Unit 2 Genetics- Imprinting Epigenetics

What is Genomic Imprinting?

An epigenetic process where only one allele of a gene is expressed depending on its parent of origin

• The other allele is epigenetically silenced, usually via DNA methylation

Kinship Theory (Conflict Theory)

A conflict over fetal resources

• Paternal genes: Aim to promote greater fetal growth and resource extraction

• Maternal genes: Aim to limit growth to conserve resources for the mother and future offspring

Epimutation

A disease-related change in DNA methylation or chromatin structure (often at an imprinted locus) that silences a normally active gene without changing the DNA sequence

DNA Mutation

A change in the actual DNA sequence

Uniparental Disomy (UPD)

A condition where an individual inherits two copies of a chromosome (or part of one) from one parent and no copy from the other parent

• causes a disease if the region contains imprinted genes

When are imprint marks erased?

Erasure: Imprints are erased in Primordial Germ Cells (PGCs) during weeks 5–7 of development

When are imprint marks re-established?

New imprints are set during sex development (gametogenesis) based on the individual's biological sex

Describe the methylation status of imprinted genes immediately after fertilization

Imprinted gene loci are protected and are NOT remethylated/demethylated in the same way as the rest of the genome

What is the shared chromosomal region for Prader-Willi (PWS) and Angelman (AS) syndromes?

The 15q11-13 imprinted region

Prader-Willi Syndrome

Loss of paternally expressed genes

• Paternal deletion or Maternal UPD

Angelman Syndrome

Loss of maternally expressed genes (specifically UBE3A)

• Maternal deletion or Paternal UPD

What is the shared chromosomal region for Beckwith-Wiedemann (BWS) and Russell-Silver (SRS)

11p15 imprinted region

Beckwith-Wiedemann (BWS)

Overgrowth, macroglossia (large tongue), and abdominal wall defects

• Increased IGF2 (growth promoter)

• Decreased CDNKN1C (growth suppressor)

Russell-Silver (SRS)

Intrauterine and postnatal growth restriction (undergrowth)

• Decreased IGF2 (growth promoter)

• Increased CDNKN1C (growth suppressor)

How does the IC1 domain control growth genes paternally?

IC1 is methylated → Turns ON IGF2

• Losing methylation = Russel-Silver (undergrowth)

How does the IC1 domain control growth genes maternally?

IC1 is unmethylated → Turns OFF IGF2

• Gaining methylation = Beckwith-Wiedemann Syndrome (overgrowth)

Methylation-Sensitive Multiplex Ligation-Dependent Probe Amplification (MS-MLPA)

• Gold standard for diagnosing imprinting disorders

• It distinguishes between methylation abnormalities, deletions, and uniparental disomy in one test

• Negative results don't fully exclude diagnosis due to potential somatic mosaicism

How does Assisted Reproductive Technology (ART) affect the epigenome?

Interrupt oocyte maturation and the retention of imprints after fertilization

• Degrade pre-implantation reprogramming → increased risk of Multilocus Imprinting Disorders (MLID)

Multilocus Imprinting Disorders

Aberrant methylation at multiple imprinted loci across the genome

Pedigree for Prader-Willi

• Females pass on carriers (maternally imprinted)

• Males pass on the disease (paternal gene is silenced)

Pedigree for Angelman Syndrome

• Males can pass on carriers (paternally imprinted)

• Females pass on the disease (maternal gene is silenced)