Human Genetics

Human GeneticsSection 13.3: MutationsSection 14.1: Human ChromosomesSection 14.2: Human Genetic Disorders1

MutationsSection 13.32VocabularyMutationGerm MutationSomatic MutationGene MutationChromosomal MutationPoint Mutation Frameshift MutationDeletionDuplicationInversion TranslocationNondisjunctionMonosmyTrisomyPolyploidy3Types of MutationsMutations are heritable changes in genetic information.A mutation results from a mistake in duplicating genetic information (DNA replication).

4Types of Cells AffectedGerm Mutation - affects a reproductive cell (gamete or sperm/egg)Does not affect the organismPassed to offspringSomatic Mutation affects body cells (all cells except gametes)Not passed to offspring

5Types 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)6MutagensMutations can be caused by chemical or physical agents (mutagens)Chemical pesticides, tobacco smoke, environmental pollutantsPhysical 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.

8Gene Mutations Point mutations include substitutions, insertions, and deletions.

9Substitutions 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.

10Substitution - Silent Mutationa 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 Mutationa 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).

13Sickle Cell AnemiaThe 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 shapeSickle Cell Anemia

Substitution - Nonsense Mutationa 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 nonfunctionalhence the term nonsense mutation.

Substitution

Silent MutationMissense MutationNonsense Mutation18Insertions 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.

19Frameshift MutationInsertions 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.

20Frameshift Mutation:Example:Deletion:THE FAT CAT ATE THE RATTHE FAT ATA TET HER ATInsertion:THE FAT CAT ATE THE RATTHE FAT CAR TAT ETH ERA T

21Insertions

22Deletions

23Muscular DystrophyBoth Duchenne muscular dystrophy and Becker muscular dystrophy result from mutations of a gene on the X chromosome that codes for the dystrophin protein in muscle cells; this protein helps to stabilize the plasma membrane during the mechanical stresses of muscle contraction. About 2/3 of cases are due to deletion mutations. If the number of nucleotides deleted in the mRNA is not a multiple of three, this type of frameshift mutation results in a severely defective or absent version of the protein, resulting in more rapid breakdown of muscle cells and the more severe Duchenne muscular dystrophy. If the number of nucleotides deleted in the mRNA is a multiple of three, the mutation does not cause a frameshift and this typically results in a less defective version of the protein, less rapid breakdown of muscle cells, and the milder Becker muscular dystrophy. Up to one-fifth of cases of Duchenne muscular dystrophy are caused by a nonsense mutation (a point mutation that results in a stop codon).

Muscular DystrophyBecause the dystrophin gene is on the X chromosome and because the alleles for defective dystrophin are recessive, both of these types of muscular dystrophy are much more common in boys than in girls. Duchenne muscular dystrophy affects one in every 3500 male babies.

Gene Mutations:

26Chromosomal 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.

27Chromosomal Mutations Deletion involves the loss of all or part of a chromosome.

28Chromosomal DeletionExample: Cri-du-chat (5p minus) a piece of chromosome 5

29Cri du chat (cry of the cat)named for the distinctive cry affected infants make due in part to malformations of the larynxintellectual disability/delayed developmentsmall head size (microcephaly), low birth weightweak muscle tone (hypotonia) in infancywidely set eyes (hypertelorism)low-set earsa small jawa rounded face heart defect

Chromosomal Mutations Duplication produces an extra copy of all or part of a chromosome.

31Chromosomal Duplication

32Fragile X - Most people have 5-40 "repeats" at this end of their X-chromosome, those with Fragile X have over 200 repeats due to duplications

Fragile XFMR1 gene where a DNA segment, known as the CGG triplet repeat, is expanded The abnormally expanded CGG segment inactivates (silences) the FMR1 gene, which prevents the gene from producing a protein called fragile X mental retardation protein. Loss of this protein leads to the signs and symptoms of fragile X syndrome. Both boys and girls can be affected, but because boys have only one X chromosome, a single fragile X is likely to affect them more severely.Boys will have moderate mental retardation, a large head size, a long face, prominent forehead and chin and protruding ears, loose joints. Affected boys may have behavioral problems such as hyperactivity, hand flapping, hand biting, temper tantrums and autism. Other behaviors in boys after they have reached puberty include poor eye contact, perseverative speech, problems in impulse control and distractibility. Physical problems that have been seen include eye, orthopedic, heart and skin problems.Girls will have mild mental retardation.Family members who have fewer repeats in the FMR1 gene may not have mental retardation, but may have other problems. Women with less severe changes may have premature menopause or difficulty becoming pregnant.Fruit flies experience a change in eye size of when duplication occurs.

Chromosomal Mutations Inversion reverses the direction of parts of a chromosome.

36Chromosomal Inversion

37Inversions

The most common inversion seen in humans is on chromosome 9. This inversion is generally considered to have no harmful effects, but there is some suspicion it could lead to an increased risk for miscarriage or infertility for some affected individuals.

An inversion does not involve a loss of genetic information, but simply rearranges the linear gene sequence.Chromosomal Mutations Translocation occurs when part of one chromosome breaks off and attaches to another. Example: acute meyloid leukemia

39TranslocationAcute Meyloid Leukemia (AML)Between chromosome 8 and 21is a cancer of the myeloid line of blood cellscharacterized by the rapid growth of abnormal WBC that accumulate in the bone marrow and interfere with the production of normal WBCChromosomal Translocation

41NondisjunctionChromosomal mutations that involve whole chromosomes or complete sets of chromosomes results from a process known as nondisjunctionThis is the failure of homologous chromosomes to separate normally during meiosis.42Nondisjunction

43Nondisjunction

44Nondisjunction

45Effects of NondisjunctionIf one chromosome is involved, the condition of one extra is called trisomy or one less is monosomy

46Trisomy 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

Edwards 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 intelligence98% of these fetuses die before birth

Klinefelter Syndrome (XXY)Affects male sex organs (small testes, sterile). feminine body characteristics. Normal intelligence.

NondisjunctionIf 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)53Beneficial 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.

54Beneficial Effects Polyploid plants are often larger and stronger than diploid plants.Important crop plantsincluding bananas and limeshave been produced this way.Polyploidy also occurs naturally in citrus plants, often through spontaneous mutations.55Harmful and Helpful MutationsThe 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 organisms 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.

56Harmful 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 bloods principal oxygen-carrying protein.Among the symptoms of the disease are anemia, severe pain, frequent infections, and stunted growth.

57Substitution

58Beneficial 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.

59Human ChromosomesSection 14.160VocabularyKaryotypeSex ChromosomesAutosomesLinked GenesSex-Linked InheritancePedigree

61KaryotypesA 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.

62KaryotypesA karyotype from a typical human cell, which contains 46 chromosomes, is arranged in 23 pairs.

63Sex Chromosomes Two of the 46 chromosomes in the human genome are known as sex chromosomes, because they determine an individuals sex.Females have two copies of the X chromosome.Males have one X chromosome and one Y chromosome.

64Sex 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.

65Sex 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.

66Autosomal 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.

67Linked GenesGenes on chromosomes are linked together & inherited togetherChromosomes assort independently, not individual genes

68Gene MappingIn 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 MappingBy 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.Sturtevants 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.

71Sex-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.

http://www.colourblindawareness.org/

72X-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.

73Human PedigreesTo 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.

74Human Genetic DisordersSection 14.275THINK 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?76Genetic DisordersChromosomal DisordersSingle Gene DisordersDown SyndromeTurner SyndromeKlinefelters SyndromeJacobsonsSickle Cell DiseaseCystic FibrosisHuntingtons77Chromosomal DisordersThe 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:Autosomes: chromosome pairs 1-22Sex Chromosomes: chromosome pair 23

Down SyndromeTurner SyndromeKlinefelters SyndromeJacobsons

79Chromosomal DisordersIf 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.

Trisomy 21

Chromosomal DisordersNondisjunction of the X chromosomes can lead to a disorder known as Turners syndrome (Monosomy X). A female with Turners syndrome usually inherits only one X chromosome. Women with Turners syndrome are sterile, which means that they are unable to reproduce. Their sex organs do not develop properly at puberty.

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 sterileShort stature and normal intelligence98% of these fetuses die before birth

Chromosomal DisordersIn males, nondisjunction may cause Klinefelters syndrome, resulting from the inheritance of an extra X chromosome (XXY), 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.

Klinefelter Syndrome (XXY)Affects male sex organs (small testes, sterile). feminine body characteristics. Normal intelligence.

Jacobsenscaused by a loss of genetic material from chromosome 11 - deletion occurs at the end of the long arm of chromosome 11The signs and symptoms vary:delayed development, including the development of motor skills (such as sitting, standing, and walking) and speech. cognitive impairment and learning difficulties. behavioral problems and attention deficit-hyperactivity disorder (ADHD).small and low-set ears, widely set eyes) with droopy eyelids, skin folds covering the inner corner of the eyes a broad nasal bridge, downturned corners of the mouth, a thin upper lip, and a small lower jaw, large head size and a skull abnormality, which gives the forehead a pointed appearance.bleeding disorder called Paris-Trousseau syndrome - causes a lifelong risk of abnormal bleeding and easy bruising. heart defects, feeding difficulties in infancy, short stature, frequent ear and sinus infections, and skeletal abnormalities, can also affect the digestive system, kidneys, and genitalia. The life expectancy of people with Jacobsen syndrome is unknown, although affected individuals have lived into adulthood.

From Molecule to PhenotypeThere 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 genes DNA sequence can change proteins by altering their amino acid sequences, which may directly affect ones phenotype.

87Patterns of Inheritance:Autosomal RecessiveAutosomal DominantSex-Linked (X-Linked)88Autosomal Recessive Pedigree:Examples: Sickle Cell Anemia,Cystic Fibrosis, Albinism,

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IIIIIIAutosomal Recessive Pedigree:Sickle Cell Anemia

Sickle Cell AnemiaA 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 shapeHemoglobin = the oxygen-carrying protein in red blood cells.The defective polypeptide makes hemoglobin less soluble, causing hemoglobin molecules to stick together when the bloods oxygen level decreases. The molecules clump into long fibers, forcing cells into a distinctive sickle shape, which gives the disorder its name.Sickle Cell (1 min)Sickle Cell Tutorial (5 min)

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.

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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.

95Genetic 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 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.

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.

98Cystic Fibrosis CFTR normally allows chloride ions (Cl) to pass across cell membranes.The loss of these bases removes a single amino acidphenylalaninefrom CFTR, causing the protein to fold improperly.

99Cystic 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.

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, andbecause they also carried a normal allelethese individuals would not have suffered from cystic fibrosis.

Autosomal Dominant

Examples: Huntingtons Disease, Achondroplasia, Polydactyly

IIIIIIAutosomal Dominant Pedigree:Huntingtons Disease Huntingtons 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 Huntingtons disease progressive breakdown (degeneration) of nerve cells in the brainbroad impact on a person's functional abilities and usually results in movement, thinking (cognitive) and psychiatric disorders namely mental deterioration and uncontrollable movementsusually does not appear until middle age. The greater the number of codon repeats, the earlier the disease appears, and the more severe are its symptoms.

Huntington's Disease - CA Stem Cell Agency

Achondroplasiaa skeletal disorder, which is characterized by the failure of normal conversion of cartilage into bone that begins during fetal life and causes dwarfism.About 80 percent of people with achondroplasia have average-size parents; these cases result from new mutations in the FGFR3 gene. Achondroplasia

Polydactylya condition in which a person has more than five fingers per hand or five toes per foot

Sex-Linked Pedigree:Examples: Colorblindness, Hemophilia, Muscular Dystrophy

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IIIIIISex-Linked Pedigree:Sex-Linked Pedigree: