Epigenetics, Imprinting, and Uniparental Disomy

Question 1

Epigenetics

Answer 1

Study of heritable changes in gene expression or cellular phenotype caused by mechanisms other than changes in the underlying sequence

Question 2

What does pronuclear transplantation tell us about chromosomal inheritance?

Answer 2

• More than just the right number of chromosomes is needed for normal development
• Chromsomes inherited from mother vs father are different

Question 3

What is the outcome of an androgenetically fertilized egg?

Answer 3

• 2 paternal copies of each chromosome
• Membranes and placenta develop normally
• No embryo develops
• Abnormal growth (hydatidiform mole)

Question 4

What is the outcome of a gynogenetically fertilized egg?

Answer 4

• 2 maternal copies of each chromosome
• Embryo develops
• Membranes and placenta don’t develop normally
• Abnormal growth (teratoma)

Question 5

What does a pedigree look like for an imprinting-related disorder?

Answer 5

• Offspring only get gene if inherited from either mother or father
• Can look like autosomal dominant transmission from affected parent -> offspring
• Can appear to skip a generation (ie if disorder comes from father: affected grandfather => affected daughter => unaffected grandson => affected great-granddaughter)

Question 6

Genomic imprinting

Answer 6

Differential expression of alleles determined by the sex of the parent from whom each allele was inherited

Question 7

What epigenetic mechanisms are involved in imprinting?

Answer 7

• (de)methylation of cytosines
• (de)acetylation of histones
• (de)methylation of histones
• RNAi’s

Question 8

How does methylation cause imprinting?

Answer 8

• Methylation of CpG-rich promoter regions => reduced transcription
• Methylation patterns are conserved in cell division and may be inherited
• Methylation patterns can be affected by environmental conditions

Question 9

What are the symptoms of Prader-Willi syndrome?

Answer 9

• Hypotonia and failure to thrive in infancy
• Obesity and hyperphagia
• Characteristic facies
• Small hands/feet
• Hypogonadism

Question 10

What is the genetic cause of Prader-Willi?

Answer 10

Lack of paternal 15q11 due to paternal deletion or maternal uniparental disomy

Question 11

Uniparental disomy

Answer 11

• When both copies of a chromosome come from 1 parent

- Heterodisomy (one of each copy from one parent) or isodisomy (two of the same copy from one parent = homozygosity)

Question 12

What are the symptoms of Angelman syndrome?

Answer 12

• Postnatal growth deficiency
• Severe intellectual disability
• Paroxysms of inappropriate laughter
• Ataxia and jerky arm movements
• Seizures

Question 13

What is the genetic cause of Angelman syndrome?

Answer 13

Depetion of maternal 15q11-13

Question 14

What is an imprinting center?

Answer 14

Region of a chromosome that acts differently on maternal and paternal chromosomes to silence genes

Question 15

How are chromosomes epigenetically re-programmed in primordial germ cells?

Answer 15

• Haploid gametes generated in an individual
• Demethylation of chromsomes to remove the M/F signature from that individual’s parents
• Chromosomes methylated to give all gametes the imprint of that individual (M or F)

Question 16

What are the symptoms of Beckwith-Wiedemann syndrome?

Answer 16

• Macrosomia (big fetus)
• Macroglossia (big tongue)
• Visceromegaly (big liver)
• Omphalocele (intestines in umbilical cord)
• Renal abnormalities
• Ear creases
• Neonatal hypoglycemia
• Tumors

Question 17

What are the genetic causes of Beckwith-Wiedemann syndrome?

Answer 17

Loss of imprinted genes on maternal chromosome 11p15.5 either due to:

• Loss of methylation of IC2 on maternal chromsome
• Paternal uniparental disomy of 11p15.5
• Other small mutations/deletions/translocations, etc

Question 18

What are some determinants of epigenetic variation?

Answer 18

• nutrition
• smoking
• environmental exposures
• alcohol
• medications
• early experiences viz parents’ behaviors