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Sem 1: Genetics > Week 9 > Flashcards

Week 9 Flashcards

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1
Q

What are the 2 examples of numerical chromosome aberrations?

A

Polyploidy
Aneuploidy

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2
Q

What are 4 examples of structural chromosome abberrations?

A

Deletions
Duplicaions
Inversions
Translocations

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3
Q

How many conceptions involve chromosome abnormalities?

A

25%

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4
Q

How many fetus with chromosome abnormalities involve live births?

A

0.3%

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5
Q

What is aneuploidy?

A

Numerical chromosome abberation (the number is not an exact multiple of the haploid number)= 2n + or - x
Through abscence of whole chromosome or presence of additonal chromosome

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6
Q

What are types of aneuploidy?

A

Monosomy= 2n-1
Trisomy= 2n+1

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7
Q

What are euploidy?

A

Effects to multiples of n

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8
Q

What are examples of euploidy?

A

Polyploidy = 3n, 4n, 5n …
Triploidy= 3n
Tetraploidy= 4n
Autopolyploidy= Multiples of the same chromosome
Allopolyploidy= Multiples of closely related genomes

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9
Q

Where does ployploidy occurs?

A

Occurs in some animals
More common in invertebrates
Vertebrate examples include amphibians, lizards and fish
Causes prenatal death in mammals
Several examples in plants include many crop species

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10
Q

Where is the specific case where polyploidy occurs in humans?

A

It can exist in differentiated tissues such as muscle and liver cells

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11
Q

Where is aneuploidy common?

A

In interspecies crosses but rare within species

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12
Q

What problem can cause aneuploidy?

A

Arrises due to non-disjunction- failure of chromosomes to segregate properly during cell division

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13
Q

What are the two ways non-disjunction can occur in an organism?

A

Constitutional- problems with meiosis
Somatic mosaic- problem occured during mitosis

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14
Q

What are the problems caused by aneuploidy?

A

Developmental abnormalities and reduces fitness in all species studied

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15
Q

What is treated better monosomies and trisomies?

A

Monosomies are treates less well than trisomes

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16
Q

How many conceptions in humans are monosomic or trisomic?

A

5%

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17
Q

What is the outcome of most monosomic or trisomic conceptions?

A

Most are lethal and aneuploidy is the leading known cause of miscarriage

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18
Q

What is the primary outcome for monosomic or trisomic conceptions?

A

Leading cause of congenital birth defects and learning disabilities

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19
Q

What is a likely outcome for somatic aneuploidy?

A

Feature of most cancers:
Trisomy 12 in chronic lymphocytic leukaemia (CLL)
Trisomy 8 in acute myeloid leukaemia (AML)

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20
Q

What is FISH method?

A

Fluorescence in situ hybridisation uses fluorescent DNA probes to target specific chromosomal locations within the nucleus

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21
Q

What is Karyotyping?

A

Chromosomes are stained during metaphase using Giesma dye to stain to create black bands

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22
Q

What is monosomy?

A

Loss of a single chromosome
2n-1

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23
Q

How can monosomy be compensated in animals?

A

In animals this is only seen for sex chromosomes- dosage compensation not seen in autosomes

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24
Q

What happens if there is a loss of an autosome?

A

It is not tolerated and is lethal

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25
Q

What amount of a heterozygous genome is tolerated?

A

Less than or equal to of 0.5% loss is tolerated

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26
Q

What haplo-insuffciency?

A

Single gene copy may not produced an acceptable dosage of gene expression

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27
Q

What is hemizygous?

A

Remaining genes may include formaly recessive, lethal alleles

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28
Q

What causes mosiac monosomy individuals?

A

Mitotic errors during early development

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29
Q

What is Turner’s syndrome?

A

A women has 45 chromosomes with only 1 x

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30
Q

How comman is Turners syndrome?

A

1:2000 female births

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31
Q

What happens to most 45 X feotuses?

A

They die before utero

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32
Q

Which X chromosome is most likely to be present im turners syndrome?

A

70-80% of all 45 X conceptions have a maternal X chromosome

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33
Q

When does meitic error most commonly during spermatogenesis?

A

Most meiotic error occurs during spermatogenesis

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34
Q

What are common features of Turner syndrome?

A

Low hairline
Webbed neck
Widely spaces nipples
Primary ovarian failure
Short stature

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35
Q

What are variables features of Turner syndrome?

A

Learning disabilities
Coarctation of aorta

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36
Q

What is trisomy>

A

Addition of extra chromosome
2n+1

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37
Q

Why are trisomies more tolerated than monosomies?

A

It is more likely to be viable if occurs with small autosomes or sex chromosomes
X-inactivation and relatively few on Y chromosomes reason why extra sex chromosomes are tolerated)

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38
Q

What happens with the addition of a large chromosome?

A

A large chromosome additon is usually lethal

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39
Q

What autosomal trisomies can survive birth?

A

Chromsome 21, 18 and 13
Occasionally 9 and 8

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40
Q

What are examples of trisomes in sex chromosomes?

A

Klinefelter syndrome
XYY syndrome
Triple X Syndrome

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41
Q

What is Klinefelter syndrome?

A

A man with 47 chromosomes with two XXs and a Y

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42
Q

How frequent is Klinefelter syndrome?

A

1:660 births

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43
Q

What are variations in Klinefelter syndrome?

A

48 XXXY
49 XXXXY and more

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44
Q

What causes symptoms to become more severe?

A

Manifestations are more severe the more X chromosomes

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45
Q

How can Klinefelter syndrome effect women?

A

XXX chromosomes

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46
Q

What are common features of Klinefelter syndrome?

A

Gynaecomastia (partial development of boobs in men)
Elongated forearms and lower legs
Small testes and azoospermia

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47
Q

What are variable features of Klinefelter syndrome?

A

Learning disabillities

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48
Q

What is XYY syndrome?

A

A man with 47 chromosomes due to extra Y chromosome

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49
Q

How frequent is XYY syndrome?

A

1:1000 births

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50
Q

What are symptoms of XYY syndrome?

A

Very tall stature: >6 feet
Large teeth
Learning disabilities
Motor coordination problems

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51
Q

What happens with trisomy of chromosome 8?

A

If feotus survives they will have a condition called trisomy 8

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52
Q

What happens with trisomy of chromosome 9?

A

If feotus survives they will have a condition called trisomy 9

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53
Q

What happens with trisomy of chromosome 13?

A

If feotus survives they will have a condition called Patau syndrome

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54
Q

What happens with trisomy of chromosome 18?

A

If feotus survives they will have a condition called Edward syndrome

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55
Q

What happens with trisomy of chromosome 22?

A

If feotus survives they will have a condition called cat eye syndrome

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56
Q

What happens with trisomy of chromosome 21?

A

A person will have downs syndrome

57
Q

How common is patau syndrome?

A

1:19,000 live births

58
Q

What is the life expectancy of a person with patau syndrome?

A

~3 months

59
Q

What is the average of parents with a child with patau syndrome?

A

32 years old

60
Q

What are the common features of Patau syndrome?

A

Holoproscencephaly
Hypotelorism
Skin defects on scalp
Severe development inpairment
Congential malformations of organs

61
Q

What is the ratio of male to female for Edward syndrome?

A

20% male to 80% female

62
Q

How common is Edward syndrome?

A

1:8000 live births

63
Q

What is the life expectancy of a person with Edward syndrome?

A

<4 months

64
Q

What is the average maternal age of a parent with a Edward syndrome child?

A

34.7 years old

65
Q

What are the common features of a person with Edward syndrome?

A

Heart defects
Low birth weight
Finger flexion deformity
Severe developmental impairment
Prominant occiput

66
Q

How common is Down syndrome?

A

1:1000 births to 1:30 births (depends on mothers age)

67
Q

What is the common cause for downs syndrome?

A

95% attributed to nondisjunction in meiosis
Ovum is source of 95% of trisomy 21 cases

68
Q

What is the Down syndrome Critical region (DSCR)?

A

A position on chromosome 21 that is a key region causing the down syndrome symptoms

69
Q

When do most Down syndome births occurs?

A

> 50 of Down syndrome births occur in mother >35 years old

70
Q

What are common symptoms of down syndrome?

A

Flat face profile
Epicanthal fold
5th finger clinodactyl
Space between 1st and 2nd toes
General hyptonia (decreased muscle mass)

71
Q

What are variable symptoms of down syndrome?

A

Congenital heat defects (expecially AV canal)
Increased risk of leukaemia
Duodenal atreis
Hypothyroidism

72
Q

What is the life expectancy of someone with Down Syndrome?

A

Average in UK is 58

73
Q

When is non-disjunction likely to occur in mothers?

A

During oogenesis

74
Q

When does meiosos start in women?

A

In all eggs in fetus but is arrested in meiosis I during synapsis of homologues

75
Q

When does meiosis restart?

A

Meiosis restarts at puberty but is again arrested in meiosis II and is not completed until fertilisation

76
Q

Why is maternal age relevant for chromosomal disease?

A

Ova produced at 30 ot 40 are therefore significantly older than those produced 10-20 years earlier

77
Q

What causes structural abnormalities?

A

Chromosomal breakages- sticky ends can rejoin other broken ends

78
Q

Where do breakages occur most?

A

Some chromosomal sites are more susceptible to breakage is not randomly distrubuted throughout genome

79
Q

When can breaks occurs?

A

They can occur spontaneously

80
Q

What increases frequency of breaks?

A

Ionising radiation
Chemical mutagens
Rare inherited disorders (eg Fanconi’s anaemia and bloom syndrome)

81
Q

What is nonreciprocal translocation?

A

The broken section of DNA gets added to the other chromosome rather than the original chromosome

82
Q

What is reciprocal translocation?

A

Both chromosomes recieve a double stranded break and effectively swap sections as the repair mechanisms rettatched the chromsome break to the wrong chromosome

83
Q

What is Cri Du Chat syndrome?

A

Variable deletion of terminal portion of chromosome 5- hTERT gene (maintenance of telomeres)

84
Q

What is the gentic constitution of Cri Du chat?

A

46 chromosomes but with deleted region on 5th chromosme

85
Q

What are the symptoms of Cri Du Chat?

A

Malformed larynx- eerie cry sounds
Profound learning difficulties
Various anatomical abnormaliries

86
Q

How frequent is Cri Du Chat syndrome?

A

1:25000 to 1:50000 births

87
Q

How do people get Cri Du Chat syndrome?

A

It is not inherited

88
Q

What causes Familial down’s syndrome?

A

Robetsonian translocation- section of chromosome 21 is broken along side another chromosome often 14. Translocation occurs meaning that the section chromsome 21 is repaired onto the other chromosome

89
Q

How do people get Familial down’s syndrome?

A

It is inherited when the trisomal 21 occurs. A person can be a carrier when they are diploid but still have the translocation

90
Q

What are 90% of solid tumours and 50% of blood cancers

A

They are aneuploid

91
Q

What can cause cancers?

A

Deletions, duplications and translocations

92
Q

What diseases are caused by unstable DNA repeats?

A

Fragile X syndrome (discovered 1991)
Kennedy’s disease (discovered 1991)
Mytotonic Dystrophy (discovered 1992)
Huntungton’s (discovered 1993)

93
Q

What causes unstable DNA repeat diseases?

A

Repeats greater than a certain threshold number become unstable, this causes problems with DNA replication as the DNA polymerase struggles with the large number of repeat sequences

94
Q

What is the mechanism for DNA repeat expansion?

A

It is not clearly understood.
Potential mechanisms include replication, DNA repair and recombination association

95
Q

What can happen to to triplet repeat sequences?

A

They can expand or contract

96
Q

What could potentially add to the DNA repeats during DNA replication?

A

DNA polymerase can add to the cells DNA through DNA slippage or something similar. When that DNA replicates then there will a cell with both strands having the extension

97
Q

What is anticipation?

A

“The Sherman Paradox”- symptoms of a disease appear earlier with increased severity from generation to generation

98
Q

What was discovered that provided an explanation for anticipations?

A

The discovery of dynamic triplet repeat expansions

99
Q

What are the outcomes of longer repeat sequences?

A

Longer repeats cause more severe symptoms which appear earlier
Longer repeats sequences are unstable with an expansion bias between generations

100
Q

What are the two major classes of repeats?

A

1- In an untranslated region (UTR) or promoter of the gene
2- In a coding region generating an aberrant protein

101
Q

What effects and disease are caused by repeats in a promoter region?

A

Transcriptional silencing
Loss of function mutation
Seen in fragile X syndrome

102
Q

What effects and disease are caused by repeats in an Intron region?

A

Impaired transcription
Loss of frataxin function
Seen in friedreich ataxia

103
Q

What effects and disease are caused by repeats in an Exon region?

A

Expanded polyglutamine tracts confers new propeties
Gain of function
Altered protien
Seen in Huntingtons disease

104
Q

What effects and disease are caused by repeats in the 3’ untranslated region?

A

Expanded CTG repeats confers new properties on RNA (toxic RNA)
Can result in splicing factor sequestration model
Gain of function
Seen in Myotonic dystrophy 1

105
Q

What is Fragile X syndrome also known as?

A

Martin-bell syndrome

106
Q

What are common symptoms of Fragile X syndrome?

A

Learning difficulties (most common inherited learning difficulties)
Autistic behaviour
Long face, large ears and flat feet
Hyperextensible joints espcially fingers
Increased density of long, immature-looking dendritic spines in neurones of the brain
Disturbance of synpase function

107
Q

What is the difference between males and females?

A

Effects twice as many males 1:4000 compared to 1:8000
Boys are more severly effected than girls
80% of males have learning difficulties compared to 305 of females

108
Q

What causes Fragile X syndrome?

A

Repeats on the q section of the X chromosome
Exapansion of the 5’ CGG triplet in the unstranslated region of the FMR1 (fragile X mental retardation 1) gene

109
Q

What are the number of repeats with normal allele, premutaion or disease causing?

A

Normal allele= 6-55
Premutation alleles= 55-200 (late onset neurodegeneration (male) or ovarian failure (female)
Disease causing alleles= >200

110
Q

How does the CGG repeats impact gene expression?

A

Aberrant hypermethylation of CpG island causing loss of FMR1 expression and FMRP function

111
Q

What is the function of the FMRP protein?

A

Selective RNA binding protein which associated with polyribosomes to control local protein synthesis by supressing translation of the mRNA it binds to. It binds to RNAs containing G-quartets and ‘kissing complexes’ (hairpin loops)

112
Q

What does FMRP do when interacting with microRNAs?

A

The facilitates selections and repression of target RNAs

113
Q

Where does FMRP play a crucial role?

A

In the dynamically regulating nRNA translation at the synapse

114
Q

What can cause severe Fragile X without being caused by a repeats?

A

It can be caused by a point mutation in KH2 domain as resulting in nonfunctional FMRP protein

115
Q

When does Huntington’s disease manifest?

A

Typically manifests in midlife but also in childhood and late onset
Death typically within 10-15 years of onset of symptoms
Increase in repeats in successive generations results in earlier age of onset
Instability of repeat length greater in spermatogenesis rather oogenesis

116
Q

What are the symptoms of Huntingtons disease?

A

Chorea- involuntary muscle jerks and twitches
Memory deficits- dementia
Personality changes
Depression

117
Q

How frequent in Huntington’s disease?

A

4-10 cases per 100,000

118
Q

What is the historical context for Huntington’s disease?

A

People with the disease were thought to be possed by the devil and at least one of the witches of Salem executed in the 1690s probably had HD

119
Q

What is the neuropathology of Huntingtons Disease?

A

Severe atrophy of caudate nucleus and putamen regions of the brain
Medium spiny GABAinergic neurons are most affected

120
Q

What causes Huntingtons disease on Ch4?

A

HTT gene on IT15 (Ch4)
CAG repeat in N-terminus of Huntingtin
6-34 repeats- unaffected
36-121- HD

121
Q

What does repeats of CAG cause?

A

CAG codes for glutamine (Q)
Poly-Q disease- toxic gain of function

122
Q

What does HTT protein do?

A

The 348 kDa involved with numerous protein-protein interactions so the extra polyglutamines severly impact its function. This results in multiple cellular pathogenic mechanisms

123
Q

What processes within the neurone are impacted by HD causing HTT protein?

A

Abnormal protein folding
Ca2+ signalling impaired
Blocked protein degradation pathways
Mitochondrial dysfunction

124
Q

When and who first described Myotonic Dystrophy (Steinhardt disorder)?

A

1909 by Steinhardt, Batten and Gibb

125
Q

How frequent is muscular dystrophy?

A

1 in 8000 people
Autosomal dominance

126
Q

When was the second type of Myotonic Dystrophy identified?

A

First identified in 1999

127
Q

What is Myotonic disease?

A

A multisystemic diseas
Endocrine- insulin reistance
Eyes- Cataracts
Respiratory- Alveolar hypoventilation
Skeletal muscle- Muscle weakness and wasting

128
Q

What is mosaicisim of Mytonic disease?

A

Repeat length is highly heterogeneous within tissues, so can vary in length. Vary in length means vary in severity of symptoms

129
Q

What can happen to the repeats in Mytonic disease?

A

Repeats accumulate in post-miotic tissues
Repeats expand in the germline between generations

130
Q

What could be the cause of Maternal bias in myotonic and fragile X?

A

Extended oogenic meiosis could expalin maternal expansion bias

131
Q

What were the two main hypotheses for Myotonic dystrophy?

A

1- Loss of function of genes in vicinity of DMPK CTGn - DMI of DMPK, SIX5 or DMWD
2- Gain of function of mutant RNA- DM1 DM2. Also potential gain of function for MBNL1

132
Q

What evidence for loss of function of genes causing Myotonix dystrophy?

A

DMPK is a protein kinase with unknown function- knockout mice have a few DM like symptoms
SIX5 is a homeodomain transcription factor- knockout mice have cataracts but no other symptoms
Effects on these genes cant explain all the phenotypes

133
Q

What causes DM1 myotonic dystrophy?

A

CTG repeats in the DMPK exon on chromsome 19

134
Q

What causes DM2 myotonic dystrophy?

A

CCTG repeats in the ZNF9 intron on chromosome 3

135
Q

Whats the difference between wildtype cells and cells with myotonic dystrophy?

A

Wildtype cells both in nucleus and cytoplasm
Both types of myotonic dystrophy retained in the nucleus with longer RNA sequences, collecting in foci

136
Q

How can splicing factor sequestration hypothesis explain the wide ranging symptoms of myotonic dystrophy?

A

Muscle Bind Like 1 (MBNL1) colocalises with nuclear foci of CUGn mRNA. MBNL1 proteins co-localise with repeat containing RNA, these MBNL1 proteins are used in the regulation of RNA splicing, particually alternative splicing

137
Q

How does MBNL1 being sequestered by CUGn mRNA in the nucleus cause type 2 diabetes?

A

As MBNL1 is being sequestered this means that it cant be involved in splicing thus alternative splicign of the insulin receptor causes type 2 diabetes in DM patients

138
Q

How does MBNL1 being sequestered by CUGn mRNA in the nucleus cause mytotonia in DM patients?

A

Alternative splicing of skeletal muscle chloride channel causes myotonia, this is due to alternative splicing bringing in other exons or loss of exons which result in permature stop codons

139
Q

How did toxic RNA explain the wide ranging symptoms of myotonic dystrophy?

A

Toxic RNa affects splicing in multiple other genes mRNA can help explain multiple phenotypes

Sem 1: Genetics (10 decks)

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