genomic imprinting and epigenetics Flashcards
what is required for mammalian development?
two parents
what happens if there are not two parents for mammalian development?
androgenesis - when there is no mother so complete father genome
or parthenogenesis where there is not father resulting in 46XX
where is parthenogenesis common?
in other parts of the animal kingdown such as reptiles, insects and fish - mourning gecko
when is the mammalian egg fertilised?
around the second prophase of the second meiotic division - around this time the first polar body has already been extruded and DNA has already replicated by the first meiotic division
what is the result by the second meiotic division?
two haploid pro nuclei
what happens if meiotic division goes wrong?
can retain the second polar body resulting in a diploid egg or products of the second meiotic division can be lost resulting in an empty egg with fertilisation from doubled up sperm or two sperm - same genetic material but all from father
what is a hydatidiform mole?
it is an androgenetic origin - complete moles have no recognisable embryo in pregnancy and are mostly 46 XX homozygous. there is proliferation of trophoblasts - tissue that is usually derived from embryo that goes on to form largest part of placenta and the uterus on USS will show vesicular, abnormal overgrown placenta
what is a complication of hydatidiform moles?
can develop into a malignant trophoblastic tumour and are non compatible with life so must be treated
what is an ovarian teratoma?
it is a very biologically abnormal tumour in the ovary from parthenogenic activation. It derives from parthenogenic conceptions and is derived from oocytes that have undergone their first or both meiotic divisions
what are characteristics of ovarian teratomas?
they are predominantly epithelial with no skeletal muscle, muscle and placenta. They are radio-opaque on an Xray with skin, hair and teeth and are developmental tumours
what happens if you induce a uniparental genome in a mouse?
it will mirror human pathologies
what have mouse studies shown us about angro and partenogenetic conception?
in parthenogenetic the embryos die due to failure to develop extraembryonic structures such as trophoblast or yolk sac, in androgenetic the embryo will die at the 6 somite stage due to overdeveloped extraembryonic membranes and little development of foetus itself
why does uniparental conception fail?
there are different roles of maternal and paternal genes in developing developmental fate
what is genomic imprinting?
mothers and fathers will imprint their genes with memory of their paternal or maternal origin - respective parents so have memory of origin
why does genomic imprinting mean that uniparental conception fails?
although the karyotype and the gene dosage is normal the imprinting results in a mechanism that ensures the functional non-equivalence of maternal and paternal genomes so that they are non exchangeable and non equivalent
how does genomic imprinting work?
it is not encoded in the DNA sequence - there is no systematic difference in the mother and father that explains the difference in parental origins. Instead it occurs through epigenetics – the modifications to the genome that occur and are laid down during gametogenesis which affects the expression of a small subset of 1-200 genes that are evolutionarily conserved
what is gametogenesis called for sperm and eggs?
spermatogenesis and oogenesis
what are the characteristics of angelman syndrome and how does it occur?
epigenetics can result in clinical pathologies. Angelman results in facial dysmorphism (prognthism, wide mouth, drooling and smiling appearance), seziure disorder, severe neurodevelopmental disorder, mental handicap (microcephaly and absent speech) and ataxic, jerky movements
what is prognathism?
it is jaw jut - relation of the mandible and maxilla to skeletal base
what is prader-willi syndrome?
it is a disorder that presents early on with neonatal floppy baby. It results in infantile hypotonia with feeding problems and gross motor delay, metal handicap, male hypogenitalism and cryptorchidism, small hands and feet, hyperphagia, stereotypic behaviour, early motor delay, neurodevelopmental delay
what is hyperphagia?
desire to eat a lot - around 4 years old will compulsively eat which leads to obesity
what is the genetic difference between AS and PWS?
they are both the deletion of chromosome 15 but due to functional non equivalence, and using molecular techniques have identified that PWS is deletion of paternal and AS maternal.
what is the recurrence risk of AS/PWS?
the recurrence risk is very low and it is always a de novo mutation that is highly likely to result in significant phenotype. It is not found in parents as is a significant genetic event.
where is the deletion on chromosome 15 for AS/PWS?
it is a del 15q11-q13
what is the other genetic mechanism in both AS and PWS?
uniparental disomy - two maternal in PWS and two paternal in AS - indistinguishable from loss clinically
what is the third genetic mechanism in AS?
point mutation of single gene that results in inactivation on maternal copy. Therefore loss of function of maternally inherited UBE3A
in PWS what is the epidemiology of deletion and UPD?
25% UPD and 70% deletion
in AS what is the epidemiology of deletion, mutation and UPD?
deletion is 75%, UPD is 1% and point mutation will be 2-5%
how does imprinting result in conditions?
there are a selection of genes that are only expressed from paternal or maternal genome therefore a loss of function will result in a condition and monoallelic expression of a cluster of genes
what does epigenetic mean?
modifications on top of the DNA sequences
where does DNA methylation most commonly occur and when?
it occurs after the DNA has been replicated and it occurs predominantly at CG dinucleotides
what does methylation usually do?
silence the gene
what is DNA methylation?
it is a post synthetic DNA modification that is epigenetic and therefore does not usually alter the DNA sequence. it uses DNA methytransferases and is reversible so has to be maintained after replication. it occurs at CG dinucleotides, and many promoter regions which are CpG islands are spared
what is the distribution of modification site?
the distribution is not random - in most regions on genome there is a relative lack of CG dinucleotides except where transcription of genes starts where there is a higher density of CG or CpG islands.
what is the bulk of DNA?
methylated CG dinucleotides except CpG islands where it is not - this is modifiable
what does modification almost always result in?
change in transcription status of the gene - one which expressed gene is unmethylated and one which does not is methylated
what do imprinted genes show?
monoallelic expression - epigentic differences between paternal and maternal copies of alleles which is a memory of distinct gametogenetic history
what other structures differ between the alleles that are expressed/non expressed?
chromatin features
how are histones modified?
with Poly-A tails
how does imprinting occur?
it has evolved in mammals for foetal growth and selection of growth - evolution determines which way the process goes
where are constraints in foetal growth higher?
in the mother
what happens if the baby is too big?
there is high mother mortality and poor long term reproductive potential
what is the link between baby size and father?
larger baby means higher fetal fitness and evolutionary advantage for father - if there is increased foetal mortality it means there is decreased paternal reproductive fitness
what are involved in epigenetic modification?
DNA methyltransferase, protein kinases, histone methytransferases, ubiquitin protein ligases and histone deacetylases
what is the genetic cause of Beckwith-Weidmann syndrome?
it is a sporadic occurrence with epigenetic abnormalities in 11p15
what are the presenting features of BWS?
fetal overgrowth with high birthweight and potentially abnormal sized adult, organomegaly with exomphalos, hypoglycaemia, asymmetry, tumour risk
what are the presenting features of Russel Silver Syndrome?
growth retardation (foetal or persistent postnatal growth failure), asymmetry, triangular face due to preserved brain size
what are the genetic similarities between BWS and RSS?
they are both sporadic and due to abnormalities on chromosome 15 in same region. There is an important gene insulin like growth factor 2 that is a major regulator of foetal growth during pregnancy and is imprinted so usually only expressed paternally.
what happens genetically in BWS and RSS?
in BWS there is methylation of the maternal allele so biallelic expression of IGF2 and in RSS methylation is lost on both meaning that both are silences. This is an indirect mechanism that also involves the neighbouring gene H19
what is imprint switching?
it is the requirement to be rearranged and reset in order not to disrupt the Mendelian inheritance rules. There must be reversible changes and imprinting must be remembered during somatogenesis and forgotten before gametogenesis for the erasure of the grandparental imprint and learning of the new parental imprint.
when is the parental imprint established?
gametogenesis - oogenesis for most genes
where are most genes?
the X chromosome - the Y is mostly junk / heterochromatin
what does lyonisation depend on?
X inactivation uses epigenetics - in females monoallelic expression is needed and therefore we epigenetically silence one of the copies - there is genetic memory and somatic cells will remember the silences status but this is reversed in germ cells
what happens in X inactivation?
a whole X chromosome is inactivated - not just the genes. There is a random choice of parental chromosome that is different in different cells - somatic cell clones will remember
when does X inactivation occur?
at the blastocyst stage of embryogenesis - when there is only a few precursor cells
what dos fertilisation result in?
a zygote that gives you paternal and maternal chromsomes
what is a Barr Body?
an inactivated X chromosome
where are there clinical consequences of X inactivation?
in X linked genetic disorders - a female is heterozygous for an IL condition so get random patchy X inactivation - random skewing is possible - variation in phenotypes and affects clinical expression depending on normal : mutant gene
how can you identify the mix of normal and abnormal genes?
in hyphohidrotic ectodermal dysplasia use a starch and iodine test - sweat will be released dissolved iodine and react with starch - can see where the sweat glands are and therefore where mutated genes are etc
what are other examples of X linked?
Duchenne muscular dystrophy and haemophilia
what are the consequences of X inactivation?
females are epigenetic mosaics that are composed of patches of cells working on one or the other X chromosome. There are some functionally defective and some normal cells - functional mosaicism - unpredicatable and can be disease specific
