1.4 Central dogma of molecular biology

The central dogma of molecular biology outlines the flow of genetic information from DNA to RNA to proteins. This fundamental concept underpins our understanding of how cells store, transmit, and express genetic information, forming the basis for many bioinformatics applications.

From DNA structure to gene expression regulation, the central dogma encompasses key processes like transcription, RNA processing, and translation. Understanding these mechanisms is crucial for interpreting genomic data, predicting gene function, and developing tools for sequence analysis and protein structure prediction.

DNA structure and function

• Fundamental to bioinformatics studies DNA structure and function provide the basis for understanding genetic information storage and transmission
• Bioinformatics tools analyze DNA sequences to identify genes, regulatory elements, and structural variations crucial for interpreting genomic data

Double helix model

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• Proposed by Watson and Crick in 1953 revolutionized understanding of DNA structure
• Consists of two antiparallel strands coiled around a common axis forming a right-handed helix
• Stabilized by hydrogen bonds between complementary base pairs (adenine-thymine, guanine-cytosine)
• Sugar-phosphate backbone forms the exterior of the helix while nitrogenous bases face inward

Nucleotide composition

• Building blocks of DNA composed of three parts: a nitrogenous base, a deoxyribose sugar, and a phosphate group
• Four types of nitrogenous bases in DNA: adenine (A), guanine (G), cytosine (C), and thymine (T)
• Purines (A and G) have a double-ring structure while pyrimidines (C and T) have a single-ring structure
• Phosphodiester bonds link nucleotides together forming the sugar-phosphate backbone

Base pairing rules

• Complementary base pairing ensures accurate DNA replication and transcription
• Adenine (A) pairs with thymine (T) via two hydrogen bonds
• Guanine (G) pairs with cytosine (C) via three hydrogen bonds
• GC base pairs contribute more to DNA stability due to the extra hydrogen bond
• Base pairing rules allow for the prediction of complementary DNA sequences crucial in bioinformatics applications (PCR primer design, DNA sequencing)

Transcription process

• Transcription initiates the flow of genetic information from DNA to RNA essential for protein synthesis
• Bioinformatics tools analyze transcription factor binding sites and gene regulatory elements to predict gene expression patterns

RNA polymerase function

• Enzyme responsible for synthesizing RNA molecules using DNA as a template
• Catalyzes the formation of phosphodiester bonds between ribonucleotides
• Moves along the DNA template in the 3' to 5' direction synthesizing RNA in the 5' to 3' direction
• Exhibits high fidelity in base pairing with error rates around 1 in 10^4 to 10^5 nucleotides

Initiation, elongation, termination

• Initiation begins with RNA polymerase binding to the promoter region of DNA
• Elongation involves RNA polymerase moving along the template strand synthesizing complementary RNA
• Termination occurs when RNA polymerase encounters a terminator sequence signaling the end of transcription
• In prokaryotes, transcription and translation can occur simultaneously while in eukaryotes, these processes are separated by the nuclear membrane

Promoter and terminator regions

• Promoter regions contain specific DNA sequences recognized by RNA polymerase and transcription factors
• TATA box common promoter element in eukaryotes located about 25-35 base pairs upstream of the transcription start site
• Terminator regions in prokaryotes often contain palindromic sequences forming hairpin structures
• Rho-dependent and Rho-independent termination mechanisms exist in prokaryotes while eukaryotes use more complex termination signals

RNA processing

• RNA processing modifies primary transcripts to produce mature functional RNA molecules
• Bioinformatics algorithms predict RNA secondary structures and splicing patterns crucial for understanding gene expression

5' capping

• Addition of a 7-methylguanosine cap to the 5' end of eukaryotic mRNA
• Protects mRNA from degradation by 5' exonucleases
• Facilitates recognition by ribosomes during translation initiation
• Involves three enzymatic steps: removal of 5' phosphate, addition of GMP, and methylation of the guanine

3' polyadenylation

• Addition of multiple adenine nucleotides to the 3' end of eukaryotic mRNA
• Poly(A) tail typically 150-250 nucleotides long in mammals
• Enhances mRNA stability and facilitates export from the nucleus
• Polyadenylation signal sequence (AAUAAA) directs the cleavage and polyadenylation process

Splicing and introns

• Removal of introns and joining of exons to form mature mRNA
• Spliceosome complex of snRNPs and proteins catalyzes the splicing reaction
• Alternative splicing allows production of multiple protein isoforms from a single gene
• Splice site recognition involves conserved sequences at intron-exon boundaries (GT-AG rule)

Translation mechanism

• Translation converts genetic information from mRNA into functional proteins
• Bioinformatics tools predict protein-coding regions and analyze codon usage patterns to optimize gene expression

Ribosome structure and function

• Ribosomes consist of two subunits (small and large) composed of rRNA and proteins
• Three binding sites: A (aminoacyl), P (peptidyl), and E (exit) for tRNA molecules
• Peptidyl transferase activity catalyzes peptide bond formation between amino acids
• Ribosomes move along mRNA in 5' to 3' direction during translation elongation

tRNA and codon recognition

• Transfer RNA (tRNA) molecules serve as adapters between mRNA codons and amino acids
• Anticodon loop of tRNA base pairs with complementary mRNA codon
• Aminoacyl-tRNA synthetases ensure correct amino acid attachment to tRNA
• Wobble base pairing allows some tRNAs to recognize multiple codons (flexibility in third base position)

Initiation, elongation, termination

• Initiation involves assembly of ribosomal subunits, mRNA, and initiator tRNA at the start codon
• Elongation cycles add amino acids to the growing polypeptide chain through codon-anticodon recognition
• Termination occurs when a stop codon enters the A site triggering release of the completed polypeptide
• Recycling of ribosomal subunits allows for multiple rounds of translation

Genetic code

• Genetic code defines the relationship between mRNA codons and amino acids
• Bioinformatics tools use codon usage tables to optimize gene expression in different organisms

Codon table

• 64 possible codons (4^3) encoding 20 standard amino acids and stop signals
• Each codon consists of three consecutive nucleotides in mRNA
• AUG serves as both the start codon and codes for methionine
• UAA, UAG, and UGA function as stop codons signaling the end of translation

Degeneracy of the code

• Multiple codons can specify the same amino acid (synonymous codons)
• Degeneracy varies among amino acids (leucine has six codons while tryptophan has only one)
• Third base wobble allows for some flexibility in codon-anticodon pairing
• Codon bias refers to preferential use of certain synonymous codons in different organisms

Start and stop codons

• AUG initiates translation and codes for methionine (or formylmethionine in prokaryotes)
• Alternative start codons (GUG, UUG) occur in some prokaryotic genes
• UAA (ochre), UAG (amber), and UGA (opal) function as stop codons
• Release factors recognize stop codons and trigger termination of translation

Regulation of gene expression

• Gene expression regulation ensures appropriate protein production in response to cellular needs
• Bioinformatics approaches identify regulatory elements and predict gene expression patterns

Transcriptional regulation

• Transcription factors bind to specific DNA sequences to activate or repress gene expression
• Enhancers and silencers modulate transcription from distant locations on DNA
• Chromatin remodeling affects accessibility of genes to transcription machinery
• Epigenetic modifications (DNA methylation, histone modifications) influence gene expression patterns

Post-transcriptional regulation

• Alternative splicing generates multiple mRNA isoforms from a single gene
• RNA editing alters nucleotide sequences in mRNA (A-to-I editing in mammals)
• microRNAs (miRNAs) and small interfering RNAs (siRNAs) regulate mRNA stability and translation
• RNA localization directs mRNAs to specific cellular compartments for localized protein synthesis

Translational regulation

• Internal ribosome entry sites (IRES) allow cap-independent translation initiation
• Upstream open reading frames (uORFs) modulate translation of main coding sequences
• RNA-binding proteins influence mRNA stability and translation efficiency
• Phosphorylation of translation factors (eIF2α) regulates global protein synthesis rates

Exceptions to central dogma

• Exceptions to the central dogma reveal alternative information flow in biological systems
• Bioinformatics tools identify and analyze non-canonical genetic elements and processes

Reverse transcription

• RNA-dependent DNA synthesis observed in retroviruses and retrotransposons
• Reverse transcriptase enzyme catalyzes the conversion of RNA to DNA
• Crucial for retroviral replication and integration of viral genomes into host DNA
• Telomerase uses reverse transcription to maintain chromosome ends in eukaryotes

RNA-dependent RNA synthesis

• RNA viruses use RNA-dependent RNA polymerases for genome replication
• RNA interference (RNAi) pathway involves production of double-stranded RNA
• RNA-dependent RNA polymerases amplify small RNAs in some organisms (plants, fungi)
• RNA editing in trypanosomes involves RNA-guided insertion or deletion of uridines

Prion replication

• Prions propagate through protein-based inheritance without nucleic acid involvement
• Misfolded prion proteins induce conformational changes in normal cellular proteins
• Associated with neurodegenerative diseases (Creutzfeldt-Jakob disease, mad cow disease)
• Yeast prions demonstrate non-Mendelian inheritance of phenotypic traits

Bioinformatics applications

• Bioinformatics tools analyze and interpret biological data to gain insights into molecular processes
• Integration of computational approaches with experimental data accelerates biological discoveries

Sequence alignment tools

• BLAST (Basic Local Alignment Search Tool) rapidly compares query sequences against databases
• Multiple sequence alignment algorithms (ClustalW, MUSCLE) identify conserved regions across species
• Hidden Markov Models (HMMs) detect subtle sequence patterns and protein domains
• Next-generation sequencing data analysis pipelines align millions of short reads to reference genomes

Gene prediction algorithms

• Ab initio methods use statistical models to identify coding regions in genomic sequences
• Comparative genomics approaches leverage evolutionary conservation to predict genes
• RNA-seq data integration improves gene structure predictions and identifies novel transcripts
• Machine learning algorithms (support vector machines, neural networks) enhance gene prediction accuracy

Protein structure prediction

• Homology modeling predicts 3D protein structures based on similar known structures
• Ab initio methods attempt to predict protein folding from amino acid sequences alone
• Molecular dynamics simulations model protein behavior and conformational changes
• Protein-protein interaction prediction algorithms identify potential binding partners

Evolutionary implications

• Molecular evolution studies provide insights into the history and mechanisms of genetic change
• Bioinformatics tools analyze evolutionary relationships and patterns across species

Molecular clock hypothesis

• Assumes constant rate of molecular evolution over time for specific genes or proteins
• Used to estimate divergence times between species based on sequence differences
• Calibrated using fossil evidence or known geological events
• Variations in evolutionary rates among lineages and genes challenge the strict molecular clock model

Comparative genomics

• Analyzes similarities and differences in genome sequences across species
• Identifies conserved regulatory elements and functional domains in proteins
• Reveals gene duplication events and the evolution of gene families
• Synteny analysis examines conservation of gene order and chromosomal organization

Phylogenetic analysis

• Reconstructs evolutionary relationships among species or genes using molecular data
• Maximum likelihood and Bayesian methods estimate phylogenetic trees
• Molecular markers (mitochondrial DNA, ribosomal RNA genes) widely used in phylogenetics
• Horizontal gene transfer events complicate phylogenetic reconstruction in prokaryotes