Genetics 2 Mutations.pdf

Mutations  Molecular Basis for Relationship between Genotype and Phenotype genotype DNA DNA sequence transcription RNA translation amino acid protein...

Mutations  Molecular Basis for Relationship between Genotype and Phenotype genotype DNA DNA sequence transcription RNA translation amino acid protein sequence function phenotype organism  Gene Mutations A gene mutation occurs when the nucleotide sequence of the DNA is altered.  Causes of gene mutations? Mutations can occur spontaneously or be caused by exposure to mutation-inducing agents. Spontaneous -Spontaneous Replication Errors -Spontaneous Chemical Changes Induced -Chemically Induced Mutations -Radiation  A spontaneous mutation occurs as a result of natural processes in cells, for example, DNA replication errors. These can be distinguished from induced mutations; those that occur as a result of interaction of DNA with an outside agent or mutagen that causes DNA damage. Mutagens may be of physical, chemical, or biological origin. Mostly they act on the DNA directly, causing damage which may result in errors during replication. However, severely damaged DNA can prevent replication and cause cell death.  Significance of Mutations Most mutations are neutral – have little or no effect on the expression of genes or function of proteins Harmful mutations – producing defective proteins – disrupt normal biological activities Source of genetic variability in a species Cause genetic disorders Associated with many types of cancer  Categories of Mutations -Somatic Mutations -Germ-line Mutations Gene vs. Chromosomal Mutations  Types of mutations Base substitution (point mutations) Insertions & deletions (frameshift mutations) Base substitution The simplest type of gene mutation Involves the alteration of a single nucleotide in the DNA Base substitution is of two types: Transition: Purine is replaced with a purine A G G A Pyrimidine is replaced with a pyrimidine C T T C Transversions: A purine is replaced by a pyrimidine A C A T G C G T or a pyrimidine is replaced by a purine C G C A T G T A Missense mutation: also called nonsynonymous mutations a base is substituted that alters a codon in the mRNA resulting in a different amino acid in the protein product Adenine (A) is replaced by thymine (T), and the codon is altered, resulting in histidine (His) being replaced by proline (Pro) in the protein product A>T (His>Pro)  Missense mutations can be classified as conservative or non-conservative based on the properties of the substituted amino acid and how much they differ from the original. 1. Conservative Missense Mutations: In conservative mutations, the substituted amino acid has similar chemical properties to the original amino acid. As a result, the overall structure and function of the protein may not be significantly affected. Example: Substituting glutamic acid (negatively charged) with aspartic acid (also negatively charged) may have a minimal impact on the protein's function. 2. Non-Conservative Missense Mutations: In non-conservative mutations, the substituted amino acid has different chemical properties compared to the original. This type of mutation is more likely to affect the protein's structure or function, potentially leading to diseases. Example: Substituting glutamic acid (negatively charged) with valine (non-polar) can disrupt the protein's function, as happens in sickle cell anemia. Examples: Sickle cell anemia: A missense mutation in the HBB gene changes the hemoglobin protein, causing red blood cells to become sickle-shaped. Cystic fibrosis: Certain missense mutations in the CFTR gene affect the function of a protein involved in ion transport, leading to the disease. Cancer: Missense mutations in genes like TP53 can disrupt tumor suppression functions, contributing to cancer development. Some missense mutations may have little to no effect on the protein's structure or function, and these are considered "neutral" or "benign" mutations. For example: Silent regions: If the mutation occurs in a part of the protein that is not crucial for its function (such as in regions that don't directly interact with other molecules or perform essential tasks), it may not cause any harm. Functional redundancy: Sometimes, a protein may still function properly even with the substitution of one amino acid, especially if the new amino acid has similar properties to the original one. Silent mutation: also called Synonymous mutations alters a codon but the same amino acid is specified synonymous mutations Neutral mutation: Mutation that alters the amino acid sequence of the protein but does not change its function as the replaced amino acid is chemically similar or the affected aa has little influence on protein function. GAA G>T TAA CUU AUU Leu Leu>Ile Ile Leucine replaced by isoleucine Nonsense mutation: changes a sense codon into a nonsense codon. Nonsense mutation early in the mRNA sequence produces a greatly shortened & usually nonfunctional protein.  Cystic Fibrosis: Some cases are caused by nonsense mutations in the CFTR gene, leading to defective chloride channels and thick mucus production. Duchenne Muscular Dystrophy (DMD): Many mutations in the dystrophin gene, including nonsense mutations, can lead to the absence of functional dystrophin, resulting in muscle degeneration. Hemophilia B: Caused by nonsense mutations in the F9 gene, leading to a deficiency of clotting factor IX. Beta-Thalassemia: Nonsense mutations in the HBB gene can disrupt the production of beta-globin chains, affecting hemoglobin and leading to anemia. Marfan Syndrome: Some cases are associated with nonsense mutations in the FBN1 gene, leading to defects in fibrillin-1, which is crucial for connective tissue. Phenylketonuria (PKU): Certain forms result from nonsense mutations in the PAH gene, affecting the metabolism of phenylalanine. Nonsyndromic Hearing Loss: Some forms of this condition are linked to nonsense mutations in genes like GJB2, which is essential for proper ear function. Insertion and deletion mutations 2nd major class of gene mutation Addition or the removal, respectively, of one or more nucleotide pair Usually changes the reading frame, altering all -amino acids encoded by codons following the mutation frameshift frameshift mutations Additions or deletions in the multiples of three nucleotides will lead to addition or deletion of one or more amino acids These mutations are called in-frame insertions and deletions, respectively.  Small Insertion and Deletion Mutations Change Protein Length Another type of mutation is the gain or loss of one or more base pairs. i. Insertion mutations occur when one or more base pairs are added to the wild-type sequence. i. Deletion mutations are due to the loss of one or more base pairs. Insertion and deletion mutations are collectively referred to as indels. The DNA sequence from the start codon to the stop codon is referred to as a reading frame. Frame after the mutation, resulting in a frameshift mutation. Because nucleotides are decoded in triplets, an indel mutation of only one or two base pairs in the coding sequence of a protein throws off the reading Truncated Protein: Insertions and deletions can introduce a premature stop codon, resulting in a truncated protein. -Frameshift mutations: Deletions or insertions (not divisible by 3) result in translation of incorrect amino acids, stops codons (shorter polypeptides), or read-through of stop codons (longer polypeptides).  Chromosomal mutation Changes in the number or structure of chromosomes termed chromosomal mutations, chromosomal abnormalities, or chromosomal aberrations. Changes in number may occur by the Types of chromosomal abnormalities: (a) Structural (b) Numerical a. Structural Chromosomal Mutations Deletion: A portion of the chromosome is missing. Duplication: Extra copies of a portion of the chromosome. Inversion: A portion of the chromosome breaks off, flips, and reattaches. Translocation: A portion of one chromosome attaches to another chromosome  Changes in the structure of chromosomes may occur by inversion when a chromosomal segment rotates 180 degrees within the same location; by duplication, when a segment is added; by deletion, when a segment is lost; or by translocation, when a segment changes from one location to another in the same or a different chromosome. Inversions, translocations, fusions, and fissions do not change the amount of DNA. The importance of these mutations in evolution is that they change the linkage relationships between genes. Genes that were closely linked to each other become separated and vice versa; this can affect their expression because genes are often transcribed sequentially, two or more at a time. Normal 1st & 2nd meiotic division Two types of non-disjunction Non-disjunction leading to aneuploid gametes b. Numerical Chromosomal Mutations Aneuploidy The occurrence of one or more extra or missing chromosomes in a cell or organism. Aneuploidy refers to any chromosome number that is not an exact multiple of the haploid number of chromosomes (23 in humans).  Mechanism of Aneuploidy Non-disjunction: failure of separation of chromosomes during cell division. Formation of 2 types of gametes (both abnormal) Fusion of either of these abnormal gametes with a normal gamete can result in trisomy or monosomy May involve autosomes or sex chromosomes Types of Aneuploidy Monosomy: Loss of one chromosome (2n-1) Nullisomy: Loss of both chromosomes in a pair (2n-2) Trisomy: Gain of an extra chromosome (2n+1) Tetrasomy: Gain of two additional chromosomes (2n+2) Monosomy (2n-1) Loss of one chromosome from a diploid set Example: Turner syndrome (45, X) - monosomy of the X chromosome Symptoms: Short stature – Most girls with Turner syndrome grow more slowly than their peers and may be significantly shorter as adults. Delayed puberty – Due to underdeveloped ovaries, girls with Turner syndrome often experience delayed or absent puberty. They may also be infertile. Heart defects – Some individuals may have heart problems, which can be serious. Kidney problems – Kidney abnormalities may be present, though they usually do not cause major health issues. Learning difficulties – While intelligence is usually normal, some girls may have difficulty with spatial reasoning and math. Occurs only in females (absence of one X chromosome) Often lethal in autosomes, but viable in some sex chromosomes Turner’s syndrome XO Nullisomy (2n-2) Loss of both members of a homologous chromosome pair. Example: Rare in humans, usually lethal in early development. In plants, nullisomy might sometimes be tolerated, especially in polyploid species (plants with more than two sets of chromosomes), but it can lead to severe developmental abnormalities. May be present in hexaploidy wheat.  Trisomy (2n+1) Presence of an extra chromosome, Presence of 3 copies of a chromosome Examples: Trisomy of Autosomes Down syndrome (Trisomy 21 or G-trisomy): Three copies of chromosome 21 Symptoms: Developmental delays, distinct facial features, intellectual disability Edwards syndrome (Trisomy 18 or E-trisomy): Three copies of chromosome 18 Symptoms: Severe developmental delays, physical abnormalities, high infant mortality, 80% females, 2nd most trisomy Patau syndrome (Trisomy 13 or D-trisomy): Three copies of chromosome 13 Symptoms: Severe intellectual disability, physical deformities, heart defects.. Trisomy of Sex Chromosomes (XXX, XXY) Down syndrome 21 Edward syndrome 18 Klinefelter’s syndrome XXY Male with an extra X chromosome (47, XXY). Frequency: 1 in 1,000 male births. Symptoms: Tall stature, longer limbs. Infertility or reduced fertility. Low testosterone levels. Learning difficulties, especially in language and reading. Some may have mild breast development (gynecomastia). Diagnosis & Treatment: Chromosomal analysis, hormone therapy (testosterone replacement), fertility treatment. XYY Male Male with an extra Y chromosome (47, XYY). Frequency: Occurs in 1 in 1,000 male births. Symptoms: Tall stature. Typically, normal sexual development and fertility. Slightly increased risk of learning disabilities and behavioral problems. Often goes undiagnosed. Diagnosis & Treatment: Chromosomal analysis, special education support if needed. Female with an extra X chromosome (47, XXX). Frequency: Occurs in 1 in 1,000 female births. Symptoms: Usually mild or no symptoms. Taller than average. May have learning difficulties (especially in speech and motor skills). Normal sexual development and fertility. Diagnosis & Treatment: Often undiagnosed; no specific treatment is needed unless learning difficulties exist.  Tetrasomy (2n+2) Presence of two extra chromosomes from the same homologous pair Example: Tetrasomy X (48, XXXX) in females Symptoms: Learning disabilities, delayed motor skills, normal lifespan Rare and more viable when occurring in sex chromosomes  Parthenogenesis: This is a type of asexual reproduction where an egg develops into an organism without being fertilized by a sperm. In this process, the egg cell contains only one set of chromosomes (monoploid) and can still develop into a full organism. It is common in certain plants, insects (like bees), and some reptiles. Haploid production in plants: In plants, monoploid organisms can also be produced through methods like anther or microspore culture in tissue culture, which bypasses the need for fertilization.  Polyploidy Polyploidy is a condition in which an organism has more than two complete sets of chromosomes. It occurs due to errors in cell division and can lead to variations in plants, animals, and some microorganisms. The causes of polyploidy can be classified into several categories: 1. Errors in Meiosis Non-disjunction: During meiosis, chromosomes may fail to separate properly (non-disjunction), leading to gametes with extra sets of chromosomes. When such gametes fuse during fertilization, polyploid offspring are formed. Failure of chromosome separation: If chromosomes do not separate into distinct cells, the resulting gametes may carry double or even higher chromosome numbers. 2. Errors in Mitosis Endomitosis: This is the process where chromosomes replicate but the cell does not divide, leading to doubled chromosome numbers within a single cell. It can happen during normal cell division. Mitotic slippage: Sometimes, errors in mitosis result in the failure of the cell to split, which leads to doubling the chromosome set. 3. Hybridization Allopolyploidy: This occurs when two different species hybridize, and the resulting hybrid inherits chromosome sets from both parents. If the chromosome sets double in the hybrid, it becomes an allopolyploid, which can often result in fertile offspring despite coming from different species. 4. Chemical Induction Colchicine treatment: Colchicine is a chemical that disrupts spindle formation during cell division, preventing chromosomes from separating. This method is commonly used in plant breeding to artificially induce polyploidy.  Types of Polyploidy 1. Autopolyploidy: even-numbered multiples of haploid number of chromosomes. e.g.- (a) Tetraploidy (23x4 or 92 chromosomes) (b) Hexaploidy (23x6 or 138 chromosomes) (c) Octaploidy (23x8 or 184 chromosomes) etc.  Types of Polyploidy 2. Allopolyploidy: odd-numbered multiples of haploid number of chromosomes. e.g.- (a) Triploidy (23x3 or 69 chromosomes)-commonest (b) Pentaploidy (23x5 or 115 chromosomes) (c) Heptaploidy (23x7 or 161 chromosomes) etc.  Polyploidy in Animals Parthenogenesis - development of an unfertilized egg into an embryo. polyploidy in leeches, flatworms, brine shrimp polyploidy in salamanders, lizards Polyploid frogs and toads undergo sexual reproduction. Polyploid fish (such as salmon, and trout) are not unusual. Triploid oysters are of economic value. In general, polyploid mammals are not viable.