Genomic Imprinting

• The process that leads to the expression of an allele

that is inherited from one parent and the inactivation
of its counterpart in the other parent is an epigenetic
phenomenon called genomic imprinting.
• The two salient features of genomic imprinting are
heritability and reversibility.
• Heritability signifies the biological transmission of
either an active or an inactive allele from a parent to
an offspring.
• Reversibility denotes the ability of the transcriptional
status of an allele to be wiped clean during each
generation before the establishment of a new imprint
that is determined by the sex of the parent.
• There are about 50 known loci, and possibly as
many as 200, where the parent-of-origin
specifies whether an allele is transcribed or
inactivated in
human somatic cells.
• Many of the loci that are subject to genomic
imprinting occur in clusters.
• In some cases, an activated allele is expressed in
all somatic cells.
• For other loci, transcription of the active allele
occurs in a specific tissue or cell type.
 Gene Silencing
• Genomic imprinting is a cyclical process that normally endures
for only one generation.
• Both imprints from the previous generation are erased in
primordial germ cells and replaced with a paternal and a
maternal imprint during spermatogenesis, and oogenesis,
respectively.
• If an active imprinted allele is not transcribed in all cell types, it
is turned on at the appropriate time and cellular site.
• The specificity of the parent-of-origin effect remains the same
from generation to generation.
• In other words, a paternally silenced allele is always inactivated
during spermatogenesis and a maternally silenced allele during
oogenesis.
 DNA methylation
• Attention has focused on DNA methylation as the
principal means of parent-of-origin allele silencing
and, less often, activation.
• Specifically, DNA methylation entails the addition
of a methyl (CH3) group to the 5-position of a
cytosine residue in DNA
• The cytosine of a CpG dinucleotide is methylated.
• DNA methylation is established and maintained by
DNA methyltransferases.
• The extent of DNA methylation is inversely
correlated with gene activity.
• The regions of CpG repeats (CpG islands) that
precede commonly expressed genes
(housekeeping genes) are not methylated.
• On the other hand, genes that are
transcriptionally inactive are frequently heavily
methylated (hypermethylated).
• DNA methylation can affect gene transcription either directly or
indirectly.
• Briefly, a methylated promoter region may block transcription
by preventing the binding of transcription factors.
• Or the DNA methyl groups may bind a protein that, in turn,
binds other proteins that change the conformation of the
chromosome and make the promoter region inaccessible to
transcription.
• On the other hand, DNA methylation could enable gene
expression if the methyl groups are required for the binding of
specific transcription factors or if methylation prevents
repressor molecules from binding to a promoter region.
• A more complicated scheme for imprinted gene
silencing requires enhancer DNA elements and DNA
methylation of a discrete small regulatory sequence
called the imprinting control region (ICR).
• Enhancer DNA sequences are located a considerable
distance either upstream or downstream from their
target DNA sequences.
• When these sequences combine, transcription of a
gene is facilitated.
• The interaction of an enhancer DNA element(s) and an
ICR causes the transcription of a nearby gene while a
more distant gene remains silent because the enhancer
elements are not available to expedite its transcription.
• If the ICR is methylated, then the enhancer
DNA element(s) cannot bind to it, transcription
of
• The nearby gene is blocked, and the enhancer
DNA element is free to initiate transcription of
the second gene
 Uniparental disomy
• Uniparental disomy (UPD) occurs when a person receives two
copies of a chromosome, or part of a chromosome, from one
parent and no copies from the other parent.
• UPD can occur as a random event during the formation of egg or
sperm cells or may happen in early fetal development.
• In many cases, UPD likely has no effect on health or development.
• Because most genes are not imprinted, it doesn’t matter if a
person inherits both copies from one parent instead of one copy
from each parent.
• In some cases, however, it does make a difference whether a gene
is inherited from a person’s mother or father.
• A person with UPD may lack any active copies of essential genes
that undergo genomic imprinting.
• This loss of gene function can lead to delayed development,
intellectual disability, or other health problems.
 Prader–Willi Syndrome

• The Prader–Willi syndrome (PWS) is a rare

neurodevelopmental disorder with a prevalence
of about 1 in 12,500 that affects both sexes.
• Newborns and infants have reduced muscle tone
(hypotonia), there is a failure to thrive unless
forced feeding is implemented.
• From 1 to 6 years of age, weight gain is
exceedingly rapid, leading to extreme obesity.
• Developmental motor skills are delayed.
• About 70% of the cases of PWS have a 3- to 5-Mb
deletion of 15q11–q13.
• In these cases, the deleted chromosome is
invariably inherited from the father.
• Another 25% of PWS patients have maternal
uniparental disomy for chromosome 15
[upd(15)mat].
• Both of these genetic features indicate that there
is one or more imprinted gene within the 15q11–
q13 region and PWS occurs when no functional
product(s) from a paternally expressed gene(s) is
formed.
 Angelman Syndrome
• Interestingly, the loss of all activity of the only
maternally expressed, paternally silenced gene (UBE3A)
of the 15q11–q13 cluster causes Angelman syndrome,
which is phenotypically distinct from PWS.
• The clinical features of AS include severe developmental
delay, mental retardation, awkward gait, tremors,
seizures, protruding tongue, absence of speech,
frequent uncontrolled outbursts of laughter, and a
happy disposition.
• The disorder becomes clinically evident from 12 to 24
months after birth.
• The UBE3A gene encodes ubiquitin protein ligase 3A that is
monoallelically expressed only in the brain.
• This enzyme adds the protein ubiquitin to intracellular proteins,
which marks them for degradation.
• The prevalence of AS is about 1 in 16,000.
• About 70% of the cases of AS have a maternal chromosome
with a deleted UBE3A gene, 7% paternal uniparental disomy of
chromosome 15 [upd(15)pat], 4% mutations of the imprinting
center that silence the UBE3A gene during oogenesis, and 5%
point mutations in the UBE3A gene.
• Functional ubiquitin ligase 3A is not produced under any of
these conditions.
• It is not understood why the absence of this enzyme causes AS.