2.4 Molecular genetics and genomics

Molecular genetics and genomics explore the fundamental building blocks of life: DNA, RNA, and proteins. These molecules store, transmit, and execute genetic information, shaping the diversity of life on Earth. Understanding their structure and function is crucial for grasping how organisms evolve and adapt.

This topic delves into the intricate processes of DNA replication, transcription, and translation. It also examines genetic mutations, variation in populations, and cutting-edge genomic technologies. These concepts are essential for comprehending human evolution, diversity, and the genetic basis of diseases.

DNA, RNA, and Protein Structure & Function

Nucleic Acid Structure and Function

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• DNA (deoxyribonucleic acid) forms a double-stranded helix composed of nucleotides
  • Contains genetic instructions for all living organisms
  • Nucleotides consist of a sugar (deoxyribose), phosphate group, and nitrogenous base (adenine, thymine, cytosine, guanine)
• RNA (ribonucleic acid) exists as a single-stranded molecule with crucial roles in gene expression
  • Types include messenger RNA (mRNA), transfer RNA (tRNA), and ribosomal RNA (rRNA)
  • Differs from DNA by containing ribose sugar and uracil instead of thymine
• Nucleic acids store and transmit genetic information through base pairing (A-T/U, C-G)
  • Complementary base pairing enables DNA replication and RNA transcription

Protein Structure and Function

• Proteins comprise complex molecules made up of amino acids joined by peptide bonds
• Serve diverse functions in cellular processes (structural support, enzymatic catalysis, signal transduction)
• Four levels of protein structure determine function:
  • Primary: linear sequence of amino acids
  • Secondary: local folding patterns (alpha helices, beta sheets)
  • Tertiary: overall three-dimensional shape
  • Quaternary: interactions between multiple polypeptide chains
• Examples of protein functions:
  • Enzymes catalyze biochemical reactions (DNA polymerase, lactase)
  • Structural proteins provide cellular support (collagen, keratin)
  • Transport proteins move molecules across membranes (hemoglobin, ion channels)

Central Dogma of Molecular Biology

• Describes the flow of genetic information from DNA to RNA to proteins
• DNA acts as the template for RNA synthesis during transcription
  • RNA polymerase reads DNA sequence and produces complementary RNA
• RNA serves as the template for protein synthesis during translation
  • Ribosomes read mRNA codons and assemble amino acids into polypeptides
• Regulatory mechanisms influence genetic information expression within this framework:
  • Epigenetic modifications alter gene accessibility (DNA methylation, histone modifications)
  • Gene regulatory networks control timing and level of gene expression (transcription factors, enhancers)

DNA Replication, Transcription, and Translation

DNA Replication

• Semiconservative process producing two identical copies of the original DNA molecule
  • Essential for cell division and genetic inheritance
• Key enzymes and proteins involved:
  • DNA polymerases synthesize new DNA strands
  • Helicases unwind the DNA double helix
  • Primase creates RNA primers for DNA synthesis
  • Ligase joins Okazaki fragments on the lagging strand
• Replication occurs bidirectionally from multiple origins of replication
• Error-checking mechanisms ensure high fidelity of DNA replication
  • Proofreading activity of DNA polymerase
  • Mismatch repair systems correct errors post-replication

Transcription and RNA Processing

• Transcription involves RNA synthesis from a DNA template, catalyzed by RNA polymerase
  • Produces mRNA, tRNA, and rRNA molecules
• Eukaryotic RNA processing includes:
  • Addition of 5' cap (7-methylguanosine) for mRNA stability and recognition
  • 3' poly-A tail addition enhances mRNA stability and translation efficiency
  • Splicing removes introns and joins exons
    • Alternative splicing increases protein diversity from a single gene
• Prokaryotic transcription couples directly with translation
  • No nuclear membrane separates transcription and translation processes

Translation and Protein Synthesis

• Ribosomes decode mRNA genetic code to produce specific amino acid sequences
• Process involves:
  • Initiation: ribosome assembles on mRNA at start codon (AUG)
  • Elongation: amino acids added to growing polypeptide chain
  • Termination: synthesis stops at stop codon (UAA, UAG, UGA)
• Genetic code characteristics:
  • Degeneracy: multiple codons can code for the same amino acid
  • Near universality across all living organisms
• Post-translational modifications further diversify protein function
  • Examples: phosphorylation, glycosylation, ubiquitination

Molecular Genetics and Genetic Variation

Genetic Mutations and Their Effects

• Mutations occur through various mechanisms:
  • Point mutations: single nucleotide changes (substitutions)
  • Insertions: addition of nucleotides
  • Deletions: removal of nucleotides
  • Chromosomal aberrations: large-scale changes in chromosome structure
• Types of mutations and their impacts:
  • Silent mutations: no change in amino acid sequence
  • Missense mutations: change in amino acid
  • Nonsense mutations: premature stop codon
  • Frameshift mutations: alter reading frame of codons
• Epigenetic modifications alter gene expression without changing DNA sequence
  • DNA methylation typically represses gene expression
  • Histone modifications can activate or repress genes

Genetic Variation in Populations

• Single nucleotide polymorphisms (SNPs) represent common genetic variations
  • Contribute to individual differences and disease susceptibility
  • Example: SNPs in MC1R gene influence skin and hair pigmentation
• Copy number variations (CNVs) involve large-scale duplications or deletions
  • Impact phenotypic traits and disease risk
  • Example: CNVs in AMY1 gene affect amylase production and starch digestion
• Genetic mutations lead to various hereditary disorders:
  • Cystic fibrosis: caused by mutations in CFTR gene
  • Sickle cell anemia: results from mutation in HBB gene
  • Huntington's disease: expansion of CAG repeats in HTT gene

Applications of Molecular Genetics

• Understanding molecular genetics crucial for developing targeted therapies
  • Example: CFTR modulators for cystic fibrosis treatment
• Personalized medicine approaches based on individual genetic profiles
  • Pharmacogenomics tailors drug treatments to genetic variations
• Gene therapy aims to treat genetic disorders by introducing functional genes
  • Example: AAV-mediated gene therapy for spinal muscular atrophy

Genomics and Human Evolution & Diversity

Genomic Technologies and Their Applications

• Next-generation sequencing revolutionized genome analysis capabilities
  • Enables study of human genetic diversity on unprecedented scale
  • Examples: Illumina sequencing, nanopore sequencing
• Comparative genomics identifies conserved and divergent genetic elements across species
  • Provides insights into evolutionary relationships and adaptive traits
  • Example: Comparison of human and chimpanzee genomes reveals genes under positive selection
• Large-scale genomic studies reveal complexity of human genetic variation
  • Human Genome Project provided first complete human genome sequence
  • 1000 Genomes Project cataloged human genetic variation across populations

Genetic Basis of Human Diversity and Disease

• Genome-wide association studies (GWAS) identify genetic loci associated with complex traits and diseases
  • Enhances understanding of human genetic architecture
  • Example: GWAS identified multiple loci associated with height
• Ancient DNA sequencing provides insights into human history
  • Reveals migration patterns and admixture events
  • Example: Neanderthal DNA in modern human genomes indicates interbreeding
• Integration of genomic data with other omics technologies enables comprehensive understanding
  • Transcriptomics studies gene expression patterns
  • Proteomics analyzes protein abundance and modifications
  • Metabolomics examines small molecule metabolites

Gene Editing and Ethical Considerations

• CRISPR-Cas9 and other gene editing technologies offer powerful research tools
  • Enables precise modification of DNA sequences
  • Potential for treating genetic disorders
• Ethical considerations in human genetic modification
  • Germline editing raises concerns about heritable genetic changes
  • Debate over enhancement vs. therapeutic applications
• Balancing scientific progress with ethical and societal implications
  • Need for regulatory frameworks and public engagement
  • Consideration of long-term consequences and unintended effects