Genetic Imprinting

Question 1

Molecular Basis of Imprinting

Answer 1

Allele-specific methylation of CpG dinucleotides in the promoter regions of imprinted genes, established in one of the two germ lines and then maintained throughout embryogenesis, has been implicated in the maintenance of imprinting in somatic cells

Question 2

there is some evidence that DNA methylation need not be placed within the transcriptional control regions of imprinted genes in order to affect the ________ of those genes

Answer 2

silencing

Question 3

recent investigations have revealed that in rare cases, DNA methylation is present in the ________ allele of imprinted genes, and is ________ from the silenced allele

Answer 3

expressed

excluded

Question 4

approximately 100 autosomal genes in the mammalian genome are inherited in a silenced state from one of the two parents, and in a transcriptionally active state from the other, thereby rendering the individual functionally ________ for these genes.

Answer 4

hemizygous

Question 5

Explain DNA methylation as a gene silencing mechanism

Answer 5

Hypermethylation may directly inhibit transcription either by repelling transcription factors (some DNA binding factors are known to be methylation-sensitive), or methylation may actively recruit factors that repress transcription

Question 6

Explain DNA methylation as a gene activation mechanism

Answer 6

The molecular basis of this activation is poorly understood, but a current model postulates that DNA methylation may prevent the binding of a transcriptional repressor

Question 7

Characteristics of imprinted genes (3)

Answer 7

1. These genes tend to be clustered together rather than spread throughout the entire genome.
2. These clusters contain both maternally and paternally imprinted genes.
3. The imprinted genes encode both proteins and non-coding RNAs.

Question 8

Essential characteristics of the epigenetic mark (3)

Answer 8

1. The modification must be established in the gametes, the point in time when the maternal and paternal alleles of imprinted genes reside in separate cells and can be differentially modified.
2. The allelic modification of imprinted genes must be stably maintained after fertilization.
3. The modification must be capable of being erased and reset during the production of germ cells such that the appropriate sex-specific imprint is transmitted to the progeny

Question 9

DNA demethylation ________ gene expression, and ________ the parental methylation patterns in developing gametes

Answer 9

reactivates

erases

Question 10

Demethylation could result from the inhibition of the maintenance ________, or indirectly, through the inactivation of ________

Answer 10

methyltransferase, DNMT1

chromatin-remodeling proteins

Question 11

Erasure and resetting of the imprint appears to occur at ________, which contain non-coding DNA sequences that bind imprinter RNA transcripts (called BD transcripts) and recruit DNA methyltransferase (DNMT) complexes that methylate CpG islands located near the IC on the same chromosome (cis).

Answer 11

imprinting centers (IC)

Question 12

Erasure and resetting of the imprint appears to occur at imprinting centers (IC), which contain ________ that bind imprinter RNA transcripts (called BD transcripts) and recruit DNA methyltransferase (DNMT) complexes that methylate CpG islands located near the IC on the same chromosome (cis).

Answer 12

non-coding DNA sequences

Question 13

Erasure and resetting of the imprint appears to occur at imprinting centers (IC), which contain non-coding DNA sequences that bind ________ and recruit DNA methyltransferase (DNMT) complexes that methylate CpG islands located near the IC on the same chromosome (cis).

Answer 13

imprinter RNA transcripts (called BD transcripts)

Question 14

Erasure and resetting of the imprint appears to occur at imprinting centers (IC), which contain non-coding DNA sequences that bind imprinter RNA transcripts (called BD transcripts) and recruit ________ that methylate CpG islands located near the IC on the same chromosome (cis).

Answer 14

DNA methyltransferase (DNMT) complexes

Question 15

Erasure and resetting of the imprint appears to occur at imprinting centers (IC), which contain non-coding DNA sequences that bind imprinter RNA transcripts (called BD transcripts) and recruit DNA methyltransferase (DNMT) complexes that ________ located near the IC on the same chromosome (cis).

Answer 15

methylate CpG islands

Question 16

Mutations at imprinting centers are

Answer 16

heritable lesions that can generate the same abnormal phenotypes brought about by deletions or uniparental disomies involving imprinted loci

Question 17

Once sex-specific patterns of methylation are established during gametogenesis (by an unknown mechanism), the patterns are retained in somatic cells by ________, which is responsible for methylating the newly synthesized daughter strand of DNA after replication

Answer 17

maintenance methylation

Question 18

Prader-Willi syndrome is characterized by

Answer 18

obesity, excessive and indiscriminate eating, short stature, small hands and feet, hypogonadism, and intellectual disabilities

Question 19

Prader-Willi syndrome is the result of

Answer 19

a cytogenetically observable deletion involving the long arm of chromosome 15 (15q11-q13), occurring on the chromosome 15 homolog inherited from the patient’s father. These patients have a normal, maternally derived homolog of chromosome 15, but this region on the maternally derived chromosome is methylated, and transcriptionally silenced

Question 20

The 15q11-q13 region contains ________

Answer 20

three paternally expressed genes

Question 21

Angelman syndrome is characterized by

Answer 21

an unusual facial appearance, short stature, severe intellectual disabilities, spasticity, and seizures

Question 22

Angelman syndrome is the result of

Answer 22

a deletion of approximately the same region of chromosome 15 as Prader-Willi syndrome, but on the maternally derived homolog. The information contained on the normal paternally derived chromosome 15 is inactivated due to DNA methylation

Question 23

Uniparental disomy most commonly occurs

Answer 23

• when a trisomic conceptus loses one of its extra chromosomes due to mitotic nondisjunction in early gestation
• This chromosomal sorting error in effect “rescues” the developing pregnancy from spontaneous abortion but may result in an abnormal phenotype if both remaining homologs are derived from the same parent

Question 24

Uniparental disomy trisomy 15 example

Answer 24

• trisomy 15, maternal nondisjunction leading to two maternal, one paternal 15s
• reduction of the trisomy 15 genome above to the normal 46 chromosomal complement by loss of the paternally derived homolog
• Since both remaining 15 homologs are maternal in origin, both carry maternally repressed loci. Normal development is dependent on expression of genes at the missing paternal 15q11-13 locus

Question 25

definition of epigenetics

Answer 25

relates to gene silencing through methylation patterns on DNA

Question 26

Genetic Imprinting

Answer 26

a small number of autosomal genes in the mammalian genome are inherited in a silenced state from one of the two parents, and in a transcriptionally active state from the other of the two parents

Question 27

Imprinting makes the offspring functionally ________ for the genes inherited

Answer 27

hemizygous

Question 28

Imprinting takes place during ________, before ________

Answer 28

gametogenesis

fertilization

Question 29

Imprinting must be

Answer 29

reversible:
- -If a paternally derived allele is inherited by a female, it must be converted in her germline so that she can pass it on with a maternal imprint to her offspring, and vice-versa

Question 30

DNA methylation as a gene silencing mechanism

Answer 30

Hypermethylation may directly inhibit transcription either by repelling transcription factors (some DNA binding factors are known to be methylation-sensitive), or methylation may actively recruit factors that repress transcription

Question 31

DNA methylation as a gene activation mechanism

Answer 31

The molecular basis of this activation is poorly understood, but a current model postulates that DNA methylation may prevent the binding of a transcriptional repressor.

Question 32

Parent of origin effect:

Answer 32

the phenotype of an observed condition will depend on which homolog (parentally or maternally derived) in the affected person’s genome has been deleted or duplicated.