FLS Genetics and Pathology Lectures.pdf

# Mechanisms and consequences of genetic mutations A mutation is a permanent alteration in the DNA sequence, arising from replication errors or DNA damage, with consequences ranging from silent changes to severe diseases. ## 1. Mechanisms and consequences of genetic mutations ### 1.1 Mechanisms of DNA replication errors Mutations can occur during DNA replication through several mechanisms. DNA polymerase has proofreading capabilities to minimize errors, but the high rate of cell division over a lifetime means mutations are still possible [1](#page=1). #### 1.1.1 Mispairing of bases DNA's flexibility allows bases to shift position, leading to erroneous pairings, known as wobbles. Additionally, bases can transiently convert into rare chemical forms called tautomers, causing them to bond with incorrect partners [1](#page=1). #### 1.1.2 Strand-slippage During replication, DNA polymerase can inadvertently add or omit a base. This is particularly common in regions with repeated sequences of the same base [1](#page=1). ### 1.2 Chemical reactions that damage DNA Spontaneous chemical reactions within the cell can cause physical damage to DNA. If this damage is not repaired before DNA replication, it can lead to permanent mutations [1](#page=1). #### 1.2.1 Depurination This occurs when water interacts with DNA, leading to the spontaneous removal of a purine base (adenine or guanine) from the DNA backbone, creating a gap in the sequence [1](#page=1) [5](#page=5). #### 1.2.2 Deamination When water interacts with cytosine, its amine group is removed, converting it into uracil. This altered base can then lead to a mismatch during replication. Another common deamination involves methylated cytosine at CpG sites spontaneously converting to thymine [1](#page=1) [6](#page=6). ### 1.3 Environmental stressors that damage DNA External factors can also damage DNA, but these only result in permanent mutations if unrepaired before replication [1](#page=1). #### 1.3.1 Ultraviolet radiation UV radiation can cause two adjacent thymine bases on the same DNA strand to form a covalent bond, creating a thymidine dimer. This distorts the DNA helix and can stall replication. Ionizing radiation can cause breaks in the DNA [1](#page=1) [6](#page=6). #### 1.3.2 Reactive Oxygen Species (ROS) These molecules can attack purine and pyrimidine rings, causing damage to DNA bases [5](#page=5). ### 1.4 DNA repair systems Cells possess sophisticated systems to repair DNA damage and replication errors. #### 1.4.1 Mismatch repair system This system corrects replication errors that escape the proofreading activity of DNA polymerase. The process involves [2](#page=2) [6](#page=6): 1. Identifying the mismatch and distinguishing the newly synthesized strand from the template strand, often by detecting a break in the new strand [2](#page=2). 2. Excising the segment of the new strand containing the error [2](#page=2). 3. DNA polymerase filling the gap with the correct nucleotides [2](#page=2). 4. DNA ligase sealing the DNA backbone to complete the repair [2](#page=2). ### 1.5 Types of point mutations Point mutations are single base pair substitutions, frequently caused by wobble-induced errors during replication [2](#page=2). #### 1.5.1 Transitions A purine base is replaced by another purine, or a pyrimidine base is replaced by another pyrimidine [2](#page=2). #### 1.5.2 Transversions A purine base is replaced by a pyrimidine base, or vice versa [2](#page=2). ### 1.6 Frameshift mutations The genetic code is read in codons of three bases. Insertions or deletions of nucleotides in numbers that are not multiples of three shift the reading frame. This alters every amino acid coded for downstream of the mutation and often leads to a premature stop codon. Frameshift mutations will always result in missense or nonsense mutations [2](#page=2) [7](#page=7). ### 1.7 Consequences of mutations on protein synthesis The impact of a mutation is heavily dependent on its location within the DNA sequence [2](#page=2) [5](#page=5). #### 1.7.1 Mutations in untranslated regions These are often silent and do not affect protein sequence or structure [2](#page=2). #### 1.7.2 Mutations in exons, splice sites, or regulatory regions These can lead to various outcomes: * **Missense mutations:** The substitution changes the amino acid sequence. The severity depends on whether the amino acid change is conservative (similar properties, minor effect) or non-conservative (different properties, drastic effect on protein structure and function). Sickle cell anemia is a classic example, caused by a transversion in the beta-globin gene replacing glutamic acid with valine [2](#page=2) [3](#page=3) [6](#page=6). * **Nonsense mutations:** The mutation introduces a premature stop codon, leading to a truncated protein or degradation of the mRNA transcript [2](#page=2) [7](#page=7). * **Splice site mutations:** These occur at the boundaries of introns and exons. Mutations at splice sites can cause exons to be skipped or intron sequences to be incorporated into the mRNA, leading to significant alterations in protein size and composition [7](#page=7). ### 1.8 Germline and somatic mutations The type of cell in which a mutation occurs determines its heritability and impact. #### 1.8.1 Germline mutations These occur in egg or sperm cells and are heritable, meaning they are present in all cells of the offspring [6](#page=6). #### 1.8.2 Somatic mutations These occur in non-germline tissues and are not heritable; they are confined to the affected individual's body [6](#page=6). ### 1.9 DNA sequence variants: Mutations vs. Polymorphisms * **Mutations:** Harmful sequence variants that alter gene function and phenotype [5](#page=5). * **Polymorphisms:** Non-harmful sequence variants that are common in the population. They may occur in non-functional DNA, or within a gene without changing the amino acid, or even change the amino acid without affecting protein function [5](#page=5). #### 1.9.1 Single Nucleotide Polymorphisms (SNPs) SNPs are the most common type of variation, involving a change in a single base at a specific genomic location (e.g., C to T). To be classified as an SNP, the change must occur in greater than 1% of the population [5](#page=5). ### 1.10 Copy Number Variants (CNVs) Small triplet repeats within coding sequences can be unstable and prone to expansion. Such expansions, like the CAG repeats in the Huntington's disease gene (HTT), can disrupt gene function. Larger CNVs, often resulting from unequal crossing-over during meiosis, involve significant deletions or duplications of DNA segments. The clinical effects of CNVs depend on the number and genes involved [7](#page=7). ### 1.11 Impact of genome variations on health The effect of genomic variations on health is contingent on the type of variation and its location [5](#page=5). * **Normal Variation:** Some variations result in observable physical traits, such as eye color [5](#page=5). * **Response to Medication:** Genetic differences can influence an individual's response to drugs [5](#page=5). * **Likelihood of Disease:** Certain variations can increase the probability of developing complex diseases like diabetes [5](#page=5). * **Direct Genetic Conditions:** Specific pathogenic variations can directly cause diseases, such as sickle cell anemia [5](#page=5). ### 1.12 Genomics Genomics is the comprehensive study of all genes in an individual (the genome), including their interactions with each other and the environment. Techniques like sequencing, microarray analysis, and Fluorescence In Situ Hybridization (FISH) are used to study the genome [7](#page=7). --- # Genome variation and its impact on health Genome variation and its impact on health encompasses the spectrum of changes in an individual's DNA and their consequences for well-being. ## 2. Genome variation and its impact on health Every individual harbors a substantial amount of genomic variation, with approximately 20 million single nucleotide polymorphisms (SNPs) and around 60 de novo changes that arise during an individual's lifetime. Despite this variation, humans share about 99.5% of their DNA sequence, with the remaining small percentage accounting for observed differences [4](#page=4). ### 2.1 Types of variation found in the genome Genomic variations can be categorized by their physical manifestations: * **Alterations in base sequence:** These include changes in a specific section of DNA, such as single nucleotide polymorphisms or small deletions or duplications of a few bases [4](#page=4). * **Microsatellites:** These are tandem repeats of 2-6 base pairs within DNA sequences less than 100 base pairs long [4](#page=4). * **Minisatellites:** These consist of tandem repeats of 10-60 base pairs and are prone to mismatches, deletions, or duplications [4](#page=4). * **Larger deletions/duplications:** These involve significant segments of DNA [4](#page=4). * **Chromosomal changes:** Variations can also affect the number or structure of entire chromosomes [4](#page=4). ### 2.2 Classification of genome variants Genome variants are classified based on three primary characteristics: * **Size:** Variants range from single base changes to large chromosomal rearrangements [4](#page=4). * **Frequency:** Variants can be common, such as SNPs found widely in a population, or rare, like mutations specific to a family [4](#page=4). * **Clinical effects:** Variants can be non-pathogenic polymorphisms that have no harmful effect, or pathogenic mutations that disrupt gene function and lead to disease [4](#page=4). ### 2.3 Impact of genome variations on health The health implications of a genomic variation are determined by its type and location within the genome, whether in coding or non-coding regions [5](#page=5). * **Normal variation:** Some variations manifest as physical traits, such as eye color, without causing disease [5](#page=5). * **Response to medication:** Genetic differences significantly influence how individuals metabolize and respond to drugs, including antidepressants [5](#page=5). * **Likelihood of disease:** Certain variations can increase or decrease an individual's probability of developing complex diseases like diabetes [5](#page=5). * **Direct genetic conditions:** Specific pathogenic variations can directly cause monogenic disorders, such as sickle cell anemia [5](#page=5). #### 2.3.1 DNA sequence variants: Mutations and polymorphisms * **Mutations:** These are defined as harmful sequence variants that alter gene function and consequently affect the phenotype [5](#page=5). * **Polymorphisms:** These are non-harmful sequence variants often found in non-functional DNA or within genes where they do not alter the resulting amino acid or protein function [5](#page=5). #### 2.3.2 Single nucleotide polymorphisms (SNPs) SNPs are the most prevalent type of genetic variation across the genome. An SNP represents a change of a single base at a specific DNA location (e.g., a cytosine being replaced by a thymine). Since individuals inherit one DNA copy from each parent, they can possess one of three genotypes for a given SNP (e.g., CC, CT, or TT). For a base change to be officially classified as an SNP, it must be present in more than 1% of the population [5](#page=5). #### 2.3.3 Causes of mutations Mutations can arise spontaneously due to errors during DNA replication or repair processes. They can also be induced by intrinsic factors or external environmental agents attacking the DNA. Specific mechanisms include [5](#page=5): * **Depurination:** The loss of adenine or guanine bases from the DNA helix [5](#page=5). * **Deamination:** The spontaneous conversion of cytosine into uracil [5](#page=5). * **Reactive Oxygen Species (ROS):** These molecules can damage both purine and pyrimidine rings in DNA [5](#page=5). #### 2.3.4 Types of mutations and their effects Mutations can be further classified by their impact on protein synthesis: * **Non-sense mutations:** These mutations introduce a premature stop codon (UAA, UAG, or UGA) into the mRNA sequence, leading to the production of a truncated protein or triggering the degradation of the mRNA transcript via nonsense-mediated decay [7](#page=7). #### 2.3.5 Splice site mutations Splice sites are critical regions located at the boundaries of introns and exons. Proper splicing relies on conserved sequences: GU at the splice donor site (beginning of an intron) and AG at the splice acceptor site (end of an intron). Mutations at these sites can have severe consequences. A mutation at the acceptor site, for instance, may cause the cellular machinery to skip an entire exon or to include intron sequences in the final mature mRNA. This disruption prevents correct pre-mRNA splicing, leading to significant alterations in the protein's size and composition [7](#page=7). #### 2.3.6 Frameshift mutations Frameshift mutations occur when insertions or deletions of nucleotides are not in multiples of three. Since the genetic code is read in triplets (codons), such changes alter the reading frame, causing all subsequent amino acids in the protein sequence to be different from the original. This often leads to the premature encounter of a stop codon, resulting in a shortened protein or mRNA degradation [7](#page=7). #### 2.3.7 Copy number variants (CNVs) Small triplet repeats within coding sequences are inherently unstable and prone to expansion. These expansions can disrupt gene function; for example, Huntington's disease is caused by an expansion of CAG repeats in the *HTT* gene, where numbers above 11-34 repeats lead to the disease. These expansions can also increase the likelihood of larger deletions and duplications in the region. Such large CNVs often arise from unequal crossing-over during meiosis between repeat sequences on homologous chromatids. If these sequences misalign during recombination, one chromatid may lose a segment while the other gains one. The clinical impact of CNVs depends on the number and specific genes involved in the variation [7](#page=7). ### 2.4 Genomics and variation detection Genomics is the study of an organism's entire set of genes (the genome), including their interactions with each other and the environment. Various techniques are employed to study the genome and identify variations [7](#page=7): * **Sequencing:** This method is used to identify single base changes [7](#page=7). * **Microarray analysis:** This technique is employed for detecting large blocks of DNA [7](#page=7). * **Fluorescence In Situ Hybridization (FISH):** This is also used for detecting large DNA segments [7](#page=7). --- # Inheritance patterns and genetic disorders This topic explores the fundamental ways genetic information is passed down through generations and how variations in this inheritance can lead to various diseases. ### 3.1 Classification of genetic disorders Genetic disorders can be broadly categorized based on their underlying cause and the number of genes involved [9](#page=9). * **Single Gene Disorders:** These are caused by mutations in a single gene and often result in a loss of gene function. They follow predictable Mendelian inheritance patterns [9](#page=9). * **Multifactorial Diseases:** These arise from variants in multiple genes interacting with environmental influences [9](#page=9). * **Chromosome Disorders:** These involve imbalances in chromosomal structure or number, leading to altered gene dosage [9](#page=9). * **Mitochondrial Disorders:** These affect organ systems with high energy demands and are linked to mutations in mitochondrial DNA [9](#page=9). * **Somatic Mutations:** These occur in non-reproductive cells and can lead to diseases like cancer through the inactivation of growth-regulating genes [9](#page=9). ### 3.2 Single gene inheritance patterns Single gene disorders are classified based on the location of the mutated gene and whether the inheritance pattern is dominant or recessive [9](#page=9). #### 3.2.1 Autosomal dominant inheritance Autosomal dominant disorders occur when a mutation on a non-sex chromosome results in a disease phenotype even with only one copy of the mutated allele present [10](#page=10). * **Characteristics:** * The mutated allele is strong enough to be expressed in a heterozygous state [10](#page=10). * There is a 50% chance of inheriting the disease if one parent is affected [10](#page=10). * Homozygotes for the dominant allele typically exhibit very severe, often lethal, phenotypes and are rarely observed [10](#page=10). * Males and females are equally affected [10](#page=10). * All forms of transmission (e.g., male-to-male, male-to-female) are possible [10](#page=10). * An affected individual is usually present in every generation [10](#page=10). * **Pedigree clues for autosomal dominant disorders:** 1. Affected individual in every generation [10](#page=10). 2. Equal affection rates in males and females [10](#page=10). 3. All forms of transmission observed [10](#page=10). * **Examples of autosomal dominant disorders:** * **Achondroplasia:** Caused by a mutation in the *FGFR3* gene, resulting in dwarfism [10](#page=10). * **Marfan Syndrome:** A connective tissue disorder due to a mutation in the *FBN-1* gene [10](#page=10). * **Neurofibromatosis (NF1):** A mutation in the gene controlling neurofibromin production, a tumor suppressor protein [10](#page=10). * **Factors influencing autosomal dominant expression:** * **Variation in expression:** Family members with the same mutation may show different severity of symptoms due to modifying genes [10](#page=10). * **Penetrance:** The probability that an individual with a specific genotype will exhibit the expected phenotype. Incomplete penetrance means not everyone with the gene shows traits [10](#page=10). * **New mutations:** A child can be born with a dominant condition due to a spontaneous new mutation, even with unaffected parents [10](#page=10). * **Anticipation:** The disorder appears earlier and/or with greater severity in successive generations, often linked to repeat expansions in DNA (minisatellites and microsatellites) [11](#page=11). * **Mosaicism:** An individual has two or more cell populations with different genetic makeups, derived from a single fertilized egg. Somatic mosaicism affects only tissues developing from the mutated cell line [11](#page=11). * **Mechanisms of autosomal dominant diseases:** * **Altered structural proteins:** A mix of normal and abnormal proteins disrupts the overall structure (e.g., Marfan Syndrome) [11](#page=11). * **Haploinsufficiency:** Half the normal amount of a gene product is insufficient to maintain function (e.g., Familial Hypercholesterolemia due to insufficient active lipoprotein receptors) [11](#page=11). * **Altered functions:** Mutations lead to proteins with altered functions (e.g., Huntington's disease) [11](#page=11). * **Cancer-causing diseases:** Mutations in genes like *BRCA1/2* can predispose to certain cancers [11](#page=11). #### 3.2.2 Autosomal recessive inheritance Autosomal recessive disorders require two copies of the mutated allele on a non-sex chromosome to manifest the disease [11](#page=11). * **Characteristics:** * A single copy of the recessive allele has no phenotypic effect [11](#page=11). * Heterozygotes (carriers) are typically unaware they carry the gene [11](#page=11). * If both parents are carriers, there is a 25% chance of an affected child, a 50% chance of a carrier child, and a 25% chance of an unaffected, non-carrier child [11](#page=11). * Males and females are equally affected [11](#page=11). * Affected individuals are often siblings, indicating horizontal transmission [12](#page=12). * The disorder does not necessarily appear in every generation [12](#page=12). * Consanguinity (parents being related) can increase the likelihood of autosomal recessive disorders [12](#page=12). * **Pedigree clues for autosomal recessive disorders:** 1. Affected individuals may not appear in every generation [12](#page=12). 2. Equal affection rates in males and females [12](#page=12). 3. Affected individuals are often siblings (horizontal transmission) [12](#page=12). 4. Evidence of consanguinity [12](#page=12). * **Example of an autosomal recessive disorder:** * **Cystic Fibrosis:** Affects lungs, pancreas, and sweat glands, caused by mutations in the *CFTR* gene, disrupting chloride transport. It affects approximately 1 in 2500 individuals, with a carrier rate of 4% in Caucasians [12](#page=12). #### 3.2.3 X-linked recessive inheritance X-linked recessive disorders are caused by mutations on the X chromosome [9](#page=9). * **Characteristics:** * **Males:** As males have only one X chromosome, a single altered gene makes them affected hemizygotes [12](#page=12). * **Females:** Females have two X chromosomes. If one X chromosome carries the mutated allele, they are carrier heterozygotes and usually unaffected [12](#page=12). * If the mother is a carrier and the father is unaffected: 50% of sons will be affected, and 50% of daughters will be carriers [12](#page=12). * If the father is affected and the mother is unaffected: All daughters will be carriers, but no sons will be affected (as sons inherit the Y chromosome from the father) [12](#page=12). * There is a higher incidence of the disorder in males than females [12](#page=12). * The gene is transmitted from an affected man to all his daughters [12](#page=12). * The gene is never transmitted from father to son [12](#page=12). * The disease can skip generations [12](#page=12). * **Pedigree clues for X-linked recessive disorders:** 1. Higher incidence in males than females [12](#page=12). 2. Affected males transmit the gene to all daughters [12](#page=12). 3. No father-to-son transmission [12](#page=12). 4. The disease may skip generations [12](#page=12). * **Examples of X-linked recessive disorders:** * **Duchenne's Muscular Dystrophy:** Caused by a mutation in the *DMD* gene, leading to progressive muscle loss [12](#page=12). * **Haemophilia A:** A deficiency in clotting factor VIII, resulting in uncontrolled bleeding [12](#page=12). * **Affected females in X-linked recessive disorders:** Females rarely express X-linked recessive traits but can if they have skewed X-inactivation, Turner syndrome (a missing X chromosome), or are homozygous for the recessive trait [13](#page=13). * **X-inactivation:** In females, one of the two X chromosomes is randomly inactivated early in development to balance gene dosage with males. This inactive state is heritable and passed to daughter cells via epigenetic mechanisms [13](#page=13). #### 3.2.4 X-linked dominant inheritance X-linked dominant diseases are uncommon and occur when a mutation on one X chromosome is sufficient to cause the disorder [13](#page=13). * **Characteristics:** * Pedigrees resemble autosomal dominant patterns but typically show an excess of affected females [13](#page=13). * There is no male-to-male transmission [13](#page=13). ### 3.3 Mitochondrial inheritance Mitochondrial DNA (mtDNA) has a high mutation rate and is inherited exclusively from the mother [13](#page=13). * **Characteristics:** * An affected mother passes the trait to all her children, regardless of sex [13](#page=13). * An affected father passes the trait to none of his children because sperm mitochondria are expelled during fertilization [13](#page=13). * Mitochondrial diseases often affect tissues with high energy requirements [9](#page=9). * **Features of mitochondrial diseases:** * They result from primary defects in oxidative phosphorylation [13](#page=13). * Clinical presentations vary widely and can appear in childhood or adulthood [13](#page=13). * These diseases are often severe and progressive [13](#page=13). * **Preventing transmission of mitochondrial disorders:** Mitochondrial donation, an IVF technique, can prevent transmission. It involves transferring the nucleus from a mother's egg into an enucleated donor egg containing healthy mitochondria [13](#page=13). --- # Meiosis and chromosomal abnormalities Meiosis is a specialized cell division process that reduces the chromosome number by half, ensuring that gametes receive a haploid set of chromosomes, while also contributing to genetic diversity through independent assortment and crossing over. ### 4.1 The process of meiosis Meiosis is a reduction division process critical for sexual reproduction, ensuring that each gamete contains 23 chromosomes. Its primary functions are to reduce the chromosome number by half and to re-assort genes through independent segregation and crossing-over. During meiosis, homologous chromosomes replicate, forming two chromatids each, and then pair up. Genetic material is exchanged between non-sister chromatids through crossing-over, a process made visible by chiasmata [14](#page=14). #### 4.1.1 Meiosis I and II Unlike mitosis, where duplicated homologous chromosomes align independently at the metaphase plate, in meiosis I, duplicated homologous chromosomes pair up before aligning [14](#page=14). ##### 4.1.1.1 Meiosis I * **Metaphase I:** Kinetochore microtubules of sister chromatids point in the same direction, and sister chromatid arms become unglued to facilitate separation [15](#page=15). * **Anaphase I:** Homologous chromosomes separate, but sister chromatids remain attached [15](#page=15). ##### 4.1.1.2 Meiosis II * **Metaphase II:** Cohesins in the centromere are degraded, allowing for sister chromatid separation [15](#page=15). * **Anaphase II:** Sister chromatids finally separate [15](#page=15). #### 4.1.2 Independent assortment Independent assortment occurs during metaphase I of meiosis I and is a significant source of genetic variation. It describes the random orientation of homologous chromosome pairs (tetrads) along the metaphase plate, meaning the separation of one pair does not influence the separation of others. This random alignment ensures that each gamete receives a unique combination of chromosomes [14](#page=14). #### 4.1.3 Crossing over (recombination) Crossing over is the exchange of genetic material between non-sister chromatids of homologous chromosomes during prophase I of meiosis I. This process involves [14](#page=14): 1. **Synapsis:** Homologous chromosomes pair up to form a tetrad [14](#page=14). 2. **Chiasmata formation:** Non-sister chromatids cross over at specific points, exchanging corresponding DNA segments, which are physically visible as chiasmata [14](#page=14). 3. **Recombination:** After the exchange, chromatids carry a new combination of maternal and paternal genes [14](#page=14). 4. **Separation:** When these recombined chromosomes separate, each gamete receives a genetically unique mix, not purely maternal or paternal chromosomes [14](#page=14). #### 4.1.4 Gametogenesis: Spermatogenesis and Oogenesis * **Spermatogenesis:** The production of sperm requires numerous cell divisions. By age 15, a spermatogonium results from 30 divisions. From puberty onwards, spermatogonia divide every 16 days, yielding four spermatozoa from each precursor cell [15](#page=15). * **Oogenesis:** In contrast, human egg production involves fewer divisions. By 5 months of development, 22 divisions create a fixed stock of 2.6 million oocytes. Meiosis I completes at ovulation, and Meiosis II completes only upon fertilization, resulting in one zygote and three polar bodies [15](#page=15). ### 4.2 Chromosome abnormalities Chromosome abnormalities are broadly classified by number and structure, and by their distribution within the body [15](#page=15). * **Constitutional:** The abnormality is present in all cells [15](#page=15). * **Somatic:** The abnormality is found only in specific tissues or cells [15](#page=15). A **karyotype** describes the total number of chromosomes, sex chromosome constitution, and any abnormalities [15](#page=15). #### 4.2.1 Numerical chromosome abnormalities Numerical abnormalities involve the gain or loss of complete chromosomes, most frequently due to non-disjunction associated with maternal age [17](#page=17). * **Aneuploidy:** The presence of an abnormal number of chromosomes, such as trisomy (an extra chromosome) or monosomy (a missing chromosome). This leads to gene product imbalance, causing significant developmental issues or lethality, with monosomy being more severe [16](#page=16). * **Polyploidy:** Having more than two complete sets of chromosomes, such as triploidy or tetraploidy. This is rare and usually fatal [16](#page=16). ##### 4.2.1.1 Non-disjunction Non-disjunction is the failure of chromosome separation during meiosis, where a chromosome pair fails to split. This error can occur in sex chromosomes or autosomes [16](#page=16). * **Non-disjunction in Meiosis I:** Homologous pairs fail to separate, resulting in all four daughter cells being abnormal [16](#page=16). * **Non-disjunction in Meiosis II:** Sister chromatids fail to separate, leading to two abnormal haploid daughter cells and two normal ones [16](#page=16). * **Non-disjunction in the egg:** In females, non-disjunction in Meiosis I or II can lead to eggs with abnormal chromosome numbers. For example, an XX egg fertilized by a Y sperm results in XXY (Klinefelter syndrome), and an XX egg fertilized by an X sperm results in XXX (Trisomy X). Y-bearing eggs are not viable due to essential X-linked genes [16](#page=16). * **Non-disjunction in the sperm:** In males, non-disjunction can occur during sperm production. Meiosis I non-disjunction yields XY sperm, leading to an XXY zygote. Meiosis II non-disjunction can produce XX or YY sperm, potentially leading to XXX or XYY zygotes [16](#page=16). > **Tip:** Sex chromosome abnormalities are generally less severe than autosomal trisomies due to X-inactivation in females, where one X chromosome is randomly inactivated in somatic cells to balance gene dosage [17](#page=17). ##### 4.2.1.2 Specific numerical abnormalities and conditions * **Trisomy 21 (Down syndrome):** Characterized by the karyotype 47,XX,+21 or 47,XY,+21. It primarily arises from non-disjunction during meiosis (usually Meiosis I), with 80% of cases involving an extra maternal chromosome. The risk increases with maternal age. The condition is a gene dosage problem, with three copies of chromosome 21 [16](#page=16). * **Klinefelter Syndrome (XXY):** Affects males, who are usually infertile but have a normal IQ [17](#page=17). * **Turner Syndrome (X):** Affects females, characterized by short stature, webbed neck, broad chest, and infertility due to streak ovaries [17](#page=17). * **Trisomy X (XXX):** Individuals are typically normal females, some of whom are fertile [17](#page=17). * **Jacob’s Syndrome (XYY):** Affects tall or very tall males who are relatively infertile [17](#page=17). * **Common viable trisomies:** Include trisomies 21, 13, and 18. Autosomal monosomies are generally catastrophic [17](#page=17). > **Tip:** The risk of non-disjunction and subsequent Trisomy 21 increases sharply with maternal age, particularly after age 35-40. This is attributed to the long interval between the start of meiosis (in fetal ovaries) and its completion (at ovulation), allowing for accumulated damage to spindle formation [17](#page=17). #### 4.2.2 Structural chromosome abnormalities Structural abnormalities involve changes in the structure of chromosomes, including translocations, deletions, duplications, inversions, ring chromosomes, and marker chromosomes [17](#page=17). ##### 4.2.2.1 Translocations Translocations involve the movement of chromosome segments [18](#page=18). * **Balanced Reciprocal Translocation:** An exchange occurs between chromosomes without any net gain or loss of genetic material. Carriers are typically normal but can produce gametes that lead to unbalanced zygotes, resulting in miscarriage or congenital abnormalities due to partial trisomy or monosomy [18](#page=18). * **Balanced Robertsonian Translocation:** Occurs in acrocentric chromosomes (13, 14, 15, 21, 22) where centromeres are near the ends. It involves breakage near the centromeres of two chromosomes and fusion of their long arms (q-arms), with the short arms (p-arms) usually lost. A carrier has 45 chromosomes but a normal phenotype due to no gene imbalance [18](#page=18). * **Unbalanced Robertsonian Translocation:** Can lead to conditions like Down syndrome if an individual has two normal copies of chromosome 21 plus a translocation chromosome, effectively resulting in three copies of chromosome 21 material [18](#page=18). > **Example:** Most cases of Down syndrome (95%) are due to standard Trisomy 21 from non-disjunction. However, 4% are caused by Robertsonian translocations, and 1% by mosaicism (a mix of normal and trisomic cell lines), which typically presents with milder features [18](#page=18). ##### 4.2.2.2 Chromosomal deletions Deletions involve the loss of a small chromosome segment, leading to monosomy for that segment and affecting multiple genes [18](#page=18). > **Examples:** > * **Prader-Willi syndrome:** Caused by a deletion on chromosome 15, characterized by poor muscle tone and behavioral problems [18](#page=18). > * **Cri-du-chat syndrome:** Caused by a deletion on chromosome 5 [18](#page=18). ##### 4.2.2.3 Somatic chromosomal translocations Somatic chromosomal translocations can contribute to diseases such as cancer [18](#page=18). > **Example:** A translocation between chromosomes 9 and 22 creates the BCR-ABL fusion protein, which drives uncontrolled cell proliferation and leads to Chronic Myeloid Leukaemia [18](#page=18). --- ## Common mistakes to avoid - Review all topics thoroughly before exams - Pay attention to formulas and key definitions - Practice with examples provided in each section - Don't memorize without understanding the underlying concepts

| Term | Definition | |------|------------| | Mutation | A permanent alteration in the DNA sequence. | | DNA Replication | The biological process of producing two identical replicas of DNA from one original DNA molecule. | | DNA Polymerase | An enzyme crucial for DNA replication that synthesizes DNA molecules by adding nucleotides to the 3' end of a DNA strand. It also possesses proofreading capabilities to correct errors. | | Mispairing of Bases | An error during DNA replication where an incorrect nucleotide is incorporated into the new DNA strand, often due to the flexible nature of DNA bases or tautomeric shifts. | | Tautomers | Rare chemical forms of DNA bases that can hydrogen bond with the wrong complementary base, leading to mispairing during replication. | | Strand-Slippage | An error during DNA replication where the DNA polymerase either adds an extra base or omits a base, particularly common in repetitive DNA sequences. | | Depurination | A chemical reaction where a purine base (adenine or guanine) is spontaneously removed from the DNA backbone by hydrolysis, leaving a gap. | | Deamination | A chemical reaction where an amine group is removed from a base, such as cytosine, converting it into uracil, which can lead to mismatch pairing. | | Ultraviolet Radiation | Electromagnetic radiation from the sun that can damage DNA, most notably by causing covalent bonds between adjacent thymine bases, forming thymidine dimers. | | Thymidine Dimer | A covalent bond formed between two adjacent thymine bases on a DNA strand due to exposure to UV radiation, distorting the DNA helix and hindering replication. | | Mismatch Repair System | A cellular mechanism that corrects errors, such as mispaired bases, that escape the proofreading activity of DNA polymerase during replication. | | DNA Ligase | An enzyme that joins DNA fragments by catalyzing the formation of phosphodiester bonds, essential for sealing the DNA backbone after repair. | | Point Mutation | A mutation that affects a single nucleotide base pair, typically involving the substitution of one base for another. | | Transition | A type of point mutation where a purine base is replaced by another purine (adenine to guanine or vice versa), or a pyrimidine is replaced by another pyrimidine (cytosine to thymine or vice versa). | | Transversion | A type of point mutation where a purine base is replaced by a pyrimidine, or vice versa (e.g., adenine to thymine). | | Untranslated Regions (UTRs) | Regions of a gene’s mRNA that are transcribed but not translated into protein. Mutations here are often silent. | | Exons | The segments of a gene's DNA or mRNA that are translated into proteins. | | Splice Sites | Nucleotide sequences at the boundaries between introns and exons that are recognized by the splicing machinery to remove introns from pre-mRNA. | | Missense Mutation | A point mutation that results in a codon change leading to the substitution of one amino acid for another in the protein sequence. | | Nonsense Mutation | A point mutation that changes a codon specifying an amino acid into a premature stop codon, leading to a truncated protein. | | Frameshift Mutation | A mutation caused by the insertion or deletion of nucleotides in a number not divisible by three, altering the reading frame of the genetic code and changing all subsequent amino acids. | | Single Nucleotide Polymorphism (SNP) | A variation in a single nucleotide base at a specific position in the genome, occurring in at least 1% of the population. | | Microsatellites | Short, repetitive sequences of DNA, typically 2-6 base pairs long, that are tandemly repeated. | | Minisatellites | Longer repetitive sequences of DNA, typically 10-60 base pairs long, that are tandemly repeated. | | Genome Variant | Any difference in DNA sequence among individuals, ranging from single nucleotide changes to large chromosomal alterations. | | Pathogenic Mutation | A mutation that disrupts the normal function of a gene and can lead to disease. | | Coding Regions | The parts of a gene that are transcribed into mRNA and subsequently translated into proteins. | | Non-coding Regions | DNA sequences that are not transcribed into protein, including regulatory elements and intergenic regions. | | Reactive Oxygen Species (ROS) | Highly reactive molecules containing oxygen that can damage cellular components, including DNA. | | Methylation at CpG | The addition of a methyl group to a cytosine base in a CpG dinucleotide sequence, an epigenetic modification often associated with gene silencing. | | CpG Islands | Regions of DNA that are enriched in CpG dinucleotides, often found in gene promoter regions. | | Germline Mutations | Mutations that occur in egg or sperm cells and are therefore heritable by offspring. | | Somatic Mutations | Mutations that occur in non-germline cells and are not inherited by offspring; they are confined to the affected individual. | | Silent Mutation | A mutation that alters the DNA sequence but does not change the amino acid sequence of the resulting protein, often due to redundancy in the genetic code. | | Conservative Change | An amino acid substitution where the new amino acid has similar chemical properties to the original one, usually resulting in a minor impact on protein function. | | Non-Conservative Change | An amino acid substitution where the new amino acid has significantly different chemical properties from the original one, potentially drastically altering protein structure and function. | | Splice Site Mutation | A mutation occurring at the boundary between an intron and an exon, interfering with the proper splicing of pre-mRNA. | | Copy Number Variants (CNVs) | Variations in the number of copies of a particular DNA segment, ranging in size from a few kilobases to millions of base pairs. | | Genomics | The study of the entire set of genes in an organism (the genome), including their interactions with each other and the environment. | | DNA Sequencing | A laboratory technique used to determine the exact order of nucleotides within a DNA molecule. | | Mendelian Diseases | Genetic disorders caused by mutations in a single gene, typically inherited in a predictable pattern (e.g., autosomal dominant, autosomal recessive). | | Multifactorial Diseases | Diseases that result from the combined effects of multiple genes and environmental factors. | | Precision Medicine | A medical approach that tailors disease prevention and treatment strategies to individuals based on their genetic makeup, lifestyle, and environment. | | Unifactorial Disease | A disease caused by a single factor, such as a mutation in a single gene. | | Phenotype | The observable physical or biochemical characteristics of an organism, determined by its genotype and environmental influences. | | Genotype | The genetic makeup of an organism, specifically the alleles present at a particular locus or for a set of genes. | | Allele | One of two or more alternative forms of a gene that arise by mutation and are found at the same place on a chromosome. | | Autosomal Dominant | A mode of inheritance where a disease or trait is caused by a mutation in one copy of a gene located on an autosome (non-sex chromosome), and only one copy is needed to express the trait. | | Autosomal Recessive | A mode of inheritance where a disease or trait is caused by a mutation in both copies of a gene located on an autosome, and two mutated copies are required for the trait to be expressed. | | X-Linked Disorders | Genetic disorders caused by mutations in genes located on the X chromosome. | | Carrier | An individual who possesses one copy of a recessive allele and can transmit it to their offspring, but typically does not express the trait themselves. | | Penetrance | The proportion of individuals with a particular genotype who exhibit the expected phenotype. | | Incomplete Penetrance | A situation where individuals with a specific genotype do not always express the corresponding phenotype. | | Anticipation | A phenomenon where a genetic disorder appears at an earlier age and/or with greater severity in successive generations, often associated with unstable repeat expansions. | | Mosaicism | The presence of two or more genetically distinct cell lines within a single individual, all derived from a single fertilized egg. | | Haploinsufficiency | A condition where having only one functional copy of a gene (instead of two) is insufficient to maintain normal function, leading to a phenotype. | | Consanguinity | The state of being descended from the same ancestor; marriage or breeding between closely related individuals. | | X-Inactivation | The process in female mammals where one of the two X chromosomes is randomly inactivated early in development to equalize gene dosage between sexes. | | X-Linked Dominance | A mode of inheritance where a mutation on the X chromosome is sufficient to cause a disorder, and it is expressed in both males and females who carry the mutation. | | Mitochondrial Inheritance | Inheritance of genetic material located in the mitochondria, which is passed down exclusively from the mother to all her offspring. | | Oxidative Phosphorylation | The metabolic pathway in mitochondria that generates ATP, the main energy currency of the cell, through a series of redox reactions. | | Meiosis | A type of cell division that reduces the number of chromosomes by half, producing gametes (sperm and egg cells) for sexual reproduction. | | Independent Assortment | The random orientation of homologous chromosome pairs at the metaphase plate during meiosis I, leading to diverse combinations of maternal and paternal chromosomes in the gametes. | | Crossing Over (Recombination) | The exchange of genetic material between non-sister chromatids of homologous chromosomes during meiosis I, creating new combinations of alleles. | | Tetrad | A pair of homologous chromosomes, each consisting of two sister chromatids, that are paired up during prophase I of meiosis. | | Chiasmata | The visible points of contact between non-sister chromatids where crossing over has occurred during meiosis. | | Spermatogenesis | The process of producing mature sperm cells from spermatogonia. | | Oogenesis | The process of producing mature egg cells (ova) from oogonia. | | Oocyte | An immature female reproductive cell that has the potential to develop into an ovum after fertilization. | | Polar Bodies | Small cells produced during meiosis in females that contain excess chromosomes but little cytoplasm; they are non-functional. | | Chromosome Abnormalities | Any deviation from the normal number or structure of chromosomes. | | Constitutional Abnormality | A chromosome abnormality present in all cells of an individual, originating from the germline or early embryonic development. | | Somatic Abnormality | A chromosome abnormality that occurs in somatic cells after fertilization and is confined to certain tissues or cells. | | Karyotype | The complete set of chromosomes in a cell or organism, arranged in homologous pairs and ordered by size and shape. | | Aneuploidy | The condition of having an abnormal number of chromosomes, such as an extra chromosome (trisomy) or a missing chromosome (monosomy). | | Polyploidy | The condition of having more than two complete sets of chromosomes (e.g., triploidy, tetraploidy). | | Trisomy | A type of aneuploidy where there are three copies of a particular chromosome instead of the usual two. | | Monosomy | A type of aneuploidy where there is only one copy of a particular chromosome instead of the usual two. | | Non-disjunction | The failure of homologous chromosomes or sister chromatids to separate properly during meiosis, leading to aneuploidy. | | Trisomy 21 (Down Syndrome) | A genetic disorder caused by the presence of an extra copy of chromosome 21, characterized by intellectual disability and characteristic physical features. | | Klinefelter Syndrome (XXY) | A chromosomal disorder in males characterized by the presence of an extra X chromosome, often leading to infertility and sometimes developmental delays. | | Turner Syndrome (X) | A chromosomal disorder affecting females, characterized by the absence of one X chromosome, leading to short stature, infertility, and other physical characteristics. | | Trisomy X (XXX) | A chromosomal condition in females where there are three X chromosomes, often with minimal or no noticeable effects. | | Jacob’s Syndrome (XYY) | A chromosomal condition in males characterized by the presence of an extra Y chromosome, often associated with increased height. | | Translocation | A type of chromosomal abnormality where a segment of one chromosome breaks off and attaches to another chromosome. | | Reciprocal Translocation | A type of translocation where segments of two non-homologous chromosomes are exchanged. | | Robertsonian Translocation | A specific type of translocation that occurs between two acrocentric chromosomes (chromosomes with centromeres near their ends), involving the fusion of their long arms. | | Chromosomal Deletion | A type of chromosomal abnormality where a segment of a chromosome is lost. | | Ring Chromosome | A type of chromosomal abnormality where a chromosome breaks at both ends and the ends fuse to form a ring. | | Marker Chromosome | A small, structurally abnormal chromosome of unknown origin that cannot be identified by standard banding techniques. | | Unbalanced Translocation | A translocation where there is a net gain or loss of genetic material. | | Acrocentric Chromosome | A chromosome with a centromere located very close to one of its ends. | | Chronic Myeloid Leukaemia (CML) | A type of cancer of the blood and bone marrow characterized by the uncontrolled proliferation of myeloid cells, often associated with the BCR-ABL fusion gene. |