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

10.9 Ecogenetics

!  Ecogenetics •  The study of genetic variation that affects

responses to environmental chemicals

!  Some individuals may be sensitive or resistant to environmental chemicals such as pesticides •  Important in research, medicine, and public policy