From Proteins to Phenotypes
Chapter 10
10.1 Proteins Are the Link Between Genes and the Phenotype
! Proteins are the end product of the gene expression pathway
! Proteins link genes and phenotype • Involving cell structure, metabolic reactions,
hormonal responses, cell-to-cell signaling systems, and the immune system
Mutant Gene Products
! Some genes encode proteins that act as growth hormones, receptors, and growth factors
Keep In Mind
! Phenotypes are the visible end product of a chain of events that starts with the gene, the mRNA, and the protein product
10.2 Enzymes and Metabolic Pathways
! Biochemical reactions in the cell are linked together to form metabolic pathways
! Mutations that block one reaction in a pathway can produce mutant phenotypes in several ways
Enzymes, Substrates, and Products
! Substrate • The specific compound acted on by an enzyme
! Product • The specific compound that results from
enzymatic action
! A chemical compound can be the product of one reaction and the substrate for the next reaction
Metabolism
! Metabolism • The sum of all biochemical reactions by which
cells convert and utilize energy
A Metabolic Reaction
! Enzyme, substrates, and product
Reactions in a Metabolic Pathway Genetic Disorders and Metabolism Are Related
! Inborn error of metabolism • The concept advanced by Archibald Garrod that
many genetic traits result from alterations in biochemical pathways
An Inborn Error of Metabolism
! Alkaptonuria • An autosomal recessive trait with altered
metabolism of homogentisic acid • Affected individuals do not produce the enzyme
needed to metabolize this acid, and their urine turns black
Alkaptonuria: Metabolic Pathways of Phenylalanine
Fig. 10-4b, p. 234
10.3 Phenylketonuria (PKU): A Mutation That Affects an Enzyme
! Phenylalanine is an essential amino acid and the starting point for a network of metabolic reactions
! Essential amino acids • Amino acids that cannot be synthesized in the
body and must be supplied in the diet
Phenylalanine Metabolism and PKU
! A mutation in a gene encoding the enzyme that controls the first step in the breakdown of phenylalanine causes phenylketonuria (PKU)
PKU
! Phenylketonuria (PKU) • An autosomal recessive disorder of amino acid
metabolism that results in mental retardation if untreated
! The phenotype is caused by the buildup of phenylalanine and the products of secondary reactions
PKU and Other Disorders of the Metabolic Pathways of Phenylalanine PKU Can Be Treated With Diet
! Infants with PKU can develop normally before birth, then develop neurological damage when fed a diet containing protein
! A PKU diet must contain phenylalanine levels high enough for normal development, but low enough to prevent mental retardation
Genetic Journeys: Dietary Management and Metabolic Disorders
! For PKU, a formula is prepared from enzymatically digested proteins (or synthetic mixtures of amino acids), fats, carbohydrates, and vitamin and mineral supplements
! A typical lunch might include vegetable soup, crackers, fruit cocktail, and formula
Screening Newborns for PKU
Keep In Mind
! Phenylketonuria and several other metabolic disorders can be treated by dietary restrictions
What Happens When Women With PKU Have Children?
! A pregnant woman with PKU who eats a normal diet has high levels of phenylalanine in her blood
! Excess phenylalanine does not affect the mother because her nervous system has already formed
! Phenylalanine crosses the placenta and damages the fetus, no matter what its genotype is
10.4 Other Metabolic Disorders in the Phenylalanine Pathway
! The mutation that results in PKU is only one of several genetic disorders caused by the mutation of genes in the phenylalanine pathway
! Others include defects of thyroid hormone, albinism, and alkaptonuria, the disease investigated by Garrod
10.5 Genes and Enzymes of Carbohydrate Metabolism
! Mutations in genes encoding enzymes can affect the metabolic pathways of other biological molecules, including carbohydrates
! Galactosemia is a genetic disorder caused by lack of an enzyme in sugar metabolism
! Liver failure, brain damage, cataracts and infant death are the consequences if not treated
Monosaccharides and Disaccharides Galactosemia is Caused by Enzyme Deficiency
! Galactosemia • A heritable trait associated with the inability to
metabolize the sugar galactose • If left untreated, high levels of galactose-1-
phosphate accumulate, causing cataracts and mental retardation
• Dietary treatment does not prevent long-term complications
Chr 9p13
Galactosemia and Inheritance
! Galactosemia is an autosomal recessive disorder with a frequency of 1 in 57,000 births
! Galactosemia is a multiple-allele gene system • Normal allele G, recessive allele g, and the
Duarte allele GD with half normal enzyme activity
Multiple Alleles of Galactosemia
Lactose Intolerance
! Levels of lactase (the enzyme that digests lactose) drop off during middle to late childhood
! Lactose intolerance is not a genetic disorder but a genetic variation that affects millions of adults worldwide
Metabolic Pathway of Lactose and Galactose
Inherited Diseases of Glycogen Metabolism 10.6 Mutations in Receptor Proteins
! Defects in receptor proteins, transport proteins, structural proteins, and other nonenzymatic proteins can cause phenotypic effects in the heterozygous state • Many show an incompletely dominant or
dominant pattern of inheritance
! Mutations in receptor proteins cause familial hypercholesterolemia
Heritable Traits Caused by Defective Receptors
10.7 Defects in Transport Proteins: Hemoglobin
! In 1949, James Neel identified sickle cell anemia as a recessively inherited disease caused by a mutation in a gene encoding beta globin
! Beta globin is a component of hemoglobin, a quaternary protein that transports oxygen from the lungs to cells and tissues of the body
Studies of Sickle Cell Anemia
! Sickle cell anemia was the first example of inherited variation in protein structure • First direct proof that mutations result in a change
in amino acid sequence in proteins • Evidence that a change in a single nucleotide can
cause a genetic disorder
! Molecular organization of globin gene clusters shows how gene expression is regulated
A Heme Group
! In hemoglobin, each heme carries an iron atom which binds oxygen for transport to cells
Hemoglobin and Sickle Cell Mutation
! The location of the mutation in beta globin responsible for sickle cell anemia
The Alpha-Globin Cluster
! Two copies of alpha-globin genes, the zeta gene, and pseudogenes
The Beta-Globin Cluster
! Some genes are active in fetal development, some are transcribed after birth
Epsilon hemoglobin: expressed during embryogenesis Fetal hemoglobin: 2 alpha, 2 gamma subunits
Pseudogenes
! Pseudogenes • Nonfunctional genes that are closely related (by
DNA sequence) to functional genes present elsewhere in the genome
Two Categories of Genetic Disorders of Hemoglobin
! Hemoglobin variants • Alpha and beta globins with variant amino acid
sequences • More than 400 hemoglobin variants identified
! Other mutations cause thalassemia • An imbalance in production of globins, which
affects transport of oxygen within the body
Beta Globin Chain Variants
Sickle Cell Anemia: An Autosomal Recessive Trait with Many Symptoms
Sickle Cell Anemia: An Autosomal Recessive Trait with Many Symptoms
A Single Amino Acid Substitution in HbS Thalassemias: Another Inherited Hemoglobin Disorder
! In thalassemia, synthesis of alpha or beta globin is reduced or absent • Usually, equal amounts of alpha and beta globin
are produced
! Thalassemias • Disorders associated with an imbalance in the
production of alpha or beta globin • Effects on oxygen binding can be lethal
Alpha and Beta Thalassemia
! Alpha thalassemia • Genetic disorder associated with an imbalance in
the ratio of alpha and beta globin caused by reduced or absent synthesis of alpha globin
! Beta thalassemia • Genetic disorder associated with an imbalance in
the ratio of alpha and beta globin caused by reduced or absent synthesis of beta globin
Thalassemias
Deletions of Alpha-Globin Genes in Alpha Thalassemia
Treating Hemoglobin Disorders Through Gene Switching
! Fetal hemoglobin has two alpha globins and two gamma globins • Gamma globins, part of the beta cluster, are
switched off at birth, and beta gene is activated
! Treatment with an anticancer drug, hydroxyurea, reactivates gamma genes • Fetal hemoglobin reappears in red blood cells • Sodium butyrate also switches on the synthesis of
fetal hemoglobin
Globin Gene Expression During Development 10.8 Pharmacogenetics
! Individual differences in reactions to therapeutic drugs represent a “hidden” set of phenotypes that are not revealed until exposure occurs
! Understanding the genetic basis for these differences is the concern of pharmacogenetics and may lead to customized drug treatment for infections and other diseases
Pharmacogenetics
! Pharmacogenetics • A branch of genetics concerned with inheritance
of differences in the response to drugs
! Variations in the amino acid sequences of proteins affect the way individuals react to prescription drugs and chemicals in the environment
Genetic Differences in Ability to Taste
! PROP compounds (related to PTC) in kale, cabbage, broccoli and Brussels sprouts taste bitter to some people
PTC tasters may avoid strong tastes including cigarettes and coffee
PTC tasters (Tt), non tasters (tt) and super tasters (TT) Taste Receptor Anatomy
Is there a link between PTC non-tasters and obesity? Genetic Differences in Ability to Smell
! Two-thirds of people tested could smell pink flowers but not red ones; the rest could smell red flowers but not pink ones
Drug Sensitivities are Genetic Traits
! Succinylcholine sensitivity • Having a form of serum cholinesterase that
breaks down the anesthetic very slowly
! Gene variations and breast cancer therapy • Estrogen sensitivity is treated with tamoxifen • Women with poor tamoxifen metabolism have
higher risk of recurrence
• Tamoxifen is also used to treat gynecomastia, it is an estrogen antagonist
Pseudocholinesterase sensitivity leads to slower metabolism of certain anesthetic drugs
Pseudocholinesterase Deficiency
Leads to anesthesia sensitivity. The enzyme normally breaks down choline ester drugs.
Keep In Mind
! Small differences in proteins can have a large effect on our ability to taste, smell, and metabolize medicines
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