Imprinting and Epigenetics Flashcards
1
Q
prader willi and angelman
A
- best known microdeletion
- both appear to have same deletion of 15q 11
- two diseases are completely different
2
Q
prader willi
A
- patients are small and hypotonic at birth
- gain weight rapidly
- small hands/feet
- hypogonadism
- bad temper
- developmentally delayed, but do well in special ed
- group homes
3
Q
angelman
A
- severely mentally retarded
- can’t carry on a normal conversation and discourse is often punctuated by bursts of inappropriate laughter
- hyperactivity, short stature, microcephaly, seizures, ataxia
4
Q
15q deletion
A
- could be detected 60% of the time for PW but only 10-20% of the time for AS
- FISH 65-85% for both
- still need clinical features because it’s the same deletion
5
Q
evolving
A
- PW found in kids with deletion on paternal chromosome, or with maternal disomy
- AS found in kids with deletion on maternal chromosome, or with paternal disomy
6
Q
disomy
A
-presence of 2 chromosomes
7
Q
UPD
A
- inheritance of a chromosome or chromosomes from 1 parent to the exclusion of the other parent
- need to use molecular probe to find
- can be heterodisomy or isodisomy
- isodisomy leads to loss of heterozygosity
- come from meiotic non-disjunction
8
Q
disomy transmission
A
-from a non-disjunction and embryo rescue through duplication of a single chromosome or deletion of a trisomy
9
Q
CF
A
- dad is carrier and mom isn’t
- child inherits two deltaF508 from dad
10
Q
rescue of a trisomy
A
- 2/3 of the time will still give you bi parental heterodisomy
- 1/3 gives uniparental heterodisomy
11
Q
translocation family
A
- girl with anomalous features and no apparent reason
- MR, seizures, coarse hair, frontal bossing, kyphoscoliosis, prominent maxilla and mandible
- father was a balanced carrier of a robertsonian translocation of 13 and 14
- child had same thing and appeared balanced, but she had the translocation from dad and then the single 14 was also from dad- so both 14s came from dad
- could be from non-disjunction in both parents- translocation and 14 from dad and just 13 from mom, but unlikely
- more likely that the dad gave translocation and 14, mom gave normal, and mom’s 14 happened to be kicked out of embryo instead of dad
12
Q
imprinting
A
- differential modification of the maternal and paternal genetic contributions to the zygote
- resulting in the differential expression of parental alleles during development and in the adult
- for some chromosomal regions, it may be important to have maternal and paternal contribution
- not all genes or all chromosomes
- usually associated with methylation, an epigenetic modification
13
Q
methylation
A
- addition of methyl groups to cytosine residues in the DNA
- can occur within a single gene or a group of adjacent genes
- can occur over a portion of a single chromosome
- can occur over the full length of one or more chromosomes
- the pattern of methylation can be different between males and females
14
Q
imprinting 2
A
-lasts one generation, change occurs at meiosis
15
Q
meiotic imprinting
A
- get one copy from mom, one from dad
- at meiosis, both chromosomes are changed back to original pattern depending on gender
- paternal gametes changed to paternal pattern and same for maternal
- if there is an imprinting failure, child can end up with two copies of a gene that are imprinted the same even if it came from the right parent ( dad can pass on a maternal imprinted chromosome)
16
Q
PW/AS
A
- can now also occur through imprinting error
- so PW is paternal deletion, maternal disomy, or imprinting error resulting in only maternal alleles
- AS is maternal deletion, paternal disomy, or imprinting error resulting in only paternal alleles
17
Q
detection now
A
- FISH 70-80% for PW, 70% for AS
- UPD 15-20% of PW, only 2-3% AS
- imprinting failure 2-4% for PW, 2-3% for AS
- other mutations- 25% UBE3A in AS
- chromosome rearrangement 1% for both
18
Q
differences in paternal imprints
A
- maternal copy has UBE3A expression (SNRPN and necdin methylated)
- paternal copy has SNRPN and necdin expressed (UBE3A methylated)
- if correctly inherited, get all 3 expressed at right amount
- if missing paternal- have all copies of UBE3A but no SNRPN or necdin
- if missing maternal, will only have SRPN and necdin, no UBE3A
19
Q
imprinting 3
A
- important mutational mechanism
- high frequency of developmental genes
- probably very important in very early development of the zygote
- important to actually have one chromosome from mom and one from dad
- errors can be an important mutational mechanism
20
Q
epigenetics
A
- study of heritable changes in gene function that are not caused by change in the DNA sequence
- modification of transcription that alters gene expression and thus phenotype
- normal process required for normal cell function
- change in epigenetic effects can result in up or down regulation of genes and can result in disease
21
Q
categories of epigenetic modifications
A
- methylation
- histone modification
- chromatin remodeling
22
Q
methylation
A
- results in modification of function or complete inactivation
- can affect a single gene, a group of adjacent genes, or a whole chromosome
- x inactivation
- imprinting-specific patterns associated with the parent of origin
23
Q
transcription modification
A
- TFs, repressors
- increase or decrease expression
24
Q
histone and nucleosome modification
A
- 5’ and 3’ regions of a transcriptionally active gene promoter are nucleosome free, which allows for assembly and disassembly of transcription machinery
- methylated DNA is condensed so nucleosomes will be in their normal patterns
- methylation and histone positioning can block transcription, whereas unmethylated DNA without histones is open to transcription
25
Q
development
A
- stem cells retain the ability to differentiate into any cell type
- as the organism develops, differentiation occurs, resulting in different cell types with different functions
- a specific patterns of genes must be active whereas others are inactivated to create specific tissue and organ phenotypes
- mechanisms include DNA methylation, histone modification, remodeling of chromatin structure
26
Q
TFs
A
- bind to DNA and alter gene transcription
- can act as an activator or repressor
- bind specifically to enhancer or promoter regions of the DNA adjacent to a specific gene
27
Q
microRNA
A
- small, non-coding RNAs
- miRNA binds to mRNA to regulate gene expression
- this can prevent translation or interfere with the translation process
- down regulation of miRNA caused by hypermethylation at the miRNA promotors is reported in a number of tumors
- miR15a and miR-16-1 downregulated in leukemia
- down regulation of miR107 is linked to pathogenesis in AD
- miR21 is upregulated in breast cancer
- present targets for therapy and drug development
28
Q
epigenetics and human disease
A
- cancer-breast, ovarian, pancreatic, melanoma, leukemia, lymphoma
- AI- arthritis, diabetes, MS
- neurodevelopmental disease-Rett,Coffin-Lowry
- neurological and neurodegenerative-fragile X, AD, PW/AS, Parkinson, Huntingtons
- aging
29
Q
Rett syndrome
A
- neurodevelopmental disorder
- affects primarily females
- normal early development followed by arrested development the regression
- disruption of motor functions, problems with control of hands and feet
- intellectual disability
- loss of speech
- seizures
- variable phenotype-partially dependent on the frequency of mutant alleles that are inactivated
- Xq28
- MECP2- TF that can activate or repress transcription
- normal function required for maturation of neurons and normal development
30
Q
conclusions
A
- understanding epigenetics is critical for understanding many common diseases
- moves genetics beyond realm of purely inherited entities
- epigenetics expands targets for drug and therapy development
