Lecture 22- Genomic Imprinting and Dynamic Mutation Flashcards Preview

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Genomic Imprinting

Restriction of the expression of a gene (to either paternal or maternal allele). Expression of only one!

an 'epigenetic phenomenon'

When an epigenitic trait occurs to only one parent

~0.1 mammalian genes show imprinting



an epigenetic trait is a stably heritable phenotype resulting from changes in a chromosome WITHOUT alterations in the DNA sequence. (altering instead gene expression)

Different expression from genetically identical alleles

a change in phenotype without a change in genotype

Operates at transcriptional level, eg)
-DNA (eg: to Cytosine) methylation: CPG islands placed at start of gene (promotor)
-Histone modification


Two syndromes that occur when genetic imprinting occurs due to methylation at the region of chromosome 15 at q11
-A deletion of 15q11-q13

Prader-willi Syndrome (70-75% paternal copy deleted)

Angleman Syndrome (60% maternal copy deleted)

Both have overlapping clinical phenotypes


Prader-Willi Syndrome CF

-failure to thrive
-neonatal hypotonia
-rapid weight gain after one year
-behavioural obesity/ short stature
-small hand and feet
-behavioural issues


Prader-Willi Syndrome

Loss of PATERNAL segment of chromosome 15q11-q13

Due to imprinting, the MATERNAL normal copy is usually imprinted (and therefore silenced).

BOTH issues need to occur to get this syndrome


Why chromosome 15q11-q13

recognised that distinct segments of this are required for normal development


Anglemans Syndrome CF

-'happy children'
-mental retardation

overlapping phenotypes


Anglemans Syndrome

Loss(deletion) of MATERNAL segment of chromosome 15q11-q13

THe paternal segments is usually imprinted (silenced) (by methylation usually)


Other ways (apart from having one deleted + one imprinted allele) you can get anglemans and prader-willi syndrome

Uniparental disomy= embryo inherits 2 copies of a locus from one parent and non from the other (PW only two imprinted maternal alleles. AM only 2 imprinted paternal alleles)

Imprinting Centre mutations: or deletions: screw up the switches of taking away methyl group

This is because 15q11-q13 contains BOTH paternally and maternally expressed genes


Role of DNA methylation in imprinting

Methylation of DNA plays a huge role in controlling gene expression.
-Occurs at cytosine residues in 'CpG islands'

CpG methylation at promoters causes 'transcriptional silencing'

CpG methylation is transmitted through cell divisions by methytransferase enzymes

Gamete specific methylation


CpG islands

>200bp regions of DNA with lots of G+C , located mainly in PROMOTER regions


Application and removal of imprinting

Female: imprinting established during oocyte maturation

male: imprinting establish prior to meiosis in primary spermatocyte

demethylation of these occur in early embryo. Primordial germ cells remain unmethylated.

This may vary between tissues and rarely parent dependent


Methylation changes are also associated with cancer

Methylation of things that usually prevent cancer, 'tumor suppressant genes'

-inherited predisposition: by inheriting a copy of gene from a parent thats methylated and that turns of a preventative cancer gene, and if the other parents gene gets damaged > cancer

-Somatic methylation changes: meethylation 'turns on' a tumor.
eg) one parent has mutated BRCA gene, and the other parents normal gene gets turned off by methylation > cancer


Inherited predisposition: Beckwith-Wiedemann syndrome

Pre/post natal overgrowth.

Increased tumor predisposition. (wilms tuor)

inherited methylation of genes that normally stop genes growthing (growth suppressors)


Somatic methylation changes in cancer.

CCND1: gene that drives mitotic cell division

the more methylation (turning off) of this genes, the SLOWER GROWING the tumor is

The less methylation, the more genes and the more rapid the tumor growth!


Dynamic Mutation

With each round of inheritance there is progressive expansion of 'repeat sequences', many 'triplet repeats'. If in a coding region it will lead to repeated aa production

~20 diseases involved with repeated expansion

Symptoms in later generations occur at younger ages and are more severe = anticipation
This is bc each generation is inheriting more and more triplets!


Huntingtons is a neuromuscular disease...

On chromosome 4 p arm has a huntingtons gene. Trinucleotide CAG repeats

Normal: 26 or less
Intermediate: 27-35 (nosymptoms but possibility of child inheriting 'mutant allele' if parent male)
Mutant: >36
36-39 reduced penetrance
40+ full penetrance

the more repeats... the more significant the symptoms! THey result in polyglutamine expansion, which have an effect on neuronal cells by 'gain-of-function'.


How are dynamic Mutations detected

Direct mutation analysis
Via PCR-based methods that detect alleles upto ~115 CAG repeats

Southern blotting: detects smaller repeat #


Genotype-phentype correlation

The more repeats the earlier/more severe disease onset is = anticipation!!



Juvenile-onset (usually ~ 60+ repeats) and the expanded allele is usually from the father!

Occurs more commonly with paternal transmission

Due to instability of CAG during spermatogenesis


Risk to family

Most with HD have an affected parent, BUT de novo mutations can occur.
-Asymptomatic father of an affected individual may have an intermediate allele.
-Either asymptomatic parent may have a reduced penetrance allele (36-39 repeats)

AD dominant so 50% to offspring.