Week 2: Genetic diseases Flashcards
(89 cards)
1
Q
What is the Boveri-Sutton chromosome theory?
A
Shows that chromosomes are the basis of all genetic information
Each gene is found on a specific loci on a specific chromosome
The behaviour of chromosomes in meiosis undermines Mendels law of inheritance
2
Q
What are Mendels Law?
A
Law of dominance
Law of segregation (chromosomes exist in pairs that seperate during gamete formation - each gamete will only contain one copy of each chromosome)
Law of independent assortment (Different pairs of chromosomes seperate independently of each other)
3
Q
What two processes do chromosomes undergo in meiosis?
A
- Segregation
- Independent assortment
4
Q
What is a reciprocal cross?
A
Genetic testing to identify the importance of parental sex in inheritance
Uses two crosses of pure breed parents
1. Affected female x unaffected male
2. Affected male x unaffected female
Compare the proportion of affected offspring
5
Q
What is a pattern of inheritance?
A
How genetic variant are distributed and passed on in families
6
Q
Define autosomal dominany
A
One copy needed for trait to be expressed and person affected.
Either inherited or mutated
7
Q
Give an example of an autosomal dominant condition?
A
Huntington disease
Achondroplasia
8
Q
Define autosomal recessive
A
Both copies of gene must have the mutated allele in order to be expressed and the person affected.
Typically skip generations
9
Q
Give examples of autosomal recessive conditions
A
Hurler syndrome
Cystic fibrosis
Sickle cell disease
10
Q
Define X-linked dominant
A
Gene loci on x-chromosome, one mutated version sufficient to express trait and person be affected
11
Q
Give an example of an X linked dominant condition?
A
Fragile X syndrome
12
Q
Define X-linked recessive
A
Gene carried on X-chromosome, all copies of allele must be mutated allele is needed to express the trait and person be affected.
More common in males
13
Q
Give some examples of x linked recessive conditions
A
Colour vision deficiency
Duchennes Muscular Dystrophy
Hemophilia
Hunter syndrome
14
Q
What is a Y-linked genetic condition?
A
Gene carried on Y chromosome
Passed from father to son
15
Q
Give an example of a Y linked condition?
A
Y chromosome infertilltiy
16
Q
What is meant by co-dominance?
A
Both alleles of a gene are apparent in the phenotype
(Striped flower)
17
Q
What is meant by incomplete dominance?
A
Pink flower
An allele has a partial effect over the other allele
18
Q
What is an example of a codominant condition?
A
ABO blood group
19
Q
What is meant by mitochondrial inheritance?
A
Also known as maternal inheritance
Genes in mitochondrial DNA, only eggs contribute to zygote mitochondrial DNA.
Only passed through maternal lines but can affect daughters and sons
20
Q
What is an example of a mitochondrial inherited condition?
A
Leber hereditary optic neuropathy
21
Q
What is huntington disease?
A
Autosomal dominant
Brain disorder causing uncontrolled movement, emotional problems and loss of cognition.
Characterised by progressive breakdown of nerves and atrophy of cortex
22
Q
What is cystic fibrosis?
A
Autosomal recessive
Thick sticky mucus build up in the lungs and other organs
Mutation affects the ability to regulate chloride and water movement across the cell membrane
23
Q
What is fragile X syndrome?
A
X-linked dominant
Causes a range of development problems including learning disabilities and cognitive impairment
24
Q
What type of genetic disease is an example of non-medelian pattern of inheritance?
A
Mitochondrial DNA diseases
Affected mother - all children will be affected
Affected father - no children will be affected
Only one copy of gene, always inherited from mother
25
What is meant by genomic imprinting?
Occurs in gametogenesis before fertilisation
When the ability of a gene to be expressed depends on the sex of the parent who passed on the gene.
The imprinting is erased with each meiotic division, although is maintained by mitosis
New imprinting pattern forms by epigenetics - CpG hypermethylation and histone hypoacetylation.
Typically the same pattern of genes are imprinted in each human
The imprinted gene is silenced and the other allele expressed
26
What is epigenetics?
Heritable changes in gene expression, without altering the base sequence of DNA.
Caused by changes in the envrionment
Mainly includes DNA methylation and histone tail acetylation
27
WHat are some examples of epigenetic changes?
DNA packing - folding of DNA into compact structure to fit within the nucleus
DNa methylation
Dietary impacts
Environmental impacts
Transposable elements - DNA sequences that move from one area to another
Regulatory genes
Individual lifestyle
28
What are some disorders related to epigenetics?
Cancers
Mental retardation associated disorders
Immune disorders
Pediatric disorders
Neuropsychiatric disorders
29
What are the enzymes associated with different blood groups?
Type A: gene codes for GTA glycotransferase that adds N-acetylgalactosamine
Type B: gene encodes GTB: glycotransferase that adds galactose
Type O: no enzyme
Note the two enzymes are almost identical with only four different amino acid changes
30
Describe the patterns of inheritance of blood groups
Rhesus independent of ABO, RhD antigen is dominant
AB dominant over O
A and B are co-dominant
Gives a total of eight different possible blood groups
31
How common are the different types of blood groups?
O - 47%
A - 42%
B - 8%
AB - 3%
32
Draw a table to show the antigens expressed on the rbcs and the antibody made in each blood group?
33
What is the physiological state of chemical alteration of DNA?
DNA is subject to many chemical alteration, these changes must be corrected to ensure the genetic information encoded is not corrupted.
A failure to repair DNA results in a amutation
34
What is a transition mutation?
A type of substitution mutation that replaces a pyrimidine with a pyrimide and a purine to purine.
35
What is a transversion mutation?
A type of substition mutation with changes the base from a pyrimidine to a purine and vice versa
36
What DNA bases are purines?
Adenine and guanine
37
What DNA bases are pyrimidines?
Thymine and cytosine
38
What are the different ways a mutation can affect protein activity?
Expression
Activity
Localisation
Degradation (of protein or mRNA)
39
What is polymorphism in reference to DNA?
The idea that different version of genes (alleles) exist at high frequencies, implies that neither version is normal or abnormal in comparison to the other.
They cause natural variations in amino acid sequences between individuals
And do not necessarily affect protein activity
40
What are the key differences between a mutation and polymorphisms?
POlymorphism - variation in DNA sequences of a gene, tend to exist in high frequency, have no abnormal affect, not affected by natural selection. Can affect susceptibility to a disease
Mutation - specific change in DNA sequence of a gene, exists in lower frequencies of the population, implies an abnormal effect on phenotype, affects natural selection. Can cause disease
Both can occur in coding and non-coding regions of a gene
41
Describe the genetic changes of Huntingtons disease
Huntingtons disease is caused by an increase in he number of CAG repeats in the coding sequence of huntingtin (ITI15 gene).
Normal polymorphism range from 4-36 repeats, this allows for intermolecular interactions between amino terminus of huntingtin (N17) and a carboxyl-terminal polyproline (polyP) stretch.
More than 40 repeats disrupts this interaction resulting in full penetrance Huntington disease - fatal neurodegenerative disorder.
Is autosomal dominant condition
42
What are the outcomes of a regulatory mutation?
A normal protein that is over or underexpressed due to changes in the promotor or regulatory region
43
What is meant by gene amplification?
Multiple copies of the same gene behind the same promotor, leading to over expression
44
What are chromosome rearrangement mutations?
Changes in chromosome structure - deletion, inversion, duplication or translocation
Nearby regulatory sequence causes changes in how often the protein is transcribed
Fusion to an actively/under-transcribed gene produces a hyperactive fusion protein.
45
What is a mis-sense mutation?
Change the triplet codon and change the amino acid
46
What is a non-sense mutation?
Change the triplet codon to code for a premature stop codon
47
What are the features of an inherited mutation?
Mutations are present in the germ line and somatic cells of one or both of the parents
Are passed to offspring
48
What are the features of a sporadic mutation?
De novo mutations - occur in germ line of parent or in the newly fertilised egg
Neither parent has the mutation in their somatic cells
49
What are the mendelian patterns of inheritance?
An indivdual has two alleles for a gene, one from each parent - segregation
Each allele is inherited independent of other alleles - independent assortment
Dominant alleles mask recessive alleles
Classification of genetic diseases is based on how the allele is inherited and if it masks other alleles or not (not the type of mutation)
50
What influences the level of dominance?
The nature of the mutation
The function of the protein
All relative
51
What are the genetic changes in achondroplasia?
Autosomal dominant disease
Mutation in Fibroblast Growth Factor 3 (FGFR3), glycine to arginine sub at residue 380 in most scenarios
80% sporadic 20% inherited
Mutated receptors is active even in the absence of ligand interaction.
Over expression of function: limiting growth plate expansion in long bones - results in dwarfism.
52
What is the presentation of achondroplasia?
Form of dwarfism
Shortened long bones, enlarged head and normal torso length
Limited growth plate expansion in long bones
53
Can achondroplasia be lethal?
Autosomal dominant
One mutant allele - presents with achondroplasia
Two mutant alleles - fatal
54
What is the pathophysiology/genetic behind Hurler Syndrome?
Is an autosomal recessive condition
Mutation causing deficient alpha-L-iduronidase (IDUA) enzyme.
Loss of function - unable to degrade GAGs
Results in accumulation of heparan sulfate and dermatan sulfate
These accumulate within the tissue, resulting in developmental delay, skeletal, respiratory and cardiac abnormalities.
55
What is the pathophysiology/genetics behind Duchennes Muscular Dystrophy?
X linked recessive disorder
Mutation, typically deletion or non-sense, in dystrophen gene
Dystropehn normally linked muscle cytoskeleton (N terminus binds to cytoskeletal F-actin) and ECM (C terminus binds to dystrophin associated protein complex in sarcolemma) eventually links to endomysium
Mutation breaks this link, weakness membrane integrity resulting in an influx of calcium ions damaging the mitochondria and causing necrosis of muscle cells.
56
What is the pathophysiology/genetics behind Hunter syndrome?
X-linked recessive disease
Mutation causes deficient Iduronate-2-sulfate (IDS) enzyme
Loss of functions means unable to degrade GAGs
Results in accumulation of heparan and dermatan sulfate in tissue
Leads to skeletal problems (hunched posture and tip toe walking), prominent facial features and cognitive delays
57
What is the pathogenesis/genetics of fragile X syndrome?
X-linked Dominant condition
Mutation in FMR1 gene, located in the 5' UTR region of FMRP gene.
Mutation = increase in CGG repeats, 6-50 is normal, -200 is premutation, >200 is mutation
Mutation results in hypermethylation and silencing of FMR1 gene.
58
What are some symptoms of fragile X syndrome?
Intellectual delays
Some physical characteristics that become noticeable at puberty and more prominent as the person ages, include large forehead, narrow face, large ears
Sensory issues - overwhelmed by light, noise to certain textures
Behavioural issues - girls tend to be anxious, boys can be aggressive, both may have attention problems
Difficulty with speech and language
59
What genes are typically affected in Y chromosome infertility?
Typically deletions of genes in AZF region - responsible for sperm production
60
What type of antibodies are made against blood types that are not your own?
IgM
61
What is the genetics/pathophysiology behind leber hereditary optic neuropathy?
Mitochondrial DNA mutation
In any 4 genes coding for subunits of NADH dehydrogenase
leads to increased superoxide radicals.
Causes degeneration of retinal ganglion cells leading to vision loss
62
How do epigenetic mechanism affect disease?
Alter the presentation of disease
63
What is Lyon Law or Inactive X chromosome role in gene expression?
Idea that in early embryonic life
Expression of Xist gene on chromosome to be inactivated, its RNA coats the surrounding chromosome inactivating it.
One of the X-chromosomes in each cell is hypermethylated and histone hypoacetylation (alongside other epigenetic modifications)
Causing it to become inactivated
Mosoiac pattern - different one of pair is inactivated in different cell lineages.
64
What is the genetics behind Angelman/Prader Willi?
Results from chromosome 15 imprinting
A 4 million bp region is deleted - this region contains SNRPN gene and UBE3A gene
On paternal chromosome imprinting silences UBE3A, but mutated SNRPN would still be expressed - involved in mRNA splicing - results in Prader Willi Syndrome
On maternal chromosome imprinting silences SNRPN, but mutated UBE3A would be expressed - involved in ubiquitin pathway - results in Angelman Syndrome
Hence both syndromes are caused by the same mutation, the phenotype (which syndrome expressed) depends on if mutation in the paternal or maternal chromosome
65
What is the genetics of Kallman Syndrome?
35-45% of the causes are unknown
Prevents progression of GnRH releasing neurons from the nasal placade to the hypothalamus
Or to do with olfactory neurons in the olfactory bulb
66
What is the clinical presentation of Kallman Syndrome?
Lack/reduced sense of smell
Hypogonadotropic hypogonadism (low secretions of FSH and LH and low Oesotrgen/testosterone)
Unable to start or complete puberty
Typically infertile, lack secondary sex characteristics and risk of osteoporosis
67
low importance
WHat are some of the genes associated with kallman syndrome?
KAL1 - X-linked
FGFR1 - Autosomal D/R
NELF - Autosomal D
68
What are the different processes of interphase?
G1 - cell growth, increase volume, proteins and organelles
S - DNA replicates
G2 - cell growth and cell organisation
69
What is the process of mitosis?
INterphase: DNA, organelles and proteins replicate and cell growth
Prophase: Chromosome condense, spindle apparatus develops, nuclear envelope distingrate
Metaphase: independent assortment - centromere
Anaphase: sister chromatids pulled to opposite poles
Telophase: Nuclear envelope reforms and spindle apparatus disintigrate
Cytokineses: Cytplasm separates and cell membrane forms
Two genetically identical diploid daughter cells
70
Describe the process of meiosis?
Split into meiosis 1 and 2, both of which follows the phases of interphase, prophase, metaphase, anaphase and telophase
M1: division of homologous chromosomes
M2: division of sister chromatids
Results in four genetically different haploid cells
71
What is a non-dysjunction mutation?
Is a numerical chromosomal abnormality
Failure of homologous chromosomes to seperate in M1 or failure of sister chromatids to seperate in M2
72
What is a structural chromosomal abnormality?
Deletion (of region)
Insertion (of region)
INversion
Translocation
73
Define aneuploidy
Cells with an inbalance of chromosomes due to a nondisfunction mutation
74
What is the outcome on gametes of a non-dysfunction mutation in meiosis 1?
2x diploid daughter cells
2x daughter cells with no copies of that particular chromosome
75
What is the outcome on gametes of a non-dysfunction mutation in meosis 2?
2x haploid (normal)
1x diploid (identical sister chromatids as as two copies)
1x no copy
76
What is a disomic gamete?
Gamete with two copies of a chromsome
77
What is a nullsomic gamete?
Gamete with no copies of a chromosome
78
What are the different types of aneuploidy?
Nullisomy (no copes) 2n-2
Monosomy - one copy - 2n-1
Trisomy - three copies - 2n+1
Tetrasomy - four copeies (2n+2)
79
What are the genetic of down syndrome?
Trisomy 21
Mostly caused by non-dysjunction in M2 resulting in diploid gamete (2x C21), then on fertilisation results in 3x C21 as one gained from other gamete
Most common in maternal gamete, more likely in older mothers
May also arise from a non-dysjunction in mitosis in an early zygote division.
80
What are the clinical presentations of Down syndrome?
Characteristics facial features - flattened appearance
Shorter than normal growth
Hearing loss (ear infections)
Vision loss
Dental problems
Obstructive sleep apnoae
Congenital heart disease
Behavioural and learning problems
81
What is the genetics of Klinefelter Syndrome?
47 XXY
Non-dysjunction mutation
May have more additional copies of X resulting in severe mental disability
Symptoms include under secually developed, defects in speech, motor, social skills and attention, low mental ability and increased risk of autoimmune
Typically have long delicate fingers, skin and nails.
82
What is the genetics and presentation of Turner Syndrome?
45 XO
Only viable monosomy in humans
Individuals are genetically female but do not sexually mature.
Very low survival rate,
Typically short stature, broad chest and low hairline, skeletal disorders, webbed neck, lack of ovarian development, typically have normal intelligence.
83
What is Cri du Chat or 'cat cry syndrome'?
Structural chromsomal abnormality
Deletion of Chromosome 5p
Have high pitched cry, poor muscle tone, small head size and low birth weight
84
What is Pallister Killian Syndrome?
Structural chromsomal abnormality
result of extra chromsome 12 material
Often mosaic
Results in a multitude of problems
Including weak muscle tone, intellectual defects and more birth defects
85
What are the different types of chromosomal tests?
Prenatal: combined test, quadruple test, family history etc
Infertility: abnormality in gametes cause recurrent miscarriage or mother is primary infertility
Postnatal: karyotyping, observation of learning and development
Triple test
86
What is the triple test for chromosomal abnormalities?
Blood test
Alpha fetoprotein - detects most neural tube defects and small amount of T21
hCG and estriol - indicate increased risk of T21 or T18
87
How can FISH help with screening for aneuploidy?
Can be done on an amniocentesis sample
FISH probes for X, Y and 21
Can develop full karyotype over time
88
What are some new techniques for identifying aneuploidy/genetics in foetus?
qPCR or digital PCR - to quantify the number of copies of chromosomes
Cell free fetal DNA - taken from maternal plasma, is none invasive look for fragments of y chromosome to identify gender
89
What are the treatments for genetic disroders?
Management of symptoms/palliative care
Genetic testing and counselling
Charities and support groups
Gene replacement therapy (BMT for HSC in very young babies)
Genome editing
