Genetics in Medicine Flashcards
What is Human genetics
The science of heredity and variation in humans
What is medical genetics
The subset of human genetics that is important In medicine and medical research
What is the genotype
The written genetic make up
What is the phenotype
How the gene variations manifest within the body
What was the 100kg
100,000 patients were going to have there entire geneome processed which was funded by £300m from the government
Why are people referred to clinical genetics
Child: Birth abnormalities, Dysmorphic features, Learning difficulaties
Adult: Diagnosis Predictive testing Carrier testing Family history
Pregnancy:
Known genetic disorders
Abnormality detected on screening
Fetal loss or recurrent miscarriages
What is the purpose of different genetic tests
Diagnostic:
Answer specific or broad questions
Predictive testing:
Tells patient whether they will have a problem in the future
Carrier testing:
For autosomal and X-linked recessive genes
Prenatal testing:
For diagnosing and preventing genetic disease
Screening:
For testing of whole populations
Why are rare diseases a priority
Individually rare but they add up to a lot of chronic diseases
Disproportionally effect children (1/4 to 1/3 of children in hospital)
Tell us a huge amount about Biology and therefore inform us of other clinical diseases
What drugs act on BCR-ABL translocation gene
Imatinib
Nilotinib
What is the molecular anatomy of the body
Almost all inheritable information is written in DNA sequences
Some information is in other chromatin features
How long is a heritable information DNA sequence
3 x 10^9 nucleotides
What are epigenetics
Information stored outwit the genome
What is the stability difference between DNA and RNA
DNA is incredibly stable but RNA is very transient and breaks down quickly
How is a DNA sequence written
In a 5’ to 3’ direction
Written as a single strand but infers that it is a double strands as that is how DNA is written
The sense strand is the one which is written (the one which ends up in the mRNA when transcribed)
How many human chromosomes are there
46 chromosomes in 23 pairs
What happens in telomeres over time
Due to lack of telomerase as the body ages, telomeres shorten with somatic cell division and so there are a finite number of cell divisions
What is a chromosome ideogram
An idealised graphical representation of the chromosome
What is haploinsufficiency
Loss of one copy of the gene, resulting in pathological clinical presentation
What is a gene family
Most genes belong to a family of structurally related genes which may be clustered together or widely dispersed
What is a pseudogene
A gene which would have been functional a long time ago but, due to evolution, no longer is
What is a processed gene
Intronless copies of other genes which are usually remote from parent gene
The result of reverse transcription and reintegration
Occasionally remain functional but most non-functional
What are the types of repetitive DNA
Satellite DNA:
Large blocks of repetitive DNA sequence
Interspersed repeats:
Scattered around the genome
What are molecular genetics
The study of the structure and function of individual genes
What are clinical genetics
The application of genetics for diagnosis and patient care (in individuals and families
What is the purpose of modern genetics
To understand the fundamental role of the gene in basic life processes
What are the types of inherited disorders
Single gene
Chromosomal
Mitochondrial
Imprinted
What is the point of pharmacogenetics
To understand who will respond to different treatments and in what way
What are the three routes of determining a genetic diagnosis
Family tree
Physical examination
Genetic tests
What are the two ways of testing for genetic disorders
Non-genetic tests
Genetic tests
What are examples of non-genetic tests
Blood tests
Xrays
What are the advantages of testing for genetic disorders
Early diagnosis allowing for early interventions
Carrier testing to inform of reproductive choices
Prenatal testing to inform of reproductive choices
What are disadvantages of testing for genetic disorders
Is the information something which the patient actually wants to know?
Will it affect other things in life such as insurance prospects?
What is genetic counselling
An education process which seeks to assist affected or at risk individuals to understand the nature of the genetic disorder, its transmission and the options open to them in management and family planning
What are pharmacogenomics
Analysing entire genomes across groups of individuals, to identify the genetic factors influencing responses to a drug
What are pharmacogenetics
Studying an individual’s genetic make up in order to predict responses to a drug and guide prescription
What is multifactorial/ complex genetic classification and an example
The interaction of multiple genes in combination with environmental factors
EG: type II diabetes
What is single gene genetic classification and an example
A mutation in a single gene
Mendelian inheritance
EG: cystic fibrosis
What is chromosomal genetic classification and an example
An imbalance or rearrangement in chromosome structure
EG: aneuploidy, deletion, translocation
What is mitochondrial genetic classification
A mutation in mitochondrial DNA
What is somatic mutation genetic classification and an example
Mutation within a gene in a defined population of cells that results in disease
EG Breast cancer
What are the single gene modes of inheritance
Autosomal dominant
Autosomal recessive
X-linked
Mitochondrial
What is autosomal dominant inheritance
A trait or disease runs from one generation to the next
Males and females are equally affected
Chance of offspring affected 50%
Affected individuals are heterozygous for the mutation
Affects structural proteins, receptors, transcription factors
What are examples of autosomal dominant inheritance
Myotonic dystrophy
Marfan syndrome
Huntington disease
What is penetrance
The frequency with which a specific genotype is expressed by those individuals that possess it, usually given as a percentage
What is expressivity
Variation in expression between different people
What is anticipation
The symptoms of a genetic disorder become apparent at an earlier age as it is passed from one generation to the next.
What is a new dominant or de novo mutation
New mutation that has occurred during gametogenesis or in early embryonic development
What is autosomal recessive inheritance
Disease seen in one generation
Does not tend to pass from one generation to the next
Offspring of affected individual has low risk of disease
Relatives may be asymptomatic carriers of disease
Affects males and females equally
Gene mutations, not chromosomes
Affected individuals are homozygous or compound heterozygous for the mutation
What is the difference between being homozygous and compound heterozygous for a mutation
Homozygous: same type of mutation for same gene
Compound heterozygous: Same gene disrupted but it’s a different mutation but still means they have the disease
What are examples of autosomal recessive inheritance
Cystic fibrosis
Many of the metabolic disorders
Haemachromatosis
Sickle cell disease
What is X-linked inheritance
Males more severely affected
Females may be unaffected, mildly through to fully affected
Cannot have male to male transmission
Gene mutations and chromosome deletions/ duplications
Carrier mother: 1/4 normal girl and 1/4 carrier girl, 1/4 normal boy and 1/4 affected boy
Affected father: all daughters are carriers, all sons are unaffected
What are examples of X- linked inheritance
Duchenne Muscular dystrophy
Fragile X syndrome
Red/green colour blindness
Haemophilia
What are the two main factors for why females can have such variable phenotypes with x linked inheritance
X inactivation
X linked dominant vs X linked recessive inheritance
What are examples of X linked dominant and recessive inheritance
Dominant:
Rett syndrome
Fragile X syndrome
Recessive:
Red-green colour blindness
Haemophilia
Duchene musclular dystrophy
How are mitochondria inherited
All from our mother
How do you draw a family pedigree
Build up the tree from the bottom starting with affected child and siblings
Record names, dates of birth and maiden names
Choose one parent, ask about sibling and their children, then parents
Always create a key with the symbols used
Date and sign
What is consanguinity
Couples who are blood relatives
Potentially share recessive gene mutations
Risk of congenital birth defect 5-6% (2-3% general population) if no family history of genetic condition
Seen in all ethnic groups
What are genome analysis methods
PCR DNA sequencing Array CGH Karyotyping FISH
What pathologies are analysed in genome analysis methods
Single-gene variants
Copy number variants
Chromosome number
Structural changes
What is the hybridisation principle
Two DNA molecules will anneal (hybridise) into a duplex only if their sequences are complimentary according to the Watson-Crick base-pairing rules
What are the steps of PCR
Target strands forced apart by heating 94 degrees Primer anneals at 55 degrees Primer extension at 72 degrees Heat denaturation at 94 degrees Repetition
What are some applications of PCR
Detect presence or absence of a genetic sequence
Generate template for analysis of specific mutations
What is allele-specific mutation detection
Distinguishes two alleles that may only differ by a single nucleotide
What happens when the identity of a disease-causing mutation is unknown
It must be searched for by sequencing of DNA of the region of interest
Pathogenic changes must be distinguished from harmless ones
What is an exome
The smaller, more interesting, coding part of the genome
What are the methods for detecting copy number variation
Whole genome: G-banding, next generation sequencing, microarrays
Targeted testing: FISH, MLPA, QF-PCR
What are the phases of mitosis
Interphase, prophase, metaphase, anaphase, telophase, cytokinesis
What is karyotyping
Determination of a karyotype by:
Cell culture
G-banding
Variable resolution >5Mbp
What are the DNA-based methods for copy number
Array comparative genomic hybridisation
Whole genome sequencing
MLPA: multiplex ligation-dependent probe amplification
Quantitative fluorescent PCR
Why is DNA nor always used
DNA based methods are good for dosage as cheaper and heavier and provide higher resolution
Cytogenetic analysis is still needed for genome rearrangements such as translocations
What is cytogenetics
Study of chromosomes
Anything more than a single gene
What are the types of CNV
Copy number variations
Numerical:
aneuploidy: gain (trisomy) or loss (monosomy)
polyploidy: gain whole sets (triploidy or tetraploidy)
mosaicism: diploidy and aneuploidy
Structural:
deletion
duplication
How do cytogenetic abnormalities produce an abnormal phenotype
Dosage effect (loss is worse than gain) Disruption of a gene at a breakpoint/ inappropriate activation or inactivation of genes Position effect: gene in a new chromosomal environment functions inappropriately Unmasking of a recessive disorder
What are the consequences of mosaicism
Variable phenotype Variable lethality Non-identical identical twins Tissue-specificity lateral asymmetry Recurrence risk if gonadal
What is a microarray CGH
Genome-wide screen
Hybridise sample and control DNA to a microarray BACs or SNPs or oligonucleotides
Genomic imbalances at high resolution
Has replaced some karyotyping as 1st line test
Which patients would an array CGH be used for
Moderate to severe learning and developmental disability
Dysmorphic infants
Pregnancies with abnormal ultrasound
What are the advantages of array CGH
Early diagnosis 1st line test, reduces need for other tests and avoids the diagnostic odyssey
High resolution = increased diagnostic hit rate
Greater accuracy of location/ size of imbalances
Information on relevant genes
What are the disadvantages of array CGH
Dosage changes only Not balanced rearrangements or mutations Low level mosaics not detected Non-pathogenic and uncertain pathogenic changes detected Needs good quality DNA
What are application of molecular cytogenetics
Non-invasive prenatal testing
Pregnancy loss
Pre-implatation ctudies
Cancer
What is NIPT
Non-invasive prenatal testing Maternal blood sample Extract circulating free foetal DNA Assess aneuploidy of 13, 18, 21 Risk of aneuploidy - invasive test to confirm Reduces number of invasive tests
How is cytogenetics used in cancer
Disease specific acquired chromosome changes:
Mostly translocation
Several different acquired abnormal clones
Diagnosis
Prognosis
Treatment
Leukaemia: bone marrow
Solid tumour: tumour tissue
What are the two types of translocation
Reciprocal:
Break and exchange
Robertsonian:
Whole arm fusion
What is genetic bottleneck effect
Caused by:
Speciation, migration, environment, disease
Diversity in the form of genetic variation is reduced
What are exogenous and endogenous factors causing uncorrected errors
Exogenous factors: radiation, chemicals
Endogenous factors: segregation (e.g. Downs syndrome, Edwards syndrome)
Recombination (translocation)
DNA replication errors (mispaired bases, slippage)
Inadequate DNA repair mechanisms (mismatch repair, base excision repair)
What are the two classes of genetic variation
Variation that does not alter the DNA content as number of nucleotides is unchanged (single nucleotide replacements, balanced translocations or inversions)
Variation that results in a net loss or gain of DNA sequence (can by whole chromosome or single nucleotides)
What is a neutral variation
DNA changes are small scale and have no obvious effect on phenotype
Is common but detrimental variation is rare
What are the types of normal genetic variation
Single nucleotide variants (SNVs)
Single nucleotide polymorphisms (SNPs)
Copy number variation (CNVs)
Indels (insertion or deletion of one or more nucleotides)
What is minor allele frequency
The frequency of the less common variant in a population
What are the types of exotic variants
Missense mutation: an amino acid change
Nonsense mutation: change of amino acid to a stop codon
Silent mutation: The codon for an amino acid is changed but the same amino acid is still coded for
What is the meaning of a Mendelian genetic condition
Obey Mendel’s laws of segregation
Dominant, recessive, X-linked
Single gene influencers
What is the meaning of a complex genetic condition
Tends to be used vaguely to describe something with an inherited but non-mendelian component
What is polygenic genetics
The result of the action of multiple genes
What are multifactorial genetics
The result of multiple factors, usually including both genetic and environmental factors
What does lamna s mean
Relative risk to second children
Comparison of risk of having condition to the population risk
What are examples of congenital malformations which are multifactorial
Cleft lip
Congenital hip dislocation
Congenital heart defects
Neural tube defects
What are examples of acquired diseases pf childhood and adult life which are multifactorial
Asthma Autism Cancer Diabetes Epilipsy Hypertension Inflammatory bowel disease
What is a genome wide association study
Detects common genetic variants conferring susceptibility to complex phenotypes
Controls should match cases and be a representative sample of the population
What is a Manhattan plot
Visualisation of GWAS results
All SNP results are plotted on one graph
X-axis shows the position in the genome
Y-axis shows the significance (-log10 of the p-value)
What is Alzheimer disease
Most common form of dementia after 40yr
Symptoms:
inability to cope, loss of memory, brain damage
Shrinkage of brain, tangles of B-amyloid protein in nerve fibres of hippocampus
Different genes involved in different families bur give same end result
What are the genetics of Alzheimer disease
Sequence variants at a polymorphic locus have a large effect on the age of onset
Much of that is due to a gene implicated in heart disease (apo-lipoprotein E)
What are the three haplotypes of APOE and what do these confer in the genetics of Alzheimer disease
APOEE2: protective effect
APOEE3
APOE*E4: increase in susceptibility
What is an allele
A variant form of genes or genetic marker
What is a genetic anticipation
A phenomenon whereby as a genetic disorder is passed on to the next generation, the symptoms become apparent at an earlier age with each generation
What is a genetic association
When one or more genotypes within a population co-occur with a phenotypic trait, more often than it would be expected by chance
What is a haplotype
A set of DNA variants or polymorphisms that tend to be inherited together
What is Hardy Weinberg Equilibrium
The situation where allele and genotype frequencies in a population remain constant from generation to generation in the absence of other evolutionary influences
What is heritability
A statistic used in breeding and genetics work that estimates how much variation in a phenotypic trait in a population is due to genetic variation among individuals in that population
What are hyper normal controls
Unaffected individuals selected from the extreme of a quantitative trait
What is linkage disequilibrium
The occurrence in members of a population of combinations of linked genes in non-random proportions
What is microsatellite
A tract of repetitive DNA in which certain DNA motifs are repeated typically 5-50 times
What is the minor allele frequency
The frequency of the less common variant in a population
What does monomorphic mean
Existing in one form only
What is population genetics
The branch of science that deals with the statistical analysis of the inheritance and prevalence of genes in a population
What is a quantitative trait
A measurable phenotype that depends on the cumulative actions of many genes and the environment. These traits can vary among individuals, over a range, to produce a continuous distribution of phenotypes
What is a genetic trio
A set of individuals comprising of a father, a mother and their child.
What are the different types of mutations in a gen
Large deletions or insertions
Gross rearrangements
Point mutations
Trinucleotide repeat expansions
What are the types of point mutations
Silent: Change in nucleotide still codes for the same amino acid
Missense: Change in nucleotide results in change in amino acid coded for
Nonsense: Change in nucleotide results in formation of a stop codon causing a truncated protein to be produced
Frameshift mutation: deletion/insertion of one nucleotide alters protein sequence beyond mutation
What is Huntington’s disease
Neurodegenerative disorder Symptoms: Involuntary movement Psychiatric changes Cognitive loss -> dementia Neuronal loss
Autosomal dominant:
Heterozygous CAG repeat expansions
Mutational instability
Anticipation
What is fragile X syndrome
One of the more common single-gene causes of mental handicap X-linked Semi dominant males severely affected Females less so Peculiar inheritance
What is a germlin mutation
Inherited from parents at birth
What is a somatic cell mutation
A mutation that develops in one particular cell that has divided and cloned
What is the function of caretaker genes
Improve genomic stability
What is the function of gatekeeper genes
Monitor and control cell division and death, preventing accumulation of mutations
What is the function of Landscaper genes
Control the surrounding environment
What is the penetrance of a cancer gene
Percentage of people with a gene change who develop the condition
May be modified by other genetic variations
May be modified by environmental factors
What are tumour suppressor genes
Protects cells from becoming cancerous
Loss of function increases the risk of cancer
What are oncogenes
Regulate cell growth and differentiation
Gain of function/activating mutations increase the risk of cancer
What is Knudson’s two hit hypothesis
Recessive at the cellular level so both copies of the gene inactivated to have the effect
Most cancer syndromes show autosomal dominant inheritance pattern
What are sporadic vs familial cancers
Sporadic:
Onset at older age
One cancer in individual
Unaffected family members
Familial: Onset at younger age Multiple primaries in individual Other family members affected Same type/ genetically-related cancers
What is the purpose of genetic assessment
Diagnosis/explanation of family history Counselling of advantages and disadvantages of testing Risk of further cancers for affected case Risk of cancer for unaffected relatives Screening Prevention Treatment Research
What is retinoblastoma
Childhood ocular cancer Very rare 30-50 children/year in uk Classic example following Knudson 2-hit hypothesis Retinoblastoma (Rb1) gene
What is familial adenomatous polyposis
Hundreds of bowel polyps from teens onwards
Accounts for about 1% of bowel cancers
High risk of bowel cancer if untreated
APC tumour suppressor gene
Autosomal dominant inheritance
Colonoscopies, total colectomy late teens/early 20s
What is hereditary non-polyposis colorectal cancer
Accounts for about 2-3% of bowel cancers Polyps are common but not polyposis 60-80% risk of bowel adenomas or cancer from mid 20s onwards Other cancer risks Mismatch repair genes Autosomal dominant inheritance
What is the Amsterdam criteria of HNPCC
One member diagnosed with colorectal cancer before 50
Two affected generations
Three affected relatives, one first-degree relative of the other two
FAP should be excluded
Tumours should be verified by pathologic examination
What is the BRCA1 and BRCA2 gene
BRCA1 and 2 are involved in DNA repair
Around 10% of cases of breast under 40 and around 25% of those with strong FH
Common mutations in Jewish and some other founder populations
Autosomal dominant inheritance
Risk of breast cancer 80%, ovarian BRCA1 40%, BRCA2 10-20%
Some increased risk of other cancers
What is Morphology
The scientific study of the structure and form of either animals and plants or words and phrases
What are congenital malformations
2-3% of births Single malformations often isolated events More likely to be genetic if: Multiple malformations Dysmorphic Family history of similar problems
What is achondroplasia
around 1 in 20,000 Autosomal dominant- often new mutation Risk increases with paternal age Rhizomelic limb shortening Short stature Foramen magnum compression/hydrocephalus
What is Beckwith- Wiedemann syndrome
around 1 in 10,000 Large tongue Ear pits/ creases Exomphalos Hemihypertrophy Neonatal hypoglycaemia Increased risk of Wilms tumour (nephroblastoma)
What is down syndrome
Commonest chromosomal disorder around 1 in 800 live births Learning difficulties Congenital heart disease Hypotonia in neonates Single palmar cease Cataracts Hearing impairment Hypothyroidism Leukaemia Atlanta-axial instability Alzheimer's disease
What is Kabuki syndrome
around 1 in 30,000 Learning difficulties Congenital heart disease (50%) Poor growth Hearing impairment Cleft palate Premature breast development Persistent fetal finger pads (96%)
What is mosaicism
Hypo- and/or hyper- pigmented patches
May follow Blaschko’s lines
Diagnosis often requires skin biopsy
What is Peutz Jeghers syndrome
<1 in 50,000 Gastointestinal polyps: Bleeding Obstruction Malignancies: Colorectal Gastric Pancreatic Breast Ovarian
What is Treacher-collins syndrome
around 1 in 50,000 Autosomal dominant Very variable Cleft palate Hearing impairment
What is Waardenburg syndrome
Around 1 in 250,000 Sensorineural hearing impairment Iris heterochromia Premature greying White forelock Areas of skin hypo pigmentation Congenital malformations
What is William’s syndrome
7q11 deletion Around 1 in 20,000 Learning difficulties Hypercalcaemia Congenital heart disease: Supravalvular aortic stenosis Peripheral pulmonary artery stenosis
What is androgenesis
Initiation of development using only paternal genetic material
What is parthenogenesis
Initiation of development using only maternal genetic material
Common in some other animals: insects, fish and reptiles
What is a hydatidiform mole
Androgenetic
Mostly homozygous 46, XX
Proliferation of abnormal trophoblast tissue
Can develop into malignant trophoblastic tumour
No remaining embryo
What is an ovarian teratoma
Parthenogenetic conceptions Derive from oocytes which have completed first or both meiotic divisions Diploid Wide spectrum of differentiated tissues: -predominantly epithelial -no skeletal muscle -no membranes/ placenta
Why do uniparental conceptions fail
Different roles of maternal and paternal genes in determining developmental fate
Karyotype and gene dosage are normal
Genomic imprinting
What is genomic imprinting
Mothers and fathers somehow imprint their genes with a memory of their paternal or maternal origin
Mechanism ensures the functional non-equivalence of m and p genomes
Not encoded in the DNA nucleotide sequence (epigenetic)
Depends on modification to the genome laid down during gametogenesis (spermatogenesis vs oogenesis)
What is angelman syndrome
Facial dysmorphism (prognathism, wide mouth, drooling, smiling/laughing appearance)
Mental handicap (microcephaly, absent speech)
Seizure disorder
Ataxic, jerky movements
What is prader-willi syndrome
Infantile hypotonia (feeding problems, gross motor delay) Mental handicap Male hypogenitalism/ cryptorchidism Small hands and feet Hyperphagia (resulting in obesity) Stereotypic behaviour
What causes prader-willi and angelman syndrome
Deletion of chromosome 15 (q11-q13)
De novo
Recurrence risk is very low
Deletion on maternal copy in angelman syndrome
Deletion on paternal copy in Prader-Willi syndrome
What is uniparental disomy
When an offspring inherits two copies of one gene from now parent and none of that gene from the other parent
What is DNA methylation
Post-synthetic DNA modification Epigenetic (does not alter DNA sequence) DNA methyltransferases Reversible Has to be maintained after replication Occurs at CG dinucleotides Involved in gene regulation Usually unmethylated CG islands at promotor region but if methylated then gene is silenced
What is Beckwith-Wiedemann syndrome
Fetal overgrowth (high birthweight >5kg) Organomegaly (exomphalos) Asymmetry Tumour risk Sporadic occurence Epigenetic abnormalities Too much IGF2 in pregnancy
What is Russel-silver syndrome
Growth retardation (fatal, persistent postnatal growth failure)
Triangular face (brain size more preserved
Asymmetry
Sporadic occurrence
Too little IGF2 in pregnancy
What is hypothesis independent genetic research
Without any prior knowledge we can identify which genes, proteins and pathways are involved in development and disease
Gene identification allows accurate diagnosis and counselling
Gene identification gives us a starting point for deciphering its function
Identifies targets for therapy
How is genetics used in medicine
Diagnosis: presymptomatic, prenatal, preimplantation Counselling Treatment Therapy Personalised medicine Prevention
What are the types of prenatal diagnosis
Amniocentesis (17 weeks)
Chorionic villus sampling (11 weeks)
NIPD- New non-invasive method based on NGS of mothers blood (10 weeks)
What is classic gene therapy
Introduction of functional genes, in the form of DNA to replace mutated genes
Can repair mutated genes, silence overactive genes, provide immune cells with the tools needed to recognise and kill cancer cells and infections
What is genetic counselling
A communication process which deals with human problems associated with the occurrence or the risk of occurrence of a genetic disorder in a family
What is hypertrophic cardiomyopathy
Thickening of the heart muscle due to irregular pattern of muscle cells, can obstruct valves or affect heart rhythm
Not same as hypertrophy
Lifestyle implications
Medications, implantable devices, surgery
Small risk of sudden death from arrhythmia usually
Screening from 10-12
Autosomal dominant
What is human genetics
The science of heredity and variation in humans
What is medical genetics
The subset of human genetics that is important in medicine and medical research
What is molecular genetics
The study of the structure and function of individual genes
What is clinical genetics
The application of genetics to diagnosis and patient care in individuals and families
What does nt mean
Nucleotide
What does bp mean
Base pair
What is a karyotype
The number and visual appearance of the chromosomes in the cell nuclei of an organism
What are the chromosome landmarks
Centromere: middle bit
Arms: Short (p) and long (q)
Telomere: ptel and qte
What is a telomere
TTAGGG telomeric repeat sequence
Made by telomerase (TERT) which is inactive in somatic cells
Telomeres shorten somatic cell division so finite number of cell division to senescence
Chromosomes are unstable without telomeres
How do cancer cells bypass senescence
Telomerase (TERT) reactivation
What are pseudoautosomal regions
Regions that are present on the X and the Y chromosomes
What is the SRY gene
Sex determining region which determine production of testis and male traits
What is the mitochondrial genome layout
Circular not linear
Cytoplasmic not nuclear
What is in the human genome
Single copy sequences: -genes Repetitive sequences: -interspersed repeats -satellite DNA: large blocks of repetitive sequences, heterochromatin
What are Genes comprised of
Functional units of DNA: -Genes are expressed : -transcribed into RNA -Translate RNA into protein (not all) Components (exons, introns, regulatory sequences - promoters, enhancers, locus control regions)
What is the Alphoid DNA’s role
Required for assembly of centromere
What is an example of intragenic pathology
Duchenne Muscular dystrophy
What are the features of large deletions or insertions
Effects may vary
May be missed by PCR based screening methods if heterozygous
Examples:
Duchenne Muscular Dystrophy (deletion)
Charcot-Marie-tooth disease (duplication)
What is an example of a gross rearrangement mutation
Haemophilia A
What is a single-nucleotide indel
Insertion or deletion of a single nucleotide
What is the hyper mutability of CG dinucleotides
C is methylated in to C-CH3
Undergoes deamination to T
Mismatch repair turns G to A so it matches T
How is a molecular change described unambiguously
Reference sequence needed
Genomic DNA (g.)
cDNA (c.)
Protein (p.)
What is a polymorphism
Variant that’s more common than 1%
What is a rare variant
Variant that’s less common than 1%
What is the process of FISH
1 Prepare short sequences of single stranded DNA that match a portion of the gene desired (called probes)
2 Label probes by attaching colours of fluorescent dye
3 Probes are able to bind to the complementary strand of DNA wherever it may reside on a person’s chromosomes
4 When a probe bends to a chromosome, the fluorescent tag provides a way to see that DNA location
What is FISH used for
Locus specific probes: used to determine on which chromosome the gene is located or how many copies of a gene exist in a particular genome
Alphoid or centromeric repeat probes: Used to determine if individual has correct number of chromosomes. Can be used in combination with locus specific probes to determine whether individual is missing genetic material.
Whole chromosome probes are collections of smaller probes which each bind to different sequences along the length of chromosome. Allows each chromosome to be labelled unique colour resulting in a full colour map of the chromosome known as a spectral karyotype. Useful for examining chromosomal abnormalities.
What is array CGH
An ultra high resolution way of objectively and quantitatively detecting whether a patient’s DNA has losses (deletions) or gains (duplications, triplications etc) which are pathogenic and therefore explain clinical problems
What is the process of array CGH
Genomic BAC, P1, cosmic or cDNA clones are used for hybridisation and fluorescence ratios along the length of chromosomes provide a cytogenetic representation of the relative DNA CNVs
Fluorescence ratios at arrayed DNA elements provide a locus by locus measure of DNA Copy number variation and represent a means of achieving increased mapping resolution
What are the two methods of prenatal testing
Amniocentesis
Chorionic villus sampling
How is an amniocentesis performed
A sample of amniotic fluid is removed from uterus by insertion of a long thin needle through abdomen into uterus to withdraw a small amount of fluid which is then sent to lab for evaluation. It can be tested for genetic abnormalities, infection, signs of lung development
How is Chorionic villus sampling performed
CVS removes a small sample of placenta tissue from uterus which is sent to the lab for testing. Sample can be taken by:
-A catheter through vagina, passed through the cervix and into uterus
-A needle through the abdomen which withdraws placenta tissue
Ultrasound used in both methods to guide.
What is non disjunction in meiosis
Failure of chromosome or chromatid to separate
What are the advantages and disadvantages of array CGH
Advantages:
- Early diagnosis
- High resolution (increased diagnostic hit rate)
- Greater accuracy of location/size of imbalances
- Information on relevant genes
Disadvantages:
- Dosage changes only not balanced rearrangements or mutations
- Low level mosaics not detected
- Non pathogenic and uncertain pathogenic changes detected
- Needs good quality DNA
What happens in Quantitative fluorescent PCR
PCR amplification of short tandem repeats using fluorescent primers
What is locus heterogeneity
A single disorder, trait or pattern of traits caused by mutations in genes at different chromosomal loci
What is allelic heterogeneity
Different mutations at the same locus lead to the same or very similar phenotypes
What is dysmorphology
The study of human congenital malformations (birth defects) particularly those affecting the anatomy (morphology) of the individual
