Epigenetics

EPIGENETICS

Prepared by: JCPIELAGO (reference: useful genetics couseraonline.org)

EPIGENETICS (mostly imprinting)

• Outline– Define ‘epigenetics’– Functions– Mechanism– Genomic imprinting– Function (Parental Conflict Theory)– DNA methylation mechanism– Diseases affected by imprinting– Pedigrees

EPIGENETICS (mostly imprinting)

• Learning objectives– Define epigenetics– Diagram genomic imprinting (in several

different ways)– Use the parental conflict theory to explain why

specific gene are imprinted in the male or female parent

– Explain how patterns of Methylation of CG dinucleotides are heritable

– Track imprinting effects through a simple pedigree

Epigenetics:

Mechanisms of gene regulation that can be stably inherited through mitosis and (sometimes) meiosis, but can be established and released without changing the DNA sequence

Wikipedia’s definition:The study of heritable changes in gene activity that

are not caused by changes in the DNA sequence.

This definition is much too broad – includes all forms of gene regulation

Functions of epigenetic regulation

• All our cells contain the same genes• Different cells and tissues differ in which genes they

express.• These differences are created and maintained by gene

regulation, not by changes in the DNA sequence (yes, there are exceptions…).

• Some gene regulation has evolved to respond fluidly to changing conditions within the lifetime of a single cell.

• Other regulation needs to be stable

Functions of epigenetic regulation

• Regulation that needs to be stable– Terminally differentiated cells– Specialized progenitor cells (stem cells)– Stably differentiated dividing cells– X inactivation (an extreme example)

Mechanism of epigenetic regulation

Some of the same processes

used for other gene regulation

must be heritable but not

reversible especially regulation

that changes how the gene’s

DNA is packaged by chromatin

proteins.– Modification of chromatin proteins– Methylation of DNA (removed in zygote, reestablished in the

embryo and later); usually prevents gene expression.

What Mendel found out about peas:

6. Each seed, and thus each organism, results from one

ovum being fertilized with one pollen grain (not many, as

some had previously thought)

7. The two parents make up equal contribution to the

character

8. The effect of an allele is independent of whether it comes

from the ovule or the pollen.

Mendel’s results revealed the haploid-diploid sexual cycle

What Mendel found out about peas:

6. Each seed, and thus each organism, results from one

ovum being fertilized with one pollen grain (not many, as

some had previously thought)

7. The two parents make up equal contribution to the

character

8. The effect of an allele is independent of whether it comes

from the ovule or the pollen.

Mendel’s results revealed the haploid-diploid sexual cycle

Points 7 and 8 are NOT TRUE for some mammalian genes

Genomic imprinting:

For a few special genes, alleles inherited from the father are expressed differently than alleles inherited from the mother.

Father Mother

Offspring

Genomic imprinting:

For a few special genes, alleles inherited from the father are expressed differently than alleles inherited from the mother.

Father Mother

Offspring

Allele from the father Is inactive

Genomic imprinting:

For a few special genes, alleles inherited from the father are expressed differently than alleles inherited from the mother.

Father Mother

Offspring

Allele from the father Is inactive

Allele from the fatherIs inactive

Genomic imprinting:

The identity of the allele doesn’t matter, just which parent it came from.

Father Mother

Offspring

Allele from the father Is inactive

Allele from the fatherIs inactive

Paternal imprinting

Genomic imprinting:

Here’s an example of a different gene, where the maternal allele is always imprinted.

Father Mother

Offspring

Allele from the mother Is inactive

Allele from the motherIs inactive

Maternalimprinting

Genomic Imprinting

Genomic Imprinting

Genomic Imprinting

Notes:1. The alleles behave normally in meiosis; only their expression in the

offspring is affective.2. Dominance is meaningless… imprinted loci are effectively HEMYZTGOUS.

What is the function of genomic imprinting? (Why did it evolve?)

The best explanation: Parental Conflict Hypothesis

Parental Conflict Theory

Parental Conflict Theory

DNA Methylation

DNA Methylation

Think about how genomic imprinting works:

All of the inherited imprinting marks are erased when the

germ line develops.

A gene that’s evolved to be paternally imprinted has a sequence-tag that says:

If you’re male, methylate this gene before you make gametes.

A gene that’s evolved to be maternally imprinted has a sequence-tag that says:

If you’re female, methylate this gene before you make gametes.

Imprinting has evolved to a state where both parents’ interest are roughly in balance.

But it causes problems if something goes wrong with normal

inheritance:

a.) Defective allele from the non-imprinted parent

b.) Deletion from the non-imprinted parent

c.) Both alleles inherited from one parent (‘uniparental disomy’)

b.) and c.) are especially bad because imprinted genes are

often clustered together on one chromosome.

Imprinting causes problems if something goes wrong with the normal inheritance:

One segment of chromosome 15 includes genes that are paternally imprinted and genes that are maternally imprinted.

Imprinting causes problems if something goes wrong with the normal inheritance:

One segment of chromosome 15 includes genes that are paternally imprinted and genes that are maternally imprinted.

Inherit deletion from father

Inherit deletion from mother

Prader-Willi Syndrome

Angelman Syndrome

Inactive allelesFrom mother (M-I)

Inactive allelesFrom father (P-I)