PHM2113 Module 2: Chromosomes & Genes PDF

Table of Contents MODULE 2- CHROMOSOMES & GENES....................................................................................................... 1 DEOXYRIBONUCLEIC ACID (DNA).......................................................................................................................

Table of Contents MODULE 2- CHROMOSOMES & GENES....................................................................................................... 1 DEOXYRIBONUCLEIC ACID (DNA)......................................................................................................................... 1 DNA Structure................................................................................................................................................... 1 Double Helix Formation............................................................................................................................................. 1 Varieties of DNA in Organisms..................................................................................................................... 2 Organization of DNA into Chromosomes.................................................................................................... 2 CHROMOSOMES.......................................................................................................................................................3 Types of Chromosomes— Karyotype............................................................................................................3 X Chromosome............................................................................................................................................................. 3 Y Chromosome............................................................................................................................................................. 4 Chromosome Numbers and Ploidy............................................................................................................... 4 GENES..................................................................................................................................................................... 4 The Central Dogma: DNA → RNA → Protein...............................................................................................5 Transcription: From DNA to mRNA........................................................................................................................ 5 RNA Processing: Preparing mRNA for Translation............................................................................................. 6 Translation: From mRNA to Protein........................................................................................................................ 6 Post-Translational Modifications............................................................................................................................ 7 Regulation of Gene Expression......................................................................................................................7 Lyon’s Hypothesis: X Chromosome Inactivation....................................................................................... 8 DNA REPLICATION................................................................................................................................................. 8  Module 2- Chromosomes & Genes Deoxyribonucleic Acid (DNA) DNA serves as the hereditary material, encoding the blueprint of life in all organisms. Its durable, resilient structure enables genetic information to be preserved and passed on across generations, ensuring continuity and functionality in cells. Chemically, DNA consists of three main components—nitrogenous bases, deoxyribose sugars, and phosphates—combined into nucleotides that link to form long, stable strands. DNA Structure Nitrogenous Bases: DNA has four bases: o adenine (A)— purine o thymine (T)— pyrimidine o guanine (G)— purine o cytosine (C)— pyrimidine Purines pair with pyrimidines via hydrogen bonds, creating stable base pairs. Double Helix Formation Hydrogen Bonding: Complementary base pairs (A-T and G-C) form stable hydrogen bonds, contributing to the double-helix structure. Phosphodiester Bonds: DNA’s backbone comprises sugar- phosphate chains linked by phosphodiester bonds. Breakdown of DNA: Decomposition involves 1 cleaving phosphodiester bonds (releasing nucleotides) and breaking hydrogen bonds between bases, usually through enzymatic or chemical means. DNA’s two strands run antiparallel, with the bases paired inwardly. This configuration twists into a double-helix shape, stabilizing the structure and protecting genetic information. Varieties of DNA in Organisms Although all DNA forms a double helix and follows the same base-pairing rules, organisms contain distinct types of DNA with specialized roles. Nuclear DNA: Housed in the nucleus, nuclear DNA governs most cellular functions and physical traits (phenotypes). It is organized into chromosomes, inherited from both parents. Humans have 22 pairs of autosomes and two sex chromosomes. Sequencing the genome refers to decoding nuclear DNA’s base pair order. Mitochondrial DNA (mtDNA): Found in mitochondria, mtDNA is small (17,000 base pairs), circular, and essential for cellular metabolism. Inherited maternally, mtDNA contains 37 genes that support the cell's energy production. Organization of DNA into Chromosomes In eukaryotic cells, DNA undergoes several levels of condensation to fit within the nucleus. 1. It wraps around histone proteins to form nucleosomes, each comprising 147 base pairs around a histone core. 2. This nucleosome chain creates a 10nm fibre, known as primary chromatin. 2  3. This further coils into a denser 30nm fibre (secondary chromatin) and eventually forms chromatin loops. 4. Higher-order folding organizes these loops into chromatids, leading to the fully condensed chromosome visible during cell division. Chromosomes Chromosomes are tightly packed DNA structures that become visible during cell division, enabling efficient gene distribution. Chromosomes consist of chromatin, which includes two types: 1. Euchromatin: Loosely packed, accessible for gene expression. 2. Heterochromatin: Densely packed, generally inactive. Chromosomes have a centromere for spindle attachment during division, and two arms: a shorter p arm a longer q arm Telomeres are protective sequences at chromosome ends, maintained by telomerase, which prevent gene loss during replication. Types of Chromosomes— Karyotype 1. Autosomes: Chromosomes 1-22, identical in both sexes. 2. Sex Chromosomes: XX in females and XY in males, determining sex. Homologous chromosomes, one from each parent, contain similar genes but may have different alleles. X Chromosome The X chromosome is relatively large, with approximately 150 million base pairs and 3  contains around 800-900 genes, crucial for human development. A zygote cannot develop without at least one X chromosome. The X chromosome appears as an "X" shape with a centrally located centromere, making it a metacentric chromosome. Most female traits are controlled by genes on autosomes, with only one X-linked gene influencing the female phenotype. Y Chromosome The Y chromosome, the smallest human chromosome (about 58 million base pairs), carries the SRY gene, responsible for male sex determination. Chromosome Numbers and Ploidy Diploid (2n): Humans are diploid, with two complete sets of chromosomes (one from each parent). Aneuploid: Abnormal number of chromosomes, such as in monosomy (one chromosome missing) or trisomy (one extra chromosome). Polyploid: More than two sets of chromosomes, commonly seen in plants, fish, and amphibians (e.g., triploidy). Genes A gene is a functional unit of heredity composed of a specific sequence of DNA that encodes the instructions for the synthesis of proteins or RNA molecules. Genes consist of coding regions (exons) and non-coding regions (introns). During gene expression, DNA is transcribed to messenger RNA (mRNA), which then undergoes splicing to remove introns, allowing mRNA to be translated into proteins. 4 DNA Coding: Coding sequences (exons) specify amino acids, organized into codons, each representing an amino acid for protein synthesis. Cells use signal transduction pathways to respond to external cues, regulating gene expression to influence functions like cell growth and survival. The Central Dogma: DNA → RNA → Protein The Central Dogma describes the fundamental flow of genetic information in a cell, outlining how DNA is transcribed into RNA, which is then translated into proteins. This central concept involves a series of coordinated steps—transcription, RNA processing, and translation— each crucial for gene expression. Transcription: From DNA to mRNA The first step in gene expression is transcription, the process by which a segment of DNA is copied into messenger RNA (mRNA). The genetic information in DNA is encoded in a sequence of nitrogenous bases (A, T, C, G), which are transcribed into mRNA, where uracil (U) replaces thymine (T). The mRNA serves as a complementary copy of the sense strand of the DNA, with the opposite strand being used as the template (the antisense strand). The enzyme RNA polymerase II is responsible for synthesizing mRNA. It binds to the promoter region of the gene on the DNA, unwinds the double helix, and begins adding ribonucleotides to the growing RNA strand in the 3′ to 5′ direction. The mRNA is synthesized as a complementary strand, meaning each base on the DNA template pairs with its complementary ribonucleotide (A-U, T-A, C-G, G-C). The 5 mRNA is synthesized continuously until the polymerase reaches a termination sequence in the DNA, signalling the end of transcription. RNA Processing: Preparing mRNA for Translation After transcription, the mRNA undergoes several processing steps before it can be exported from the nucleus and translated into a protein. These steps are necessary for the mRNA to be functional and stable: 1. 5′ Capping: Soon after transcription begins, a 5′ cap is added to the mRNA molecule. This cap is a modified guanine nucleotide, and it protects the mRNA from degradation, facilitates its transport out of the nucleus, and is essential for ribosome attachment during translation. 2. Splicing: The initial mRNA, or pre-mRNA, often contains non-coding regions called introns, which must be removed. The coding regions, or exons, are then spliced together; facilitated by spliceosome. 3. Polyadenylation: The mRNA is then modified by the addition of a poly(A) tail at its 3′ end. This tail consists of around 200 adenine nucleotides and plays a crucial role in mRNA stability, export from the nucleus, and translation initiation. After these modifications, the mRNA is considered mature and is ready to be transported out of the nucleus into the cytoplasm, where it will direct protein synthesis. Translation: From mRNA to Protein Once in the cytoplasm, the mature mRNA is translated into a protein at the ribosome, which consists of ribosomal RNA (rRNA) and proteins. The ribosome reads the mRNA in groups of three bases, known as codons, each of which specifies a particular amino acid in the polypeptide chain. The decoding of the mRNA sequence into a protein is facilitated by Transfer RNA (tRNA), which carries the amino acids to the ribosome. Each tRNA molecule has an anticodon that is 6 complementary to the mRNA codon, ensuring the correct amino acid is added to the growing polypeptide chain. Translation occurs in three main stages: 1. Initiation: The small ribosomal subunit binds to the mRNA and scans for the start codon (AUG). The initiator tRNA, carrying methionine, binds to this start codon, and the large ribosomal subunit associates with the small subunit to form the complete ribosome. 2. Elongation: The ribosome moves along the mRNA in the 5′ to 3′ direction, reading the codons and recruiting the appropriate tRNA molecules. Each tRNA brings a specific amino acid, and peptide bonds are formed between the amino acids to build the polypeptide chain. 3. Termination: When a stop codon is encountered, translation halts. The polypeptide chain is released from the ribosome, and the ribosome dissociates from the mRNA. Post-Translational Modifications After translation, many proteins undergo further modifications before they become fully functional. These may include: Phosphorylation, acetylation, or methylation of amino acid side chains Glycosylation or lipidation (adding carbohydrate or lipid groups) Proteolytic cleavage, such as the conversion of proinsulin into insulin. These modifications are essential for the protein's function, stability, localization within the cell, or secretion. Regulation of Gene Expression Gene expression is primarily regulated at transcription, but control mechanisms can also occur at RNA processing, mRNA stability, and translation levels. RNA-Mediated Gene Expression: siRNAs and miRNAs play critical roles in gene regulation, guiding mRNA degradation or translation inhibition in RNA interference pathways. 7 Alternative Isoforms: About 95% of human genes undergo alternative splicing, producing diverse protein isoforms, contributing significantly to proteomic complexity. Lyon’s Hypothesis: X Chromosome Inactivation Lyon's Hypothesis, proposed in 1961 by Mary Lyon, explains X-chromosome inactivation in female mammals, ensuring dosage compensation between males and females. Females, with two X chromosomes, randomly inactivate one X chromosome in each cell early in development, making gene expression in females similar to males, who have one X chromosome. Dosage Compensation: Inactivation prevents females from producing double the number of X-linked gene products compared to males. Random Inactivation: One X chromosome is randomly inactivated in each cell, and this inactivation is permanent in all daughter cells, creating a mosaic pattern of X-chromosome expression in tissues. X-Inactivation and Traits: Female carriers of X-linked diseases may show varying symptoms depending on which X chromosome (healthy or mutated) is inactivated in different tissues. Barr Body: The inactivated X chromosome forms a condensed structure called a Barr body. Escape from Inactivation: Some genes on the inactivated X chromosome remain active, contributing to gene expression differences between males and females. Evolutionary Significance: Random inactivation ensures balanced gene expression, promoting survival and adaptability. DNA replication (discussed in Module 3) is semiconservative, with each new double helix containing one parental and one new strand. This ensures genetic stability. Helicase unwinds the DNA, and DNA polymerase synthesizes complementary strands, ensuring accurate copying of genetic information. While genetic information typically flows from DNA to RNA to protein, retroviruses have shown that RNA can serve as a template for DNA synthesis, a process termed RNA-directed DNA synthesis. This reverse transcription may have therapeutic implications in treating genetic diseases. 8