L296 Gene Dosage and Genomic Imprinting

Question 1

Bi-allelic expression vs mono-allelic expression of genes

Answer 1

• Biallelic expression = genes expressed from both gene copies
  Monoallelic expression = genes expressed from only one gene copy

Question 2

Aneuploidy vs euploidy

Answer 2

• Aneuploidy = abnormal # chromosomes

- Euploidy = abnormal sets of chromosomes

Question 3

Most aneuploidy embryos survive: T/F?

Answer 3

False - most aneuploidies are incompatible with life

Question 4

Trisomy vs monosomy

Answer 4

• Trisomy = > 2 copies of a chromosome

- Monosomy = 1 copy of a chromosome

Question 5

Full-term trisomies

Answer 5

trisomy 13, 18, 21 and XXY, XXXY, XYY etc

Question 6

Full-term monosomies

Answer 6

XO, no autosomal monosomies

Question 7

When do we see aneuploidies affecting normal function?

Answer 7

When they affect dose-sensitive genes - that must have a particular range of protein expressed

Question 8

Trisomy 18 =

Answer 8

Edwards syndrome (47,XX+18 or 47,XY+18)

Question 9

If a baby with trisomy 18 survives, what does this mean?

Answer 9

not every cell in the body is trisomic: they are mosaics

Question 10

Trisomy 21 =

Answer 10

Down syndrome (47,XX+21 or 47,XY+21)

Question 11

Which genes contribute to the development of the down syndrome phenotype?

Answer 11

• Gene loci at many regions of chromosome 21 play a role in the development of the overall phenotype of Down syndrome

Question 12

Autosomal recessive inheritance: how many altered copies of a gene are required to cause a phenotype?

Answer 12

• Two altered/non-functional copies cause phenotype

- One normal copy is sufficient for cell function

Question 13

Autosomal dominant inheritance: how many altered copies of a gene are required to cause a phenotype?

Answer 13

• Alteration/loss of a single gene copy causes a specific phenotype

Question 14

Why might having one altered gene cause a new phenotype (in autosomal dominant inheritance)?

Answer 14

• One altered copy of a gene might have a novel ‘gain-of-function’ to cause phenotype OR
• Having only one normal copy of a gene is not sufficient to support normal cell function (haploinsufficiency)

Question 15

How might monoallelic gene expression come about?

Answer 15

Inactivation of one of the gene copies

Question 16

Examples of mechanisms that operate to inactivate a genetic copy for monoallelic gene expression

Answer 16

1. X chromosome inactivation in females (epigenetic)

2. Genomic imprinting (epigenetic and genetic)

Question 17

Epigenetics =

Answer 17

= change in gene expression/repression with no change in DNA sequence, passed on through cell division

Question 18

X-inactivation: at which cell stage does it occur at, and what does it leave behind?

Answer 18

• Occurs at 8-100 cell stage of embryo

- Barr body = condensed, inactive X chromosome remnant

Question 19

Comment on the heritability of X-inactivation

Answer 19

Heritable: when cell divides, same chromosome is inactivated i.e. every cell from that cell in chromosomally similar

Question 20

X-inactivation: does it mean that females only need one X chromosome? Why/why not?

Answer 20

No - some genes must be expressed from the inactivated X e.g. Turner syndrome (45, X) is a monosomy X

Question 21

What is genomic imprinting?

Answer 21

Describes the process whereby the parental origin of a particular gene is “marked” by a reversible epigenetic mechanism

Question 22

What do we say expression of genes in genomic imprinting is regulated by?

Answer 22

Parent-of-origin effects: expression of certain genes depends on whether they are inherited from maternal/paternal gamete

Question 23

When does imprinting occur?

Answer 23

• Imprints are erased during gametogenesis in haploid cell, re-established in a parental-specific pattern in mature gametes and maintained during embryogenesis

Question 24

Which chromosomes in particular have clusters of imprinted genes?

Answer 24

Chr 11 and 15

Question 25

Abnormal embryogenesis that leads to all 46 chromosomes being from father/mother - what is this called, and what can this lead to?

Answer 25

- Parthogenesis: all from mother, androgenesis: all from father - typically lead to non-viable embryos and risk of cancer

Question 26

Which hypothesis explains the need for parent-of-origin effects, and explain this hypothesis.

Answer 26

“Parental conflict hypothesis” - Maternally expressed genes tend to limit foetal growth – involved in resource conservation and less flow to the fetus - Paternally expressed genes tend to promote foetal growth - involved in resource extraction to give more energy to the fetus

Question 27

Name 4 changes that underlie recognised imprinting disorders

Answer 27

1. Loss of heterozygosity (LOH) 2. Uniparental disomy (UPD) 3. Epimutation 4. DNA mutations in genes that are usually imprinted or in imprinting control centres

Question 28

LOH results from...?

Answer 28

Large deletions or duplications of chromosome regions that contain imprinted genes → loss of heterozygosity

Question 29

What is UPD?

Answer 29

Embryo ends up with two copies of one-parental chromosome

Question 30

List 4 ways UDP might occur

Answer 30

1. Meiotic non-disjunction in both gametes 2. Meitoic non-disjunction in one gamete with duplication in zygote 3. Loss of chromosome in zygote and duplication of other chromosome during mitosis 4. Meiotic non-disjunction in one gamete followed by loss of chromosome in zygote

Question 31

Epimutation =

Answer 31

= alteration of epigenetic changes at imprinted loci without changes in DNA sequence

Question 32

Describe two types of epimutation that might result in imprinting disorders

Answer 32

- Primary epimutation: = change in epigenetics without any change to DNA sequence e.g. loss of co-factors in environment - Secondary epimutation: mutation in cis/trans-acting regulator of epigenetic change

Question 33

Inheritance of mutations in imprinted genes: mutation in active paternal/inactive maternal allele - what are the inheritance rules?

Answer 33

- Carrier males and affected males can have affected children but not carrier children - Carrier females and affected females cannot have affected children but can have carrier children

Question 34

Inheritance of mutations in imprinted genes: mutation occurs in active maternal or inactive paternal allele - what are the inheritance rules?

Answer 34

- Carrier females and affected females (with paternal inactive allele that is mutated) can have affected children but not carrier children - Carrier males and affected males cannot have affected children but can have carrier children

Question 35

Three examples of imprinting disorders, and which chromosome they occur on

Answer 35

1. Beckwith-Wiedemann syndrome (BWS) - Chr 11 2. Prader-Willi syndrome (PWS) - Chr 15 3. Angelman syndrome (AS) - Chr 15

Question 36

BWS, PWS and AS - what kind of changes result in these disorders?

Answer 36

- BWS: epimutation | - PWS, AS: LOH

Question 37

BWS, PWS and AS - which allele is most commonly affected, maternal or paternal?

Answer 37

- BWS: maternal epimutation - PWS: paternal deficiency (25% from maternal UDP) - AS: maternal deficiency