A 9744.2.4 Mutations Lecture Notes_2024.pdf

CATHOLIC JUNIOR COLLEGE H2 Biology JC1 CORE IDEA 2] GENETICS AND INHERITANCE 2.4 DNA MUTATIONS Narrative: Mutation arises from imperfect replication of genetic information; together with other biological processes, such mutations increase genetic variation. Based on the central do...

CATHOLIC JUNIOR COLLEGE H2 Biology JC1 CORE IDEA 2] GENETICS AND INHERITANCE 2.4 DNA MUTATIONS Narrative: Mutation arises from imperfect replication of genetic information; together with other biological processes, such mutations increase genetic variation. Based on the central dogma, a change in the sequence of the DNA nucleotide, i.e. gene mutation, may affect the amino acid sequence in the polypeptide and hence the phenotype of the organism. Many mutations are detrimental to the individual. They may give rise to dysfunctional proteins and affect the normal functioning of the normal gene product, resulting in genetic diseases such as sickle cell anaemia. Others are neutral, often because they have no effect on the phenotype, e.g. a change in a DNA triplet may not change the amino acid inserted into a polypeptide. Occasionally, mutations may be beneficial. For example, individuals that are heterozygous for a mutated haemoglobin gene that causes sickle cell anaemia have a selective advantage in areas where malaria is common. Besides mutation of genes, chromosomal mutation and changes in chromosome number may also occur. Down syndrome arises due to the presence of an additional copy of chromosome 21. Mutation, meiosis and sexual reproduction give rise to genetic variation within a population. LEARNING OUTCOMES Candidates should be able to: Subtopic Learning Outcomes Gene 2(l) Explain what is meant by the term gene mutation (and chromosomal aberration.) Mutations For gene mutation, knowledge of how substitution, addition, deletion could change and Genetic the amino acid sequence (e.g. including frameshift) is required. Diseases 2(m) Explain how gene mutations can result in diseases (including sickle cell anaemia). Chromosomal 2(l) Explain what is meant by the term gene mutation and chromosome aberration. Aberration For chromosomal aberration, knowledge of numerical aberration (e.g. including aneuploidy, as in the case of trisomy 21, i.e. Down syndrome) and structural aberration (including translocation, duplication, inversion, deletion) is required. CONTENT PAGE CONCEPT MAPS 2-3, 20 1 GENE MUTATION 4 – 11 1.1 Base-Pair Substitution, Addition and Deletion 5 1.2 Mutation effects: Silent, Missense, Nonsense & Frameshift 6 2 GENE MUTATIONS AND EXAMPLE OF DISEASES 11 – 18 2.1 Consequence of gene mutations on cellls 11 2.2 Substitution : Sickle Cell Anemia* 14 2.3 Deletion : Cystic Fibrosis (FYI only) 17 3 CHROMOSOMAL ABERRATION (MUTATION) 19 – 26 3.1 Numerical Aberration : Aneuploidy, Polyploidy 20 3.2 Structural Aberration : Deletion, Duplication, Inversion, Translocation 24 4 HUMAN DISORDERS DUE TO CHROMOSOMAL ABERRATION 26 – 28 4.1 Numerical Aberration : Down Syndrome * (Trisomy 21) 26 4.2 Structural Aberration : Cri-Du-Chat Syndrome (Deletion); Chronic Myeloid Leukaemia 27-28 (Translocation) (FYI only) 5 APPENDIX: GENETIC CODE 29 @ Biology Department Catholic Junior College 1 CONCEPT MAP Concept Map 1: Types of Mutations and the Genetic Outcomes GERM-LINE mutation SOMATIC mutation Fig. 1: Comparison of Germ Line Mutations and Somatic Mutations @ Biology Department Catholic Junior College 2 CONCEPT MAP How does the genetic make-up of an organism and the environment influence the organism's appearance, behaviour and survival? How does the inheritance of genetic information ensure continuity of humans as a species? Concept Map 2: Impact of Mutations on the Individuals and Species @ Biology Department Catholic Junior College 3 1] GENE MUTATION Fig. 2: The gene product may be a polypeptide or RNA A gene is a specific length of DNA coding for a functional product (either a polypeptide or RNA) occupying a position on a chromosome Eye colour gene Brown called a locus. The DNA base sequence of the gene determines the linear amino acid sequence, which in turn determine the structure and shape of the protein. Hair colour gene Hazel Fig. 3: A gene determines the phenotype of a trait Gene mutation is a change in the sequence of DNA nucleotides of a gene. There 3 main causes for mutations: i) Spontaneous mutation (randomly occurring) ii) DNA replication errors (more common in prokaryotes without proofreading) iii) Mutagens (e.g. UV light, chemicals, carcinogens) Point mutation refers to a mutation affecting only one or very few DNA nucleotides within the gene. Point mutation may occur anywhere in the promoter, intron and exon regions of the gene, resulting in different consequences of gene expression. Point mutations can be divided into three main categories*: i) nucleotide-pair / base-pair Substitution ii) nucleotide-pair / base-pair Addition (insertion) or iii) nucleotide-pair / base-pair Deletion *To help you to remember the 3 types of gene mutation, remember SAD (nucleotide-pair Substitution, Addition or Deletion) @ Biology Department Catholic Junior College 4 1.1 BASE-PAIR SUBSTITUTION, ADDITION & DELETION 1.1.1 BASE-PAIR SUBSTITUTION: (a) A single nucleotide-pair / base-pair substitution is the replacement of one nucleotide and its complementary base from the other DNA strand by another pair of nucleotides. (b) A single nucleotide-pair / base-pair substitution at exon regions changes the base sequence on the mRNA and may eventually change the amino acid that is coded by the genetic code. (c) The consequence or effect on the gene product (protein) can be: I. Silent II. Missense III. Nonsense SINGLE BASE-PAIR SUBSTITUTION or Normal Fig. 4: The effect of a nucleotide-pair / base-pair substitution mutation 1.1.2 BASE-PAIR ADDITION / DELETION: (a) Nucleotide-pair / base-pair additions or deletions are additions or losses of one or more nucleotides in a sequence of nucleotides in a gene. (b) A single nucleotide-pair / base-pair addition or deletion at exon regions changes the base sequence on the mRNA and this usually results in the sequence from the change onwards being read entirely different due to the triplet genetic code. (d) The consequence or effect on the gene product (protein) can be: I. Frameshift II. Nonsense @ Biology Department Catholic Junior College 5 1.2.1 MUTATION EFFECTS: SILENT MUTATION 1.2.1 SILENT MUTATION (a) A silent mutation means that the DNA mutation had no effect on the encoded protein. (b) This is usually caused by a single DNA base-pair substitution. (c) The change in a nucleotide-pair changed one codon into another that is translated into the same amino acid as the original codon. (d) For example, if 3’-CCG-5’ on the DNA template strand is mutated to 3’-CCA-5’, the mRNA codon that used to be GGC would become GGU, and a glycine would still be coded for at the same location in the polypeptide (Fig. 5). This occurs most commonly when the third nucleotide of a codon is substituted with a different nucleotide. Due to the degeneracy of the genetic code, mutations that result in silent mutations do not alter the amino acid sequence of the polypeptide even though the DNA sequence has changed. DNA template strand DNA coding strand mRNA polypeptide DNA template strand DNA coding strand mRNA polypeptide Fig. 5: Single base-pair substitution resulting in a silent mutation @ Biology Department Catholic Junior College 6 1.2.2 MUTATION EFFECTS: MISSENSE MUTATION 1.2.2 MISSENSE MUTATION (a) In DNA mutation that results in missense mutation, there is an alteration in only one amino acid in the polypeptide chain (Fig. 6). Note: Sense is referring to the fact that the DNA / polypeptide sequence makes “sense”. Hence a “mis-sense” mutation implies “wrong sense”. (b) This is usually caused by a single DNA base-pair substitution. (c) A change in the DNA sequence changes a single codon on the mRNA, resulting in an amino acid replaced by a different amino acid in the resulting polypeptide sequence. (d) The amino acid that was replaced may have an R-group with a different property. (e) For example, if an amino acid with non-polar R-group (Proline) is replaced with another amino acid with charged R-group (Histidine), it may affect the intra- molecular interactions that maintain the functional shape of the protein. (f) Hence, a missense mutation may alter the property and function of the original protein. (g) For example, if the binding or catalytic amino acid(s) at the active site of an enzyme is replaced, the activity of the enzyme is significantly affected. This leads to loss of function of the enzyme. (h) Another well known example of a missense mutation occurs in the human sickle cell anaemia disease. Original DNA coding sequence that determines the amino acid sequence DNA template strand amino acid Replacement of a Histidine single nucleotide Incorrect amino acid, which may produce a malfunctioning protein Fig. 6: Single base-pair substitution resulting in a missense mutation @ Biology Department Catholic Junior College 7 1.2.3 MUTATION EFFECTS: NONSENSE MUTATION 1.2.3 NONSENSE MUTATION (a) A mutation resulting in nonsense mutation involves a change of a codon from one that codes for an amino acid into a STOP codon. Note: Sense is referring to the fact that the DNA / polypeptide sequence makes “sense”. Hence a “non-sense” mutation implies “no sense”. (b) This is usually caused by a single base-pair substitution but can also be caused by base-pair addition or deletion that results in a codon being changed into a stop codon. (c) Nonsense mutation causes translation to be terminated prematurely, hence producing a truncated polypeptide that is shorter than the polypeptide encoded by the normal gene, therefore highly unlikely to function properly. (d) Nearly all nonsense mutations lead to non-functional proteins. Original DNA coding sequence that determines the amino acid sequence DNA coding strand amino acid Replacement of a single nucleotide polypeptide Incorrect sequence causes shortening / truncation of protein Fig. 7: Single base-pair substitution resulting in a nonsense mutation @ Biology Department Catholic Junior College 8 1.2.4 MUTATION EFFECTS: FRAMESHIFT MUTATION 1.2.4 FRAMESHIFT MUTATION (a) When addition or deletion mutations add or remove the number of nucleotides that are not in multiples of three, this results in a frameshift mutation: The genetic code on the mRNA is read as a series of nucleotide triplets during translation, the addition or deletion of nucleotides may alter the reading frame (triplet grouping) of the genetic message. All nucleotides that are downstream of the addition or deletion will be grouped into different codons, resulting in a completely different sequence of amino acids after the addition / deletion (see Fig. 9). Analogy: YOU HAD ONE JOB BUT NOW NOT YOU HAD XON EJO BBU TNO WNO T The result will be extensive missense and can even be accompanied by the generation of a stop codon and premature termination of the polypeptide chain. (b) Frameshift mutations due to addition / deletion mutations have a disastrous effect on the resulting protein more often than the effects caused by base-pair substitutions. (c) Unless the frameshift is very near the end of a gene, it will produce a protein that is almost certain to be non-functional. @ Biology Department Catholic Junior College 9 1.2.4 MUTATION EFFECTS: FRAMESHIFT MUTATION Original DNA coding sequence that determines the amino acid sequence DNA coding strand amino acid Insertion of a single nucleotide Incorrect amino acid sequence, which may produce a malfunctioning protein Fig. 8: Single base-pair addition/insertion resulting in a frameshift mutation Original DNA coding sequence that determines the amino acid sequence DNA coding strand amino acid Deletion of a single nucleotide Incorrect amino acid sequence, which may produce a malfunctioning protein Fig. 9: Single base-pair deletion resulting in a frameshift mutation @ Biology Department Catholic Junior College 10 GENE MUTATION What type of mutation has occurred in each example? @ Biology Department Catholic Junior College 11 2] GENE MUTATIONS AND DISEASES Fig. 10: Gene mutations lead to altered gene product and phenotype (a) A change in the sequence of DNA nucleotides in a gene (gene mutations) may change the sequence of amino acids in a polypeptide; leading to the production of an abnormal or non- functional product. This may subsequently affect the phenotype (observable traits) of an organism. Gene mutations can also result in heritable diseases. [This occurs when the gene mutations occur in the gametes (egg and sperm cells) or germ cells (cells producing gametes). As a result, these mutations can be passed down to future generations.] (b) Diseases that are caused by gene mutations include: Sickle Cell Anemia [example in the syllabus] Cystic Fibrosis [FYI only] @ Biology Department Catholic Junior College 12 2.1 CONSEQUENCES OF GENE MUTATIONS ON CELLS Proteins have many roles and functions in the cells. Some examples are enzymes, hormones, receptors, haemoglobin, channel / carrier proteins etc. Gene mutations may be random and have different consequences on cellular functions, some of which may be advantageous, but more often than not they are disadvantageous or even fatal, depending on the extent the proteins are affected. Generally, there are three possibilities: (a) LOSS-OF-FUNCTION MUTATION A normal [+] allele produces functional proteins A mutant [m] allele produces non- functional proteins OR no proteins at all A heterozygote [+m] has lower amount of functional proteins, may have normal or deficient phenotype A homozygote [mm] will not have functional proteins, therefore has a condition/disease (b) LOSS-OF-FUNCTION MUTATION A normal [+] allele produces functional proteins A mutant [m’] allele produces partially functional proteins A heterozygote [+m’] has both types of proteins, may have normal or deficient phenotype A homozygote [m’m’] has only partially functional proteins, therefore lower efficiency but not as severe as case (a) (c) GAIN-OF-FUNCTION MUTATION A normal [+] allele produces functional proteins A mutant [M] allele produces new functional or hyperactive proteins A heterozygote [+M] has both types of proteins, may have normal or a changed phenotype due to more / hyperactive proteins A homozygote [MM] has only the more / hyperactive proteins and Fig. 11: Effect of Mutation on Protein Function may give rise to new phenotypes; new phenotype may be advantageous or diseased @ Biology Department Catholic Junior College 13  2.1 GENETIC DISEASE: SICKLE CELL ANAEMIA (a) In a normal adult, haemoglobin A (Hb) is produced in the red blood cells. It is a tetramer at the quaternary structure, consisting of two different types of polypeptide chains. 2 α-globin chains (each made up of 141 amino acids) and two β-globin chains (each made up of 146 amino acid molecules) The α-globin and β-globin chains are coded by two different genes found on two different chromosomes. (b) In people afflicted with sickle-cell anaemia, a variant sickle cell haemoglobin, haemoglobin S (Hb S) is produced instead of Hb A due to a mutation in the β-globin gene (Fig. 12). A single nucleotide-pair / base-pair substitution in the gene coding for the β-globin chain. On the DNA template strand, the second base of the 6th codon, a thymine, in the normal -globin gene (wild-type) is replaced by adenine in the mutant gene, resulting in a missense mutation. OR On the DNA non-template / coding strand, the second base of the 6th codon, an adenine, in the normal -globin gene (wild-type) is replaced by thymine in the mutant gene, resulting in a missense mutation. In the mRNA produced, one of the codons is hence changed from GAG (codon coding for amino acid glutamic acid) to GUG (codon coding for amino acid valine). The resultant β-globin chain has a VALINE residue instead of a GLUTAMIC ACID residue. Note: Pay attention to the bases given which may be different due to the strand on which the mutation is described i.e. the DNA code on the template strand / non-coding strand; the non-template / coding strand; mRNA codon. Amino acid at position-6 Glutamic acid Valine Glutamic acid Valine DNA template strand bases CTT CAT CTC CAC DNA non-template / coding strand bases GAA GTA GAG GTG mRNA codons GAA GUA GAG GUG 3’ 5’ Template strand Non-template strand 5’ 3’ Amino acid sequence 3’ 5’ Template strand Non-template strand 5’ 3’ Amino acid sequence Fig. 12: A single nucleotide pair substitution changed the amino acid in the 6th position of the -globin chain from glutamic acid to valine. @ Biology Department Catholic Junior College 14 2.1 GENETIC DISEASE: SICKLE CELL ANAEMIA (c) This single nucleotide-pair / base-pair substitution alters the properties of the haemoglobin protein and phenotype of the red bood cells in individuals with sickle cell anaemia. Glutamic acid is hydrophilic but valine is hydrophobic. This substitution decreases the solubility of deoxygenated sickle-cell haemoglobin molecules. When the level of oxygen in blood is low (e.g. at high altitudes or under physical stress), the sickle-cell haemoglobin exposes a hydrophobic patch. The hydrophobic patch due to the valine residue of the β-chain is able to associate with the hydrophobic patch on a β-chain of another deoxygenated sickle-cell hemoglobin molecule, thus the sickle-cell haemoglobin molecules polymerise and precipitate out of cytosol to form rigid rod-like fibres which distort and damage the red blood cells (See Fig. 13, right). This causes the red blood cells (not haemoglobin) to change from a circular biconcave shape to a sickle shape under low oxygen concentration. NORMAL HAEMOGLOBIN SICKLED-CELL HAEMOGLOBIN Fig. 13: The effect of mutation on haemoglobin @ Biology Department Catholic Junior College 15 2.1 GENETIC DISEASE: SICKLE CELL ANAEMIA (d) The phenotype of the sickle-shaped red blood cells causes anaemia: The sickle-shaped red blood cells may clump and obstruct blood vessels due to their pointed and elongated shape, therefore interfere with blood circulation (Fig. 14). This deprives multiple organs of oxygen, resulting in various organ damage, particularly of bone and kidney. Other symptoms include physical weakness, pain and even paralysis. The sickle-shaped red blood cells are more fragile than normal red blood cells. They haemolyse (break down) easily. Poor oxygen supply to tissues and organs and lower numbers of red blood cells results in anaemia. Sickle cell anaemia is a homozygous recessive disorder, sufferers have two copies of the mutant alleles on chromosome 11. Fig. 14: The effect of sickled red blood cells on blood flow Table 1: Comparison between normal condition and sickle cell anaemia. Features Normal Condition Sickle-Cell Anaemia 6th genetic code on DNA non-template … GAG … … GTG … strand of β-globin gene 6th genetic code on DNA template strand … CTC … … CAC … of β-globin gene 6th codon on mRNA … GAG … … GUG … 6th amino acid residue Glutamic acid Valine Resultant haemoglobin Haemoglobin A (HbA) Haemoglobin S (HbS) Solubility of haemoglobin Soluble in water Less soluble in water At low oxygen concentration HbA remains soluble HbS crystallises into rigid fibres Appearance of red blood cell Biconcave shaped Sickle shaped (low oxygen) @ Biology Department Catholic Junior College 16 2.2 GENETIC DISEASE: CYSTIC FIBROSIS (FYI only) Cystic fibrosis gene resides on chromosome 7 and the gene codes for the protein cystic fibrosis transmembrane conductance regulator (CFTR). The normal membrane protein functions in chloride ion transport between epithelial cells (lining the respiratory tract and the intestinal tract) and the extracellular fluid. Cystic fibrosis is caused most commonly by a mutation due to deletion of three nucleotide- pairs i.e. GTT which codes for phenylalanine, on position 508 in the CFTR protein of 1480 amino acids. Fig. 15: Deletion of nucleotides from CFTR gene As a result the protein does not fold normally and is non-functional or these chloride transport channels are absent in the plasma membranes of individuals who inherit two recessive alleles for cystic fibrosis. This recessive inherited disorder gives rise to debilitating consequences. An abnormally high concentration of intracellular chloride (Fig. 16) causes the mucus that coats epithelial cells to become thicker than normal. The mucus builds up in the pancreas, lungs, digestive tract and other organs, leading to mutiple effects which include poor absorption of nutrients from the intestines and chronic bronchitis. Fig. 16: Loss of function mutation of CFTR protein Antibiotics are used to suppress lung infections and gene therapy aims to cure some of the effects of cystic fibrosis. @ Biology Department Catholic Junior College 17 2.2 GENETIC DISEASE: CYSTIC FIBROSIS (for Info Only) Fig. 17: Gene mutations in Cyctic Fibrosis. More than 1000 different mutations that have been found in patients with cystic fibrosis. The most common mutation is F508 deletion. Fig. 18: The effects of Cystic Fibrosis Disorder @ Biology Department Catholic Junior College 18 3] CHROMOSOMAL ABERRATION Concept Map for Chromosomal Aberration (a) Chromosomal aberration is a form of mutation where there is a change in: i) the number of chromosomes (Numerical aberration) ii) the structure of chromosomes (Structural aberration) (b) Chromosomal aberration can also affect an organism’s phenotype. (c) Physical and chemical disturbances, as well as errors during meiosis, can damage chromosomes in major ways or alter their number in a cell. (d) Chromosomal aberration in humans and other mammals often lead to spontaneous abortion (miscarriage) of a fetus, and individuals born with genetic defects rising from such chromosomal aberration commonly exhibit various developmental disorders. @ Biology Department Catholic Junior College 19 3.1 CHROMOSOMAL ABERRATION: NUMERICAL (a) Numerical aberration refers to the change in the number of chromosomes in a cell. The two main forms of numerical aberration are ANEUPLOIDY and POLYPLOIDY. (b) Ideally, the meiotic spindle distributes chromosomes to daughter cells without error. Occasionally, an error called a NONDISJUNCTION can occur in which the members of a pair of homologous chromosomes do not move apart properly during meiosis I, or non-sister chromatids fail to separate during meiosis II (Fig. 19). [Note: Nondisjunction is preferably spelled as one word or hyphenated non-disjunction] Fig. 19: Nondisjunction at Meiosis I (a) and at Meiosis II (b). Note that chromatids for meiosis II can be sister or non-sister depending if crossing over has occurred. (c) During nondisjunction in meiosis, one gamete receives two of the same particular chromosome and another gamete receives no copy. The other chromosomes (did not encounter any errors) are usually distributed normally. (d) If either of the aberrant gametes unites with a normal one at fertilisation, the zygote will have an abnormal number of a particular chromosome, a condition known as aneuploidy. [Note: Aneuploidy may involve more than one chromosome.] (e) Some organisms have more than two complete chromosome sets in all somatic cells. The general term for this numerical aberration is polyploidy. This phenomenon is relatively common in plants. @ Biology Department Catholic Junior College 20 3.1.1 CHROMOSOMAL ABERRATION: ANEUPLOIDY (a) Aneuploidy is a condition in which the zygote has an abnormal number of a particular chromosome because an aberrant gamete, after nondisjunction, fuses with a normal gamete during fertilisation. Fig. 20: Aneuploidy resulting in offspring with (2n+1) or (2n-1) chromosomes (b) Fertilisation involving a gamete that has no copy of a particular chromosome (n-1) will lead to a missing chromosome in the zygote so that the cell has 2n-1 chromosomes (e.g. 45 instead of 46 chromosomes). This aneuploid zygote is said to be monosomic for that chromosome. Example of monosomy: - Turner syndrome, where the female has a missing X chromosome (XO). (c) Fertilisation involving a gamete that has an extra copy of a particular chromosome (n+1) will lead to a triplicate in the zygote as the cell has 2n+1 chromosomes (e.g. 47 chromosomes). This aneuploid zygote is said to be trisomic for that chromosome. Examples of trisomy: - Down syndrome, due to extra chromosome 21 - Klinefelter syndrome, due to extra X chromosome in male (XXY) - Male with extra Y chromosome (XYY) - Trisomy X, where females have an extra X chromosome (XXX) (d) Nondisjunction can also occur during mitosis. If such an error takes place early in embryonic development, then the aneuploid condition is passed along by mitosis to a large number of cells and is likely to have a substantial effect on the organism. @ Biology Department Catholic Junior College 21 3.1.2 CHROMOSOMAL ABERRATION: POLYPLOIDY (a) Polyploidy is a condition in which an organism has more than two complete chromosome sets in all somatic cells (i.e. 3n, 69 chromosomes) (Fig. 21). Triploidy (3n) refers to having 3 chromosome sets. A triploid cell may arise from the fertilisation of an abnormal diploid gamete produced by nondisjunction of all its chromosomes and a normal haploid gamete. Tetraploidy (4n) refers to having 4 chromosome sets. Tetraploidy could result from the failure of a 2n zygote to divide after replicating its chromosomes. Subsequent normal mitotic divisions would then produce a 4n embryo. Autoploidy – having 2 or more sets of chromosomes derived from the same species or by self fertilisation. Alloploidy – having 2 or more sets of chromosomes derived from different species Fig. 21: Polyploidy - Autoploidy and Alloploidy (b) In general, polyploids appear more normally than aneuploids. One extra (or missing) chromosome seems to disrupt genetic balance more than an entire extra set of chromosomes. @ Biology Department Catholic Junior College 22 3.1.2 CHROMOSOMAL ABERRATION: POLYPLOIDY Polyploid plants are commonly created in agriculture, using colchicine. Colchicine induces polyploidy by inhibiting microtubule polymerisation thus preventing the formation of spindle fibres during cell division. As a result, chromosomes are not segregated during mitosis or meiosis. Fig. 22: Application of polyploidy in plants Fig. 23: Examples of polyploid plants Fig. 24: Polyploid plants with odd ploidy e.g. triploids are sterile and sometimes seedless @ Biology Department Catholic Junior College 23 3.2 CHROMOSOMAL ABERRATION: STRUCTURAL Structural aberration refers to the change in the structure of a chromosome. Errors in meiosis or damaging agents such as radiation can cause breakage of a chromosome, which can lead to four types of changes in chromosome structure (Fig. 25), which are: i) Deletion ii) Duplication iii) Inversion iv) Translocation (a) A DELETION occurs when a chromosomal fragment is lost. The affected chromosome is then missing certain genes. This is usually lethal as the loss of genes significantly affects the development of the embryo. (b) A “deleted” fragment may become attached as an extra segment to a sister chromatid. Since the chromatid already contains this segment, it becomes repeated hence producing a DUPLICATION. (c) The same chromosomal fragment that was detached may also reattach to the original chromosome but in the reverse orientation, producing an INVERSION. (d) A fourth possible result of chromosomal breakage is for the fragment to join a non- homologous chromosome, a rearrangement called a TRANSLOCATION. (e) Deletions and duplications are especially likely to occur during meiosis. In crossing over, non-sister chromatids sometimes exchange unequal-sized segments of DNA, so that one partner gives up more genes than it receives. The products of such an unequal crossover are one shorter chromosome with a deletion and one longer chromosome with a duplication. Fig. 25: Types of Structural Aberration of Chromosomes @ Biology Department Catholic Junior College 24 3.2 CHROMOSOMAL ABERRATION: STRUCTURAL What mechanism of mutation has occurred in each example? @ Biology Department Catholic Junior College 25 4] HUMAN DISORDERS DUE TO CHROMOSOMAL ABERRATION Chromosomal aberrations are associated with a number of serious human disorders. As described in the previous section, nondisjunction in meiosis results in aneuploidy in gametes and any resulting zygotes. Although the frequency of aneuploid zygotes may be quite high in humans, most of these chromosomal alterations are so disastrous to development that the affected embryos are spontaneously aborted long before birth even before any detection of pregnancy. However, some types of aneuploidy appear to upset the genetic balance less than others, with the result that individuals with certain aneuploid conditions can survive to birth and beyond. These individuals have a set of traits, a syndrome, that is characteristic of the type of aneuploidy. 4.1 HUMAN DISORDER: TRISOMY 21 DOWN SYNDROME One aneuploid condition, Down syndrome, is usually the result of an extra chromosome 21 resulting in aneuploidy, so that each somatic cell has a total of 47 chromosomes (2n+1). Down syndrome is often called trisomy 21 (Fig 26). Fig. 26: Extra chromosome 21 is detectable in a karyogram of Trisomy 21 cell (a) Down syndrome includes characteristic facial features, short stature, correctable heart defects, and developmental delays. (b) Individuals with Down syndrome have an Flattened nose increased chance of developing leukemia and face, and Alzheimer’s disease, yet have a lower upward slanting eyes rate of high blood pressure, atherosclerosis (hardening of the arteries), stroke, and many types of solid tumors. (c) Almost all males and about half of females with Down syndrome are sexually underdeveloped and sterile. (d) Although people with Down syndrome on Single palmer crease, short average have a life span shorter than 5th finger that Widely normal, most with proper medical treatment curves inward separated first live to middle age and beyond. and second toes and increases (e) A mosaic condition of Down syndrome can skin creases occur when there are two or more cell types in the body with differences in chromosome number and structure. This condition arises Fig. 27: Characteristics of Down Syndrome due to nondisjunction in mitosis in early fetal development. (f) The frequency of Down syndrome increases with the age of the mother. While the disorder occurs in just 0.04% of children born to women under age 30, the risk climbs to 0.92% for mothers at age 40 and is even higher for older mothers. The correlation of Down syndrome with maternal age has not yet been explained. @ Biology Department Catholic Junior College 26 4.2 HUMAN DISORDER: CRI-DU-CHAT SYNDROME (FYI only) Many deletions in human chromosomes, even in a heterozygous state, cause severe problems. One such syndrome, known as cri-du-chat (cry of the cat), results from a specic deletion in chromosome 5 (Fig. 28). Fig. 28: Chromosamal Aberration such as deletion is detectable in a karyogram (a) A child born with this deletion is severely intellectually disabled, has a small head with unusual facial features, and has a cry that sounds like the mewing of a distressed cat. (b) Such individuals usually die in infancy or early childhood. @ Biology Department Catholic Junior College 27 4.2 HUMAN DISORDER: CHRONIC MYELOID LEUKAEMIA (FYI only) The Philadelphia translocation or the Philadelphia chromosome is a specific genetic abnormality in chromosome 22 of leukaemia cancer cells particularly chronic myeloid leukaemia (CML) cells. The altered chromosome 22 is defective and unusually short because of reciprocal translocation of genetic material between chromosome 9 and chromosome 22. The altered chromosome 22 contains a fusion gene called BCR-ABL1 which consists of the ABL1 gene of chromosome 9 juxtaposed onto th BCR gene of chromosome 22. The fusion gene BCR-ABL1 codes for a hybrid protein: a tyrosin kinase signalling protein that is “always on”, causing the cell to divide uncontrollably. Since the ABL protein activates a number of cell cycle controlling proteins and enzymes, the BCR-ABL fusion speeds up cell division. The hybrid protein also inhibits DNA repair, causing genomic instability. Fig. 29: Reciprocal Translocation associated with Chronic Myeloid Leukemia (CML) @ Biology Department Catholic Junior College 28 5] APPENDIX: GENETIC CODE Fig. 30: The Genetic Code on the DNA non-template strand Fig. 31: The mRNA Codons @ Biology Department Catholic Junior College 29