Week 1: Genetics Flashcards
Autosomal Dominant
Genetic disorder transferred from parent to offspring. Vertical pedigree pattern, expressed in heterozygotes, variable expressivity, may be incomplete penetrance.
Eg genetic breast/colon cancer
Autosomal recessive
Musy be homozygous to show phenotype. Horizontal pedigree pattern, expressed in homozygotes, may be consanguinity.
Eg Sickle Cell Anaemia, Cystic Fibrosis
X-linked
RECESSIVE: affects males, show Knight’s move pattern, all daughters carriers
DOMINANT: vertical transmission, all daughters affected
Variable inheritance
individuals in the same family are affected differently by the same gene
Incomplete penetrance
Severity of the same mutation differs from person to person. Common in autosomal dominant conditions
Genetic Anticipation
increased severity and earlier age of onset of mutation through generations. Eg Huntington’s
Mitochondrial inheritance
Genetic material only comes from mother. Disorders tend to affect the muscles, brain and eyes
What does the future of medical genetics involve?
NIPT/NIPD Next Generation Sequencing of whole exomes Personalised Medicine Treating specific genes Tailoring treatments to tumour genotypes
What does gene therapy involve?
Exon skipping in DMD (so you convert DMD to BMD)
Gene editing in CRISPR-CAS9 system
Base editing
How do you do a pre-implantation diagnosis?
remove a couple of cells at 3 days then use PCR/FISH to look at the DNA
What is genetic counselling?
It provides advice or information. The advice should be non-directive
Explain genetic screening
The whole population is offered a genetic test. It can be:
Prenatal (US, maternal blood markers)
Neo-natal (blood spot from heel, Guthrie card, mass spectrometry)
Post Natal (Tay Sachs for Jewish people)
What is heteroplasmy?
Presence of more than one type of organellar genome (mitochondrial DNA or plastid DNA) within a cell or individual
What are the symptoms of Huntington’s disease
progressive chorea (jerking/writhing movements), dementia, psychiatric symptoms, muscle dystonia, slow or abnormal eye movements
Genetics of Huntington’s
Autosomal dominant w/ genetic anticipation.
Caused by unstable length of chromosome 4 by CAG codon repeats
What are the symptoms of myotonic dystrophy?
progressive muscle weakness, myotonia, cataracts, ptosis
Genetics of myotonic dystrophy
Autosomal dominant w/ genetic anticipation
Unstable length of CTG repeat (causing abnormal DMPK mRNA)
What is cystic fibrosis?
Thicker mucus (recurrent lung infections) CFTR mutation causes defective chloride ion channel which makes mucus thicker. Autosomal recessive
What is neurofibromatosis
Symptoms: cafe au lait macules, neurofibromas, short stature
Autosomal dominant
Complications: hypertension, scoliosis
What are Duchenne Muscular Dystrophy and Becker’s Muscular Dystrophy?
X linked recessive, show knight’s move pattern
Creatinine kinase leaks out of damaged muscle into the blood
Symptoms: Muscle weakness, difficulty standing, unsteady, waddling gait.
DMD = out of frame reading mutation
BMD = in frame reading mutation
What is Fragile X syndrome?
X linked recessive disorder w/ genetic anticipation. Is on the FMR1 gene
Inherited condition characterised by an X chromosome that is abnormally susceptible to damage, especially by folic acid deficiency. Affected individuals tend to have limited intellectual functions.
What is Down’s Syndrome?
trisomy 21
symptoms: learning difficulty, heart defects, hypothyroidism
What is trisomy?
This arises from maternal non-disjunction. The risk increases with maternal age
What are the properties of a cancerous cell?
proliferative signalling; avoidance of apoptosis; bypass replicative senescence; insensitive to anti-growth signalling; needs its own blood supply
What are the functions of Tumour Suppressor Genes?
Act as brakes; inhibit progression through the cell cycle and cell proliferation; promote apoptosis; act as stability genes
What is a stability gene?
a type of tumour suppressor gene that acts to minimise genetic alterations
What are proto-oncogenes
these participate in normal cellular resposne to growth factors. They stimulate the cell cycle to promote cell division/growth. Activation by mutation turns them into oncogenes
Name the types of cancer and explain what they are
SPORADIC: common, late onset, single primary tumour
FAMILIAL: uncommon, early onset, often have multiple primary tumours
What is DNA methylation?
This switches off a gene without changing the sequence
What genes can cause breast cancer?
BRCA1, BRCA1, TP53, PALB2
What is the function of BRCA1/2?
repair by homologous recombination of double stranded breaks
What genes cause ovarian cancer?
BRCA1, BRCA2, HNPCC, PTEN
What is the treatment of ovarian cancer?
PARP inhibition (olapirib). This blocks all types of DNA repair which forces the cells to die. It only kills tumour cells
Colon cancer
Genetics: autosomal dominant, MLH1, MSH2, MSH6
Screening: colonoscopies every 2 years after 25 years
What is familial adenomatous polyposis?
A faulty APC gene on chromosome 5
The bowel is full of small tumours - these can become malignant so you must remove the large bowel
What is Li Fraumeni Syndrome?
Autosomal dominant cancer predisposition syndrome
There is a mutation in TP53 which can cause a range of cancers
What is supercoiling?
DNA is tightly wound around a nucleosome made of histones (like beads on a string)
What is RNA/DNA polymerase?
RNA polymerase = RNA making enzyme
DNA polymerase = DNA making enzyme
What does tRNA do?
It carries amino acids which link together
What does splicing do?
It gets rid of introns
What are some examples of post translational modification?
Glycosylation, peptide bond cleavage, protein splicing, lipidation, sumoylation [ie adding sugar, glucose, lipids]
What is X inactivation?
The X chromosome is switched off. This is triggered by the Xist gene
Give examples of DNA based detection
Detection of point mutations: DNA sequencing, ARMS PCR
Detection of sub-microscopic duplications and deletions: MLPS, aCGH
Rapid detection of aneuploidies: QF-PCR
Give examples of chromosome based analysis
Karyotyping, Fluorescence In-Situ Hybridisation (FISH)
Give examples of DNA sequencing
Sanger sequencing, Next Generation Sequencing (Illumina method)
What are the stages of data analysis?
DNA —(massively parallel sequencing, eg Illumina)—> FASTQ file —(sequence alignment)—> BAM file —(variant calling, identification)—> VCF file —(data filtering steps, eg removing common variants)
