Describe the structure of a chromosome
Genome - DNA content of cell = all nuclear DNA and the 17000 base pairs of DNA (and 37 genes) in mitochondria
Nuclear - haploid one set of 23 chromosomes or diploid - 46 chromosomes
46 chromosomes - 22 pairs autosomes and 2 sex chromosomes (X/Y -female XX, male XY)
- Centromere divides the chromosome - short and long arm
- chromosomes can be metacentric, sub metacentric and acrocentric depending on position of centromere and relative lengths short and long arm
Describe how genes are organised on the chromosome
2% genome is coding DNA = exons of protein coding genes
20000 protein-coding genes contain large intron and other regulatory sequences
Coding sequences can be cut up and rejoined
Allows plasticity in genome
Also RNA genes encode RNA molecules - functionally important but not translated into polypeptides
Describe the major modes of Mendelian-monogenic inheritance
Monogenic inheritance - caused by defects in one particular gene and often simple and predictable inheritance
But can be variable penetrance (chance that a genotype results in expected phenotype) Seen with eg Hereditary Heamochromatosis (low penetrance), Huntington’s Chorea (near complete penetrance) and inherited cancers
and can be Mutifactorial - genetic + environmental
Describe polygenic inheritance, and discuss the contribution of genetic factors to commmon multifactorial diseases
Polygenic inheritance - inheritance and expression of phenotype determined by many genes at different loci
- each allele exerts small additive effect
Traits with continuous distribution eg Blood Pressure and Height often determined by interplay of many alleles at different loci
Multifactorial - require interaction of environmental and genetic factors eg Diabetes, Cardiovascular Disease and Schizophrenia
- can see in eg twin studies - same genetic make up
Demonstrate the methods for constructing a family history diagram, and for recognising the inheritance patterns for the major modes of Mendelian inheritance
Use symbols and notation to systematically record a genetic family history known as pedigree diagram
80% rare diseases have genetic cause - approx 1 in 2000 population or 1 in 17 people
Databases/Resources
OMIN (Online Mendelian Inheritance in Man) 4000 genetic diseases
Genetics Home Reference - 1000 rare diseases
Discuss the role of genetic changes in carcinogenesis
Alterations that functionally alter the cell are inherited as the cell reproduces
3 types:
- Inactivation of tumour suppressor genes - normal role is to restrain uncontrolled cell division - recessive genetic changes at cellular level
- Dominant activation of oncogenes - oncogenes involved in pathways regulating growth - usually just one allele
- Alterations in regulation of expression of genes - epigenetic changes - do not alter gene sequence but include DNA modifications such as methylation of DNA. Can lead to gene expression occurring in wrong place at wrong time
Changes in DNA lead to changes in RNA which lead to changes in proteins
Timing of mutations - genetic damage throughout life occurs through process of replication or through environmental/lifestyle factors. Most repaired. Some persist and have functional effects initaiting cancer development. Need further mutations eg resistance to therapy
Mutations divided into 2 groups
- DRIVER mutation - alteration in genome of a cancer cell that gives a growth advantage
- PASSENGER mutation - no effect on fitness of cell but detected as in same cell as mutation in driver gene. Repliactes rapidly as cell multiplying rapidly = hitchhiker in evolutionary biology
Discuss the patterns of inheritance and types of mutation associated with the common muscular dystrophies and ataxias
Duchenne Muscular Dystrophy
- X linked recessive
- alterations to Dystophin coding gene (large gene) - 60% large insertions/deletions and 40% point mutations/small frameshifts. 1/3 are new mutations (de novo) = Frameshift
- Incidence - 1 in 3500 males.
- Dystrophin stops muscle cell membrane tearing with contraction and relaxation.
- See increase in CK in blood
Becker Muscular Dystrophy - X linked - affects Dystrophin - milder than DMD therefore later onset
Myotonic Dystrophy - Autosomal dominant
Friedrich’s Ataxia - Progressive neurodegenerative movement disorder usually onset symptoms from 10-15 years age Autosomal Recessive 1 in 50 000 - affects ability to co-ordinate voluntary movements. Trinuclotide repeat expansion
Autosomal Dominant Cerebellar Ataxia - Trinucleotide repeat expansion - onset as adult
What are the features of Duchenne Muscular Dystrophy
X linked recessive
Progressive degeneration of muscle fibres and Weakness - Dystrophin affected (stabilises membrane, bridge between intracellular cytoskeleton and extracellular matrix, involved in differentiation into fast twitch fibres and synapses
1 in 3500 males
Onset 3-5 years
Difficulty walking and Waddling gait
Gowers’ sign (getting up from floor by going on all fours and walking hands up legs) and Toe walking
Pseudohypetropy - especiallly calves as muscle replaced by collagen and adipose tissue
Scoliosis and Contractures
Low IQ
Dilated cardiomyopathy
Death 15-25 years from cardiac or respiratory failure
What are features of Becker Mscular Dystrophy
X linked recessive- in frame mutation of Dystrophin gene
1 in 30000 males
Slowly progressive
Onset from 7 yeras (mean 11y)
Proximal muscle more affected
Gowers’ sign and Toe walking
Severity depends on Dystrophin levels (milder than Duchenne)
Calf pseudohypertrophy, cardiomyopathy, respiratory muscle involvement, scoliosis, mild learning difficulties
Myotonic Dystrophy
Autosomal dominant
1 in 8000
Adult onset
Slowly progressive multisystem - get eg myotonic facies, cardiomyopathy, muscle wasting, cataracts, endocrine - diabetes
Can show anticipation - disease gets progressively worse/ symptoms earlier in generations
