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Sem 1: Genetics > Week 8 > Flashcards

Week 8 Flashcards

1
Q

What forms a Hydatidiform mole?

A

46, XX of paternal origin

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2
Q

What are the two ways a hydatidiform mole can form?

A

Fertilisation of enucleated oocyte by haploid sperm which duplicates
Fertilisation of enucleated oocyte by two sperms

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3
Q

What is Ovarian Teratoma?

A

46, XX of maternal origin
Parthenogenetic conceptus

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4
Q

What is imprinting?

A

The remarkable feature od imprinted genes that both active and inactive alleles coexist in the same cell resulting in parental origin monoalllic expression
Maternally expressed = Patnerally imprinted and visa versa

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5
Q

What is biallelic expression?

A

When both aleles form both parents are expressed

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6
Q

What is an example of maternal suppression and paternal expression?

A

Maternally methylates promoter of the paternally expressed KCNQ1OT1 ncRNA
Expressive = H3K4me2
Repressive = H3K9me3

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7
Q

How can tissue expression vary between tissues?

A

Maternal expression of UBE3A is only observed in neurons but is biallelically expressed in all other tissues
Maternal expression of TFPI2 is restricted to the placenta, one of the only tissues expressing the gene

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8
Q

What is the imprinting relationship between mammals?

A

Imprinting is hightly conserved between mammalians species
Approximately 50% of imprinted genes are conserved between human and mouse

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9
Q

What is the relationship between location of imprinted genes?

A

Imprnted genes often cluster together.
A single ICR (inmprinting control region) can influence the allelic expression for neighbouring genes, often several 100Kb away

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10
Q

What are the key events in the discovery of imprinting?

A

Johnson 1974 - hairpin tail allele
Surani et al 1984 - Development of reconstitute mouse eggs
Cattanach and Kirk 1985 - Generated mice with sub-chromosomal maternal duplication
DeChiara et al 1990 - mice inheriting patrnal deletions

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11
Q

What was the work of Johnson 1974?

A

The hairpin-tail allele (T^hp) presents with a phenotype in heterozygous offspring depending on parental transmission

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12
Q

What was the work of Surani et al 1984?

A

Development of reconstituted mouse eggs suggests imprinting of the genome during gametogenesis

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13
Q

What was the work of Cattanach and Kirk 1985?

A

Generated mice with sub-chromosomal maternal duplications/paternal deficiencies (and the reciprocals), most mouse chromosomes highlighting opposing phenotypes

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14
Q

What was the work of DeChiara et al 1990?

A

Igf2 imprinting: Heterozygous mice inheriting paternal deletions were small with phenotyoes same as homozygous null. Heterozygous mice inheriting maternal deletions were normal

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15
Q

What is the relationship between gene methylation and gene unmethlyated pre and post fertilisation?

A

Sperm- Unmethylated Gene A
Oocyte - Methylated Gene A
Blastocyst- Gene A Paternal copy expressed Gene A Maternal copy silenced

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16
Q

What happens to the DNA from sperm after fertilisation?

A

DNA becomes rapidly unmethylated by the enzyme Tet3 throught the process of active demethylation

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17
Q

What happens to the DNA from the oocyte after fertilisation?

A

Undergoes a passive demethylation due to the lack of DMNT1 enzyme not copying the methylation, passively dilluting the methylation

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18
Q

Why dont imprinted genes lose methylation?

A

Two transcription factors bind to the imprinted genes.
The TFs are ZFP57 and DPPA3

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19
Q

How are sex specfic epigenetic coordinated?

A

Primoridal germ cell goes through a erasure process removing all methylation to then allow for establishment phase to occur selecting sex specific epigenome to be added

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20
Q

What is the time frame of methylation for spermagenesis?

A

Sperm-derived gDMRs acquired before birth

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21
Q

What is the time frame of methylation for oogenesis?

A

OOcyte-derived gDMRs acquired after birth

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22
Q

What was the case study of Imprinting may exist due to genetic conflict?

A

Mice- multiple males per litter
Maternally expressed genes limit growth- higher all survive more equally distrubuted nutrients and lower demand
Paternally expressed genes enhance growth- higher offspring survive

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23
Q

What are the key feaures of X chromosome inactivation?

A

Only chromosome capable of global silencing
Caused by epigenetics
Model for understanding developmental epigenetics and silencing by non-coding RNAs
Important implication for X-linked diseases

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24
Q

What happens with X chromosome inactivation?

A

Female embryos transcriptionally silence one of the two X chromosomes. Therefore both females and males express one X chromosome

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25
Q

What is XIC?

A

X inactivation centre
A 17Kb transcript expressed exclusively from the Xi an accumultes over the Xi territory

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26
Q

What is the function of XIC?

A

XIC is necessary and sufficint to drive chromosomal silencing
XIC contaisn several non-coding RNAs eg Xist

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27
Q

Why is Xist special?

A

It is the “only” gene expressed from that chromosome

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28
Q

What is the function of Tsix?

A

Tsix is an antisense transcript that is a repressor of Xist. Therefore, Tsix plays a major role in the repression of Xist in the Xa

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29
Q

What are the steps of XCI?

A

1- Counting
2- Allelic choice
3- Chromosome coating

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30
Q

What happens if you delete Xist in differentiated cells?

A

It does not lead to reactivation of X-linked genes. Therefore Xist is needed to initiatation of XCI but is dispensible for maintenance of silencing

31
Q

How does Xist work?

A

Loss of euchromatin-associated histone modification (H3K9ac, H3K4me2 and H3K4me3) and RNA polymerase II

32
Q

What are the repressive epigenetic modifications added to X chromosome?

A

H3K27me3, H3K9me3, H4K20me1 and H2A119ub with H3K27me3 preceding the other heterochromatin marks

33
Q

What locks in Xi silencing?

A

DNA methylation

34
Q

What happens with epigenetic error in the first 5 days?

A

Infertility- implantation problems
ART-associated defects

35
Q

What happens with epigenetic error in the blastocyst stage?

A

Placenta and IUGR problems
Imprinting disorders

36
Q

What happens with epigenetic error with adult cells?

A

Cancer
Metabolic syndrome
Imprinting disorders

37
Q

How can str markers show paternal origin of hydatidiform?

A

Repeats markers with a length eg 171 which matches with paternal not maternal

38
Q

What is the most severe form of imprinting defect?

A

Biperental hydatidiform mole- Had DNA form both parents like normal and can been seen occuring across families
Caused by a gene NLPR7

39
Q

What is the cause of NALP7?

A

It is maternal effect mutations

40
Q

What is a maternal effect mutation?

A

Homozygous mother or compound heterozygous has child with wildtype father and the heterzygous child expresses the trait for molar pregnancy

41
Q

What is the penetrance of NLRP7?

A

100% all pregnancies will be molar

42
Q

How many imprinting syndromes in humans are there?

A

There are 11 known syndromes

43
Q

What are imprinting syndromes commonly associated with?

A

Gene mutants
Copy number varients
Uniparental disomy
Epigenetic errors

44
Q

What is the frequency of the four types of molecular alterations?

A

It varies between the different syndromes

45
Q

What are the features of transient diabetes mellitus (TNDM)?

A

Intra-Uterine Growth retardation
Hyperglycaemia
Low C peptide and insulin level
Absent Auo-islet cell antibodies
Absent Type 1 diabetes-related HLA type

46
Q

What are the possible features of type 1 TNDM?

A

Macroglossia
Dysmorphic features
Umbilical hernia

47
Q

What are the possible features of type 2 TNDM?

A

Ketacidosis
Developmental delay
Epilepsy

48
Q

What duplication causes TNDM?

A

Paternal repeats on 6q24- PLAGL1
Maternal is epigenetically silenced
29% cases

49
Q

What is UPD and how does it cause TNDM?

A

Uniparenal disomy, for TNDM both alleles are paternal so overexpression
41% of TNDM cases

50
Q

How can imprinting defect cause TNDM?

A

The silent maternal gene has lost its methylation so overexpression happens again

51
Q

What is the prevalence of Silver-Russel syndrome?

A

1/75,000 to 1/100,000

52
Q

What chromosomes impact Silver-Russel syndrome?

A

7
11p15
12q14
8q12

53
Q

What can cause Silver-Russel syndrome?

A

upd(7)mat (5-10%)
HMGA2, PLAG1 point mutations (rare)

54
Q

What are the main clinical features of Silver-Russel syndrome?

A

Relative macrophagey at birth, body asymmetry, prominant forehead and feeding difficulties

55
Q

What is the prevalence of Beckwith-Wiedemann syndrome?

A

1/15,000

56
Q

What can molecular defects cause Beckwith-wiedmann syndrome?

A

Upd (11p15)pat (20%)
CDKN1C point mutations (5% sporadic, 40-50% in families)

57
Q

What are the main clinical features of Beckwith-Wiedemann syndrome?

A

Macroglossia (enlarged tongue), exomaphalos, lateralised overgrowth, wilms tumour, hyperinsulinism, placental mesenchymal dysplasia

58
Q

WHat is the yin and yang of Silver-Russel syndrome and Beckwith-Wiedemann syndorme?

A

H19-IGF2:Ig-DMR LOM - no paternal methylation at H19 like there should be 30-60% of cases - S-R syn
H19-IGF2:Ig-DMR GOM - too much paternal methylation at H19 5% of cases - B-W syn

59
Q

What is the wildtype function of CTCF on H19?

A

CTCF is a insulated unmethylated genes so paternal is silence due to epigenetics but maternal has CTFT. CTFT is loctated between two genes.
Paternal = no block = enhancer binding to Igf2
Maternal = block = enhancer binding to H19

60
Q

What happens with CTCF with people with Beckwith-Wiedemann syndrome?

A

No CTCF on either maternal or paternal due to hypermethylation.
So both express Igf2

61
Q

What happens with CTCF with people with Silver Russel Syndrome?

A

Hypomethylation causes CTCF at both maternal and paternal genes
So both express H19
Igf2 is growth factor so baby is smaller

62
Q

How does the KCNQ1OT1 region work?

A

KCNQ1 is an antisense RNA so causes repressive histone modifications H3K27me3 and H3K9me2 to be placed on the paternal genome

63
Q

How does the KCNQ1OT1 region work with Beckwith-Weidemann syndrome?

A

Silencing occurs on both the maternal and paternal genome. As CDKN1C gene is silenced so cells divide more so overgrowth occurs

64
Q

What is the prevalence of Angleman syndrome?

A

1/20,000 to 1/12,000

65
Q

What are the molecular deletions causing Angelman syndrome?

A

15q11-q13 Mat deletion (70-75%) UBE3A gene
Upd (15)pat (3-7%)
SNURF:TSS-DNMR LOM

66
Q

What are the main clinical features of Angelman sydrome?

A

Severe intelectual disability, Mucorcephaly, no speech, unmotavated laughing, ataxia, seizures, scoliosis and fascination with water

67
Q

What is the prevalence to Prader-Willi syndrome?

A

1/10,000 to 1/25,000

68
Q

What molecular defects causing Prader-Willi syndrome?

A

15q11-q13 pat deletion (75-80%) can be MKRN3 MAGEL2 and NDN
Upd(15)mat (20-25%)
SNURF:TSS-DNMR GOM

69
Q

What are the main clinical features of Prader-Willi syndrome?

A

Intellectual disabilities, hyotania, obesity, hyperphagia, hypopigmentation

70
Q

How can Angelman syndrome be inherited?

A

Passed down through males as they wont show symptoms

71
Q

How can prader-Willi syndrome be inherited?

A

Passed down through females as they wont show symptoms

72
Q

What else can be caused by 15q12-13 inherited duplications?

A

Associated with autism and other neuroloical disorders

73
Q

What is th relationship between cases of ART-conceived children with AS or BWS?

A

Potential link with epigenetic mutations of imprinted regions

Sem 1: Genetics (10 decks)

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