Imprinting and X inactivation

hydatidiform mole

• androgenetic

  • complete hydatidiform moles

  • mostly homozygous 46, XX

  • proliferation of abnormal trophoblast tissue

  • can develop into malignant trophoblastic tumour

  • no remaining embryo

androgenesis

• offspring’s genome comes entirely from the sperm

• maternal nuclear genome is eliminated or inactive

parthenogenesis

• offspring’s genome comes entirely from the egg

• no sperm

ovarian teratomas

• parthenogenetic conceptions

• derived from oocytes which have completed first or both meiotic divisions

  • diploid

  • wide spectrum of tissues

    • predominantly epithelial

    • no skeletal muscle

    • no membranes/placenta

why do uniparental conceptions fail

• different roles of maternal vs paternal genes in determining developmental fate

• genomic imprinting

  • mothers and fathers somehow imprint their genes with memory of their paternal or maternal origin

genomic imprinting

• ensures functional non-equivalence of maternal and paternal genomes

• not encoded in DNA nucleotide sequence→ epigenetic

• depends on modifications to genome laid down during gametogenesis

• affects expression of 100-200 genes

Angelman syndrome

• facial dysmorphism→ wide mouth, drooling, smiling/laughing appearance

• microcephaly, absent speech

• seizure disorder

• ataxic jerky movements

Prader-Willi syndrome

• infantile hypotonia→ feeding problems, gross motor delay

• mental handicap

• male hypogenitalism/cryptorchidism

• small hands and feet

• hyperphagia

• stereotypic behaviour

cytogenic abnormalities in Angelman syndrome/Prader Willi

• deletion of chromosome 15

• always de novo

• condition depends on which chromosome 15 is deleted

  • maternal→ Angelman

  • paternal→ Prader-Willi

moelcular mechanisms in Prader-Willi

• deletion of paternal 15q11-13→ 70%

• uniparental disomy→ 25%

moelcular mechanisms in Angelman syndrome

• 75% deletion in maternal 15q11-13

• uniparental disomy→ 1%
  point mutation in UBE3A→ 2-5%

DNA methylation

• post synthetic DNA modification

• epigenetic

• DNA methyltransferases

• reversible→ has to be ‘maintained’ after replication

• occurs at CG dinucleotides→ many promoter regions spared

  • gene regulation

where does DNA methylation occur

• CpG islands→ just before start site

• also CG dinucleotides

what distinguishes maternal and paternal alleles

• imprinted genes retain methylation→ silences gene on either maternal or paternal

  • monoallelic expression

example of why imprinting is useful

• mother→ lower IGF2 (growth factor)

  • smaller babies with better survival rate and reproductive fitness

• father→ higher IGF2

  • larger babies with lower reproductive fitness

• imprinting finds balance between two

beckwith-Wiedemann syndrome

• due to high IGF2

  • fetal overgrowth

  • organomegaly

  • hypoglycaemic

  • asymmetry

  • tumour risk

Russell Silver Syndrome

• Growth retardation

• Triangular face

• asymmetry

• sporadic occurrence

imprint switching

• imprinting must be remembered during somatic development

• forgotten before gametogenesis→ erasure of grandparental imprinting

• establishment of new parental imprint during gametogenesis

dosage compensation

• females have the same genes on each of the X chromosomes→ only need one to be expressed

• epigenetic silencing of a gene on of the two X chromosomes→ prevents two of the same gene being expressed

X inactivation

• whole X chromosome is silenced

• random choice of parental chromosome→ different in different cells

• occurs in embryogenesis

female carriers of an X-linked mutations

• in some conditions, mosaicism occurs→ because some cells have normal gene, but others have affected gene

expression of X-linked genes

• random

• unpredictable

consequences of X inactivation

• females are ‘epigenetic mosaics

  • composed of patches of cells working on one or the other X chromosome

  • carriers of X-linked mutations have some functionally defective and some normal cells

  • functional mosaicism→ may be unpredictable, disease specific