Gene dosage and genomic imprinting

Question 1

What is bi-allelic expression?

Answer 1

Genes are expressed from both gene copies

Majority of genes show bi-allelic expression

Question 2

What is aneuploidy?

When does it occur?

Answer 2

Unbalanced number of chromosomes

Due to excess or deficiency of individual chromosomes

Most often arises via non-disjunction of two homologous chromosomes or sister chromatids during cell division

Question 3

Which full term trisomies and monosomies may appear?

Answer 3

Trisomy: 13, 18, 21, XXY, XXXY, XYY

Monosomy: XO, but no autosomal

Question 4

What is the major cause of intellectual disability and congenital heart disease?

Answer 4

Trisomy 21: Down Syndrome

Question 5

What is Edwards syndrome?

Answer 5

Trisomy 18

Overlapping fingers, club foot, heart defects, developmental disability

Question 6

How can phenotypes of various severity arise from a trisomy?

Answer 6

May have full trisomy, partial trisomy, or mosaicism, all producing phenotypes of varying severity

Question 7

Define haploinsufficiency?

Answer 7

Having only one normal copy of a gene is not sufficient to support normal cell function

(e.g. in autosomal dominant inheritance)

Question 8

What is mono-allelic expression?

Answer 8

Gene must be expressed from only one copy for normal cell function and development

Question 9

How does monoallelic gene expression occur?

Answer 9

One of the copies is inactivated

X chromosome inactivation: epigenetic modification
Genomic imprinting: epigenetic and genetic modification

Question 10

What is epigenetics?

Answer 10

Change in gene expression/repression with no chnage in DNA sequence

Encompasses:
DNA methylation
Histone modifications
RNA mediated gene silencing

Question 11

Are epigenetic changes passed on through cell division?

Answer 11

Yes

Cellular ‘memory’ encoded in chromatin

Question 12

Why does X chromosome inactivation occur in females?

Answer 12

Gene dosage mechanism

One X chromosome inactivated to ensure the level of expression of X-linked genes is equal in males and females

Question 13

When does X-chromosome inactivation occur?

Answer 13

Cells of the early embryo

Somewhere between 8-100 cell stage

Question 14

Describe how X-chromosome inactivation occurs?

Answer 14

DNA methylation

Hyperchromatin structure

Non-coding RNA acting in cis (expressed by X and acts to create a wave of inactivation on the same X)

Question 15

Is the same X chromosome inactivated in every cell in females?

Answer 15

No

Females are mosaic (average 50/50)

Question 16

Is the pattern of X chromosome inactivation hertiable?

Answer 16

Yes

Question 17

What is the inactive X chromosome referred to as?

Answer 17

Barr body

Question 18

If X chromosome inactivation occurs, is monosomy X sufficient for normal development?

Answer 18

No

Turner syndrome (45,X)
Short stature
Infertility (absent or immature gonadal development)
Absence of secondary sexual development
Imapired neuro function

Question 19

Are all genes on the second X chromsome inactivated?

Answer 19

Some genes excape X inactivation

Cluster around pseudo-autosomal regiion, and line up well with Y chromosome

Question 20

What is genomic imprinting?

Answer 20

The process whereby the parental origin of a particular gene is marked by a reversible epigenetic mechanism

Expression of certain genes depends on whether they are inherited from the maternal or paternal gamete

Question 21

When does genomic imprinting occur?

Answer 21

Uniform pattern in somatic cells of all individuals >

Imprints erased during gametogenesis >

Imprints re-established in mature gametes, maintained during embryogenesis (depending on the sex of the individual)

Question 22

Approximately how may imprinted genes exist in the human genome?

Answer 22

Hundreds predicted

1-2% protein coding genes

Question 23

Define parthenogenetic and androgenetic?

Answer 23

Parthenogenetic: all 46 chromosomes from mother

Androgenetic: all 46 chromosomes from father

Question 24

Describe the outcome of parthenogenetic and androgenetic embryos?

Answer 24

Parthenogenetic: typically non-viable, ovarian teratomas

Androgenetic: Hydatiform moles > malignant choriocarcinoma

Question 25

Why are parthenogenetic and androgeneitc embryos typically non-viable?

Answer 25

Gene dosage of imprinted genes is disrupted

Question 26

Are imprinted genes expressed in the same way in every cell?

Answer 26

No, some imprinted genes show differences in tissue and developmental regulation (e.g. IGF2 is imprinted in many tissues but biallelic expression brain, adult liver and chondrocytes)

Question 27

Describe the parental conflict hypothesis?

Answer 27

Maternally expressed genes tend to limit foetal growth (resource conservation) Paternally expressed genes tend to promote foetal growth (resource extraction)

Question 28

Give three examples of imprinting birth defects?

Answer 28

Beckwith-Wiedemann syndrome Prader-Willi syndrome Angelman syndrome

Question 29

List four mechanisms by which imprinting disorders may arise?

Answer 29

1) Loss of heterozygosity (large deletions or duplications of regions that contain imprinted genes) 2) Uniparental disomy 3) Epimutation (alteration in epigenetic marks at imprinted loci without alteration in DNA sequence) 4) DNA mutations in genes that are usually imprinted or in imprinting control centres

Question 30

What is loss of heterozygosity?

Answer 30

Large deletions or duplications of chromosome regions that contain imprinted genes

Question 31

What is uniparental disomy?

Answer 31

Both copies of a chromosome inherited from the same parent

Question 32

How can uniparental disomy arise?

Answer 32

1) Meiotic non-disjunction in both gametes 2) Meiotic non-disjunction in one gamete followed by duplication in zygote 3) Loss of one chromosome in zygote and duplication of other chromosome 4) Meiotic non-disjunction in one gamete followed by loss of chromosome in zygote

Question 33

Descrinbe how loss of imprinting may occur?

Answer 33

Epimutation

Question 34

Describe the incidence of Beckwith-Wiedemann syndrome? Which chromosome os affected?

Answer 34

1 in 15000 Chromosome 11 (11p15.5)

Question 35

Describe the imprinting errors that cause Beckwith-Wiedemann syndrome?

Answer 35

60% epimutation on maternal allele 20% patUPD11 10% mutation in maternal allele of CDKN1C 1-2% cytogenetically visible depletion or duplication

Question 36

When is a pregnancy at greater risk of developing Beckwith-Wiedemann syndrome?

Answer 36

If assisted reproductive technologies are used

Question 37

Which chromsomes are associated with Prader-Willi syndrome and Angelman syndrome?

Answer 37

Chromosome 15

Question 38

How does Prader-Willi syndrome arise?

Answer 38

Deletions of paternal 15q11-13 \> deficiency of paternally-expressed genes Maternal UPD \> deficiency of paternally-expressed genes

Question 39

How does Angelman syndrome arise?

Answer 39

Deletions of maternal 15q11-13 \> deficiency of maternally-expressed genes Paternal UPD \> deficiency of maternally-expressed genes

Question 40

Describe the inheritance of mutations in imprinted genes for active paternal or inactive maternal genes?

Answer 40

Carrier males and affected males can have affected children but not carrier children (gene always expressed) Carrier females and affected females cannot have affected children but can have carrier children (gene never expressed)

Question 41

Describe the inheritance of mutations in imprinted genes for active maternal or inactive paternal genes?

Answer 41

Carrier females and affected females can have affected children but not carrier children (gene is always expressed) Carrier males and affected males cannot have affected children but can have carrier children (gene is never expressed)