Week 5 - Asthma as A Complex Disease Flashcards
DNA molecules packaged into chromosomes
- Naked DNA is unstable within cells so the packaging prevents the molecule from damage
- Compaction allows the DNA to fit within a cell
- Allows efficiency of DNA replication and transfer to daughter cells
- Organisation of genome allows for regulation of gene expression
Allele and locus
- Allele is a nucleotide sequence of a gene. Alleles are variants of the same gene that occur in the same place on a chromosome, through a mutation they are different and are responsible for variable traits within a population
- Locus refers to the position of an allele on the chromosome that serves as a marker. Different loci consist of different alleles
Genetics, genes, genomes and genomics
- Genetics is the study of heredity
- A gene is the unit of inheritance, by which hereditary characteristics are transmitted through generations. At the molecular level, a single gene consists of DNA which exerts its influence on the organisms form and function by encoding and directing the synthesis of a protein, tRNA, rRNA or other structural RNA.
- The genome is the complete DNA sequence of an organism consisting of gene encoding DNA sequences.
- Genomics is the discipline of sequencing mapping, analysing and comparing genomes.
Single nucleotide polymorphisms (SNPs)
- The most common type of genetic variation among people.
- Each SNP represents a difference in a single DNA building block (nucleotide)
- They can act as biological markers helping scientists locate genes that are associated with disease.
Epigenetics
- Refers to a change in phenotype or gene expression caused by mechanisms other than changes in the underlying DNA sequence
- Environmental factors can effect gene expression through epigenetic mechanism
- Described as a heritable regulation of gene transcription that does not alter the DNA sequence
Epigenetic regulatory factors
- Epigenetic regulation affects gene expression through three main mechanisms:
1. DNA methylation
2. Histone modification
3. Non-coding RNA
DNA methylation
- Addition of a methyl (CH3) group to DNA
- C5-methylcytosine (5-mc) occurs at cytosine that is followed immediately by guanine (CpG dinucleotide) in gene promoter by DNA methyltransferase (DNMT)
- Can cause long term inactivation of genes in cellular differentiation
- Regulates expression of either the maternal or paternal alleles of certain genes at the start of development
- A covalent modification of DNA that does not change the DNA sequence but has an influence on gene activity
- Although it is heritable, it is reversible
Histones
- Histones are a group of proteins that are found in the nuclei of eukaryotic cells that are responsible for DNA folding and chromatin formation
- Chromatin architecture, nucleosomal positioning, and ultimately access to DNA for gene transcription is largely controlled by histones
- Each nucleosome is made of two identical subunits, each of which contains 4 histones: H2A, H2B, H3 and H4
- The H1 protein acts as a linker histone to stabilise internucleosomal DNA and does not form part of the nucelosome itself
Histone modification
- A histone modification is a covalent post-translational modification (PTM) to histone proteins:
- Acetylation
- Methylation
- Phosphorylation
- Ubiquitylation
- Sumoylation (small ubiquitin- like modifier, known as SUMO, proteins are a family of small proteins that are covalently attached to and detached from other proteins)
Histone acetylation and deacetylation
Histone acetylation
- Catalysed by histone acetyl transferase (HATs) enzyme
- Adds acetyl groups to histone tails (especially H3 and H4)
- Reduces positive charge and weakens interactions of histones with DNA
- Facilitates transcription by making DNA more accessible to RNA polymerase II
Histone deacetylation
- Catalysed by histone deacetylases (HDACs) enzyme
- Removes acetyl groups from histone tails
- Increases interaction of DNA and histones
- Represses transcription
Non-Coding RNA
- ncRNA is a functional RNA molecule that is not translated into proteins
- Types:
1. microRNA
2. silencing RNA
3. small nuclear (nucleolar RNA)
4. circular RNA
microRNA (miRNA)
- A small ncRNA molecule (approx. 22 nucleotides)
- Found in plants, viruses and animals
- Functions:
1. RNA silencing
2. Post-transcriptional regulation of gene expression
microRNA and the process and function
- microRNA is transcribed as a hairpin primary RNA (pri-RNA) by RNA polymerase II
- It is cleaved into hairpin precursor miRNA (pre-miRNA) by the complex Drosha ribonuclease III and the RNA-binding DGCR8 protein in nucleus
- This pre-miRNA is then exported to the cytoplasm by exportin-5 protein
- In cytoplasm pre-miRNA is cleaved to two strands by endonuclease dicer:
1. one strand becomes a mature miRNA and silence target mRNAs through mRNA degradation or translocation repression
2. the other strand is degraded
Functional consequences of changed miRNA expression
Diagnosis, prognosis and severity of a wide range of diseases including:
- infectious disease
- autoimmune disease
- cancer
Functions of the respiratory system
- Provides an extensive area for gas exchange between air and the circulating blood
- Maintenance of homeostasis
- Exchange of gases between the body tissues and bloodstream
- Olfactory sensation (sense of smell)
- Voice production
- Defence against pathogens
Respiratory system
Upper respiratory tract
- Nose
- Nasal cavity
- Pharynx
Lower respiratory tract
- Larynx
- Trachea
- Bronchi
- Lung
Larynx
Glottis
- Superior opening: the part of the larynx consisting of the vocal cords and the opening between them. It affects voice medulation through expansion and contraction
Epiglottis
- Flap of tissues that guards the glottis, directs food and drink to the oesophagus
Function of larynx
- Maintain an open passageway for air movement
- Epiglottis and vestibular folds prevent swallowed material from moving into larynx
- Vocal cords are primary source of sound production
Trachea
- Rigid tube, 12cm long and 2.5cm in diameter, anterior to oesophagus.
- Supported by 16 - 20 C shaped cartilaginous rings (hyaline cartilage)
- Trachealis muscle (smooth muscle) spans opening in rings and adjusts airflow by expanding or contracting
- Larynx and trachea lined with ciliated pseudostratified epithelium
Tracheobronchial tree
Trachea - Pri. bronchiole - Sec. bronchi - Tertiary bronchi - Bronchioles - Terminal Bronchioles
Bronchial tree
- Bronchioles (lack cartilage) - 1mm
- Have layer of smooth muscle
- Pulmonary lobule ventilated by one bronchiole
- Divide into 50 - 80 terminal bronchioles (0.5mm) that have cilia and divide into 2 or more respiratory bronchioles
- Respiratory bronchioles divide into 2 - 10 alveolar ducts which then end in alveolar sacs which contain alveoli
Mucociliary escalator or the ciliated mucosa
- One of the major defence mechanisms which protects the lungs
- Covers most of the bronchi, nose and bronchioles
- Contains mucus-producing goblet cells and ciliated epithelium
- Continuously propels the mucus which contains dust particles and debris to the throat so it can be expelled or swallowed
Site of gas exchange
- The alveoli which increases surface area and brings air in contact with blood and takes place within 300 million air sacs so has a large surface area he alveolar membranes are thin so makes diffusion quicker
Asthma
- Common chronic disease
- Affects 5 million people in the UK
- Costs the UK health service at least £1.1 billion each year
Asthmas is characterised by: - Wheezing
- Coughing
- Chest tightness
- Shortness of breath
- Reversible airflow obstruction associated with airway hyperresponsiveness
- Bronchospasm
These features are generally attributed to an inflammatory process with progressive bronchial remodelling
Triggers of asthma: - Allergens (house dust mites, animal fur or pollen)
- Smoke, pollution and cold air
- Stress
- Exercise
- Infections like cold or flu
