected to proteins on the surface of the red blood cell. The human immune system will recognize these antigens as "self" and not develop antibodies to those antigens present. Therefore... Question; where are the antigens that produced the antibodies on the O type blood? Answer; common gut bacteria have surface sugars very similar to the A and B blood group antigens. The immune system makes antibodies to these Alike and B-like bacterial antigens. 03/19/12 BIS101001, Spring 2012--Genes and Gene Expression, R.L. Rodriguez 2012 33 Codominance of A/B blood group antigens A/B/O blood groups, both the IA and IB alleles are observed in the heterozygote. The IA and IB alleles code for different antigens (glycoproteins) displayed on the surface of the red blood cell. The (i) allele expresses no glycoproteins and produces the O blood group. As can seen at the right, the (IA) and (IB) and (i) result in six genotypes and four phenotypes. O group is called universal donor while the AB group is the universal recipient. 03/19/12 BIS101001, Spring 2012--Genes and Gene Expression, R.L. Rodriguez 2012 34 ABO Blood Groups and Blood Transfusions Universal donor Universal recipient 03/19/12 BIS101001, Spring 2012--Genes and Gene Expression, R.L. Rodriguez 2012 35 With the Rh factor, there are 8 blood types Rh (rhesus) factor is a protein on the surface of red blood cells (RBCs). Like the ABO system, people who are Rh+ (RR or Rr) do not make antibodies to this factor. Rh- (rr) individuals do not have antibodies to Rh but they can produce anti-Rh antibodies with exposure to the Rh+ blood. Unlike the ABO system, antibodies to Rh antigens don't develop naturally. They develop only as an immune response after a transfusion or during pregnancy. A+ AB+ BAB+ ABO+ O- + = RR or Rr; - = rr 03/19/12 BIS101001, Spring 2012--Genes and Gene Expression, R.L. Rodriguez 2012 36 Rh Disease If a mother is Rh- and the fetus in Rh+ (must be Rr) the mother can mount an immune response against the fetus if some of the fetal blood enters the mother's blood stream. This may happy upon deliver so the mother will have anti-Rh+ antibodies that can affect the next pregnancy. pennhealth.com/health_info/ pregnancy/000203.htm 03/19/12 BIS101001, Spring 2012--Genes and Gene Expression, R.L. Rodriguez 2012 37 Codominance Cross Match Blood for Transfusion Recipients with A+ blood can receive A+, A-, O+ and O- blood types Recipients with B+ blood can receive B+, B-, O+ and O- blood types Recipients with AB+ blood can receive AB+, AB-, A+, A-, B+, B-. O+ and O Recipients with O+ blood can receive O+ and O- blood types Recipients with A- blood can receive A- and O- blood types Recipients with B- blood can receive B- and O- blood types Recipients with AB- blood can receive AB- and O- blood types. Recipients with O- blood can receive O- blood type. http://www.oncologychannel.com/anemia/ 03/19/12 BIS101001, Spring 2012--Genes and Gene Expression, R.L. Rodriguez 2012 38 This Lecture One Gene-One Enzyme Hypothesis Inborn Errors of Metabolism. Molecular Basis of Dominant and Recessive Traits. Complete, Incomplete and Co-Dominance ABO Blood Groups Rh Disease 03/19/12 BIS101001, Spring 2012--Genes and Gene Expression, R.L. Rodriguez 2012 39 ...
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This note was uploaded on 03/18/2012 for the course BIS 101 taught by Professor Simonchan during the Winter '08 term at UC Davis.

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