1.1 DNA structure and function

DNA structure and function form the foundation of molecular biology and bioinformatics. Understanding the chemical composition, double helix structure, and packaging of DNA provides crucial insights into how genetic information is stored and transmitted.

DNA replication, mutation, and repair mechanisms ensure genetic stability while allowing for evolution. Sequencing technologies and bioinformatics tools enable researchers to analyze DNA sequences, uncover genetic variations, and explore the functional implications of genomic data.

Chemical structure of DNA

• DNA serves as the blueprint for life, storing genetic information crucial for bioinformatics analysis and interpretation
• Understanding DNA structure provides the foundation for computational approaches in genomics and molecular biology

Nucleotide composition

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• Nucleotides consist of three components forming the building blocks of DNA
• Deoxyribose sugar forms the core of each nucleotide
• Phosphate group attaches to the 5' carbon of the sugar molecule
• Nitrogenous bases (adenine, thymine, guanine, cytosine) connect to the 1' carbon of the sugar
• Nucleotides link together through phosphodiester bonds between the 3' and 5' carbons of adjacent sugars

Sugar-phosphate backbone

• Alternating sugar and phosphate molecules create the DNA backbone
• Phosphodiester bonds form between the 3' hydroxyl group of one sugar and the 5' phosphate group of the next
• Backbone provides structural stability and directionality to the DNA molecule
• 5' to 3' orientation defines the reading direction for genetic information
• Negatively charged phosphate groups contribute to DNA's overall negative charge

Base pairing rules

• Complementary base pairing ensures accurate DNA replication and transcription
• Adenine (A) pairs with thymine (T) through two hydrogen bonds
• Guanine (G) pairs with cytosine (C) through three hydrogen bonds
• Chargaff's rules state that A=T and G=C in double-stranded DNA
• Base pairing specificity allows for precise information storage and retrieval

DNA double helix

• The double helix structure of DNA enables efficient information storage and replication
• Bioinformatics tools utilize knowledge of DNA structure to analyze and manipulate genetic data

Major vs minor grooves

• Major groove provides easier access for protein binding and interaction
• Minor groove offers a narrower and deeper channel along the helix
• Groove dimensions affect DNA-protein interactions and recognition
• Major groove width measures approximately 22 Å
• Minor groove width measures approximately 12 Å

A-DNA vs B-DNA vs Z-DNA

• B-DNA represents the most common form found in living cells
• A-DNA occurs in dehydrated conditions, featuring a wider and flatter helix
• Z-DNA adopts a left-handed helical structure, often found in regions with alternating purine-pyrimidine sequences
• B-DNA has 10 base pairs per turn, while A-DNA has 11 and Z-DNA has 12
• Helical structures influence DNA packaging and protein interactions

Supercoiling

• Supercoiling results from over- or under-winding of the DNA double helix
• Positive supercoiling involves tighter winding, while negative supercoiling involves looser winding
• Topoisomerases regulate DNA supercoiling to maintain proper cellular functions
• Supercoiling affects DNA replication, transcription, and recombination processes
• Linking number (L) describes the number of times one strand crosses over the other in a closed circular DNA molecule

DNA replication

• DNA replication ensures accurate transmission of genetic information during cell division
• Bioinformatics tools analyze replication origins and patterns to understand genome organization

Semi-conservative model

• Watson and Crick proposed the semi-conservative model of DNA replication
• Each daughter molecule contains one original strand and one newly synthesized strand
• Meselson and Stahl experimentally confirmed this model using isotope labeling
• Semi-conservative replication maintains genetic stability across generations
• Ensures each daughter cell receives an identical copy of the parental DNA

Replication fork

• Replication fork forms when parental DNA strands separate during replication
• Helicase enzyme unwinds the double helix, creating a Y-shaped structure
• Single-stranded binding proteins stabilize the separated strands
• DNA primase synthesizes short RNA primers to initiate replication
• Topoisomerases relieve tension caused by unwinding ahead of the replication fork

Leading vs lagging strand

• Leading strand synthesized continuously in the 5' to 3' direction
• Lagging strand synthesized discontinuously in short Okazaki fragments
• DNA polymerase III extends both leading and lagging strands
• RNA primers removed and gaps filled by DNA polymerase I
• DNA ligase joins Okazaki fragments to complete lagging strand synthesis

DNA packaging

• DNA packaging allows for efficient storage of genetic material within the cell nucleus
• Bioinformatics approaches analyze chromatin structure to understand gene regulation and expression

Nucleosomes and histones

• Nucleosomes form the basic unit of DNA packaging in eukaryotes
• Histone octamer consists of two copies each of H2A, H2B, H3, and H4
• Approximately 147 base pairs of DNA wrap around each histone octamer
• Linker DNA connects adjacent nucleosomes, ranging from 10 to 80 base pairs in length
• Histone H1 binds to linker DNA, further compacting the chromatin structure

Chromatin structure

• Primary structure consists of the "beads on a string" arrangement of nucleosomes
• Secondary structure forms the 30 nm fiber through coiling of the primary structure
• Tertiary structure involves further compaction into loops and domains
• Quaternary structure represents the highest level of organization in metaphase chromosomes
• Chromatin structure dynamically changes to regulate gene expression and DNA accessibility

Euchromatin vs heterochromatin

• Euchromatin represents less condensed, transcriptionally active regions of chromatin
• Heterochromatin consists of tightly packed, transcriptionally inactive regions
• Constitutive heterochromatin remains condensed throughout the cell cycle (centromeres, telomeres)
• Facultative heterochromatin can switch between condensed and decondensed states
• Epigenetic modifications influence the transition between euchromatin and heterochromatin

DNA function

• DNA functions as the carrier of genetic information, essential for life processes
• Bioinformatics tools analyze DNA sequences to predict gene function and regulatory elements

Genetic information storage

• DNA stores hereditary information in the sequence of nucleotides
• Genes encode instructions for protein synthesis and functional RNAs
• Genetic code determines the correspondence between DNA sequences and amino acids
• Non-coding DNA regions play roles in gene regulation and chromosome structure
• Genome size varies widely across species, ranging from a few thousand to billions of base pairs

Gene expression regulation

• Promoter regions control gene transcription initiation
• Enhancers and silencers modulate gene expression levels
• Transcription factors bind to specific DNA sequences to activate or repress genes
• Epigenetic modifications (DNA methylation, histone modifications) influence gene accessibility
• Alternative splicing allows for multiple protein isoforms from a single gene

Genome organization

• Prokaryotic genomes typically consist of a single circular chromosome
• Eukaryotic genomes contain multiple linear chromosomes
• Repetitive DNA sequences (transposons, satellite DNA) make up a significant portion of many genomes
• Synteny describes the conservation of gene order across related species
• Genome size does not necessarily correlate with organismal complexity (C-value paradox)

DNA mutations

• DNA mutations drive genetic variation and evolution
• Bioinformatics tools detect and analyze mutations to understand their impact on phenotypes

Types of mutations

• Point mutations involve single nucleotide changes (substitutions)
• Insertions add one or more nucleotides to the DNA sequence
• Deletions remove one or more nucleotides from the DNA sequence
• Frameshift mutations alter the reading frame of a gene
• Chromosomal mutations involve large-scale changes in chromosome structure or number

Causes of mutations

• Spontaneous errors during DNA replication or repair
• Exposure to mutagens (UV radiation, chemical agents)
• Transposable elements can insert into new genomic locations
• Oxidative stress generates reactive oxygen species that damage DNA
• Errors in DNA repair mechanisms can lead to mutation accumulation

Mutation effects on function

• Silent mutations do not change the amino acid sequence of the encoded protein
• Missense mutations result in a different amino acid in the protein sequence
• Nonsense mutations introduce premature stop codons, truncating the protein
• Splice site mutations can alter mRNA processing and protein structure
• Regulatory mutations affect gene expression levels or patterns

DNA repair mechanisms

• DNA repair systems maintain genome integrity and stability
• Bioinformatics approaches analyze repair pathways to understand disease susceptibility

Base excision repair

• Removes and replaces damaged or incorrect bases
• DNA glycosylases recognize and remove specific damaged bases
• AP endonuclease cleaves the DNA backbone at the abasic site
• DNA polymerase β fills the gap with the correct nucleotide
• DNA ligase seals the nick to complete the repair process

Nucleotide excision repair

• Removes bulky DNA lesions caused by UV radiation or chemical agents
• XPC-RAD23B complex recognizes distortions in the DNA helix
• TFIIH unwinds the DNA around the damage site
• XPF and XPG endonucleases excise the damaged DNA fragment
• DNA polymerase fills the gap, and DNA ligase seals the nick

Mismatch repair

• Corrects base-base mismatches and small insertion/deletion loops
• MutS protein recognizes and binds to the mismatch
• MutL protein recruits additional repair factors
• Exonuclease removes the incorrect nucleotides
• DNA polymerase resynthesizes the correct sequence
• DNA ligase seals the remaining nick

DNA sequencing

• DNA sequencing technologies enable the determination of nucleotide sequences
• Bioinformatics tools process and analyze sequencing data to extract biological insights

Sanger sequencing

• Chain-termination method using dideoxynucleotides (ddNTPs)
• Produces DNA fragments of varying lengths terminated by fluorescently labeled ddNTPs
• Capillary electrophoresis separates fragments by size
• Laser detection of fluorescent labels determines the nucleotide sequence
• Reads lengths typically range from 500 to 1000 base pairs

Next-generation sequencing

• Massively parallel sequencing of millions of DNA fragments
• Illumina sequencing uses reversible terminator chemistry and bridge amplification
• Ion Torrent detects hydrogen ions released during nucleotide incorporation
• Produces shorter read lengths (50-300 bp) but higher throughput than Sanger sequencing
• Enables whole-genome sequencing, transcriptomics, and epigenomics studies

Third-generation sequencing

• Single-molecule sequencing technologies provide longer read lengths
• Pacific Biosciences SMRT sequencing uses zero-mode waveguides to detect nucleotide incorporation
• Oxford Nanopore sequencing measures changes in electrical current as DNA passes through a nanopore
• Produces read lengths of tens of thousands of base pairs
• Allows for direct detection of DNA modifications and improved genome assembly

Bioinformatics applications

• Bioinformatics integrates computational methods with biological data analysis
• DNA sequence analysis forms the foundation for many bioinformatics applications

Sequence alignment

• Compares DNA sequences to identify similarities and differences
• Global alignment aligns entire sequences (Needleman-Wunsch algorithm)
• Local alignment finds regions of similarity within sequences (Smith-Waterman algorithm)
• Multiple sequence alignment compares three or more sequences simultaneously
• BLAST (Basic Local Alignment Search Tool) rapidly searches sequence databases

Genome assembly

• Reconstructs complete genome sequences from short sequencing reads
• De novo assembly builds genomes without a reference sequence
• Reference-guided assembly uses a known genome as a template
• Assembly algorithms (de Bruijn graphs, overlap-layout-consensus) piece together overlapping reads
• Scaffolding combines contigs into larger structures using paired-end or long-read information

Variant calling

• Identifies genetic variations between individuals or populations
• Single nucleotide polymorphisms (SNPs) represent single base differences
• Structural variants include insertions, deletions, inversions, and copy number variations
• Variant calling pipelines align reads to a reference genome and identify differences
• Annotation tools predict the functional impact of identified variants