Genetics Flashcards
Codon
Triplet of bases, codes for an amino acid, basic unit of genetic information
Intron
Non-coding sequence
Exon
Coding sequence
Transcription
DNA -> mRNA
Translation
mRNA -> Polypeptide
Involves 3 steps: initiation, elongation, conformational change.
Post-translational modification
Occurs post-translation and pre-transcription. Introns are spliced out from mRNA.
Epistasis
Exchange of genetic material between chromosomes.
Point mutation
Involves 1-2 bases
Missense mutation
Triplet coding for one amino acid is altered to code for a different amino acid.
Nonsense mutation
Leads to a stop signal so no mRNA formed.
Silent mutation
No phenotypic consequence
Splice junction mutation
Affects way in which mRNA is spliced together
Pleiotropy
Single genetic defect causes variety of phenotypic effects
Autosomal dominant
Males and females equally affected.
Can have variable expression.
Can have reduced penetrance.
X-linked dominant
Affected male + unaffected female = all daughters affected, but no sons.
Unaffected male + affected heterozygous female = half of all children affected.
No male-to-male transmission
X-linked recessive
All male offspring manifest abnormal phenotype. All daughters of affected male will be carriers. No male-to-male transmission
Endophenotype
Any marker that is heritable and present in high proportion of family with disease. Eg, decline in working memory in schizophrenia. Also called an intermediate phenotype.
Huntington’s disease
Autosomal dominant.
Caused by expansion of CAG repeats in huntingtin gene on short arm of chromosome 4.
Severity depends on number of repeats.
Phenomenon of anticipation (earlier age of onset between generations).
Prader-Willi syndrome
Microdeletion on long arm of chromosome 15.
Inherited from father (c.f. Angelman’s).
Characterised by eating issues, learning disability, compulsive behaviours, skin picking.
Increased risk of psychosis.
Angelman’s syndrome
Mutation on long arm of chromosome 15.
Inherited from mother (c.f. Prader-Willi).
Characterised by microcephaly, severe learning disability, seizure disorder, distinctive facies with prominent jaw and wide mouth, ataxic gait, paroxysmal outbursts of laughter.
Fragile X syndrome
Caused by >200 CGG repeats on FMR1 gene on X chromosome.
X-linked dominant inheritance.
Most common cause of ID in males.
Features include learning disability (less severe in females), hand flapping, conversational difficulties, shyness/social anxiety.
Characterised by macroorchidism, elongated face, prominent/cupped ears, high arched palate, flat feet, hyperextensible finger joints.
Rett’s syndrome
X-linked dominant inheritance.
Mutation in MECP2 gene.
Mainly affects girls.
Child appears normal initially, then loss of acquired cognitive and motor skills from 5 months. Deceleration of head growth with significant microcephaly. Progressive cognitive decline, leading to severe ID. Gait and truncal apraxia. Associated with seizures.
William’s syndrome
Deletion of elastin gene on chromosome 7.
Characterised by elfin facies, skin sagging/wrinkles, hoarse voice, growth retardation.
Down’s syndrome
Trisomy 21.
Associated with increased Alzheimer’s risk as APP (amyloid precursor protein) gene is on chromosome 21.
Klinefelter syndrome
XXY syndrome.
Characterised with infertility, hypogonadism.
Symptoms usually subtle.
Jacob’s syndrome
XYY syndrome
Usually few symptoms, but may include tall, acne, increased risk of learning disabilities.
Turner syndrome
45X syndrome
Features include short webbed neck, short stature, amenorrhoea, infertility.
Edward’s syndrome
Trisomy 18
Characterised by low birthweight, microcephaly, cardiac defects, severe ID.
Velocardiofacial syndrome
DiGeorge syndrome
22q11.2 deletion on long arm of chromosome 22
Features include congenital heart defects, facial abnormalities, cleft palate, developmental delay, and learning difficulties.
Increased risk of severe psychiatric illness (25x) including schizophrenia.
Tuberous sclerosis
Autosomal dominant.
Mutation on TSC1 (hamartin gene) or TSC2 (tuberin gene).
Multisystem neurocutaneous syndrome in which non-cancerous tumours grow throughout body.
Classic triad: seizures + mental retardation + cutaneous angiofibromas.
Features include ash leaf spots.
Neuropsychiatric symptoms common (ID, ASD, ADHD, depression, behavioural issues, etc).
Phenylketonuria
Autosomal recessive.
Mutation on PAH gene.
Deficiency of PAH enzyme means dietary phenylalanine is not broken down.
If untreated, can lead to ID, seizures, behavioural and psychiatric disorders.
Lawrence-Moon syndrome
Autosomal recessive.
Characterised by ID, hexadactyly, central diabetes insipidus, blindness (from age 30).
Wilson’s disease
Autosomal recessive.
Mutation on ATP7B on chromosome 13, leading to copper accumulation.
In brain, this particularly affects globus pallidus and putamen.
Features include psychiatric (personality change, dementia, psychosis), motor (tremor, bradykinesia, dystonia, dysarthria), Kaiser-Fleischer rings, liver disease, haemolytic anaemia.
Genetics of schizophenia
Risks: both parents 45%, MZ twins 50-60%, DZ twins 12%.
Candidate genes include 22q11 (diGeorge), COMT, GRK-3, DISC-1 and DISC-2, dysbindin, neureglin, 13q.
Postmortem shows decreased expression of GAD67 (GAD1 gene) in brains of schizophrenics.
Genetics of depression
5-HTTCPR genotype influences stress reactivity (shown by Caspi). Short allele polymorphism is associated with poor SSRI efficacy compared to long variant.
Genetics of BPAD
Risks: both parents 50%, MZ twins 70%, DZ twins 20%.
Most strongly associated genes are DAOA (G72) and BDNF.
Some common genes between BPAD and schizophrenia.
Genetics of ADHD
Polygenic disorder, no single gene with large effect size.
Genes involved include D4, D5 (dopamine receptors), DAT1, serotonin transporter gene, SNAP-25.
Genetic syndromes which increase risk of ADHD include Angelman’s, Prader-Willi, Smith Magneis, William’s, Turner, Klinefelter, fragile X and Velocardiofacial.
Genetics of antisocial behaviour
Low activity of MAO-A (on chromosome X) is a risk factor for conduct issues, especially in males.
Genetics of OCD
Genes involved include serotonin receptor SLC6A4, the serotonin 1D-beta receptor gene, and glutamate transporter (SLC1A1).
Regions of interest on chromosome 9p and 10p.
Genetics of autism
Risks: MZ twins 60-90%, DZ twins 5-10%
Most heritable psychiatric disorder.
Main genes involved are ENZ (codes a protein involved in cerebellar development) and serotonin transporter SLC6A4.
Genetics of early-onset Alzheimer’s
Make up 5% of cases of Alzheimer’s.
Autosomal dominant.
Gene mutations involved include PSEN2 (abnormal presenilin 2, chromosome 1), PSEN1 (abnormal presenilin 1, chromsome 14) and APP (abnormal amyloid precursor protein, chromosome 21).
30-70% of cases due to PSEN1.
Genetics of late-onset Alzheimer’s
Most well established genetic link is APOE-e4 allele. This gene codes for apolipoprotein E. e4 allele shifts onset of disease forward. Incomplete penetrance, so even with two copies of this allele, a person only has 30% chance of developing Alzheimer’s.
Heterozygote = 3x risk
Homozygote = 10-30x risk
Genetics of Frontotemporal dementia
Autosomal dominant.
10-20% of cases due to single gene cause.
Most common genes involved are C9ORF72, MAPT (related to tau production, located on chromosome 17), and GRN.
Gelastic seizures
Autosomal dominant.
Laughing seizures.
Related to hypothalamic hamartomas, with excess production of hamartin.
Vertical transmission
Autosomal dominant
Horizontal transmission
Autosomal recessive
Knight’s move transmission
X-linked
Genetics of Lewy Body dementia
Most cases are sporadic.
Genes include APOE (increased risk), GBA, and SNCA (autosomal dominant).
Genetics of CADASIL
Notch3 gene (chromosome 19)
Autosomal dominant
Genetics of alcohol use
Heritability 45-65%.
Multifactorial inheritance.
Genes involved include ADH1B and ALDH2, both involved in metabolism of alcohol.
Lesch-Nyhan Syndrome
X-linked recessive.
Overproduction and accumulation of uric acid due to mutation in HPRT1.
Self-mutilation, dystonia, writhing movements.
Niemann-Pick A/B
11q15
Lipids collect in cells of spleen, liver and brain.
Abdominal swelling, cherry red spots, feeding difficulties.
