Genetics Flashcards
What is genetic linkage?
- 2 or more genes that are often inherited together as a result of having loci in proximity to each other on the same chromosome.
- They are often co-segregated.
What is recombination frequency?
Recombination frequency (q) = Recombinants/Total
How are distances between 2 genes measured?
q x 100 = % Recombination
1% = 1 cM = ~1Mb
How are genes ordered?
- When 3 genes are involved, the rarest event is usually a double recombination event.
- This means that even if it looked like only one combination event occurred, in fact, 2 recombination events have occurred either side of a constant single gene.
What are 4 important characteristics of model organisms in breeding studies?
- Samples need to breed true.
- Desired crosses need to be easily set up.
- Generation times need to be short.
- Large number of offsprings need to be produced.
What are genetic markers?
- Genes that are closely linked to the gene responsible for disease.
- These markers usually code for an observable phenotype, thus allowing a genetic disease to be traced throughout a population.
What does mapping a gene involve?
- Finding the chromosome it is located on.
- Finding the loci of the gene on that chromosome.
- Finding the mutation/s responsible for the disease.
What is the process of exome sequencing?
- Human genome fragmented to pieces ~500bp long.
- Fragmented DNA allowed to hybridise to a “Human Exome Array” containing all the coding strands of DNA in a human genome.
- Coding strand hybridise and non-coding strands are washed off.
- Coding strands eluted from the array and are sequenced in order to detect the disease-causing mutation.
What is the disadvantage of exome sequencing?
Does not allow mutations in regulatory sequences to be detected.
What is the cause of cystic fibrosis?
- Mutation in the CFTR (Cystic Fibrosis Transmembrane Regulator) gene.
- Located on chromosome 7 (7q31.2).
What are the characteristics of autosomal dominant diseases?
- Only affected individuals transmit the disease.
- There is a 50% chance a heterozygous individual will pass on the disease, 100% chance that a homozygous dominant individual will pass on the disease.
- Both sexes are affected equally and male to male transmission is possible.
What are some examples of autosomal dominant diseases?
- Huntington disease
- Myotonic dystrophy
- Polycystic kidney disease
- Ehlers Danlos syndrome
What is Ehlers Danlos syndrome and what is its cause?
- Connective tissue disorder.
- Symptoms include:
1. Bruising easily
2. Thin skin
3. Fragile blood vessels
4. Easily damageable hollow organ - Caused by mutations in collagen gene (esp. COL3A1)
What are the characteristics of autosomal recessive diseases?
- 2 unaffected individuals (carriers) are able to pass on the disease. There is 25% chance of this happening.
- The disease is able to skip a generation.
- Both sexes are affected equally.
What are some examples of autosomal recessive diseases?
- Cystic fibrosis
- Spinal muscular atrophy
- Congenital adrenal hyperplasia
What are chromosome aberrations?
- Mutations that affect large parts of a chromosome.
- These are usually visible on light microscope.
What are the types of chromosome aberrations?
- Numerical abnormalities: Abnormal number of chromosomes.
2. Structural abnormalities: Structural defects (e.g. translocations).
What us polyploidy?
When a cell contains an exact multiple of haploidy number which is >2.
What is aneuploidy?
When a cell contains an abnormal number of chromosomes which is not an exact multiple of haploidy number.
Which are the most commonly affected (viable) autosomal aneuploids?
- 13, 18, 21
- These are small chromosomes
What is the significance of numerical abnormalities?
The majority of spontaneous abortions (~95%) due to chromosome aberrations are caused by numerical abnormalities.
What are some examples of numerical abnormalities?
- Turner syndrome: XO
- Down syndrome: Trisomy 21
- Edward’s syndrome: Trisomy 18
What is the cause of Down syndrome?
- Trisomy 21
- Result of chromosome non-disjunction
- Most commonly occurs during meiosis, especially during egg formation
- > 90% of cases inherited maternally
- Risk of non-disjunction and thus acquiring the disease increases as maternal age increases
What is chromosome non-disjunction?
Failure of chromosomes to segregate during cell division
What are the types of non-disjunction?
- Primary non-disjunction (uniparental heterodisomy): Failure for chromosome to segregate during meiosis I, resulting in gamete containing 2 copies of it, one maternal and one paternal.
- Secondary non-disjunction (uniparental isodisomy): Failure for chromosome to segregate during meiosis II, resulting in gamete containing 2 copies of it, either maternal or paternal.
Which form of non-disjunction is more common?
Primary non-disjunction
What are the symptoms of Down syndrome?
- Memory/learning difficulties
- Cranial-facial alterations
- Congenital heart defects
- Alzheimer’s dementia
- Epilepsy
- Leukaemia
What is an accurate mouse model for chromosome 21?
Chromosome 16
What are the causes of triploidy?
- Dispermy: One egg fertilised by two sperms
- Whole genome non-disjunction: Failure for all chromosomes to segregate during meiosis, resulting in diploid sperm/egg.
Which is the most common cause of triploidy?
Dispermy
What is the origin of tetraploidy?
Zygote undergoes mitosis but first cell division does not occur.
What are the forms of chromosome translocations?
- Balanced (reciprocal)
2. Unbalanced (Robertsonian)
What are balanced (reciprocal) translocations?
- Fragments of chromosomes are swapped between different chromosomes.
- No loss of genetic information occurs, so the individuals are usually clinically normal.
- Offsprings are at risk of being chromosomally unbalanced.
What is an example of disease causing reciprocal translocation?
- Philadelphia chromosome.
- Balanced translocation between chromosomes 9 and 22.
- Found in ~95% of patients with chronic myeloid leukaemia.
What are the sequence of events during Robertsonian (unbalanced) translocation?
- Breaks occur just above centromeres on p-arm sides of 2 acrocentric chromosomes.
- This produces 2 fragments per chromosome: p-arm fragment without centromeres and q-arm fragment with centromere.
- 2 q-arm fragments join together to form dicentric chromosome and p-arm fragments are degraded.
What are insertions/deletions?
- Usually occur together.
- When there is unbalanced translocation between 2 homologous chromosomes, one will gain extra copies of certain genes while others will lose them.
What is an example of disease causing insertion/deletion?
- 22q.11.2 deletion syndrome.
- Causes schizophrenia and other associated neurological disorders.
- Causes DeGeorge’s syndrome.
What are the 2 types of inversions?
- Paracentric: Inversion involving breaks on single chromosome arm.
- Pericentric: Inversion involving breaks either side of centromere.
What techniques can be used for detecting chromosome aberrations?
- Karyotype analysis
- Fluorescent In Situ Hybridisation (FISH)
- Array comparative genomic hybridisation (aCGH)
What are the advantages/disadvantages of aCGH?
- Much higher resolution/sensitivity compared to FISH and karyotype analysis.
- Gives no information on location of deletion/duplication (in situ - on same chromosome, ex situ - on different chromosome due to crossing over).
What are the characteristics of sex chromosomes?
- Dimorphic: They are cytologically different from each other.
- In human, heterogametic sex is male, but this is not the case for other species.
What is a hemizygous state?
No masking of a recessive genotype as there is only one copy of the chromosome (X-linked recessive disorders in males).
What are the common genetic disorders caused by sex chromosome non-disjunction?
- Turner’s syndrome (45 XO)
- Klinefelter’s syndrome (47 XXY)
- XYY male
What are the symptoms of Turner’s syndrome?
- Webbed neck
- Short
- Infertility
What are the symptoms of Klinefelter’s syndrome?
- Tall and thin
- Gynecomastia
- Learning impairment (mild)
- Infertility
What are the characteristics of an X-linked recessive disorder?
- Mutations never passed from father to son
- Affected male always passes faulty allele to daughters who become carriers.
- Phenotype is able to skip a generation.
- More males affected than females.
What are examples of X-linked recessive disorders?
- Duchenne muscular dystrophy
- Haemophilia
- Red-green colour blindness
What are the causes and symptoms of DMD?
- Mutation in Dystrophin gene on X-chromosome
- Progressive muscle weakness and degeneration
What are the causes and symptoms haemophilia?
- Haemophilia A: Factor VIII affected
- Haemophilia B: Factor IX affected
- Ineffective blood clot formation results in excessive bleeding.
How is a female carrier distinguished?
- She is biological daughter of male with disease.
- She is biological mother of >1 son (ensures cause isn’t sporadic mutation) with disease.
- She is biological mother of at least 1 son with disease and has blood relative also with disease.
What are the characteristics of X-linked dominant disorders?
- Affected males always passes trait onto daughters
- Affected males don’t pass trait into sons
- There is 50% chance that an affected female will pass trait onto offsprings (assuming heterozygosity)
What is an example of an X-linked dominant disorder?
- Rett syndrome.
- Caused by a mutation in MeCP2 gene, which makes protein involved in methylation.
- Associated with neurological disorders such as seizures, inability to talk and hand movements.
What gene are responsible for ‘maleness’?
- SRY - Essential for determining maleness
- SF1
- SOX9
What is Campomelic Dysplasia?
- Mutation of SOX9 gene on chromosome 17.
- Causes sex reversal and skeletal dysplasia in males.
What structures do inactivated X chromosomes form in cells?
Barr bodies
What are the 3 principles of Lyonisation?
- Condensed X chromosome is inactive
- X inactivation occurs randomly
- Stable inheritance of inactivated X-state
What is the molecular mechanism behind Lyonisation?
- Xist RNA is expressed in genes to be inactivated.
- Histone tail modifications occur resulting in condensation of all X chromosome DNA into heterochromatin.
Which regions escape X chromosome inactivation?
- Pseudoautosomal regions (PARs): These genes are homologous between X and Y chromosomes.
- Non-PARs: Genes on the X chromosome that have functional homologues on Y.
What is genetic imprinting?
A phenomenon whereby expression of the same genes are different depending on whether it was inherited maternally or paternally. Usually, only one parental chromosome expresses the gene.
What are the forms of uniparental whole genome duplication?
- Maternal (parthenogenic): Excess embryonic development but absence of placental development. Results in formation of an ovarian teratoma.
- Paternal (androgenic): Excess placental development but absence of embryonic development. Results in formation of a hydrotidiform mole.
What are the ways in which uniparental disomy can occur?
- Maternal uniparental disomy: Disomic egg + nullisomic sperm.
- Paternal uniparental disomy: Disomic sperm + nullisomic egg.
What are the diseases associated with maternal uniparental disomy?
- 7: Silver-Russell syndrome
- 11: Silver-Russell syndrome
- 14: Maternal UPD14 syndrome (Temple syndrome)
- 15: Prader-Willi syndrome
What are the diseases associated with paternal uniparental disomy?
- 6: Transient neonatal diabetes
- 11: Beckwith-Weidemann syndrome
- 14: Paternal UPD14 syndrome (Kagami-Wang syndrome)
- 15: Angelman syndrome
What is Beckwith-Weidemann syndrome?
- Paternal uniparental disomy of chromosome 11.
- Foetal overgrowth with increased risk of childhood tumours.
- Overexpression of IGF2 in placental cells (paternal).
- No expression of CDKN1C (maternal).
What is Angelman syndrome?
- Paternal uniparental disomy 15.
- Severe developmental delays.
- Ataxic movement.
- Short attention spans.
- No expression of UBE3A.
What is Silver-Russell syndrome?
- Maternal uniparental disomy 7/11.
- Slow pre-/postnatal growth.
What is Prader-Willi syndrome?
- Maternal uniparental disomy 15.
- Neurological problems such as hypotonia, respiratory difficulties, sleeping disorders…
- Excess weight gain
- Delayed weight gain]
What are causes of imprinting-related disorders?
- Nonsense mutation in only expressed copy of imprinted gene.
- Imprinting error causing normally expressed genes to be repressed.
- Uniparental disomy.
What is the mechanism of DNA methylation?
- Methyl groups added to the C residue in CG pairs.
- Methylation is symmetrical and occurs on other strand on complementary CG pair.
- DNA methylation is preserved in DNA replication. This is a result of DNA methyltranferase 1, which uses the methylation on the parent strand as a template to methylate daughter strand.
What is the mechanism of demethylation?
- Passive: DNA isolated from DMNT, resulting in nascent DNA not being methylated and loosing methylation.
- Active
What is the significance of methylation in genomic control?
Most of the genome in differentiated cells are repressed by methylation. Only the promoter regions are not methylated.
What are the different forms of histone tail modifications?
- Methylation
2. Acetylation
What are types enzymes involved in histone tail modifications?
- Writers: Adds the histone modifications
- Erasers: Removes the histone modifications
- Readers: Interprets certain histone modifications. For example, some histone modifications recruit transcription factors.
What are the effects of methylation on histone tails?
Tighter packing of DNA → Condensation of chromosomes → Gene inactivation
What are the effects of acetylation on histone tails?
Cancels +ve charge on Lys residues → Fewer attractions between neighbouring nucleosomes → Less tight packing → Gene activation
What are the main functions of epigenetic modifications?
- Maintains architecture of chromosome: Telomeres and centromeres are heterochromatin and are essential to chromosome function.
- Represses ‘junk’ DNA: Expression of repetitive, non-coding, ‘junk’ DNA is repressed by packing into heterochromatin. This is especially important to prevent the random movement of transposons.
- Differentiation: Epigenetic modifications allow different combinations of genes to be expressed and repressed. This allows for cells to differentiate and carry out different sets of functions despite having identical genomes.
What are the epigenetic states in different stages of development?
- During migration, primordial germ cells (PGCs) lose their epigenetic modifications.
- These are re-established as the embryo develops.
- Epigenetic modifications are lost again during fertilisation (apart from imprinted genes).
- These modifications are once again re-established as the embryo develops.
What are the differences between the developmental epigenetic state in males compared to females?
- Males have a much higher methylation state compared to females.
- Epigenetic state becomes established much slower in females compared to males. Male genomes become fully methylated at birth while female genomes only become fully methylated at puberty.
What mechanism allows DNA methylation to be preserved in imprinted genes?
Recruitment of DNMT3 to imprinted genes by specific sequence-recognition proteins called ZFP57.
What are the different types of twins?
- Monozygotic twins: Genetically identical.
- Dizygotic twins: Genetically distinct.
What is concordance?
Event whereby both twins develop the same condition.
What are concordance ratios?
Ratio between the concordance of a condition in monozygotic twins compared to concordance of the same condition in dizygotic twins.
What is the significance of the concordance ratio?
- High concordance ratio means that there is a strong genetic component of the disease.
- Low concordance ratio means that there is a weak genetic component of the disease.
What is significant about the population of mitochondria in human cells?
- Population of mitochondria in cells contain genetically different mitochondria (heteroplasmy).
- Purifying selection occurs whereby more efficient mitochondria are selected for and less efficient ones are selected against.
What are the properties of the mitochondrial genome?
- Codes for 13 proteins.
- 22 tRNA.
- 12S and 16S rRNA for mitochondrial ribosomes.
What are the characteristics of the mitochondrial genome?
- No introns.
- No repeats.
- Multiple genes are transcribed simultaneously.
- 95% of DNA is coding.
What types of tissues are more likely to be affected by mitochondrial diseases?
High energy tissues
Which tissues are more likely to be affected by mitochondrial diseases?
- Brain: Can cause stroke due to inability of brain cells to respire aerobically.
- Nerves: Reduced activity due to inability to maintain resting potential.
- Heart: Arrhythmias and heart failure to insufficient energy supply to the cardiac myocytes.
- Muscle: Muscle weakness due to insufficient energy supply.
What are examples of mitochondrial diseases?
- DIDMOAD
- Kearns-Sayre syndrome
- LHON
What are the steps involved in gene editing?
- Guide RNA used to target bacterial dsDNA endonuclease (Cas9) to specific gene.
- Cas9 makes double stranded cuts at specific sites to excise faulty gene.
- Healthy gene inserted back into genome using ligase enzymes.
What are examples of trinucleotide expansion diseases?
- Fragile-X syndrome: Caused by CGG repeat
- Myotonic dystrophy: Caused by CTG repeat
- Huntington disease: Casued by CAG repeat
- Friedreich ataxia: Caused by GAA repeat
What are the mechanisms by which TNEs cause disease?
- Prevention of transcription of certain genes.
- Causes production of pre-mRNA that have pathological consequences.
- Causes production of dysfunctional proteins that have pathological consequences.
What causes fragile-X syndrome?
- CGG repeat on exon 1 of FMR1 gene on X-chromosome.
- TNEs prevent the FMR1 gene from being transcribed, preventing the production of FMRP, which is essential in cognitive development.
What are the symptoms of fragile-X syndrome?
- Learning disabilities
- Long face/large ears
- Increased risk of seizures
- Autism
What causes Friedreich’s ataxia?
- GAA repeats on intron 1 of Frataxin gene on chromosome 9.
- Trinucleotide repeats cause increased epigenetic modifications (including histone modifications) to the Frataxin gene, suppressing its transcription and expression.
What are the symptoms of Freidreich’s ataxia?
- Speech and movement abnormalities
- Heart disease
- Diabetes
What causes myotonic dystrophy?
- CTG repeats on 3’ end of DMPK gene in chromosome 19.
- Accumulation of abnormal pre-mRNA sequesters RNA-binding proteins and prevents them from carrying out their normal functions (alternative splicing).
What are the symptoms of myotonic dystrophy?
- Progressive muscular dystrophy
2. Myotonia (difficulty relaxing muscles post-contraction)
What causes Huntington’s disease?
- CAG repeats in Huntingtin gene in chromosome 4.
- CAG repeats sequence causes polyQ (Gln) strand in Huntingtin protein.
- PolyQ sequences in Huntingtin gene cause formation of polyQ-huntingtin aggregates when the protein is cleaved.
- Aggregates damage mitochondria, leading to the stimulation of apoptosis.
What are the symptoms of Huntington’s disease?
- Intellectual decline
- Myoclonus
- Dystonia
- Dementia
What are the additional assumptions made by the Hardy-Weinberg equation?
- Organisms are diploid
- Reproduction is sexual
- There’s no inter-generational mating
What is negative selection?
- Removal of deleterious alleles from the population gene pool over time.
- Occurs most commonly with mutations in protein-coding DNA, as these are the ones capable of affecting reproduction.
What is positive selection?
- Gradual increase in number of advantageous genes in the gene pool over time.
- May be inherited with number of other linked alleles. This is called selective sweep.
What is balancing selection?
- Multiple alleles are maintained at frequencies higher than would be based on natural rates of mutation.
- This usually occurs if heterozygotes have selective advantage over homozygotes.
What are the different types of single nucleotide polymorphisms (SNPs)?
- An SNP involving a change from a purine-purine/pyrimidine-pyrimidine are transitions.
- An SNP involving a change from a purine-pyrimidine or vice-versa are transversions.
