5 - Epigenetic Variation

Question 1

Epigenetics

Answer 1

Study of reversible heritable changes in gene function that occur without a change in the sequence of DNA

Question 2

Epigenetic processes

Answer 2

• Histone modification & chromatin remodeling
• DNA methylation
• Non-coding RNA mediated regulation

Question 3

Chromosomes

Answer 3

DNA + protein (Chromatin)

Question 4

Examples of epigenetic processes

Answer 4

• Cat spotting
• Honey bees (workers vs queens)
• Host immunity (e.g. against retrovirus)

Question 5

Histones

Answer 5

Nucleosomes arranged as an octamer of histone proteins with protruding N-terminal ends

Question 6

What are the four core histones

Answer 6

Two each of H2A, H2B, H3 and H4

Question 7

Histone H1

Answer 7

• The linker protein
• Bound to DNA between nucleosomes.

Question 8

Histone tags that control histones

Answer 8

• Acetyl
• Phosphate
• Methyl
• Ubiquitin

Question 9

Modifications of histone tails

Answer 9

Act as epigenetic marks that control expression of chromosomal regions (controlled by transcription factors)

Question 10

HIstone code hypothesis

Answer 10

States that no one histone modification occurs in isolation but instead effect each other

Question 11

What charge is DNA

Answer 11

negative

Question 12

What charge are histones

Answer 12

positive

Question 13

Histone acetylation

Answer 13

• Acetylation of histones occur in the lysine residues of histone tails
• Neutralises the positive charge & decreases their affinity for DNA
• DNA is less tightly wound & permits transcription
• Histones near active genes are hyperacetylated

Question 14

Acetylated lysine residues

Answer 14

Transcriptional activation (gene expression)

Question 15

Deacetylated lysine residues

Answer 15

Transcription repression (gene silencing)

Question 16

HAT & HDAC

Answer 16

Histone acetylase (HAT) & histone deacetylase (HDAC) enzymes add/remove acetyl groups

Question 17

DNA Methylation

Answer 17

• Involved in gene regulation
• Involves the addition of methyl groups to histone proteins

Question 18

Methylation normal processes

Answer 18

• Embryonic development
• X chromosome inactivation
• Imprinting
• Gene silencing

Question 19

X chromosome inactivation

Answer 19

• Silencing of one X chromosome in females (done at random, all descendants of that cell keep same pattern)
• Human females are functionally mosaic
• early female embryo has both X’s active.
• Most of the genes on one X chromosome are inactivated (by methylation) in every cell

Question 20

Mechanism of X inactivation

Answer 20

• At ~1000 cell stage, cell chooses one X to remain ON.
• Other X is inactivated via XIST
• XIST coats the X chr leading to heterochromatin spreading (silencing) & methylation

Question 21

XIST

Answer 21

• X Inactivation Specific Transcript
• An X chromosome-encoded
  lncRNA

Question 22

Skewed X inactivation

Answer 22

• X activation sometimes is non-random (skewed)
• The severity of disease can be related to how many cells are expressing the mutated allele

Question 23

Agouti mouse model

Answer 23

• When the Agouti gene is methylated (off), mice
  are brown & healthy
• When the gene is unmethylated (on), mice are
  yellow & unhealthy

Question 24

Genomic imprinting

Answer 24

• Parent-specific expression or repression of genes
  or chromosomes in offspring
• Two copies of a given gene are inherited (one from each parent) only the maternal or paternal allele is expressed.
• The non expressed allele is said to be imprinted

Question 25

Imprinting and disease

Answer 25

- Diseases are characterised by non-mendelian inheritance patterns that exhibit parental-origin effects. - Role of imprinted genes in growth regulation during embryonic and post-natal development, brain function and behavior.

Question 26

Diseases associated with genomic imprinting

Answer 26

- Beckwith–Wiedemann syndrome - Prader–Willi syndrome - Angelman syndrome - Fragile X

Question 27

Angelman syndrome

Answer 27

- Severe mental retardation - Microcephaly - Lack of speech - Frequent laughter. - Deletion of maternal 15q11-q13

Question 28

Prader-Willi syndrome

Answer 28

- Mild mental retardation - Obesity - Short stature. - Deletion of paternal 15q11-q13

Question 29

Features of Beckwith–Wiedemann syndrome

Answer 29

Embryonic and placental overgrowth, predisposition to childhood tumors

Question 30

Cause of Beckwith Wiedemann syndrome

Answer 30

- Genetic and epigenetic changes in a region of about 1 megabase on chromosome 11p - Increased expression of IGF2, and suppression of CDKN1C are major cause

Question 31

IGF2

Answer 31

- Insulin-like growth factor - Normally this gene is only expressed by the paternal chromosome

Question 32

CDKN1C

Answer 32

700kb away from IGF2 and is maternally expressed