Ch24 Genetics and Genomics.docx

CHAPTER 24: GENETICS AND GENOMICS OBJECTIVES: 1. Define the term genetics. 2. Distinguish between a gene and a chromosome, and state how many of each humans possess. State what the abbreviation DNA stands for and give the function(s) of this macromolecule. Explain the following process: DNA (gene) ---> messenger RNA —>Protein List several functions that proteins serve and state which proteins are the most important. Define the term mutation and discuss at least three results that may occur due to a mutation. Explain what is meant by the term sexual reproduction. Distinguish between gametes and somatic cells in terms of their genetic makeup. Name the cell that results from fertilization of gametes and give its genetic makeup. Define the term meiosis and explain its significance. Explain what is represented in a human karyotype. Define the term homologous chromosomes, and explain what happens between homologous chromosomes during Prophase I of meiosis. Distinguish between autosomes and sex chromosomes, and state how many pairs of each humans possess. Define the term allele, and give an example that illustrates the distinction between a gene and an allele. Distinguish between a dominant and recessive allele of a gene pair and give an example of each. State the genetic makeup of an individual who is homozygous for a trait versus one who is heterozygous for a trait, both in words and using typical letters. 17. Explain the difference between the genotype and phenotype of a trait. 18. Illustrate a Punnett square and explain why it is used. 19. Given a similar problem to those below, be able to express the results both genotypically and phenotypically: a. Brown eyes are dominant over blue eyes. If an individual who is homozygous dominant for eye color is crossed with a blue-eyed individual, what are the expected results of their offspring? b. Widow’s peak is dominant over straight hairline. If an individual who is heterozygous for hairline is crossed with an individual with a straight hairline, what are the expected results of their offspring? 20. List the three major modes of inheritance and name a disease that results from each. 21. Given a similar problem to those below, be able to express the results both genotypically and phenotypically: a. Cystic fibrosis follows autosomal recessive inheritance. If parents have a child afflicted with CF, what are the chances that their next child will be afflicted with the disease? b. Huntington’s Disease follows autosomal dominant inheritance. If a normal individual and a person carrying the HD allele become pregnant, what are the chances that this child will be afflicted with the disease? 22. Explain how sex is determined in humans. 23. Discuss the characteristics of sex-linked traits and name a disease that is transmitted in this fashion. 24. Define the term aneuploidy, explain how it may occur, and name the most common condition that results from aneuploidy in humans. 25. Define the term genomics and name the key difference between genomics and genetics. 26. Name the tests that can be performed prenatally to determine many genetic disorders. 27. Explain why genetic counseling would be useful for some couples. 28. Define the term gene therapy and discuss its significance in treating human disease. 29. Define and compare the terms: incomplete dominance and codominance; penetrance and expressivity; pleiotropy and heterogeneity; polygenic and mulitfactorial. THE EMERGING ROLE OF GENETICS AND GENOMEICS IN MEDICINE Genetics, the study of inheritance, will play a critical role in future health care and medicine. The human genome project has triggered numerous genetic discoveries since its advent. New genetic information has allowed for the explanation of several physiological processes, both at the cellular & molecular level. In this chapter we will study the science of genetics and discuss inheritance patterns using specific diseases as examples. We will also discuss the new emerging science of genomics, which looks at the human body in terms of multiple, interacting genes. GENETICS BACKGROUND WHAT IS GENETICS? Genetics is the study of INHERITANCE AND VARIABILITY. The term "genetics" is derived from the word "GENE". WHAT IS A GENE? (Review from Chapter 4) A gene codes for a particular heritable trait (or protein). i.e. blood type, hair color, eye color etc. Genes are carried on CHROMOSOMES that are composed of DNA (Deoxyribonucleic acid). See Fig 24.1, page 921. A GENE (composed of DNA) is the portion of a chromosome that codes for a particular heritable trait (or protein). More specifically, GENES TELL OUR CELLS WHICH PROTEINS TO MAKE. PROTEINS HAVE MANY IMPORTANT FUNCTIONS!!!! structure (Example = _____________________) transport (Example = _____________________) movement (Example = _____________________) chemical messengers (Example = _____________________) defense (Example = _____________________) ENZYMES. DNA HOLDS THE CODE FOR EVERY PROTEIN THAT MAKES US AND ALLOWS US TO FUNCTION! I. THE EMERGING ROLE OF GENETICS AND GENOMEICS IN MEDICINE A. GENETICS BACKGROUND 2. WHAT IS A GENE? If there is an error in the DNA code (i.e. in a gene), this is called a MUTATION. If a mutation occurs in a gene, the end-product, the protein will be altered or absent: may not be made at all. See Fig 4.26, page 126. E1 E2 E3 E4 428053512319000367093512319000306133512319000245173512319000A B C D E When an enzyme is lacking from a metabolic pathway, childhood storage diseases result. In Tay-Sachs, PKU, Niemin-Pick's. may have altered function. See Fig 24.2, page 922. In cystic fibrosis & sickle-cell anemia may be produced in excess. In epilepsy, where excess GABA leads to excess norepinephrine. HOW DO WE TRANSFER OUR GENES TO OUR OFFSPRING? (Review from chapter 22) The genetic information of living organisms is DNA (deoxyribonucleic acid) that is carried on the genes of chromosomes. In humans, each somatic (body) cell is diploid, which means the cell contains 46 chromosomes or 23 pairs. Human sex cells or gametes, however, are haploid, which means the cell contains only 23 chromosomes. Meiosis is the type of cell division that results in gametes that possess half the chromosome number of the parent cell (i.e. meiosis reduces the chromosome number by one-half). Male sperm (haploid) = 23 chromosomes (1 set) Female egg (haploid) = 23 chromosomes (1 set) Fertilization (zygote; diploid) = 46 chromosome (2 sets). I. THE EMERGING ROLE OF GENETICS AND GENOMEICS IN MEDICINE A. GENETICS BACKGROUND Development following Fertilization The zygote formed by fertilization will divide into 2, 4, 8, 16, 32, 64 ... billions of cells to make up a human organism, however the DNA/genes/chromosomes will be identical in every one of those billion cells. If a mutation exists in the zygote, it will also be in every one of those billion cells in the human organism. If a problem occurs during meiosis, a sperm or egg may have too many or too few chromosomes, and result in a zygote with more or less than 46 chromosomes: 24 egg + 23 sperm = 47 chromosome zygote Down's (trisomy 21), Patau's (trisomy 13), Edward's (trisomy 18 ). 23 egg + 22 sperm = 45 chromosome zygote Turner Syndrome. THE HUMAN KARYOTYPE: See Fig 24.4, page 925. Chromosomes and Genes Come in Pairs As humans, most of our body cells contain 46 chromosomes: 23 (1 set) from mom; 23 (1 set) from dad. A map of these chromosomes is called a karyotype. Our chromosomes are paired. homologous chromosomes. We possess 22 homologous pairs of autosomes: These chromosomes carry the genes for most of our traits (proteins). We possess 1 pair of sex chromosomes: Females have a homologous XX pair. Males have a non-homologous XY pair. See Fig 24.12, page 931. II. THE HUMAN KARYOTYPE: See Fig 24.4, page 925. A. Chromosomes and Genes Come in Pairs The karyotype of a fetus can be obtained by a pre-natal test called an amniocentesis where any chromosomal abnormalities can be detected. A gene codes for a heritable trait (or protein). hair color eye color blood type Alleles are alternate forms of genes. The gene for eye color has several alleles. Two major alleles are: brown blue Some alleles are dominant over others: Brown is dominant over blue. The dominant allele brown is written as an upper case letter (B); The recessive allele blue is written as a lower case letter (b). We inherit one (1) allele of a gene from each parent and therefore have two (2) alleles for each gene. If we inherit identical alleles, we are said to be homozygous for the trait. BB = homozygous dominant; bb = homozygous recessive. If we inherit two different alleles, we are said to be heterozygous for the trait. Bb = heterozygous. PHENOTYPE VS. GENOTYPE The phenotype is the expressed trait. brown eyes blue eyes The genotype is the genetic makeup of the trait: BB or homozygous dominant Bb or heterozygous II. THE HUMAN KARYOTYPE: See Fig 24.4, page 925. B. Dominant and Recessive Inheritance If brown eyes are dominant over blue eyes, predict the offspring of a cross between two individuals who are heterozygous for eye color. Interpret given information: What are the genotypes and resulting cross of these two individuals? Brown = B; Blue = b. Individual 1 =_______(Bb); Individual 2 = _____(Bb). Therefore cross would be _______ x _______. (Bb x Bb) What allele(s) would be present in each of the individuals' sex cells? Individual 1 = ½ ____(B) & ½ _____(b); Individual 2 = ½ ____(B) & ½ _____(b). Set up a Punnett Square illustrating the possible crosses B b B BB Bb b Bb bb Interpret the results of the cross: The genotypic ratio would be: one (1) homozygous dominant (BB) individual : two (2) heterozygous (Bb) individuals : one (1) homozygous recessive (bb) individual. The phenotypic ratio would be: three (3) individual with brown eyes: one (1) individual with blue eyes. II. THE HUMAN KARYOTYPE: See Fig 24.4, page 925. B. Dominant and Recessive Inheritance In humans, widow's peak is dominant over straight hairline. Predict the offspring of the cross between an individual who is homozygous dominant for hairline, with an individual who is homozygous recessive for hairline. Interpret given information: Widow’s peak = W; Straight hairline = w. Therefore the cross is: _________ x ___________. (WW) (ww) Determine alleles in sex cells: All of WW’s alleles would be _______(W); All of ww’s alleles would be _______ (w). Set up a Punnett Square: W W w Ww Ww w Ww Ww Interpret results: Genotypic Ratio: All individuals are heterozygous for hairline. Phenotypic Ratio: All individuals have widow’s peaks. II. THE HUMAN KARYOTYPE MODES OF INHERITANCE: Whether a trait is dominant or recessive, autosomal or sex-linked is called its mode of inheritance. The mode of inheritance has important consequences in predicting the chance that offspring will inherit an illness or trait. Three important rules: Autosomal Conditions are equally likely to affect both sexes. Sex-linked characteristics affect males much more often than females. Recessive conditions are usually inherited from two healthy heterozygous parents (carriers). Recessive conditions "skip" generations. Dominant conditions are inherited by at least one affected parent. Dominant conditions do not skip generations. Example Using Cystic Fibrosis: See Fig 24.5, page 926. Autosomal Recessive Inheritance; Both parents are heterozygous (carriers); i.e. they have one normal & one mutant allele; genotype = + , cf What alleles would be present in the female’s eggs? 1/2 = ________(+) , 1/2 = _________(cf) What alleles would be present in the male’s sperm? 1/2 = ________(+) , 1/2 = _________(cf) What are the chances that parents who are heterozygous for cf will have an afflicted child? + cf + + + + cf cf + cf cf cf Results: These parents have _____ (1/4) chance of having a normal child (+,+) ; ______ (½) chance of having a child who is carrier of CF (+, cf) ; _______ (1/4) chance of having a child with CF (cf, cf). II. THE HUMAN KARYOTYPE C. MODES OF INHERITANCE: Example Using Huntington Disease: See Fig 24.6, page 927. Autosomal Dominant Inheritance; Parents' genotypes? Affected parent = + , HD Unaffected parent = + , + Alleles or Sex cells? Affected parent: ½_____ (+), ½ _____ (HD); Unaffected parent: ½ _____ (+), ½ _____ (+). What are the chances that a male who carries the Huntington's gene & a normal female will have an afflicted child? + HD + + + + HD + + + + HD Results: These parents have the chance of having ___________ (½) their offspring that carry the allele for Huntington disease and therefore those children will develop the disease during mid-life and ____________(½) their offspring who do not carry the HD allele and therefore will be normal. II. THE HUMAN KARYOTYPE C. MODES OF INHERITANCE: Example Using Sickle Cell Anemia (or disease) in which one of the four amino acid chains in hemoglobin is incorrect causing sickling of erythrocytes. Incomplete Dominant Inheritance. The heterozygous (carrier) parents express a moderate form of the disease; called sickle cell trait. What are the chances that a male with sickle cell trait & a normal female will have an afflicted child, either with sickle cell anemia or sickle cell trait. Male: HbA, HbS Female: HbA. HbA Sperm: 1/2 = ______( HbA), 1/2 = ______( HbS) Eggs: 1/2 = ______( HbA), 1/2 = ______( HbA) Punnett Square: HbA HbS HbA HbA HbA HbA HbS HbA HbA HbA HbA HbS Results: These parents have the chance of having _______ (½) their offspring that carry sickle cell trait, ________(½) their offspring of being normal. See Fig 24.7, page 928, which illustrates incomplete inheritance involved in plasma cholesterol levels. II. THE HUMAN KARYOTYPE C. MODES OF INHERITANCE: 7. Different Dominance Relationships Incomplete dominance Results if heterozygote exhibits a phenotype halfway between dominant and recessive Person has about half of a particular protein that a homozygous dominant person would have Codominant Results when both alleles are expressed Example is AB blood type GENE EXPRESSION - how a gene affects phenotype Penetrance and Expressivity Penetrance – phenotype presentation Whether or not the allele is seen in phenotype Completely penetrant = all who have allele have trait Incompletely penetrant = only some with allele show trait Numerically, 50% penetrance = 50 out of 100 who have allele have trait Expressivity – how much the phenotype is expressed Sometimes variable intensity is seen in different people For example some people with polydactyly have 1 extra digit, some have 4 extra digits Pleiotropy When a single genotype affects many phenotypes due to protein having many locations and functions Genetic Heterogeneity When more that one genotype causes the same phenotype For example, many different clotting disorders (genotype) are known, but they all have the same symptoms (phenotype) COMPLEX TRAITS Polygenic Traits Determined by more than one gene. Height, skin color, eye color are polygenic See Fig 24.8, page 929 and 24.9 page 930. Multifactorial Traits Determined by more than one gene (polygenic) and environment. Height is Multifactorial because it is polygenic plus nutrition plays a role See Fig 24.8, page 929 and 24.9 page 930. V. MATTERS OF SEX Sex Determination: See Fig 24.11, page 931. In sexually reproducing animals, two types of chromosomes exist: Most pairs are called autosomes which determine most traits; One pair represents the sex chromosomes, which determine sex of the individual. Female = XX; Male = XY. See Fig 24.14, page 935. Following gametogenesis (sex cell formation; meiosis): In females, the ova (gametes) contain 22 autosomes and the X sex chromosome. All ova contain the X chromosome. XX ? X (ova) In males, the sperm contain 22 autosomes, but half the sperm carry the X sex chromosome and the other half of the sperm contain the Y sex chromosome: XY ? X or Y (sperm) During fertilization, the chance of: an X sperm and the X ova fusing to produce a female (XX) is 50%; a Y sperm and the X ova fusing to produce a male (XY) is 50%. V. MATTERS OF SEX Sex Chromosomes and Their Genes Example Using Hemophilia in which a clotting factor is missing that leads to bleeding disorders. Sex-linked Inheritance Traits transmitted on the X chromosome are said to be sex-linked (or X-linked). Males need only one copy of a mutant allele to possess the disorder; XaY. Females need two copies of the mutant allele to be affected (XaXa); however if they have one mutant allele, they are carriers of the disease (XaX0). What are the chances that a female hemophilia carrier and normal male will have a child afflicted with the disease? Genotypes of parents: Female = XHXh; Male = XhY. Alleles of parents: Female’s are ½ XH and ½ Xh; Males are ½ Xh; and ½ Y. Punnett square: XH Xh Xh XH Xh Xh Xh Y XHY Xh Y Results: These parents have the chance of having ______ (½) their female offspring as hemophilia carriers and _______ (½) their female offspring as normal, and the chance of having _______ (½) of their male offspring afflicted with hemophilia and _______ (½) their male offspring as normal. V. MATTERS OF SEX Gender Effects on Phenotype Sex-limited Traits Only tend to affect certain sex Reason that a woman doesn’t grow a thick beard, but her son’s can Sex-influenced Traits Traits that are dominant in one sex but recessive in the other Due to hormonal differences Reason that more men are bald than women VI. CHROMOSOMAL DISORDERS Polyploidy = more than two sets of chromosomes. Triploid = three sets of chromosomes or 69 (rather than 46); results in death as embryo or fetus. Aneuploidy = missing one or having one extra chromosome. See Figure 24.14, page 935. Trisomy 21 = Down Syndrome: See Clinical Application 24.2 on pages 936. most common autosomal aneuploid event; Characteristics: short stature straight sparse hair protruding tongue; thick lips reflexes/muscle tone poor development slow warm, loving personalities enjoy art & music Intelligence varies greatly profound mental retardation to following simple directions to reading & using a computer Many physical problems: 50% die before 1st birthday kidney defects heart defects digestive blockage Child with Down's is 15 times more likely to develop leukemia. Those who live past 40, develop amyloid protein in their brains (similar to Alzheimer's). Likelihood of giving birth to a child with Down's increases drastically with maternal age. See Table 24A, page 936. VII. GENETIC TESTING and GENETIC COUNSELING PRENATAL GENETIC TESTING See Fig 24.15, page 938 and Table 24.2, page 937. AMNIOCENTESIS indicated in women: over the age of 35, who have already given birth to a child with a chromosomal abnormality, whose family history (paternal included) shows any sign of genetic disease. performed after 14th week gestation; Needle is inserted into amnionic sac and 5ml of fluid containing fetal cells is extracted. Cells are analyzed by karyotyping. Useful in detecting many genetic disorders. 0.5% chance of miscarriage CHORIONIC VILLUS SAMPLING performed as early as 8 weeks gestation 1-2% spontaneous abortion rate FETAL CELL SORTING involves obtaining and analyzing rare fetal cells in maternal circulation. These cells may be responsible for autoimmune disorders including scleroderma (see Chapter 16). GENETIC COUNSELING Because of the unique ethical questions and dilemmas that can result from genetic testing, genetic counseling is highly recommended for couples during this time. A genetic counselor: obtains a complete family history. determines recurrence risks for certain conditions in specific relatives. provides information on the illness so families can make informed medical decisions. discusses available tests and costs. discusses options. GENE THERAPY Gene therapy corrects the genetic defect causing disease symptoms. Two types: Heritable Gene Therapy alters all genes of individual must be performed on a fertilized egg or zygote not being performed in humans, but has shown some success in animal models. Nonheritable Gene Therapy targets affected cells (not all cells) of an afflicted individual Bone marrow transplants may be used to add an absent enzyme to particular blood cells (ADA deficiency); Aerosols may be used to treat cystic fibrosis patients by introducing a functional CFTR gene. Injection of certain proteins directly into tumors. See Figure 24.17, page 942, which shows the many body locations where gene therapy is being used and for which diseases gene therapy has shown promise. Requirements for Approval of Clinical Trial for Gene Therapy Knowledge of defect and how it causes symptoms Animal model Success in human cells growing in vitro; Either the lack of alternate therapies or where existing therapies have not been successful; Experiments must be safe. Gene Therapy Concerns Which cells should be treated? What proportion of the targeted cell population must be corrected to alleviate or halt progression of symptoms? Is overexpression of the therapeutic gene dangerous? If the engineered gene “escapes” and infiltrates other tissues, is there danger? How long will the affected cells function? Will the immune system attack the introduced cells? See Clinical Application 24.3, pages 940 and 941, which discuss some successes and setbacks with gene therapy. GENOMICS AND A NEW VIEW OF ANATOMY AND PHYSIOLOGY The human genome consists of at least 40,000 protein-encoding genes. The human genome project has triggered numerous genetic discoveries since its advent. Knowing the human genome sequence has made it possible to view physiology at the microscopic level, as a complex interplay between gene functions. The science of genomics looks at the human body in terms of multiple, interacting genes, rather than the field of genetics which deals mostly with single genes. Fig 24.3, page 923 views genomics at the whole body, cellular, and microscopic level. OTHERS: Introduction on page 920, which provides a look into the future of genetics and how DNA “chips” may be used to prevent and/or treat genetic disease. Clinical Application 24.1: “It’s all in the Genes”, page 924, which discusses several common human traits that are determined by a single gene. Figure 24.8, page 929, which illustrates the continuously varying nature of height. Figure 24.9, page 930, which illustrates variations in skin color using a model of three genes. Figure 24.10, page 930, which illustrates variations in eye color using a model of two genes with two alleles each. Figure 24.13, page 933, which illustrates pattern baldness as a “sex-influenced” trait. Chapter 24: Genetics and Genomics I. The Emerging Role of Genetics and Genomics in Medicine A. Genetics is the study of inheritance of characteristics. B. Genes are sequences of nucleotides of the nucleic acid DNA. C. Chromosomes are rod shaped structures that carry genes. D. A gene’s nucleotide sequence tells a cell how to link a certain sequence of amino acids together to construct a specific protein molecule. E. A genome is the complete set of genetic instructions in a human cell. F. Somatic cells have two sets of chromosomes. G. Diploid means having two sets of chromosomes or 46 chromosomes. H. Sex cells have one set of chromosomes. I. Haploid means having one set of chromosomes or 23 chromosomes. J. Genomics is the study of the human body in terms of multiple, interacting genes. K. Proteonomics focuses on the spectrum of proteins that specific cell types produce. L. Environmental factors that affect how genes are expressed are chemical, physical, social, and biological. II. Modes of Inheritance A. Introduction 1. The probability that a certain trait will occur in the offspring of two individuals can be determined by knowing how genes are distributed in meiosis and the combinations in which they can come together at fertilization. B. Chromosomes and Genes Come in Pairs 1. Karyotypes are chromosome charts that display the 23 chromosome pairs in size order. 2. Autosomes are chromosome pairs 1 through 22 and do not carry genes that determine sex. 3. Sex chromosomes are chromosome pair 23 and determine sex. 4. Most chromosomes contain hundreds of thousands of genes. 5. Alleles are variant forms of genes. 6. Homozygous alleles are identical. 7. Heterozygous alleles are different. 8. Genotype is the particular combination of genes in a person’s genome. 9. Phenotype is the appearance or health condition of the individual that develops as a result of the ways the genes are expressed. 10. A wild type allele is associated with the most common or normal phenotype. 11. A mutant allele is a change from the wild type. C. Dominant and Recessive Inheritance 1. A dominant allele is one that masks that of another allele. 2. A recessive allele is one that is masked by a dominant allele. 3. An autosomal gene is located on a nonsex chromosome. 4. An X-linked gene is located on an X chromosome. 5. A Y-linked gene is located on a Y chromosome. 6. Mode of inheritance refers to whether a trait is dominant or recessive, autosomal or carried on a sex chromosome. 7. An autosomal condition is equally likely to affect either sex. 8. X-linked characteristics affect males much more than females. 9. Recessive conditions can skip a generation because a person most likely inherits a recessive condition from two healthy parents who are each heterozygotes. 10. Dominant conditions do not skip generations because a person who inherits the condition has at least one affected parent. 11. The disease cystic fibrosis is an example of an autosomal recessive disorder. 12. If both parents are heterozygotes for the trait that causes cystic fibrosis, there is a 25% chance that their offspring will be homozygous dominant, a 50% chance their offspring will be heterozygous, and a 25% chance their offspring will be homozygous recessive. 13. A Punnet square is a table used to predict the probabilities of particular genotypes occurring in offspring. 14. A pedigree is a diagram that depicts family relationships and genotypes and phenotypes when they are known. 15. An example of an autosomal dominant disorder is Huntington disease. D. Different Dominance Relationships 1. Incomplete dominance is a type of inheritance in which the heterozygous phenotype is intermediate between that of either homozygote. 2. An example of a trait inherited through incomplete dominance is familial hypercholesterolemia. 3. Codominant means different alleles are both expressed in a heterozygotes. 4. The genotypes of individuals with the following blood types are: type A – IAIA or IAi type B – IBIB or IBi type AB - IAIB type O - ii III. Gene Expression A. Introduction 1. The same allele combination can produce different phenotypes because of the influences of nutrition, toxins, illnesses or the activities of other genes. 2. A major goal of genomics is to identify and understand the interactions of alleles, nutrition, environmental factors, illnesses, and activities of other genes. B. Penetrance and Expressivity 1. Completely penetrant means that everyone who inherits it has some symptoms. 2. Incompletely penetrant means some individuals do not express the phenotype. 3. A phenotype is variably expressive if the symptoms vary in intensity in different people. C. Pleiotropy 1. Pleiotropy is a single genetic disorder that can produce several symptoms. 2. An example of a disease that exhibits pleiotropy is Marfan syndrome. D. Genetic Heterogeneity 1. Genetic heterogeneity is when the same phenotype may result from the actions of different genes. 2. An example of a condition that exhibits genetic heterogeneity is hereditary deafness. IV. Complex Traits A. Monogenic means the traits are determined by a single gene and their expression is not greatly influenced by the environment. B. Polygenic means the traits are determined by more than one gene. C. Variations in height are due to multiple genes. D. Variations in skin color are due to three or more genes with two alleles each. E. Variations in eye color are due to two genes, with two alleles each. F. Complex traits are traits molded by one or more genes plus the environment. G. Examples of complex traits are height, skin color, and certain illnesses. V. Matters of Sex A. Introduction 1. A human female is termed homogametic because she has two of the same type of sex chromosome. 2. A human male is termed heterogametic because his two sex chromosomes are different. B. Sex Determination 1. A male is conceived when a sperm containing a Y chromosome fertilizes and egg (which has an X chromosome). 2. A female is conceived when a sperm containing an X chromosome fertilizes and egg. 3. The gene responsible for being male is the SRY gene. C. Sex Chromosomes and Their Genes 1. The X chromosome has more than 1000 genes. 2. The Y chromosome has only a few dozen genes. 3. The three groups of Y-linked genes are genes at the tips of the Y chromosome that have counterparts on the X chromosome, genes that are very similar in DNA sequence to certain genes on the X chromosome, and genes that are unique to the Y chromosome. 4. Y-linked genes are transmitted from father to sons. 5. Any gene on the X chromosome of a male is expressed in his phenotype because he has no second allele on a second X chromosome to mask its expression. 6. An allele on an X chromosome of a female may or may not be expressed because it depends on whether it is dominant or recessive and upon the nature of the allele on the second X chromosome. 7. The male is said to be hemizygous for X-linked traits because he has half the number of genes on the X chromosome that the female has. 8. Examples of X-linked recessive traits are red-green color blindness and hemophilia. 9. If a mother is heterozygous for a particular X-linked gene, her son has a 50% chance of inheriting either allele from her. 10. X-linked genes are passed on from mother to son. 11. A daughter can inherit an X-linked disorder only if her father is affected and her mother is a carrier. D. Gender Effects and Phenotypes 1. A sex-linked trait is one that affects a structure or function of the body that is present in only males or only females. 2. Sex-influenced inheritance is a type of inheritance in which an allele is dominant in one sex but recessive in another. 3. A heterozygous male is bald and a heterozygous female is not bald because the baldness allele is dominant in males but recessive in females. 4. Genomic imprinting is an effect in which the expression of a disorder differs depending upon which parent transmits the disease-causing gene. VII. Chromosome Disorders A. Polyploidy 1. Polyploidy is the condition of having an extra set of chromosomes. 2. Polyploidy results from formation of a diploid gamete. 3. The fate of a polyploid human is death as an embryo or fetus. B. Aneuploidy 1. Aneuploid means a condition of missing a chromosome or having an extra one. 2. Euploid means a normal chromosome number. 3. Anueploidy results from nondisjunction. 4. Nondisjunction is meiotic error in which a chromosomal pair fails to separate, producing a sperm or egg that has two copies of a particular chromosome or none. 5. Autosomal aneuploidy often results in mental retardation. 5. Trisomy is the condition of having one extra chromosome. 6. Monosomy is the condition of missing one chromosome. 7. Translocation is a type of aberration in which one copy of a chromosome exchanges parts with a different chromosome. 8. Trisomy 21 is known as Down syndrome. 9. Other common autosomal trisomies are trisomy 13 and trisomy 18. 10. Turner syndrome results from missing one X chromosome. 11. Klinefelter syndrome results from having an extra X chromosome. 12. Jacobs syndrome results from having an extra Y chromosome. C. Prenatal Tests 1. An ultrasound can detect growth rate, head size, and size and location of organs. 2. Amniocentesis is a procedure in which a needle is inserted into the amniotic sac to draw amniotic fluid and can detect chromosomal abnormalities. 3. Chorionic villus sampling is of chorionic villus cells and can detect chromosomal abnormalities. 4. Maternal serum markers can detect an underdeveloped fetal liver that may indicate an increased risk of trisomy. 5. Fetal cell sorting is a process that separates and can detect genetic abnormalities. VIII. Gene Therapy A. Introduction 1. Functions of gene therapy are to alter, replace, silence or augment a gene’s function to improve or prevent symptoms. 2. Gene therapy operates at the gene level. B. Two Approaches to Gene Therapy 1. Two basic types of gene therapy are heritable gene therapy and nonheritable gene therapy. 2. Heritable gene therapy is the type that introduces the genetic change into a sperm, egg or fertilized egg, which corrects each cell of the resulting individual. 3. Heritable gene therapy is most commonly performed in plants. 4. Nonheritable gene therapy is the type that targets only affected cells and therefore cannot be transmitted to the next generation. 5. A nonheritalbe gene therapy for cystic fibrosis is an aerosol containing a virus that has had its pathogenic genes removed and a functional human CFTR gene added. C. Tools and Targets of Gene Therapy 1. Introduction a. Some tools of gene therapy are viruses, liposomes, and naked preparations of DNA. b. The challenge in nonheritable gene therapy is to target sufficient numbers of affected cells for a long enough time to exert a noticeable effect. 2. Bone Marrow a. Bone marrow tissue includes the precursors of all mature blood cells types. b. Many new gene therapy targets might be reached by bone marrow because stem cells in bone marrow can also travel to other sites, such as muscle, liver, and the brain. 3. Skin a. In the laboratory, skin cells grow well. b. Skin grafts can be used to secrete therapeutic proteins into a person’s system. 4. Muscle a. The reasons muscle tissue is a good target for gene therapy are because it comprises about half of the body’s mass, is easily accessible, and is near a blood supply. b. Treatments of Duchenne muscular dystrophy are delivery of functional genes to immature muscle cell or to direct stem cell from bone marrow to muscle tissue where they differentiate and produce needed proteins. 5. Endothelium a. Endothelium is a tissue that forms capillaries and lines the interiors of other blood vessels. b. Endothelium can be altered to secrete a substance directly into the bloodstream. 6. Liver a. The liver is a very important focus of gene therapy because it controls many bodily functions and it can regenerate. b. Liver cells that are genetically altered can relieve cholesterol buildup. 7. Lungs a. The respiratory tract is an excellent candidate for gene therapy because an aerosol can directly reach its lining cells, making it unnecessary to remove cell, alter them, and reimplant them. b. A form of gene therapy used to treat emphysema is inhalation of alpha-1-antitrypsin. 8. Nerve Tissue a. Gene therapy of neurons is not feasible because these cells do not divide. b. Routes of nerve cell gene therapy could include altering neuroglial cells or sending in a valuable gene attached to the herpes simplex virus, which remains in nerve cells after infections. 9. Gene Therapy Against Cancer a. Glioma is a brain tumor. b. A gene therapy approach for glioma is to infect fibroblasts with a virus bearing a gene from a herpes virus that makes the cell sensitive to a drug called ganciclovir. The altered fibroblasts are implanted near the tumor. c. Another genetic approach to battling cancer is to enable tumor cells to produce immune system biochemicals or to mark them so that the immune system more easily recognizes them. D. CODA 1. Gene discoveries have shed light on how the body normally functions. 2. Gene products interact with each other and environmental factors in intricate ways to build the bodies of humans and other multicellular organisms. Chapter 24: Genetics and Genomics I. The Emerging Role of Genetics and Genomics in Medicine A. Genetics is B. Genes are C. Chromosomes are D. A gene’s nucleotide sequence tells a cell E. A genome is F. Somatic cells have G. Diploid means H. Sex cells have I. Haploid means J. Genomics is K. Proteonomics focuses on L. Environmental factors that affect how genes are expressed are II. Modes of Inheritance A. Introduction 1. The probability that a certain trait will occur in the offspring of two individuals can be determined by B. Chromosomes and Genes Come in Pairs 1. Karyotypes are 2. Autosomes are 3. Sex chromosomes are 4. Most chromosomes contain genes. 5. Alleles are 6. Homozygous alleles are 7. Heterozygous alleles are 8. Genotype is 9. Phenotype is 10. A wild type allele is 11. A mutant allele is C. Dominant and Recessive Inheritance 1. A dominant allele is 2. A recessive allele is 3. An autosomal gene is located 4. An X-linked gene is located 5. A Y-linked gene is located 6. Mode of inheritance refers to 7. An autosomal condition is equally likely to affect 8. X-linked characteristics affect 9. Recessive conditions can skip a generation because 10. Dominant conditions do not skip generations because 11. The disease is an example of an autosomal recessive disorder. 12. If both parents are heterozygotes for the trait that causes cystic fibrosis, there is a chance that their offspring will be homozygous dominant, a chance their offspring will be heterozygous, and a chance their offspring will be homozygous recessive. 13. A Punnet square is 14. A pedigree is 15. An example of an autosomal dominant disorder is D. Different Dominance Relationships 1. Incomplete dominance is 2. An example of a trait inherited through incomplete dominance is 3. Codominant means 4. The genotypes of individuals with the following blood types are: type A type B type AB type O III. Gene Expression A. Introduction 1. The same allele combination can produce different phenotypes because 2. A major goal of genomics is B. Penetrance and Expressivity 1. Completely penetrant means 2. Incompletely penetrant means 3. A phenotype is variably expressive if C. Pleiotropy 1. Pleiotropy is 2. An example of a disease that exhibits pleiotropy is D. Genetic Heterogeneity 1. Genetic heterogeneity is 2. An example of a condition that exhibits genetic heterogeneity is IV. Complex Traits A. Monogenic means B. Polygenic means C. Variations in height are due to D. Variations in skin color are due to E. Variations in eye color are due to F. Complex traits are G. Examples of complex traits are V. Matters of Sex A. Introduction 1. A human female is termed homogametic because 2. A human male is termed heterogametic because B. Sex Determination 1. A male is conceived when 2. A female is conceived when 3. The gene responsible for being male is C. Sex Chromosomes and Their Genes 1. The X chromosome has genes. 2. The Y chromosome has genes. 3. The three groups of Y-linked genes are 4. Y-linked genes are transmitted from father to 5. Any gene on the X chromosome of a male is expressed in his phenotype because 6. An allele on an X chromosome of a female may or may not be expressed because 7. The male is said to be hemizygous for X-linked traits because 8. Examples of X-linked recessive traits are 9. If a mother is heterozygous for a particular X-linked gene, her son has a chance of inheriting either allele from her. 10. X-linked genes are passed on from 11. A daughter can inherit an X-linked disorder only if D. Gender Effects and Phenotypes 1. A sex-linked trait is 2. Sex-influenced inheritance is 3. A heterozygous male is bald and a heterozygous female is not bald because 4. Genomic imprinting is VII. Chromosome Disorders A. Polyploidy 1. Polyploidy is 2. Polyploidy results from 3. The fate of a polyploid human is B. Aneuploidy 1. Aneuploid means 2. Euploid means 3. Anueploidy results from 4. Nondisjunction is 5. Autosomal aneuploidy often results in 5. Trisomy is 6. Monosomy is 7. Translocation is 8. Trisomy 21 is known as 9. Other common autosomal trisomies are 10. Turner syndrome results from 11. Klinefelter syndrome results from 12. Jacobs syndrome results from C. Prenatal Tests 1. An ultrasound can detect 2. Amniocentesis is and can detect 3. Chorionic villus sampling is and can detect 4. Maternal serum markers can detect 5. Fetal cell sorting is and can detect VIII. Gene Therapy A. Introduction 1. Functions of gene therapy are 2. Gene therapy operates at B. Two Approaches to Gene Therapy 1. Two basic types of gene therapy are 2. Heritable gene therapy is 3. Heritable gene therapy is most commonly performed in 4. Nonheritable gene therapy is 5. A nonheritable gene therapy for cystic fibrosis is C. Tools and Targets of Gene Therapy 1. Introduction a. Some tools of gene therapy are b. The challenge in nonheritable gene therapy is 2. Bone Marrow a. Bone marrow tissue includes b. Many new gene therapy targets might be reached by bone marrow because 3. Skin a. In the laboratory, skin cells grow b. Skin grafts can be used to 4. Muscle a. The reasons muscle tissue is a good target for gene therapy are b. Treatments of Duchenne muscular dystrophy are 5. Endothelium a. Endothelium is b. Endothelium can be altered to 6. Liver a. The liver is a very important focus of gene therapy because b. Liver cells that are genetically altered can relieve 7. Lungs a. The respiratory tract is an excellent candidate for gene therapy because b. A form of gene therapy used to treat emphysema is 8. Nerve Tissue a. Gene therapy of neurons is not feasible because b. Routes of nerve cell gene therapy could include 9. Gene Therapy Against Cancer a. Glioma is b. A gene therapy approach for glioma is c. Another genetic approach to battling cancer is to D. CODA 1. Gene discoveries have shed light on 2. Gene products interact with