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GGE > Genetics 7 - Epigenetics > Flashcards

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
Q

gene associated with X inactivation

A

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
Q

skewed X-inactivation

A

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
Q

Rett Syndrome

type of disorder

gene mutated

A

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
Q

symptoms of Rett Syndrome

variability

A

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
Q

Duchenne Muscular Dystrophy

type of mutation

A

X-linked

dystrophin (Xp21.2)

30
Q

symptoms of Duchenne Muscular Dystrophy

A

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
Q

heterozygous female carriers - DMD

A

mild cardiomyopathy, increased CK and muscle weakness but do not present with DMD

those who do may have skewed X inactivation

32
Q
A

C?

33
Q

things to remember

A
34
Q

learning outcomes

A
35
Q

mosaic

A

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
Q
A

co colour gene is on X chr ⇒ female

37
Q

how can you get a phenotypically male tortoise shell cat

A

cat that is XXY - kleinfelter’s cat

38
Q

turner syndrome symptoms

A

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
Q

causes of Turner’s

A

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
Q

treatment options for Turner’s

A

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
Q

investigations for Turner’s

A

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
Q

genetic counselling issues with Turner’s

A

impact of infertility

not hereditary

Y positive - removal of gonads may be necessary

transition of young people with Turner’s to adult care

43
Q

why is having only 1 X chr a problem for women but not for men

i.e. why is 45, X a problem

A

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
Q
A

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
Q

chimaera =

A

an individual with 2+ populations of cells with different genotypes who arose by fusion of more than 1 fertilised zygote during embryogenesis

46
Q

mosaic =

A

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
Q
A

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
Q

how does the methylation pattern imprinted vs used change across generations

A

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
Q

why is it important that the maternal IGF2 is imprinted

A

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
Q

what would a child with paternal uniparental disomy for chr 15 have

A

2 paternal copies ⇒ missing maternal methylation pattern

⇒ Angelmans syndrome

51
Q

what would a child with maternal uniparental disomy for chr 15 have

A

Prader Willi

52
Q

Prader Willi imprinting errors

A

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
Q

angelman imprinting error

A

maternal chr may have the paternal pattern of methylation - mutations in the imprinting control centre

epigenetic (imprinting) error

54
Q

things to remember

A

GGE (33 decks)

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