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Genetics 7 - Epigenetics Flashcards

1
Q

learning outcomes

A
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2
Q

epigenetics

A

heritable/enduring change in gene expression not related to variation in nucleotide sequence

enduring in the sense of:

the life of a long lived cell

retained from mother to daughter

retained from parent to offspring

epigenetics relate to DNA factors other than nucleotide sequence that impact on gene expression

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3
Q

biochemical basis for epigenetics

A

Condensation of chromatin and replication of DNA - regulated by chemical modifications of histones - these are influenced by DNA methylation, which occurs in regions of DNA rich in cytosine and guanine and located in promoter regions upstream of genes

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4
Q

DNA methylation - on vs off gene

A
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5
Q

biallelic expression

A

both alleles expressed

RECALL

humans are diploid

23 pairs of homologous chromosomes (1 from mother, 1 from father so each have different copies of each gene)

2 copies (often different alleles) of each gene

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6
Q

monoallelic expression

A

only 1 of 2 alleles is expressed

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7
Q

expression of imprinting

proportion of genes imprinted

A

involves monoallelic expression

expression of genes in a parent of origin specific manner

only the allele inherited from a specific parent (either maternal or paternal allele) is expressed

< 1% of human genes are imprinted

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8
Q

changes that occur in DNA with imprinting

A

related to methylation of cytosines (in promoter) and histones

modification of DNA but not nucleotide sequence change

enduring but not permanent change

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9
Q

genomic imprinting

A
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10
Q

example of imprinting

what allele is expressed

what allele is imprinted

A

Insulin Like Growth Factor (IGF2)

only paternal allele is normally expressed

maternal allele is imprinted (shut down) - not transcribed or translated into protein - this is to stop too much IGF2 being produced so cell does not grow out of control

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11
Q

if Sally (daughter of Betty and Don) has a child, which allele of IGF2 gene will work

A

in any oocytes that Sally (mother) makes, whichever version of the allele is present will be switched off

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12
Q

sperm vs ova methylation pattern

A

imprints are erased in the germline and re-established in gametes

in the sperm all imprints are erased and rewritten with the paternal pattern, even the alleles that came from mum

in the ova all imprints are erased and rewritten with the maternal pattern, even the alleles that came from dad

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13
Q

for imprinted genes, what is required for normal development

expression of imprinted genes

A

inheritance of maternal and paternal alleles is required

imprinted genes are more vulnerable to mutation - haploid expression

⇒ dominant mutations

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14
Q

Angelman Syndrome symptoms

A

small

profound intellectual disability

unable to speak and with particular behaviour pattern

happy demeanour with inappropriate laughter

(similar chr area affected as with Prader-Willi)

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15
Q

Prader-Willi Syndrome symptoms

A

floppy babies - hypotonia

intellectual/cognitive disability

uncontrollable appetite - obesity

hypogonadism in males

incidence approx 1 in 22,000, but uncertainty because PWS may go undiagnosed

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16
Q

mutation associated with Angelman and Prader Willi

A

both associated with a de novo deletion on long arm of chr 15 (15q11-q13)

both usually for identical sets of genes but

Prader Willi = deletion from paternal chr 15

Angelman = deletion from maternal chr 15

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17
Q

prader willi deletion

A

paternal chr 15

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18
Q

angelman deletion

A

maternal chr 15

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19
Q

how do deletions (Angelman and Prader Willi) work

A
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20
Q

Uniparental disomy (UPD)

A

when 2 copies of a chr come from the same parent

therefore both will have either the maternal or paternal pattern of methylation

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21
Q

mechanisms of UPD

A
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22
Q

X-inactivation

heritability

A

random transcriptional silencing of all but 1 X chromosome in females (maternal or paternal)

heritable from mother cell to all daughter cells in an individual

not heritable from parent to child

23
Q

when does X inactivation occur

A

early in embryonic development (totipotent cells) both X chromosomes are active

with differentiation to pluripotent cells random X inactivation (late blastocyst stage)

inactivated X condensed on periphery of nucleus (Barr body)

24
Q

inactivation of X is retained

A

through all subsequent mitosis - all daughter cells

but NOT retained across generations

25
gene associated with X inactivation
XIST gene in X inactivation centre (Xic) produces Xist RNA transcript that covers the X chr to be inactivated (Xi) subsequent DNA methylation (epigenetic) then makes this silencing permanent in all daughter cells
26
skewed X-inactivation
ratio of inactivated maternal X to paternal X should be equal (random) but is uneven (skewed) in 10-15% of women preferential inactivation of the abnormal X in heterozygotes is the reason why there is such variability in the expression of X linked disorders if the diseased X linked allele does not cause selection, the extent of the primary stochastic skewing can influence the severity of the disease skewed X inactivation is common in cases of severe X mutation or structural anomaly
27
Rett Syndrome type of disorder gene mutated
X-linked dominant disorder usually caused by mutations in MECP2 gene (X chr) - critical for brain function if this happens with males, they miscarry early in pregnancy
28
symptoms of Rett Syndrome variability
brain/cognitive function impaired hand coordination lost (hand wringing) seizures and breathing problems substantial phenotypic variability may be influenced by skewed X inactivation skewing \> 80% is rare - asymptomatic/less severe carriers
29
Duchenne Muscular Dystrophy type of mutation
X-linked dystrophin (Xp21.2)
30
symptoms of Duchenne Muscular Dystrophy
muscle fibre weakness that presents in childhood difficulty walking and rising (Gower manoeuvre) wheelchair by teens respiratory weakness mild cognitive impairment cardiomyopathy - ventricular remodelling
31
heterozygous female carriers - DMD
mild cardiomyopathy, increased CK and muscle weakness but do not present with DMD those who do may have skewed X inactivation
32
C?
33
things to remember
34
learning outcomes
35
mosaic
an individual who arose from a single fertilisedd egg, but who has 2 or more populations of cells each with different genotypes females are all mosaics
36
co colour gene is on X chr ⇒ female
37
how can you get a phenotypically male tortoise shell cat
cat that is XXY - kleinfelter's cat
38
turner syndrome symptoms
puffy feet and hands scoliosis small stature - noticed at an older age lymphedema present from birth coarctation of aortic or bicuspid aortic valve webbed neck and lymphedema (sometimes) kidney problems - horseshoe kidney amenorrhea non-functional ovaries (streak gonads) - infertile non verbal learning disabilities and behavioural problems - variable
39
causes of Turner's
occurs due to anaphase lag, where 1 sex chromosome moves too slowly to the pole of the daughter cell during division can happen during: Gametogenesis - classical monosomy X - 45, X during early mitotic division - Turner Mosaicism - 45X/46XX or 45X/46XY **neither is inherited**
40
treatment options for Turner's
depends on symptoms and level of mosaicism - screening and management of comorbidities heart problems scoliosis ear infections high BP thyroid bone loss neuropsychological and psychosocial issues hormone treatment (oestrogen replacement therapy) infertility treatments
41
investigations for Turner's
karyotype cardiac function tests cardiac imaging - CT, MRI, MRA Y chr PCR - if Y chr DNA is present it could affect development of gonads (tumorigenesis) X chromosome could be translocated or deleted - Could be causing monosomy X
42
genetic counselling issues with Turner's
impact of infertility not hereditary Y positive - removal of gonads may be necessary transition of young people with Turner's to adult care
43
why is having only 1 X chr a problem for women but not for men i.e. why is 45, X a problem
X inactivation is incomplete gene dosing up to 25% of X chromosome genes partially or totally escape (including PAR genes) - genes outside PARs may contribute to female phenotype escape genes expressed in higher levels in normal women versus Turner women even though men only have 1 X chr they still have some expression of genes on Y chr
44
Mr X is a chimaera tetragametic chimerism - 2 00cytes + 2 sperm 2 zygotes that merge into 1 organism ⇒ 2 genomes some cells carry the allele A - make his RBCs some cells carry allele B - not included in Mr X's haematopoietic tissue some of his brother's cells included in his gonads - carried his brother's genome (twin)
45
chimaera =
an individual with 2+ populations of cells with different genotypes who arose by fusion of more than 1 fertilised zygote during embryogenesis
46
mosaic =
an individual with 2+ populations of cells with different genotypes who arose from a single fertilised egg usually a result of a somatic change during early replication can be a result of germline mosaicism - occur early in germ cell development, resulting in significant no of gametes that carry the mutation and thus can affect \> 1 child dominant disorders
47
if Robert (the father) has a child, whichever version of the allele (from Don or Betty) that is present in his sperm will be switched on
48
how does the methylation pattern imprinted vs used change across generations
robert's body cells have paternal IGF2 expressed - paternal methylation pattern and maternal IGF2 imprinted, so maternal methylation pattern is not expressed robert's primordial germ cells - methylation patterns deleted from both chr robert's gametes - paternal imprint rewritten on both chromosomes in all sperm
49
why is it important that the maternal IGF2 is imprinted
IGF2 functions in regulating growth during gestation if both alleles should begin to be expressed in a cell, that cell may develop into cancer e.g. Wilms' tumour is an embryonic kidney cancer associated with loss of imprinting (LOI) of maternal IGF2
50
what would a child with paternal uniparental disomy for chr 15 have
2 paternal copies ⇒ missing maternal methylation pattern ⇒ Angelmans syndrome
51
what would a child with maternal uniparental disomy for chr 15 have
Prader Willi
52
Prader Willi imprinting errors
the paternal chr may have a maternal pattern of methylation (effectively no paternal chr) an affected individual may have both maternal and paternal chr
53
angelman imprinting error
maternal chr may have the paternal pattern of methylation - mutations in the imprinting control centre epigenetic (imprinting) error
54
things to remember

GGE (33 decks)

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