Week 9 Flashcards
What are the 2 examples of numerical chromosome aberrations?
Polyploidy
Aneuploidy
What are 4 examples of structural chromosome abberrations?
Deletions
Duplicaions
Inversions
Translocations
How many conceptions involve chromosome abnormalities?
25%
How many fetus with chromosome abnormalities involve live births?
0.3%
What is aneuploidy?
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
What are types of aneuploidy?
Monosomy= 2n-1
Trisomy= 2n+1
What are euploidy?
Effects to multiples of n
What are examples of euploidy?
Polyploidy = 3n, 4n, 5n …
Triploidy= 3n
Tetraploidy= 4n
Autopolyploidy= Multiples of the same chromosome
Allopolyploidy= Multiples of closely related genomes
Where does ployploidy occurs?
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
Where is the specific case where polyploidy occurs in humans?
It can exist in differentiated tissues such as muscle and liver cells
Where is aneuploidy common?
In interspecies crosses but rare within species
What problem can cause aneuploidy?
Arrises due to non-disjunction- failure of chromosomes to segregate properly during cell division
What are the two ways non-disjunction can occur in an organism?
Constitutional- problems with meiosis
Somatic mosaic- problem occured during mitosis
What are the problems caused by aneuploidy?
Developmental abnormalities and reduces fitness in all species studied
What is treated better monosomies and trisomies?
Monosomies are treates less well than trisomes
How many conceptions in humans are monosomic or trisomic?
5%
What is the outcome of most monosomic or trisomic conceptions?
Most are lethal and aneuploidy is the leading known cause of miscarriage
What is the primary outcome for monosomic or trisomic conceptions?
Leading cause of congenital birth defects and learning disabilities
What is a likely outcome for somatic aneuploidy?
Feature of most cancers:
Trisomy 12 in chronic lymphocytic leukaemia (CLL)
Trisomy 8 in acute myeloid leukaemia (AML)
What is FISH method?
Fluorescence in situ hybridisation uses fluorescent DNA probes to target specific chromosomal locations within the nucleus
What is Karyotyping?
Chromosomes are stained during metaphase using Giesma dye to stain to create black bands
What is monosomy?
Loss of a single chromosome
2n-1
How can monosomy be compensated in animals?
In animals this is only seen for sex chromosomes- dosage compensation not seen in autosomes
What happens if there is a loss of an autosome?
It is not tolerated and is lethal
What amount of a heterozygous genome is tolerated?
Less than or equal to of 0.5% loss is tolerated
What haplo-insuffciency?
Single gene copy may not produced an acceptable dosage of gene expression
What is hemizygous?
Remaining genes may include formaly recessive, lethal alleles
What causes mosiac monosomy individuals?
Mitotic errors during early development
What is Turner’s syndrome?
A women has 45 chromosomes with only 1 x
How comman is Turners syndrome?
1:2000 female births
What happens to most 45 X feotuses?
They die before utero
Which X chromosome is most likely to be present im turners syndrome?
70-80% of all 45 X conceptions have a maternal X chromosome
When does meitic error most commonly during spermatogenesis?
Most meiotic error occurs during spermatogenesis
What are common features of Turner syndrome?
Low hairline
Webbed neck
Widely spaces nipples
Primary ovarian failure
Short stature
What are variables features of Turner syndrome?
Learning disabilities
Coarctation of aorta
What is trisomy>
Addition of extra chromosome
2n+1
Why are trisomies more tolerated than monosomies?
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)
What happens with the addition of a large chromosome?
A large chromosome additon is usually lethal
What autosomal trisomies can survive birth?
Chromsome 21, 18 and 13
Occasionally 9 and 8
What are examples of trisomes in sex chromosomes?
Klinefelter syndrome
XYY syndrome
Triple X Syndrome
What is Klinefelter syndrome?
A man with 47 chromosomes with two XXs and a Y
How frequent is Klinefelter syndrome?
1:660 births
What are variations in Klinefelter syndrome?
48 XXXY
49 XXXXY and more
What causes symptoms to become more severe?
Manifestations are more severe the more X chromosomes
How can Klinefelter syndrome effect women?
XXX chromosomes
What are common features of Klinefelter syndrome?
Gynaecomastia (partial development of boobs in men)
Elongated forearms and lower legs
Small testes and azoospermia
What are variable features of Klinefelter syndrome?
Learning disabillities
What is XYY syndrome?
A man with 47 chromosomes due to extra Y chromosome
How frequent is XYY syndrome?
1:1000 births
What are symptoms of XYY syndrome?
Very tall stature: >6 feet
Large teeth
Learning disabilities
Motor coordination problems
What happens with trisomy of chromosome 8?
If feotus survives they will have a condition called trisomy 8
What happens with trisomy of chromosome 9?
If feotus survives they will have a condition called trisomy 9
What happens with trisomy of chromosome 13?
If feotus survives they will have a condition called Patau syndrome
What happens with trisomy of chromosome 18?
If feotus survives they will have a condition called Edward syndrome
What happens with trisomy of chromosome 22?
If feotus survives they will have a condition called cat eye syndrome
What happens with trisomy of chromosome 21?
A person will have downs syndrome
How common is patau syndrome?
1:19,000 live births
What is the life expectancy of a person with patau syndrome?
~3 months
What is the average of parents with a child with patau syndrome?
32 years old
What are the common features of Patau syndrome?
Holoproscencephaly
Hypotelorism
Skin defects on scalp
Severe development inpairment
Congential malformations of organs
What is the ratio of male to female for Edward syndrome?
20% male to 80% female
How common is Edward syndrome?
1:8000 live births
What is the life expectancy of a person with Edward syndrome?
<4 months
What is the average maternal age of a parent with a Edward syndrome child?
34.7 years old
What are the common features of a person with Edward syndrome?
Heart defects
Low birth weight
Finger flexion deformity
Severe developmental impairment
Prominant occiput
How common is Down syndrome?
1:1000 births to 1:30 births (depends on mothers age)
What is the common cause for downs syndrome?
95% attributed to nondisjunction in meiosis
Ovum is source of 95% of trisomy 21 cases
What is the Down syndrome Critical region (DSCR)?
A position on chromosome 21 that is a key region causing the down syndrome symptoms
When do most Down syndome births occurs?
> 50 of Down syndrome births occur in mother >35 years old
What are common symptoms of down syndrome?
Flat face profile
Epicanthal fold
5th finger clinodactyl
Space between 1st and 2nd toes
General hyptonia (decreased muscle mass)
What are variable symptoms of down syndrome?
Congenital heat defects (expecially AV canal)
Increased risk of leukaemia
Duodenal atreis
Hypothyroidism
What is the life expectancy of someone with Down Syndrome?
Average in UK is 58
When is non-disjunction likely to occur in mothers?
During oogenesis
When does meiosos start in women?
In all eggs in fetus but is arrested in meiosis I during synapsis of homologues
When does meiosis restart?
Meiosis restarts at puberty but is again arrested in meiosis II and is not completed until fertilisation
Why is maternal age relevant for chromosomal disease?
Ova produced at 30 ot 40 are therefore significantly older than those produced 10-20 years earlier
What causes structural abnormalities?
Chromosomal breakages- sticky ends can rejoin other broken ends
Where do breakages occur most?
Some chromosomal sites are more susceptible to breakage is not randomly distrubuted throughout genome
When can breaks occurs?
They can occur spontaneously
What increases frequency of breaks?
Ionising radiation
Chemical mutagens
Rare inherited disorders (eg Fanconi’s anaemia and bloom syndrome)
What is nonreciprocal translocation?
The broken section of DNA gets added to the other chromosome rather than the original chromosome
What is reciprocal translocation?
Both chromosomes recieve a double stranded break and effectively swap sections as the repair mechanisms rettatched the chromsome break to the wrong chromosome
What is Cri Du Chat syndrome?
Variable deletion of terminal portion of chromosome 5- hTERT gene (maintenance of telomeres)
What is the gentic constitution of Cri Du chat?
46 chromosomes but with deleted region on 5th chromosme
What are the symptoms of Cri Du Chat?
Malformed larynx- eerie cry sounds
Profound learning difficulties
Various anatomical abnormaliries
How frequent is Cri Du Chat syndrome?
1:25000 to 1:50000 births
How do people get Cri Du Chat syndrome?
It is not inherited
What causes Familial down’s syndrome?
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
How do people get Familial down’s syndrome?
It is inherited when the trisomal 21 occurs. A person can be a carrier when they are diploid but still have the translocation
What are 90% of solid tumours and 50% of blood cancers
They are aneuploid
What can cause cancers?
Deletions, duplications and translocations
What diseases are caused by unstable DNA repeats?
Fragile X syndrome (discovered 1991)
Kennedy’s disease (discovered 1991)
Mytotonic Dystrophy (discovered 1992)
Huntungton’s (discovered 1993)
What causes unstable DNA repeat diseases?
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
What is the mechanism for DNA repeat expansion?
It is not clearly understood.
Potential mechanisms include replication, DNA repair and recombination association
What can happen to to triplet repeat sequences?
They can expand or contract
What could potentially add to the DNA repeats during DNA replication?
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
What is anticipation?
“The Sherman Paradox”- symptoms of a disease appear earlier with increased severity from generation to generation
What was discovered that provided an explanation for anticipations?
The discovery of dynamic triplet repeat expansions
What are the outcomes of longer repeat sequences?
Longer repeats cause more severe symptoms which appear earlier
Longer repeats sequences are unstable with an expansion bias between generations
What are the two major classes of repeats?
1- In an untranslated region (UTR) or promoter of the gene
2- In a coding region generating an aberrant protein
What effects and disease are caused by repeats in a promoter region?
Transcriptional silencing
Loss of function mutation
Seen in fragile X syndrome
What effects and disease are caused by repeats in an Intron region?
Impaired transcription
Loss of frataxin function
Seen in friedreich ataxia
What effects and disease are caused by repeats in an Exon region?
Expanded polyglutamine tracts confers new propeties
Gain of function
Altered protien
Seen in Huntingtons disease
What effects and disease are caused by repeats in the 3’ untranslated region?
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
What is Fragile X syndrome also known as?
Martin-bell syndrome
What are common symptoms of Fragile X syndrome?
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
What is the difference between males and females?
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
What causes Fragile X syndrome?
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
What are the number of repeats with normal allele, premutaion or disease causing?
Normal allele= 6-55
Premutation alleles= 55-200 (late onset neurodegeneration (male) or ovarian failure (female)
Disease causing alleles= >200
How does the CGG repeats impact gene expression?
Aberrant hypermethylation of CpG island causing loss of FMR1 expression and FMRP function
What is the function of the FMRP protein?
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)
What does FMRP do when interacting with microRNAs?
The facilitates selections and repression of target RNAs
Where does FMRP play a crucial role?
In the dynamically regulating nRNA translation at the synapse
What can cause severe Fragile X without being caused by a repeats?
It can be caused by a point mutation in KH2 domain as resulting in nonfunctional FMRP protein
When does Huntington’s disease manifest?
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
What are the symptoms of Huntingtons disease?
Chorea- involuntary muscle jerks and twitches
Memory deficits- dementia
Personality changes
Depression
How frequent in Huntington’s disease?
4-10 cases per 100,000
What is the historical context for Huntington’s disease?
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
What is the neuropathology of Huntingtons Disease?
Severe atrophy of caudate nucleus and putamen regions of the brain
Medium spiny GABAinergic neurons are most affected
What causes Huntingtons disease on Ch4?
HTT gene on IT15 (Ch4)
CAG repeat in N-terminus of Huntingtin
6-34 repeats- unaffected
36-121- HD
What does repeats of CAG cause?
CAG codes for glutamine (Q)
Poly-Q disease- toxic gain of function
What does HTT protein do?
The 348 kDa involved with numerous protein-protein interactions so the extra polyglutamines severly impact its function. This results in multiple cellular pathogenic mechanisms
What processes within the neurone are impacted by HD causing HTT protein?
Abnormal protein folding
Ca2+ signalling impaired
Blocked protein degradation pathways
Mitochondrial dysfunction
When and who first described Myotonic Dystrophy (Steinhardt disorder)?
1909 by Steinhardt, Batten and Gibb
How frequent is muscular dystrophy?
1 in 8000 people
Autosomal dominance
When was the second type of Myotonic Dystrophy identified?
First identified in 1999
What is Myotonic disease?
A multisystemic diseas
Endocrine- insulin reistance
Eyes- Cataracts
Respiratory- Alveolar hypoventilation
Skeletal muscle- Muscle weakness and wasting
What is mosaicisim of Mytonic disease?
Repeat length is highly heterogeneous within tissues, so can vary in length. Vary in length means vary in severity of symptoms
What can happen to the repeats in Mytonic disease?
Repeats accumulate in post-miotic tissues
Repeats expand in the germline between generations
What could be the cause of Maternal bias in myotonic and fragile X?
Extended oogenic meiosis could expalin maternal expansion bias
What were the two main hypotheses for Myotonic dystrophy?
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
What evidence for loss of function of genes causing Myotonix dystrophy?
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
What causes DM1 myotonic dystrophy?
CTG repeats in the DMPK exon on chromsome 19
What causes DM2 myotonic dystrophy?
CCTG repeats in the ZNF9 intron on chromosome 3
Whats the difference between wildtype cells and cells with myotonic dystrophy?
Wildtype cells both in nucleus and cytoplasm
Both types of myotonic dystrophy retained in the nucleus with longer RNA sequences, collecting in foci
How can splicing factor sequestration hypothesis explain the wide ranging symptoms of myotonic dystrophy?
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
How does MBNL1 being sequestered by CUGn mRNA in the nucleus cause type 2 diabetes?
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
How does MBNL1 being sequestered by CUGn mRNA in the nucleus cause mytotonia in DM patients?
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
How did toxic RNA explain the wide ranging symptoms of myotonic dystrophy?
Toxic RNa affects splicing in multiple other genes mRNA can help explain multiple phenotypes
