GiM lectures 9,10,11 Flashcards
What is morphology
scientific study of the structure and form of either animals and plants or words and phrases
What % of births have congenital malformations?
- when are these malformations more likely to be genetic?
2-3%
multiple malformations, dysmorphic, family history
22q11. 2 Deletion
- phenotype
- frequency
- dysmorphology
- also known as?
Very variable phenotype 1/5000 Learning difficulties - 70% Congenital heart defects 75% hypocalcaemia Seizures Immune deficiency Renal malformation Velopharyngeal insufficiency 32% Cleft palate 15% small lip and lower jaw slanted eyes short stature
aka - DiGeorge syndrome
Achondroplasia
- frequency
- mutation type
- risk factors?
- clinical features
1/20,000 autosomal dominant - often denovo - increased with paternal age - rhizomelic limb shortening - short stature - foramen magnum compression - hydrocephalus
Beckwith-Wiedemann syndrome
- frequency
- clinical features
1/10000
Large tongue, ear pits/creases, exomphalos (umbilical herniation of guts), hemihypertrophy, neonatal hypoglycaemia,
microcephaly
increased risk of Wilms tumour
Down syndome
- frequency
- clinical features
1/800
learning difficulties, congenital heart defects, hypotonia in neonates, single palmar crease, cataracts, hearing impairment, hypothyroidism, leukaemia, atlanto-axial instability, alzheimers
What % of the normal population have a single palmar crease?
- unilateral
- bilateral
unilateral = 4% bilateral = 1%
Kabuki syndrome
- frequency
- clinical features
1/30,000
learning difficulities, congenital eart disease 50%, poor growth, hearing impairment, cleft palate, premature breast development, persistent fetal finger pads 96%, flat broad nose, everted eyelids, cleft palate
mosaicism
- how is it diagnosied
- how can it be recognised
diagnosis by skin biopsy
can be hypo/hyper pigmented patches - may follow blaschko’s lines
What are blaschko’s lines
Blaschko lines are thought to represent pathways of epidermal cell migration and proliferation during the development of the fetus. only visible when a condition affecting the skin is present
Peutz-Jeghers Syndrome
- frequency
- clinical features
Treacher collins syndrome
Frequency
inheritance
clinical features
1/50000
autosomal dominant
very variable phenotype
cleft palate, hearing impairment,
Waardenburg syndrome
- frequency
- clinical features
1/250000
sensorineural hearing impairment, irisheterochromia, premature greying, white forelock, areas of skin hypo pigmentation, congenital malformations VSD, hirschprungs
William’s syndrome
- what is it
- frequency
- clinical features
7q11 deletion 1/20,000 learning difficulties cocktail party speech congenital heart disease - supravalvular aortic stenosis, peripheral pulmonary artery stenosis hypercalcaemia, wide mouth, sunken nasal bridge,
What is cocktail party speech
able to speak fluently in small talk but unable to go into deeper complex social issues due to learning difficulties
What is the structure of DNA
deoxyribose ring (5 carbons) -OH on C1,3,5 C1 - binds to nucleotide base C3 - binds to phosphate C5 - binds to phosphate DNA is stable RNA is unstable (transient
What direction is DNA/RNA synthesised
5’ to 3’
What does the shorthand DNA sequence of
5’ AACGT represent
5’ AACGT
TTGCA 5’
Sense strand is the one written and is the one that makes the mRNA
What is the haploid genome size of the following organisms
1) Mycoplasma genitalium
2) E. Coli
3) Schizosaccharomyces pombe
4) Caenorhabditis elegans
5) drosophila melanogaster
6) Human
7) salamander
1) 0.6Mbp
2) 5Mbp
3) 14 Mbp
4) 80Mbp
5) 165Mbp
6) 3000Mbp
7) 50000Mbp
Facts about the Human genome
- how many Mb dsDNA are there per haploid genome?
- What is the size of the largest and smaller chromosome
- what % of DNA is non coding
- How many protien coding genes are there
- 3 000 Mb dsDNA per haploid genome
- Chromosome 1 – 263 Mb
- Chromosome 22 – 39 Mb
- > 90% is non-coding DNA
- Approx. 20 000 protein-coding genes
What are single copy sequences in the human genome
genes
what are repetitive sequences within the human genome
Interspersed repeats - e.g. Alu repeats
Satellite DNA - large blocks or repetitive sequence, heterochomatin
What are Genes?
Functional unit of DNA
Transcription - copied to RNA
Translation - RNA to protein
Components of genes
exons, introns, regulatory sequences (promoters, enhancers, locus control regions)
What parts of protein synthesis occur in the nucleus
What parts of protein synthesis occur in the cytoplasm
Transcription, capping, cleavage and polyadenylation,
(splicing - takes RNA out into cytoplasm)
mRNA - Translation
Protein created
(post translational modificaitions)
What is alternative splicing
Exon Skipping
can lead to multiple mRNA forms - depending on how splicing occurs
What are gene families
All genes have an ancestral gene
Evolution of genes progress via duplication and divergence
most have similar structural families
Psuedogenes - are genes that have lost the function to express - often occur by accumulation of mutation in gene not essential for survival
Explain Processed genes
intron less copied of other genes - remote from parent gene
dispersed by reverse transcription and reintegration
some remain functional (e.g. PGK2 testis specific) but majority non functional
often one mutation away from becoming pseudogenes
How many of each of the following are present in the human genome
1) coding genes
2) short non coding genes
3) long non coding genes
4) pseudogenes
5) gene transcripts
Coding genes: 20,769 Short non-coding genes: 9,079 Long non-coding genes: 13,564 Pseudogenes: 14,165 Gene transcripts: 195,565
What is satellite DNA
Large blocks at centromeres and heterochromatic chromosomal regions Simple tandemly repeated sequences Many types e.g. alphoid DNA Centromere repeat Chromosome-specific Size of blocks may be polymorphic 1, 9, 16, Y
What is Alphoid DNA
- type of satellite DNA found at centromeres
- 171bp repeat unit
- chromosome specific variation
- needed for assembly of centromere
Explain interspersed repeats
scattered around genome
individual copies present at many location,
e.g. Alu repeat
500000 copies, 300bp, 5% genome
Dispersed by retrotransposition
can cause huntingtons
Causes of molecular pathology
Interspersed repeats causing unequal crossing over due to misalignment of sequence
- results in frameshift +/- truncation
What are the types of mutation
with examples
-Deletions and insertions
Duchenne muscular dystrophy = deletion
-Charcot-Marie-Tooth Disease = duplication
-Gross Rearrangement - haemophilia A
-Point mutation
-trinuceoptid repeat expansion - huntingtons
What is the haemophilia A mutation
Xq28
Inversion of homologous sequence within chromosome
what are the types of point mutation?
Silent
- if common = polymorphism
- causes same ammino acid to be coded for but by differnet codon
Missense
- causes different amnio acid
- can be conservative (within same amnio acid type)
- can be non conservative (different type of amnio acid, generally more damaging)
Non sense
no amnioacid coded for
truncated protein produced
can be detected
Frameshift mutation
alters protein sequence beyond mutation
truncated protein
What are the groups of amino acids? Acidic Basic Polar Non polar aromatic other
Acidic: Glu Asp Basic: Lys Arg Polar: Ser Thr Asn Gln Ser (His) Non-polar:Ala Val Leu Ile Met Aromatic: Phe Tyr Trp (His) Other: Gly Pro
what is the most common point mutation
CG –> TG =1/3 of mutations
due to hyper mutability of CpG dinucleotides
- methylation of C (addition of CH3)
- deamination (change of C to T)
- Mismatch repair G–>A
Mutation nomenclature
reference sequence needed
genomic DNA, cDNA, Protein
(g.), (c.), (p.)
What is the mutational spectrum
loss of function mutations usually recessive
50% gene function is adequate
mutational heterogeneity is frequency - affected indivuals can be compound heterozygotes, mutation testing therefore challenging
give 2 examples of a recessive condition where the affected individual are compound heterozygotes
cystic fibrosis
beta thalassaemia
What is the carrier frequency equation?
p = mutant allele freq q = 1-p = normal allele freq p2 = affected individual 2pq = 2p(1-p) = carriers
What does dominant inheritance often result in?
gain or alteration of function
- smaller mutational spectrum
- new mutation comparatively common
- e.g. achondroplasia
FGFR3 G380R
what disease are caused by Polyglutamine repeats (CAG)
Neurodegenerative disorders
- huntington’s disease
- spinocerebellar ataxias
What disease are caused by large non-coding repeat expansions
- fragile X syndrome - CGG repeat expansion (transcriptional silence)
- myotonic dystrophy
What diseases have occasional and frequent instability
occasional = huntington's frequent = fragile X
