17.2 Genomic Imprinting

Genomic imprinting breaks the rules of typical gene expression. It's like a genetic game of favorites, where some genes only work when they come from mom or dad, not both. This quirk can lead to unique inheritance patterns and even certain disorders.

The molecular mechanisms behind imprinting are like genetic on/off switches. DNA methylation and histone modifications act as tags, telling genes when to be quiet or speak up. These tags are set early on and stick around, influencing how genes behave throughout life.

Genomic Imprinting

Genomic imprinting and inheritance

• Epigenetic phenomenon where gene expression depends on parent-of-origin of allele
  • Certain genes expressed differently based on inheritance from mother or father (IGF2, H19)
• Imprinted genes typically expressed from only one allele, either maternal or paternal, while other allele silenced
• Deviates from classical Mendelian inheritance patterns, where both alleles expressed equally
• Leads to parent-of-origin effects, where offspring phenotype depends on which parent allele inherited from (Prader-Willi syndrome, Angelman syndrome)
• Influences inheritance of certain genetic disorders and traits

Molecular mechanisms of imprinting

• DNA methylation key mechanism
  • Addition of methyl groups to cytosine residues in CpG dinucleotides of DNA
  • Methylation patterns established during gametogenesis and maintained throughout development
  • Methylation of promoter regions typically leads to gene silencing
• Histone modifications also play a role
  • Acetylation and deacetylation can influence gene expression
  • Specific modifications, such as H3K9 methylation, associated with repressed chromatin states and gene silencing
• Imprinting control regions (ICRs) regulate expression of imprinted genes
  • ICRs are differentially methylated regions (DMRs) that control expression of nearby genes
  • Methylation status of ICRs established during gametogenesis and maintained in offspring

Parent-of-origin effects in genes

• Phenotype of offspring depends on which parent allele inherited from
  • Expression of allele determined by parent who passed it on, rather than allele itself
• Examples of imprinted genes:
  • IGF2 (Insulin-like growth factor 2): Expressed from paternal allele; involved in fetal growth and development
  • H19: Expressed from maternal allele; long non-coding RNA that regulates IGF2 expression
  • SNRPN (Small nuclear ribonucleoprotein polypeptide N): Expressed from paternal allele; involved in Prader-Willi syndrome
  • UBE3A (Ubiquitin-protein ligase E3A): Expressed from maternal allele in brain; involved in Angelman syndrome

Imprinting in human disorders

• Prader-Willi syndrome (PWS):
  • Caused by loss of function of paternally expressed genes on chromosome 15q11-q13
  • Characteristics include hypotonia, intellectual disability, behavioral problems, and hyperphagia leading to obesity
• Angelman syndrome (AS):
  • Caused by loss of function of maternally expressed UBE3A gene on chromosome 15q11-q13
  • Characteristics include intellectual disability, speech impairment, seizures, and happy demeanor
• Imprinting disorders arise from disruptions in normal imprinting patterns
  • Uniparental disomy (UPD): Inheritance of both copies of chromosome from one parent
  • Deletions or mutations in imprinted regions
  • Epigenetic alterations, such as abnormal DNA methylation patterns (Beckwith-Wiedemann syndrome, Silver-Russell syndrome)