Power Lecture Chapter 21 Chromosomes and Human Genetics

Power. Lecture: Chapter 21 Chromosomes and Human Genetics

Learning Objectives Describe how an understanding of chromosomes helps to account for events that compose mitosis and meiosis. Ø Name some ordinary and extraordinary chromosomal events that can create new phenotypes (outward appearances). Ø Understand how changes in chromosome structure and number can affect the outward appear ance of organisms. Ø Distinguish autosomal recessive inheritance from sex linked recessive inheritance. Ø

Learning Objectives (cont’d) Explain how changes in chromosomal number can occur and present an example of such a change. Ø List examples of phenotypic defects and describe how each can be treated. Ø Explain how knowing about modern methods of genetic screening can minimize potentially tragic events. Ø

Impacts/Issues Menacing Mucus

Menacing Mucus Cystic fibrosis (CF) is a debilitating genetic disorder. Ø l l Ø Persons with two recessive genes will suffer from excessive accumulations of mucus in their lungs. The defective gene is located on chromosome 7 and codes for a membrane transport protein called CFTR. Many thousands of prospective parents have been screened for CF; genetic testing, however, is not without controversy.

Useful References for Impacts/Issues The latest references for topics covered in this section can be found at the book companion website. Log in to the book’s e resources page at www. thomsonedu. com to access Info. Trac articles. Ø Cystic Fibrosis Foundation: Gene Therapy and CF Ø Info. Trac: Constant Battle: Kerri Marks Is One of the Survivors, Living Under a Disease’s Invisible Clock. Jennifer Becknell. Herald, July 10, 2006.

How Would You Vote? To conduct an instant in class survey using a classroom response system, access “Join. In Clicker Content” from the Power. Lecture main menu. Ø Do we as a society want to encourage women to give birth only to offspring who will not develop serious gene based medical problems? l l a. Yes, in order to prevent needless suffering and expense. b. No, the diversity represented by special needs children is important to a society.

Useful References for How Would You Vote? The latest references for topics covered in this section can be found at the book companion website. Log in to the book’s e resources page at www. thomsonedu. com to access Info. Trac articles. Info. Trac: Ohio Court Limits Relief for Fetal Testing Error; Compensation Denied for Costs of Raising Disabled Child. Judy Greenwald. Business Insurance, Mar. 13, 2006. Ø Info. Trac: In New Tests for Fetal Defects, Agonizing Choices for Parents. Amy Harmon. The New York Times, June 20, 2004. Ø Info. Trac: Offer All Pregnant Women Fetal Genetic Testing. Sherry Boschert. OB GYN News, Dec. 15, 1999. Ø

Section 1 Genes and Chromosomes

Genes and Chromosomes Understanding inheritance starts with gene chromosome connections. Ø l l l Genes, the units of instruction for heritable traits, are segments of DNA arranged along chromosomes in linear order; each gene thus has its own locus. Diploid cells have pairs of homologous chromosomes that are very much alike; homologues interact and segregate during meiosis. Alleles are different forms of a gene; they often arise by mutation.

Genes and Chromosomes l l Independent assortment dictates that genes generally move into gametes independently of one another. Crossing over leads to genetic recombination during meiosis.

Genes and Chromosomes Closely linked genes tend to stay together when gametes form. Ø l l When the distance between two genes on the same chromosome is very short, the genes are said to show linkage (they are “linked”); close genes generally travel together and are not segregated independently. Genes that are far apart on a chromosome will segregate independently as a result of crossing over between them.

Closely linked genes in parents: B A A AB b x a b B a ab meiosis, gametes form Genes stay together in gametes. B A 50% AB b a 50% ab Fig. 21. 1 a, p. 388

A Weaker linkage in parents: C AC A a x c a ac c C meiosis, gamete formation Genes less likely to stay together as gametes form. C A a c Most gametes have parent’s genotype. a A c C A few gametes have recombinant genotypes. Fig. 21. 1 b, p. 388

Closely linked genes in parents: B A A AB b x a b B a ab meiosis, gametes form Genes stay together in gametes. B A 50% AB b a 50% ab Stepped Art Fig. 21. 1 a, p. 388

A Weaker linkage in parents: C AC A a x c a ac c C meiosis, gamete formation Genes less likely to stay together as gametes form. C A a c Most gametes have parent’s genotype. a A c C A few gametes have recombinant genotypes. Stepped Art Fig. 21. 1 b, p. 388

Genes and Chromosomes The X and Y chromosomes are quite different genetically. Ø l l Sex chromosomes determine gender; males have one X and one Y chromosome while females have two X chromosomes. The X and Y chromosomes can synapse in a small region along their length, allowing them to behave as homologues during meiosis.

Useful References for Section 1 The latest references for topics covered in this section can be found at the book companion website. Log in to the book’s e resources page at www. thomsonedu. com to access Info. Trac articles. Ø Rocklin and Roseville Today: Genetic Behaviors Go Beyond X and Y Chromosomes Ø Info. Trac: Cord Blood Storage Is Big Business, But Is It Worth It? Blythe Bernhard. Orange County Register (Santa Ana, CA), June 2, 2006.

Section 2 Picturing Chromosomes with Karyotypes

Picturing Chromosomes with Karyotypes Ø A karyotype is a “picture” of a person’s chromosomes captured when the chromosomes have condensed to their metaphase (mitosis) state. Figure 21. 2 f

Picturing Chromosomes with Karyotypes Cells are harvested from a patient, grown in the lab, and arrested in metaphase of mitosis (using colchicines) before the cells are disrupted and the chromosomes recovered. Ø Once photographed, the chromosomes are arranged in their homologous pairs and analyzed. Ø

a. Add cells from a small blood sample b. Centrifugation d. Put cells on microscope © 2007 Thomson Higher Education c. Prepare cells e. Photograph cell Fig. 21. 2(1), p. 389

Animation: Karyotype Preparation CLICK TO PLAY

Useful References for Section 2 The latest references for topics covered in this section can be found at the book companion website. Log in to the book’s e resources page at www. thomsonedu. com to access Info. Trac articles. Ø Info. Trac: Microarray Analysis of Cell Free Fetal DNA in Amniotic Fluid: A Prenatal Molecular Karyotype. Paige B. Larrabee et al. American Journal of Human Genetics, Sept. 2004.

Section 3 How Sex Is Determined

How Sex Is Determined Sex is a question of X or Y. Ø l Gender of the human offspring is determined by the father’s sperm. • • If an X bearing sperm fertilizes an egg, the offspring will be female. If a Y bearing sperm fertilizes an egg, the offspring will be male. Figure 21. 3 a

female (XX) male (XY) eggs sperm diploid germ cells in female meiosis, gamete formation in both female and male sex chromosome combinations possible in new individual X x Y X x X X XX XX Y XY XY Fig. 21. 3 a, p. 390

Animation: Human Sex Determination CLICK TO PLAY

How Sex Is Determined l l l The Y chromosome has a “male determining gene” (SRY) that codes for proteins that cause testes to form; in the absence of SRY, a female forms automatically. Nonsexual traits are also coded for on the sex chromosomes, mostly on the X. Genes that are specific to the X and Y chromosomes are called X-linked genes and Y -linked genes, respectively. Figure 21. 3 b

appearance of “uncommitted” duct system of embryo at 7 weeks Y chromosome present Y chromosome absent testis ovary penis uterus vagina testis Fig. 21. 3 b, p. 390

appearance of “uncommitted” duct system of embryo at 7 weeks Y chromosome present Y chromosome absent testis ovary penis uterus vagina testis Stepped Art Fig. 21. 3 b, p. 390

Animation: Effects of the SRY Gene CLICK TO PLAY

How Sex Is Determined In females, one X is inactivated. Ø l Most or all of the genes on one of the X chromosomes are switched off in early development, a process called X inactivation; which X becomes inactivated (maternal or paternal) is random. • • The inactivated X chromosome becomes condensed into a Barr body. The female body is a mosaic of cells in which one or the other of the original pair of X chromosomes inherited from her parents is active.

How Sex Is Determined Ø Anhidrotic ectodermal dysplasia is a condition in females in which the active X chromosome in certain tissues carries a mutated gene that blocks the formation of sweat glands in patches of tissue over the surface of the body.

Fig. 21. 4 a, p. 391

Useful References for Section 3 The latest references for topics covered in this section can be found at the book companion website. Log in to the book’s e resources page at www. thomsonedu. com to access Info. Trac articles. Ø Info. Trac: The Genetic Legacy of the Mongols. Tatiana Zerjal et al. American Journal of Human Genetics, Mar. 2003.

Section 4 Human Genetic Analysis

Human Genetic Analysis A pedigree shows genetic connections. Ø l The analysis of family pedigree charts provides data on inheritance patterns through several generations. Figure 21. 5

Animation: Pedigree Diagrams CLICK TO PLAY

Human Genetic Analysis l A person who is heterozygous for a recessive trait (carrier) may show the dominant phenotype but is still capable of passing the recessive gene on. • • • The term genetic abnormality is applied to a genetic condition that is a deviation from the usual, or average, but is not life threatening. A genetic disorder is more appropriately used to describe conditions that cause medical problems. Syndrome refers to a set of symptoms that characterize a disorder by appearing together.

Human Genetic Analysis Genetic analysis may predict disorders. Ø l Genetic analysis, beginning with determination of the parental genotypes, is the first step to identifying any risks a couple may have in producing a child with a genetic disorder. Figure 21. 6

Human Genetic Analysis l Not all factors leading to disorders can be readily quantified; it is important for prospective parents to recognize that each pregnancy will hold the same risks.

Useful References for Section 4 The latest references for topics covered in this section can be found at the book companion website. Log in to the book’s e resources page at www. thomsonedu. com to access Info. Trac articles. Ø Gene. Tests: Amish Lethal Microcephaly Ø Info. Trac: LCT Announces Results for Treating Huntington’s Disease. Asia. Pulse News, Aug. 2, 2005.

Section 5 Inheritance of Genes on Autosomes

Inheritance of Genes on Autosomes Inherited recessive traits cause a variety of disorders. Ø l Recessive inheritance is characterized by the following: • • • Either parent can carry the recessive allele on an autosome. Heterozygotes are symptom free; homozygotes are affected. Two heterozygous parents have a 50% chance of producing heterozygous children and a 25% chance of a homozygous recessive child. When both parents are homozygous, all children will be affected.

Inheritance of Genes on Autosomes l Examples of autosomal recessive inheritance include: • • • Cystic fibrosis. Phenylketonuria (PKU), resulting from the abnormal buildup of phenylalanine due to the lack of an enzyme that normally breaks it down. Tay-Sachs disease, which affects primarily infants, is characterized by lack of an enzyme to break down lipids in the brain. Figure 21. 7

Animation: Autosomal Recessive Inheritance CLICK TO PLAY

Inheritance of Genes on Autosomes Some disorders are due to dominant genes. Ø l Inheritance of dominant alleles demonstrates the characteristics below: • • • Because such alleles are usually expressed (even in heterozygotes), the trait appears in each generation. If one parent is heterozygous and the other homozygous recessive, there is a 50% chance that any one child will be heterozygous. Dominant alleles, even if they cause severe genetic disorders, persist in the population due to mutation, nonreproductive effects, or post reproductive onset.

Inheritance of Genes on Autosomes l Examples of autosomal dominant inheritance include: • Marfan syndrome results from a defective form of fibrillin, found in connective tissue; one effect is to disrupt both structure and function of smooth muscle cells of the aorta. Figures 21. 8 and 21. 9

Inheritance of Genes on Autosomes • • • Achondroplasia (dwarfism) results in heights of about 4 feet, but has no other serious effects; homozygotes, though, usually are stillborn. Familial hypercholesterolemia results in elevated levels of cholesterol due to few cell receptors for low density lipoproteins. Huntington disease, a serious degenerative disease of the nervous system with an onset from age 30 onward; homozygotes always die, thus adults are always heterozygous. Figure 21. 10

Animation: Autosomal Dominant Inheritance CLICK TO PLAY

Animation: Marfan Syndrome CLICK TO PLAY

Useful References for Section 5 The latest references for topics covered in this section can be found at the book companion website. Log in to the book’s e resources page at www. thomsonedu. com to access Info. Trac articles. Ø Info. Trac: Geographic Distribution of Disease Mutations in the Ashkenazi Jewish Population Supports Genetic Drift over Selection. Neil Risch et al. American Journal of Human Genetics, April 2003.

Section 6 Inheritance of Genes on the X Chromosome

Inheritance of Genes on the X Chromosome X linked recessive inheritance. Ø l X linked recessive inheritance is demonstrated by the following: • • The mutated gene occurs only on the X chromosome. Heterozygous females are phenotypically normal because a dominant gene on the other X chromosome masks the recessive’s effects; a male will be affected if he inherits a recessive gene on his sole X chromosome.

Inheritance of Genes on the X Chromosome • A normal male mated with a female heterozygote together have a 50% chance of producing carrier daughters and a 50% chance of producing affected sons. In the case of a homozygous female and a normal male, all daughters will be carriers and all sons affected. Figure 21. 11

Animation: X Linked Inheritance CLICK TO PLAY

Inheritance of Genes on the X Chromosome l Examples of X linked recessive inheritance include: • • Duchenne muscular dystrophy is a condition in which the protein dystrophin is missing, causing muscle fibers to weaken. Red/green color blindness is an inconvenience but is not life threatening.

Inheritance of Genes on the X Chromosome • Hemophilia A, where the inability of the blood to clot because the genes do not code for the necessary clotting agent (factor VIII) can lead to death from any cut or internal bleeding. Figure 21. 12

Inheritance of Genes on the X Chromosome Some types of X linked abnormalities are quite rare. Ø l l Faulty enamel trait is one of very few known examples of a trait caused by a dominant mutant allele that is X linked; it is expressed in heterozygous females but is less pronounced than in males. Testicular feminizing syndrome (androgen insensitivity) is an abnormality of an XY individual in which a mutation in the X chromosome results in defective receptors for the male sex hormones; individuals have external female features, but no uterus or ovaries. Figure 21. 13

Inheritance of Genes on the X Chromosome Many factors complicate genetic analysis. Ø l l Before diagnosing a case, geneticists often must pool many pedigrees and make detailed analyses of clinical data to keep track of instances where multiple mutations can lead to the same phenotype. As an example, some conditions can occur because of changes to autosomes or to the X chromosome.

Useful References for Section 6 The latest references for topics covered in this section can be found at the book companion website. Log in to the book’s e resources page at www. thomsonedu. com to access Info. Trac articles. Ø Info. Trac: Significant Improvement in Spirometry after Stem Cell Transplantation in One Duchenne Muscular Dystrophy Patient. Zhiping Li et al. Chest, Oct. 2005.

Section 7 Sex Influenced Inheritance

Sex Influenced Inheritance Sex-influenced traits either appear more frequently in one sex than the other or the phenotype differs depending on whether the person is male or female. Ø l l Genes for such traits appear on the autosomes. Appearance of the trait may be due to the influence of sex hormones on gene expression.

Sex Influenced Inheritance Ø A male will develop pattern baldness if he is homozygous or heterozygous for a particular gene, but a female will develop the condition only if she is homozygous and then only late in life. Figure 21. 14

Useful References for Section 7 The latest references for topics covered in this section can be found at the book companion website. Log in to the book’s e resources page at www. thomsonedu. com to access Info. Trac articles. Ø Info. Trac: Genetic Variation in the Human Androgen Receptor Gene Is the Major Determinant of Common Early Onset Androgenetic Alopecia. Axel M. Hillmer et al. American Journal of Human Genetics, July 2005.

Section 8 Changes in a Chromosome or Its Genes

Changes in a Chromosome or Its Genes A gene mutation is a change to one or more of the nucleotides that composite a given gene. Ø Various changes in a chromosome’s structure may cause a genetic disorder. Ø

Changes in a Chromosome or Its Genes l A deletion is the loss of part of a chromosome due to breaks caused by viruses, chemicals, or irradiation. • • l Loss of a portion of chromosome 5, for example, causes the disorder cri-du-chat. Normal genes on the homologue can compensate for deleted genes. Duplication occurs when a gene sequence is repeated thousands of times. Figure 21. 15

Animation: Deletion CLICK TO PLAY

Animation: Duplication CLICK TO PLAY

Changes in a Chromosome or Its Genes l A translocation occurs when a part of one chromosome is transferred to a nonhomologous chromosome. • It is seen in some forms of cancer, such as when a segment of chromosome 8 is translocated to chromosome 14.

Animation: Translocation CLICK TO PLAY

Changes in a Chromosome or Its Genes • A chronic type of leukemia is caused by an abnormally long chromosome 9 (Philadelphia chromosome), which is due to a piece of chromosome 22 that has become attached. Figure 21. 17

Useful References for Section 8 The latest references for topics covered in this section can be found at the book companion website. Log in to the book’s e resources page at www. thomsonedu. com to access Info. Trac articles. Ø Five P Minus Society: Family Support Group for Children with Cri du Chat Syndrome Ø BBC: Translocation Ø Info. Trac: Brazilian Researchers Connect Gene Mutation to Blood Conditions. Xinhua News Agency, June 20, 2006.

Section 9 Changes in Chromosome Number

Changes in Chromosome Number Several kinds of events can change the number of chromosomes in gametes. Ø l l Aneuploidy is a condition in which the cells of an affected individual end up with one extra or one less chromosome than is the normal number. Polyploidy is a condition in which new individuals have three or more of each chromosome; it is lethal in humans.

Changes in Chromosome Number Nondisjunction is a common cause of abnormal numbers of autosomes. Ø l Nondisjunction during mitosis or meiosis results in a change in chromosome number. • • If a gamete with an extra chromosome (n + 1) joins a normal gamete at fertilization, the diploid cell will be 2 n + 1; this condition is called trisomy. If an abnormal gamete is missing a chromosome, the zygote will be 2 n – 1: monosomy.

Animation: Nondisjunction CLICK TO PLAY

n+1 n-1 chromosome alignments at metaphase I nondisjunction at anaphase I alignments at metaphase II anaphase II chromosome number in gametes Fig. 21. 18, p. 400

n+1 n-1 chromosome alignments at metaphase I nondisjunction at anaphase I alignments at metaphase II anaphase II chromosome number in gametes Stepped Art Fig. 21. 18, p. 400

Changes in Chromosome Number l Down syndrome results from trisomy 21. • • Trisomy 21 occurs in 1 out of 1, 000 live newborns in North America; children will show some form of mental retardation, and 40% have heart defects. There is an increased probability that a woman over age 35 will conceive an embryo with Down syndrome, yet 80% of trisomic infants are born to younger mothers simply because women ages 18 35 have more babies. Figure 21. 19

Changes in Chromosome Number Nondisjunction also can change the number of sex chromosomes. Ø l Turner syndrome involves females whose cells have only one X chromosome (designated XO). • • Turner’s individuals are sterile and have other phenotypic problems such as premature aging and shorter life expectancy. Approximately 1 in 1, 000 females are XXX; two of the Xs are condensed into Barr bodies, allowing normal development. Figure 21. 20

Changes in Chromosome Number l In Klinefelter syndrome, nondisjunction results in an extra X chromosome in the cells (XXY) of affected males. • l This occurs in about 1 out of 500 live born males and results in mild mental retardation and low fertility. XYY condition: XYY males result from nondisjunction of duplicated Y chromosomes during meiosis. • Affected individuals are taller than average with normal phenotype. Figure 21. 20

Victims of Neurobiological Disorders Ø John Nash; Virginia Woolf Figure 21. 21

Useful References for Section 9 The latest references for topics covered in this section can be found at the book companion website. Log in to the book’s e resources page at www. thomsonedu. com to access Info. Trac articles. Ø Info. Trac: A Very Special Wedding. Claudia Wallis. Time, July 24, 2006. Ø Info. Trac: Common Age Misconception about Down Syndrome. PR Newswire, May 2, 2006.