Transcript Mutations
Human Genetics Section 13.3: Mutations Section 14.1: Human Chromosomes Section 14.2: Human Genetic Disorders Mutations Section 13.3 Vocabulary Mutation Germ Mutation Somatic Mutation Gene Mutation Chromosomal Mutation Point Mutation Frameshift Mutation Deletion Duplication Inversion Translocation Nondisjunction Monosmy Trisomy Polyploidy Types of Mutations Mutations are heritable changes in genetic information. A mutation results from a mistake in duplicating genetic information (DNA replication). Types of Cells Affected Germ Mutation - affects a reproductive cell (gamete or sperm/egg) ◦ Does not affect the organism ◦ Passed to offspring Somatic Mutation – affects body cells (all cells except gametes) ◦ Not passed to offspring Types of Mutations All mutations fall into two basic categories: ◦ Those that produce changes in a single gene are known as gene mutations. ◦ Those that produce changes in a part of a chromosome, whole chromosomes, or sets of chromosomes are known as chromosomal mutations. Ameoba Sisters – Mutations (7 min) Mutagens Mutations can be caused by chemical or physical agents (mutagens) ◦ Chemical – pesticides, tobacco smoke, environmental pollutants ◦ Physical – X-rays and ultraviolet light Gene Mutations Mutations that involve changes in one or a few nucleotides are known as point mutations because they occur at a single point in the DNA sequence. They generally occur during replication. If a gene in one cell is altered, the alteration can be passed on to every cell that develops from the original one. Gene Mutations Point mutations include substitutions, insertions, and deletions. Substitutions In a substitution, one base is changed to a different base. Substitutions usually affect no more than a single amino acid, and sometimes they have no effect at all. Substitution - Silent Mutation a change in one base pair has no effect on the protein produced by the gene. ◦ This is allowed for by the redundancy in the genetic code. Example (as shown in picture): ◦ Both GGC and GGU code for the amino acid glycine. ◦ Thus, the mutation is “silent,” i.e. causes no change in the final protein product. Substitution - Missense Mutation a change in one base pair causes a single amino acid to be changed in the resulting protein. ◦ The result is called “missense” since the code is now different. In the following example, GGC has been changed to AGC, resulting in a different amino acid. Substitutions - Missense In this example, the base cytosine is replaced by the base thymine, resulting in a change in the mRNA codon from CGU (arginine) to CAU (histidine). Sickle Cell Anemia The effect of a missense mutation on the protein is unpredictable. A missense mutation is the cause of the disease, sickle cell anemia. ◦ a change in one base pair alters one amino acid ◦ effects hemoglobin protein, causing red blood cells to take on a strange shape Sickle Cell Anemia Substitution - Nonsense Mutation a change in a single base pair creates a stop codon. Because this kind of mutation creates a stop signal in the middle of a normally functional gene, the resulting protein is almost always nonfunctional ◦ hence the term “nonsense” mutation. Substitution Silent Mutation Missense Mutation Nonsense Mutation Insertions and Deletions Insertions and deletions are point mutations in which one base is inserted or removed from the DNA sequence. If a nucleotide is added or deleted, the bases are still read in groups of three, but now those groupings shift in every codon that follows the mutation. Frameshift Mutation Insertions and deletions are also called frameshift mutations because they shift the “reading frame” of the genetic message. Frameshift mutations can change every amino acid that follows the point of the mutation and can alter a protein so much that it is unable to perform its normal functions. Frameshift Mutation: Example: ◦ Deletion: THE FAT CAT ATE THE RAT THE FAT ATA TET HER AT ◦ Insertion: THE FAT CAT ATE THE RAT THE FAT CAR TAT ETH ERA T Insertions Deletions Gene Mutations: Chromosomal Mutations Chromosomal mutations involve changes in the number or structure of chromosomes. These mutations can change the location of genes on chromosomes and can even change the number of copies of some genes. Chromosomal Mutations Deletion involves the loss of all or part of a chromosome. Chromosomal Deletion Example: Cri-du-chat (5p minus) – a piece of chromosome 5 Cri du chat intellectual disability/delayed development small head size (microcephaly), low birth weight weak muscle tone (hypotonia) in infancy widely set eyes (hypertelorism) low-set ears a small jaw a rounded face heart defect Chromosomal Mutations Duplication produces an extra copy of all or part of a chromosome. Chromosomal Duplication Fragile X - Most people have 29 "repeats" at this end of their Xchromosome, those with Fragile X have over 700 repeats due to duplications Fruit flies experience a change in eye size of when duplication occurs. Chromosomal Mutations Inversion reverses the direction of parts of a chromosome. Chromosomal Inversion Chromosomal Mutations Translocation occurs when part of one chromosome breaks off and attaches to another. Example: acute meyloid leukemia Chromosomal Translocation Inversions Nondisjunction Chromosomal mutations that involve whole chromosomes or complete sets of chromosomes results from a process known as nondisjunction ◦ This is the failure of homologous chromosomes to separate normally during meiosis. Nondisjunction Nondisjunction Nondisjunction Effects of Nondisjunction If one chromosome is involved, the condition of one extra is called trisomy or one less is monosomy Trisomy 21 Patau Syndrome (trisomy 13) serious eye, brain, circulatory defects as well as cleft palate. 1:5000 live births. Children rarely live more than a few months Edward’s Syndrome (trisomy 18) almost every organ system affected 1:10,000 live births. Children generally do not live more than a few months Trisomy X (XXX) females. 1:1000 live births healthy and fertile - usually cannot be distinguished from normal female except by karyotype Monosomy X aka Turner Syndrome the only viable monosomy in humans only 45 chromosomes genetically female, however, they do not mature sexually during puberty and are sterile. Short stature and normal intelligence 98% of these fetuses die before birth Klinefelter Syndrome (XXY) Affects male sex organs (small testes, sterile). feminine body characteristics. Normal intelligence. Nondisjunction If nondisjunction involves a set of chromosomes: The condition in which an organism has extra sets of chromosomes is called polyploidy. ◦ Triploid (3n) ◦ Tetraploid (4n) ◦ Polyploid (many sets) Beneficial Effects Plant and animal breeders often make use of “good” mutations. For example, when a complete set of chromosomes fails to separate during meiosis, the gametes that result may produce triploid (3N) or tetraploid (4N) organisms. Beneficial Effects Polyploid plants are often larger and stronger than diploid plants. Important crop plants—including bananas and limes—have been produced this way. Polyploidy also occurs naturally in citrus plants, often through spontaneous mutations. Harmful and Helpful Mutations The effects of mutations on genes vary widely. Some have little or no effect; and some produce beneficial variations. Some negatively disrupt gene function. Whether a mutation is negative or beneficial depends on how its DNA changes relative to the organism’s situation. Mutations are often thought of as negative because they disrupt the normal function of genes. However, without mutations, organisms cannot evolve, because mutations are the source of genetic variability in a species. Harmful Effects Sickle cell disease is a disorder associated with changes in the shape of red blood cells. Normal red blood cells are round. Sickle cells appear long and pointed. Sickle cell disease is caused by a point mutation in one of the polypeptides found in hemoglobin, the blood’s principal oxygen-carrying protein. Among the symptoms of the disease are anemia, severe pain, frequent infections, and stunted growth. Substitution Beneficial Effects Some of the variation produced by mutations can be highly advantageous to an organism or species. Mutations often produce proteins with new or altered functions that can be useful to organisms in different or changing environments. For example, mutations have helped many insects resist chemical pesticides. Some mutations have enabled microorganisms to adapt to new chemicals in the environment. Human Chromosomes Section 14.1 Vocabulary Karyotype Sex Chromosomes Autosomes Linked Genes Sex-Linked Inheritance Pedigree Karyotypes A karyotype shows the complete diploid set of chromosomes grouped together in pairs, arranged in order of decreasing size. To see human chromosomes clearly, cell biologists photograph cells in mitosis, when the chromosomes are fully condensed and easy to view. Karyotypes A karyotype from a typical human cell, which contains 46 chromosomes, is arranged in 23 pairs. Sex Chromosomes Two of the 46 chromosomes in the human genome are known as sex chromosomes, because they determine an individual’s sex. Females have two copies of the X chromosome. Males have one X chromosome and one Y chromosome. Sex Chromosomes This Punnett square illustrates why males and females are born in a roughly 50 : 50 ratio. All human egg cells carry a single X chromosome (23,X). However, half of all sperm cells carry an X chromosome (23,X) and half carry a Y chromosome (23,Y). This ensures that just about half the zygotes will be males and half will be females. Sex Chromosomes More than 1200 genes are found on the X chromosome, some of which are shown. The human Y chromosome is much smaller than the X chromosome and contains only about 140 genes, most of which are associated with male sex determination and sperm development. Autosomal Chromosomes The remaining 44 human chromosomes are known as autosomal chromosomes, or autosomes. The complete human genome consists of 46 chromosomes, including 44 autosomes and 2 sex chromosomes. To quickly summarize the total number of chromosomes present in a human cell, biologists write 46,XX for females and 46,XY for males. Linked Genes Genes on chromosomes are linked together & inherited together Chromosomes assort independently, not individual genes Gene Mapping In 1911, Columbia University student Alfred Sturtevant wondered if the frequency of crossing-over between genes during meiosis might be a clue to the genes’ locations. Sturtevant reasoned that the farther apart two genes were on a chromosome, the more likely it would be that a crossover event would occur between them. If two genes are close together, then crossovers between them should be rare. If two genes are far apart, then crossovers between them should be more common. Gene Mapping By this reasoning, he could use the frequency of crossing-over between genes to determine their distances from each other. Sturtevant gathered lab data and presented a gene map showing the relative locations of each known gene on one of the Drosophila chromosomes. Sturtevant’s method has been used to construct gene maps ever since this discovery. Sex-Linked Inheritance The genes located on the X and Y chromosomes show a pattern of inheritance called sex-linked. A sex-linked gene is a gene located on a sex chromosome. Genes on the Y chromosome are found only in males and are passed directly from father to son. Genes located on the X chromosome are found in both sexes, but the fact that men have just one X chromosome leads to some interesting consequences. Sex-Linked Inheritance For example, humans have three genes responsible for color vision, all located on the X chromosome. In males, a defective allele for any of these genes results in colorblindness, an inability to distinguish certain colors. The most common form, red-green colorblindness, occurs in about 1 in 12 males. Among females, however, colorblindness affects only about 1 in 200. In order for a recessive allele, like colorblindness, to be expressed in females, it must be present in two copies—one on each of the X chromosomes. The recessive phenotype of a sex-linked genetic disorder tends to be much more common among males than among females. X-Chromosome Inactivation If just one X chromosome is enough for cells in males, how does the cell “adjust” to the extra X chromosome in female cells? In female cells, most of the genes in one of the X chromosomes are randomly switched off, forming a dense region in the nucleus known as a Barr body. Barr bodies are generally not found in males because their single X chromosome is still active. Human Pedigrees To analyze the pattern of inheritance followed by a particular trait, you can use a chart, called a pedigree, which shows the relationships within a family. A pedigree shows the presence or absence of a trait according to the relationships between parents, siblings, and offspring. Human Genetic Disorders Section 14.2 THINK ABOUT IT Have you ever heard the expression “It runs in the family”? Relatives or friends might have said that about your smile or the shape of your ears, but what could it mean when they talk of diseases and disorders? What is a genetic disorder? Chromosomal Disorders Single Gene Disorders Down Syndrome Turner Syndrome Klinefelter’s Syndrome Jacobson’s Sickle Cell Disease Cystic Fibrosis Huntington’s Genetic Disorders Chromosomal Disorders The most common error in meiosis occurs when homologous chromosomes fail to separate. This mistake is known as nondisjunction, which means “not coming apart.” Nondisjunction may result in gametes with an abnormal number of chromosomes, which can lead to a disorder of chromosome numbers. Karyotype: Down Syndrome Turner Syndrome Klinefelter’s Syndrome Jacobson’s Chromosomal Disorders If two copies of an autosomal chromosome fail to separate during meiosis, an individual may be born with three copies of that chromosome. This condition is known as a trisomy, meaning “three bodies.” The most common form of trisomy, involving three copies of chromosome 21, is Down syndrome, which is often characterized by mild to severe mental retardation and a high frequency of certain birth defects. Chromosomal Disorders Nondisjunction of the X chromosomes can lead to a disorder known as Turner’s syndrome. A female with Turner’s syndrome usually inherits only one X chromosome. Women with Turner’s syndrome are sterile, which means that they are unable to reproduce. Their sex organs do not develop properly at puberty. Chromosomal Disorders In males, nondisjunction may cause Klinefelter’s syndrome, resulting from the inheritance of an extra X chromosome, which interferes with meiosis and usually prevents these individuals from reproducing. There have been no reported instances of babies being born without an X chromosome, indicating that this chromosome contains genes that are vital for the survival and development of the embryo. From Molecule to Phenotype There is a direct connection between molecule and trait, and between genotype and phenotype. In other words, there is a molecular basis for genetic disorders. Changes in a gene’s DNA sequence can change proteins by altering their amino acid sequences, which may directly affect one’s phenotype. Patterns of Inheritance: 1. Autosomal Dominant 2. Autosomal Recessive 3. Sex-Linked (X-Linked) Autosomal Dominant • Huntington’s, Achondroplasia. Polydactyly, Myopia Huntington’s Disease Huntington’s disease is caused by a dominant allele for a protein found in brain cells. The allele for this disease contains a long string of bases in which the codon CAG—coding for the amino acid glutamine—repeats over and over again, more than 40 times. Despite intensive study, the reason why these long strings of glutamine cause disease is still not clear. The symptoms of Huntington’s disease, namely mental deterioration and uncontrollable movements, usually do not appear until middle age. The greater the number of codon repeats, the earlier the disease appears, and the more severe are its symptoms. Autosomal Recessive Pedigree: Albinism, Cystic Fibrosis, Phenylketonuria, Sickle Cell Anemia, Tay Sachs Sickle Cell Disease This disorder is caused by a defective allele for betaglobin, one of two polypeptides in hemoglobin, the oxygen-carrying protein in red blood cells. The defective polypeptide makes hemoglobin less soluble, causing hemoglobin molecules to stick together when the blood’s oxygen level decreases. The molecules clump into long fibers, forcing cells into a distinctive sickle shape, which gives the disorder its name. Sickle Cell Disease Sickle-shaped cells are more rigid than normal red blood cells, and they tend to get stuck in the capillaries. If the blood stops moving through the capillaries, damage to cells, tissues, and even organs can result. Cystic Fibrosis Cystic fibrosis (CF) is most common among people of European ancestry. Most cases result from the deletion of just three bases in the gene for a protein called cystic fibrosis transmembrane conductance regulator (CFTR). As a result, the amino acid phenylalanine is missing from the protein. Cystic Fibrosis CFTR normally allows chloride ions (Cl−) to pass across cell membranes. The loss of these bases removes a single amino acid— phenylalanine—from CFTR, causing the protein to fold improperly. Cystic Fibrosis People with one normal copy of the CF allele are unaffected by CF, because they can produce enough CFTR to allow their cells to work properly. Two copies of the defective allele are needed to produce the disorder, which means the CF allele is recessive. Sex-Linked Pedigree: Colorblindness, Hemophilia, Muscular Dystrophy Genetic Advantages Disorders such as sickle cell disease and CF are still common in human populations. In the United States, the sickle cell allele is carried by approximately 1 person in 12 of African ancestry, and the CF allele is carried by roughly 1 person in 25 of European ancestry. Genetic Advantages Most African Americans today are descended from populations that originally lived in west central Africa, where malaria is common. Malaria is a mosquito-borne infection caused by a parasite that lives inside red blood cells. Genetic Advantages Individuals with just one copy of the sickle cell allele are generally healthy, and are also highly resistant to the parasite, giving them a great advantage against malaria. The upper map shows the parts of the world where malaria is common. The lower map shows regions where people have the sickle cell allele. Genetic Advantages More than 1000 years ago, the cities of medieval Europe were ravaged by epidemics of typhoid fever. Typhoid is caused by a bacterium that enters the body through cells in the digestive system. The protein produced by the CF allele helps block the entry of this bacterium. Individuals heterozygous for CF would have had an advantage when living in cities with poor sanitation and polluted water, and—because they also carried a normal allele—these individuals would not have suffered from cystic fibrosis.