imprinting disorders Flashcards
why are gynogenetic or androgenetic diploids inviable?
due to genomic imprinting
what side is IGF-11 controlled by?
paternal side- is maternally imprinted
what side is IGFIIR controlled by?
maternal side
what phenotype to mice with a IGF11 mutation transmitted down the paternal line have?
growth defects
what is maternal imprinting?
allele inherited from the mother is transcriptionally silent, phenotype is governed by paternal side
what two situations can lead to imprinting diseases?
both copies of the gene are silenced or mutations in the expressed alllele
what causes Beckwith-Weirdemann syndrome?
maternal igf2 allele on chromosome 11 is not silenced due to imprinting defect in IC1. hypomethylation at potassium channel DMR region
what are the symptoms of BWS?
pediatric overgrowth, predisposition to tumours
inheritance pattern of BWS?
paternally inherited
symptoms of anglemans?
development difficencies, sleep disorders, seizures
inheritance pattern of anglemans?
maternally inherited, paternally imprinted chromosome 15
genetic causes of anglemans
deletions of PW region, point mutations in maternal UBE3a or paternal UPD
symptoms of prader willi
obesity, behaviour and cognitive problems
inheritance pattern of PW
paternally inheirted, maternally imprinted chromosome 15
genetic causes of PW
70% PW region deletion, 25% maternal UPD, mutations in ICR or translocations that separate ICR from PW region
symptoms of silver russel
pre and postnatal growth retardation, small triangular face, sweaty head and cardiac defects
genetic causes of silver russel
maternal UPD of chromosome 7, maternal duplication of 11p15, hypomethylation of telomeric 11p15 IC- supresses IGF2 expression
what is H3K14ac a docking site for
bromo-domain proteins
what genes are associated with birth size?
paternally expressed IGF2 and maternally expressed H19
why does epigenetic reprogramming take place in PGCs
resets imprinted genes for sex-specific reacquision, erases parental acquired epigenetic memories, facilitates gametogenesis, maintains silenicing of transposbale elements, reduces germline mutation rate
why does reprogramming take place in pre-implantation embryo
resets zygotic marks for naive pluripotency, maternal v paternal genome wars- allows more contribution from females
how are PGC epigenentic memories erased?
global DNA demethylation, genomic imprint erasure, x chromsoomes reactivation and reorganisation of histones
after pGC development what happens to XY and XX germ cells?
XY enter mitotic arrest, XX enter meiosis
when does remethylation occur in males and females?
in SSCs in males and after birth in growing oocytes in females
what happens to ICRs in PGC resetting?
imprints erased and resestabilished in sex specific manner later in development
how are embyros reset in females?
through replication dependent passive mechanisms- PRDMI and PRDM14 repress DMNT3a and b and UHRF1. UHRF1 normally activates DNMT1
how are embryos reset in males? a
active mechanisms- 5mC converted to 5hmC by TETs then removed in passive way or by base excision repair
how may imprints escape erasure during embryo restting?
these regions have higher numberrr KAP1 binding regions and may recruit DNMT1
why did dolly die young?
no restting of epigenetic marks, would not be pluripotent, demethylated in a non-speicifc and delayed way.
steps in artificial gamete production
1perform SCNT on somatic cell and induce embyro development in vitro
2. extract ESC from blastocyst
3 induce gametogenesis in vitro
4 use gamete to fertilise partners egg/sperm
5 develop embryo and implant into mother
what are man made mouse eggs made from?
in vitro system of generating a mouse oocyte from fibroblast derived pluripotent stem cells
how are bimaternal mice made?
oocyte activated, isolate parthenogenetic haploid ESCs, demethylate cells in media- loss of methylation non-specifc, then delete paternally imprinted regions- found that deleting 3 regions made basically normal mice, then implant haploid ESC into mature oocyte
how are bipaternal mice made?
mature oocyte enucleated and fertilised with sperm, androgenetic haploid ESCs isolated, demethylate in media, deleting 6 maternally imprinted regions still resullted in death, then coinject haploid ESC and sperm into enucleated oocyte.
