15.2 Genetic Imprinting

genomic imprinting

an epigenetic phenomenon in which expression of a gene depends on which parent it was inherited from

leads to monoallelic expression

monoallelic expression

if maternally imprinted, all expression comes from the paternal chromosome (and vice versa)

maternally imprinted

a small number of genes are turned off in the chromosomes inherited from our mother, gene transcriptionally silent

rely on expression from father

paternally imprinted

a small number of genes are turned off in the chromosomes inherited from our fathers, gene transcriptionally silent

rely on expression from mother

DNA methylation

can block transcription

often occurs at cytosine (C) residues next to guanine (G)

DNA methyltransferases

DNMTs transfer a methyl group from S-Adenosyl methionine (SAM) to cytosine

igf2

insulin-like growth factor

maternally imprinted

igf2R

insulin-like growth factor receptor

paternally imprinted

inactivates growth factor

normal sized mouse

igf2 = igf2R

large sized mouse

igf2 > igf2R

small sized mouse

igf2 < igf2R

picture of maternal and paternal chromosomes for igf2 and igf2R

maternal:
igf2 is OFF (methylated)
igfR2 is ON

paternal:
igf2 is ON
igfR2 is OFF (methylated)

the child on left has a frameshift mutation in igf2 that leads to a non-functional protein (let's call this the igf2-2 allele). what parent did this child inherit the igf2-2 allele from?

father (since mother is methylated and cannot express gene)

maternal imprinting (oogenesis)

genes that were methylated (silenced/imprinted) during oogenesis in egg cells

females put a maternally imprinted pattern on every gamete

methylation pattern same as mother

paternal imprinting (spermatogenesis)

genes that were methylated during spermatogenesis (in sperm cells)

males put a paternally imprinted pattern on every gamete

methylation pattern same as father

imprinting occurs during gametogenesis

imprinting patterns are erased in our germ line cells near the beginning of meiosis

reestablished during later steps of meiosis/gametogenesis (sex-specific manner)

imprinting and gametogenesis summary

every gamete from an individual receives the same imprinting pattern

the pattern depends on the sex of the person creating the gametes

all members of the same sex produce the same imprinting patterns

imprinting is independent of alleles

imprinting is common (but not universal)

not all genes are imprinted (~1% of genes in mammals and flowering plants are imprinted)

2014: 150 known imprinted genes
2019: 238 known imprinted genes

if there was an imprinting error during meiosis in a female (such that the mother no longer imprinted her genes), what is the expected size of the pups?

larger than normal

if mother's igf2 gene is not methylated, it will be transcribed along with igf2 gene on father

twice that amount of growth factor

if there was an imprinting error during meiosis in a male (such that the father no longer imprinted his genes), what is the expected size of the pups?

smaller than normal

cannot imprint igf2R on father

twice the amount of growth factor receptor, inhibiting growth factor

tigers

do not imprint igf2 or igf2R

lions are like mice

lgf2- maternally imprinted

igf2R- paternally imprinted

female tiger x male lion, what alleles will be methylated?

female tiger- igf2 on, igf2R on (transcriptionally active)

male lion- igf2 on (contributes growth factor maternally imprinted), igf2R off (paternally imprinted)

liger

hybrid of tiger and lion

has two copies igf2 growth factor, one copy of igf2R

imbalance of growth factor

do you expect the liger pups to be larger, smaller, or normal in size?

larger

excess growth factor, abnormally large size

liger hybrids health defects

enlarged hearts, organ failure, neurological disorders, prone to injury, sterile

female lion x male tiger (tigrons)

predicted to be smaller, but actually normal sized

parental conflict hypothesis

father- wants kids to be big and strong, use all maternal resources

mother- wants kids to be big enough and healthy, but save some resources for future kids

father (parental conflict)

igf2 on, igf2R off

growth factor always on, limit receptor

mother (parental conflict)

igf2 off, igf2R on

turn growth factor off, receptor on

imprinting disorders

prader willi syndrome (PWS)
angelman syndrome (AS)

prader willi syndrome symptoms

delayed development, flaccid muscles, short stature, intellectual disability, compulsive behavior

hormonal imbalances leading to constant hunger, delayed puberty

angelman's syndrome symptoms

delayed development, intellectual disability, ataxia, severe speech impairment, happy demeanor

PWS imprinting

PW genes are maternally imprinted

AS imprinting

AS genes are paternally imprinted

common cause of PWS and AS

a de novo deletion of a region on chr.15 that removes both the PW and A genes

de novo mutation occurs during meiosis

what syndrome would the offspring have if the deletion occurred during oogenesis?

angelman

on paternal chromosome, PW is on and A is methylated/off

the disorder is caused when you DON'T make the genes associated with the disease (loss of function)

what syndrome would the offspring have if the deletion occurred during spermatogenesis?

prader-willi

on maternal chromosome, PW is methylated/off and A is on

MIG1 is maternally imprinted, which of the following is true?

MIG1 will be expressed from a paternally inherited chromosome

Imprinted genes are

transcriptionally active

methylated during gametogenesis

unmethylated

trasncriptionally silenced

methylated during reproduction of somatic cells

transcriptionally silenced

methylated during gametogenesis

Imprinting leads to mono allelic expression (True/False)

True

Consider a trait caused by a particular variant of a maternally imprinted gene. An unaffected woman is heterozygous for the disease allele. Her partner is homozygous for the wild type, non-disease, allele. You expect that (indicate who will be carriers, who will develop the disease)

half of their offspring will be unaffected carriers of the disease allele

none of their offspring will develop the disease

If you examined the methylation patterns on DNA in eggs and sperm of the same species you would expect them to be (the same/different)

different

Which of the following is most accurate in describing the level of imprinting of mammalian gnees

very few ~1% are imprinted

about half are imprinted

more than half but not all, ~70% are imprinted

very few ~1% are imprinted

Genomic imprinting is an epigenetic phenomenon that

causes genes to be expressed or not depending on whetehr they are inherited from the mother or the father

explains how transcription is inactivated by histone modifications

is characterized by a rapid learning process that takes place early in the life of a social animal, and explains why baby geese will follow the first animal they meet (goose or human)

results in expression of a gene in females only

causes genes to be expressed or not depending on whether they are inherited from the mother or the father

A gene that undergoes maternal imprinting will be _______ in the paternally inherited chromosome (expressed/supressed)

expressed (turned on)

The major molecular mechanism that is used for imprinting involves

methylation of DNA near the promoter region of a gene, leading to increased gene expression

methylation of DNA near the promoter region of a gene, leading to lower levels of gene expression

methylation of DNA near the Shine-Dalgarno sequence, resulting in mRNAs to which ribosomes cannot bind, thereby lowering protein levels of the imprinting gene

deacetylation of histone tails, leading to the condensation of chromatin and reduced gene expression

methylation of DNA near the promoter region of a gene, leading to lower levels of gene expression

This pedigree is consistent with (maternal/paternal/neither)

maternal imprinting

During oogenesis (select all that apply)

all methylation patterns on chromosomes are erased

some methylation patterns are erased

erased methylation patterns are reintroduced according to the gender of the individual making the oocytes, eg female for eggs, male for sperm

erased methylation patterns are reintroduced according to the gender of the person who passed on the chromosome to the individual making the oocytes, female for the homologous chromosome inherited from mom, male for the homologous chromosome inherited from dad

Some methylation patterns are erased

Erased methylation patterns are reintroduced according to the gender of the person who passed on the chromosome to the individual making the oocytes, female for the homologous chromosome inherited from mom, male for the homologous chromosome inherited from dad

A woman is heterozygous for an imprinted gene (A1A2). During gametogenesis she will imprint gametes that inherit the A1 allele and gametes that inherit the A2 allele (True/False)

False

A woman is heterozygous for a paternally imprinted gene (A1A2). During gametogenesis, she will imprint gametes that inherit the A1 allele and gametes that inherit the A2 allele (True/False)

False

A man is heterozygous for a maternally imprinted gene (A1A2).  During gametogenesis, he will imprint gametes that inherit the A1 allele and gametes that inherit the A2 allele. (True/False)

False

A man is heterozygous for a paternally imprinted gene (A1A2).  During gametogenesis, he will imprint gametes that inherit the A1 allele and gametes that inherit the A2 allele. (True/False)

True

Imprinting does not alter Mendelian inheritance patterns of alleles.  For example, if a person is heterozygous for an imprinted gene (A1A2), then 50% of their offspring will inherit the A1 allele and 50% of the offspring will inherit the A2 allele. (True/False)

True

This pedigree is consistent with:

maternal imprinting

paternal imprinting

neither

maternal imprinting

A woman is an unaffected carrier for a gene that is maternally imprinted. Which of the following is true?

Half of her children will be affected, and the affected daughters will have affected children but the affected sons will have carrier children.

Sons that receive the disease allele will be affected while daughters that receive the disease allele will be unaffected.

The daughters that receive the disease allele will be affected while sons that receive the disease allele will be unaffected.

Her children will be unaffected, but the carrier sons will have affected children.

Her children will be unaffected, but the carrier daughters will have affected children.

Her children will be unaffected, but the carrier sons will have affected children.

ZFP57 is a maternally imprinted gene involved in insulin production. A woman with a form of diabetes is homozygous for a mutation in ZFP57. Her partner is homozygous for a wild type allele. They have 4 children.(assume Mendelian ratios and no additional environmental influences)

Which of the following is true?

only sons will have diabetes

all children will have diabetes

50% of children will have diabetes, irregardless of sex

no children will have diabetes

only daughters will have diabetes

no children will have diabetes

A is a maternally imprinted gene. There are 3 known alleles for this gene, A1, A2 and A3. Consider this family pedigree. Which alleles will be expressed in the offspring?

In II-1, A1 will be expressed and in II-2, A2 will be expressed.

In II-1, A3 will be expressed and in II-2, A2 will be expressed.

It is not possible to determine, based on the information provided.

In II-1, A1 will be expressed and in II-2, A3 will be expressed.

In II-1, A3 will be expressed and in II-2, A3 will be expressed.

In II-1, A1 will be expressed and in II-2, A2 will be expressed.

Imprinting refers to the phenomenon where only one copy of a gene in an individual is expressed (either the maternally or paternally inherited copy), while the other copy is suppressed. A gene that undergoes maternal imprinting will be _______ in the maternally inherited chromosome.

expressed (turned on)

suppressed (turned off)

suppressed (turned off)

A gene that undergoes maternal imprinting will be _____ in the paternally inherited chromosome.

suppressed (turned off)

expressed (turned on)

expressed (turned on)

Imprinting patterns are established during gametogenesis. (True/False)

True

Female offspring will receive different imprinting patterns than male offspring. (True/False)

False

An individual’s gametes all receive the same imprinting patterns (True/False)

True

Imprinted genes predominantly reside on sex chromosomes (True/False)

False

B is a maternally imprinted gene. There are 3 known alleles for this gene, B1, B2 and B3.

Consider this family pedigree that shows both the genotype and disease state of each individual. Carrier status is not indicated. The methylation state is shown (m) for Gen I only.

Which is most likely the disease causing allele?

B1

B2

B3

cannot be determined with the information provided.

B3

There are 3 known alleles for the gene C (C1, C2 and C3).

Consider this family pedigree that shows both the genotype and phenotype of each individual. Methylation state is shown for Gen I only. Note that carrier status is not indicated.

What type of imprinting is this pedigree consistent with?

autosomal recessive

it is not possible to determine with the information provided

autosomal dominant

maternal imprinting

paternal imprinting

paternal imprinting