Genetics and Epigenetics Quiz

Epigenetics and Underlying Principles

• The lecture is part of a module titled "Concepts of Disease" (BI2332).
• The module co-ordinator is Dr. Prytherch.
• The lecture focuses on epigenetics and its underlying principles.
• The speaker is Professor Ros John, Head of the Biomedicine Division.

Genomic Imprinting

• A lecture called "Human Epigenetics lecture 4" focused on genomic imprinting.
• The concept of genomic imprinting helps explain why mammals cannot develop parthenogenetically.
• Imprinted genes account for 0.4% of mammalian genes.
• These genes are differently expressed depending on whether they come from the mother (M) or father (P).

Benign Ovarian Teratoma

• A rare germ cell tumor.
• Consists of tissues derived from all three germ layers.
• Often contains hair, sebaceous glands, skin, and teeth.
• Most are benign.
• Characterized by two maternal genomes.

Hydatidiform Mole

• A rare gestational trophoblastic disorder.
• Occurs in approximately one in every 1,200 pregnancies.
• Characterized by disorganized placental tissue without a fetus.
• Most cases are benign.
• Characterized by two paternal genomes.

Mammalian Development

• For normal mammalian development, two parental genomes are essential.

Genomic Imprinting Diagrams

• Diagrams illustrate the concept of biallelic and imprinted genes, showing which allele is expressed (maternal or paternal).
• Diagrams show how the expression pattern differs in normal cells, ovarian teratomas, and hydatidiform moles.
• Teratomas exhibit loss of expression of normally paternally expressed genes, but gain in expression of maternally expressed genes.
• Hydatidiform moles show the opposite pattern, gaining expression of paternally expressed genes, and losing expression of maternally expressed genes.

Genomic Imprinting Disorders

• List of disorders associated with genomic imprinting:
  • Beckwith-Wiedemann Syndrome (BWS)
  • Silver-Russell Syndrome (SRS)
  • Prader-Willi Syndrome
  • Angelman Syndrome

Human Chromosome 11p15

• Chromosome 11p15 contains imprinted genes.
• Several genes are expressed only from the maternal allele (red).
• Others are expressed only from the paternal allele (blue).
• Some genes are non-coding RNA (H19 and Lit1).
• This chromosome has two differentially methylated regions (DMRs).

Differentially Methylated Regions (DMRs)

• H19 DMR is methylated in sperm.
• H19 DMR controls imprinted expression of IGF2 and H19.
• KvDMR1 is methylated in oocytes.
• KvDMR1 controls imprinted expression of CDKN1C and other maternally expressed genes.

Insulin-like Growth Factor 2 (IGF2)

• Paternally expressed gene IGF2 encodes insulin-like growth factor 2.
• IGF2 is a growth factor promoting cell division and growth.

Cyclin-dependent Kinase Inhibitor 1C (CDKN1C)

• Maternally expressed gene CDKN1C encodes cyclin-dependent kinase inhibitor 1C.
• CDKN1C is a cell cycle inhibitor that inhibits cell division and growth.

Beckwith-Wiedemann Syndrome (BWS)

• OMIM 130650 affects 1 in 13,700 births.
• Characterized by fetal overgrowth syndrome, macrosomia, macroglossia, omphalocele, and predisposition to Wilms' tumor..
• Some patients have paternal disomy of human chromosome 11p15.
• Point mutations, translocations, and loss of DNA methylation can contribute to BWS.

Silver-Russell Syndrome (SRS)

• OMIM 180860, affects 1 out of 100,000 births.
• Fetal growth restriction disorder with low birth weight.
• Some patients have maternal disomy of human chromosome 11p15.
• Characterized by asymmetry, lack of subcutaneous fat, night sweats.

Mode of Inheritance

• Most imprinting disorders arise from de novo mutations.
• Some inherited genetic mutations, like CDKN1C point mutations in BWS and micro-duplications in SRS, are possible.
• Imprinting disorders may exhibit unique family patterns different from classic Mendelian inheritance.
• Some disorders may act as autosomal dominant, or recessive, due to maternal or paternal transmission.

Angelman and Prader-Willi Syndromes

• These are also reciprocal imprinting disorders

Genomic Imprinting Disorders - General Traits

• Involve genetic and epigenetic mutations.
• May affect multiple genes.
• Not always simply a loss of gene expression.
• Can have dominant inheritance but present as recessive.
• Can skip generations.
• Determined by the parent-of-origin.

Cancer

• Generally, cancer is a genetic disorder caused by changes in oncogenes and tumor suppressor genes regulating proliferation and survival.
• Genomic hypomethylation and site-specific hypermethylation are frequently observed in early stages of tumorigenesis.

Developmental Origins of Disease

• Non-communicable diseases linked to metabolic, cardiovascular, and mental functions are strongly influenced by early life events.
• Diseases often become more prevalent in individuals with early-life adversity affecting the fetus and placenta.
• Examples such as the Dutch famine illustrate the impact of adverse environments.

Environmental Programming

• Environmental influences during development (e.g., maternal diet) can alter epigenetic marks, leading to observable phenotypic differences.
• Identical mice can exhibit differences in coat color due to epigenetic differences in their early development, a hallmark of environmental programming.

Exposure to Maternal Smoking in Pregnancy & Altered DNA Methylation

• Maternal smoking during pregnancy is linked to altered DNA methylation in children later in life.

Epidrugs

• Histone deacetylases (HDACs) remove acetyl groups from chromatin.
• DNA methylation inhibitors remove DNA methylation.
• Researchers are investigating using such enzymes as drugs to reactivate silent genes in vivo.

DNMT Inhibitors

• Azacitidine (Vidaza) is an FDA-approved DNMT inhibitor, used to treat myelodysplastic syndrome.
• It works by reversing DNA methylation in cancer cells.

Learning Outcomes/Summary

• Loss or inappropriate addition of DNA methylation can lead to epigenetic disorders.
• Epigenetic disorders cannot be detected by simple DNA sequencing.
• Classic epigenetic processes like X-inactivation and genomic imprinting have distinct inheritance patterns distinct from Mendelian inheritance.
• Environmental factors like diet and stress can influence epigenetic marks.
• Epigenetic diseases may be potentially reversible using epigenetic modifying drugs (epidrugs)