Genetics 7 - Epigenetics Flashcards
learning outcomes
epigenetics
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
biochemical basis for epigenetics
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
DNA methylation - on vs off gene
biallelic expression
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
monoallelic expression
only 1 of 2 alleles is expressed
expression of imprinting
proportion of genes imprinted
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
changes that occur in DNA with imprinting
related to methylation of cytosines (in promoter) and histones
modification of DNA but not nucleotide sequence change
enduring but not permanent change
genomic imprinting
example of imprinting
what allele is expressed
what allele is imprinted
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
if Sally (daughter of Betty and Don) has a child, which allele of IGF2 gene will work
in any oocytes that Sally (mother) makes, whichever version of the allele is present will be switched off
sperm vs ova methylation pattern
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
for imprinted genes, what is required for normal development
expression of imprinted genes
inheritance of maternal and paternal alleles is required
imprinted genes are more vulnerable to mutation - haploid expression
⇒ dominant mutations
Angelman Syndrome symptoms
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)
Prader-Willi Syndrome symptoms
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
mutation associated with Angelman and Prader Willi
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
prader willi deletion
paternal chr 15
angelman deletion
maternal chr 15
how do deletions (Angelman and Prader Willi) work
Uniparental disomy (UPD)
when 2 copies of a chr come from the same parent
therefore both will have either the maternal or paternal pattern of methylation
mechanisms of UPD
X-inactivation
heritability
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
when does X inactivation occur
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)
inactivation of X is retained
through all subsequent mitosis - all daughter cells
but NOT retained across generations
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
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
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
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
Duchenne Muscular Dystrophy
type of mutation
X-linked
dystrophin (Xp21.2)
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
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
C?
things to remember
learning outcomes
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
co colour gene is on X chr ⇒ female
how can you get a phenotypically male tortoise shell cat
cat that is XXY - kleinfelter’s cat
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
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
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
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
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
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
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)
chimaera =
an individual with 2+ populations of cells with different genotypes who arose by fusion of more than 1 fertilised zygote during embryogenesis
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
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
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
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
what would a child with paternal uniparental disomy for chr 15 have
2 paternal copies ⇒ missing maternal methylation pattern
⇒ Angelmans syndrome
what would a child with maternal uniparental disomy for chr 15 have
Prader Willi
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
angelman imprinting error
maternal chr may have the paternal pattern of methylation - mutations in the imprinting control centre
epigenetic (imprinting) error
things to remember
