DIFFERENCES FROM MENDELIAN Flashcards
EXPLAIN IMPRINTING
– it is a genetic phenomenon, where the level of gene expression depends on
whether it was inherited from mother or father
-genes transcribed only from 1 allele of 1 parent and the other is inactive and silent (imprinted)
WHAT ARE IMPRINTED GENES NEEDED FOR?
are genes which are needed at the beginning of development (embryonic development,
regulation of cell proliferation), however only one active allele must be present, not two, one needs to be inactive
-functionally haploid
IS THE MECHANISM OF IMPRINTING LETHAL?
As the mechanism of inactivation is methylation during gamete formation, it is an epigenetic inheritance and an epigenetic mechanism of gene expression regulation (this means errors or mutation in this process are pathological)
GIVE AN EXAMPLE OF IMPRINTING IN HUMANS
beginning of embryonic development imprinted gene which prefer paternal genes, help form the placenta (trophoblast). Imprinted genes which prefer maternal genes help in the development of embryo
EXPLAIN PRADER WILLI SYNDROME
symptoms include: obesity, small stature, hypogonadism and mental retardation
-caused by the absence of PWS genes, which are inherited from father (mothers are imprinted = inactive)
-genes for PWS and AS are on long arms of chromosome 15, right next to each other
- if there is deletion or faulty inactivation of PWS genes during spermatogenesis à child will suffer with PWS
-if PWS genes were lost or inactivated during spermatogenesis and during oogenesis these genes were not
methylated (not inactivated- remained active) à if these two defects would occur and these defected gametes would from a zygote – child would remain healthy
EXPLAIN ANGELMAN SYNDROME
symptoms include: dysmorphic features, problems with sleep, slim figure, mental retardation and uncontrolled
inappropriate laughter
-caused by the absence of AS genes, which are inherited from mother (fathers are imprinted = inactivated)
-genes for PWS and AS are on long arms of chromosome 15, right next to each other
-if there is deletion or faulty inactivation of AS genes during oogenesis à will suffer with AS
EXPLAIN BECKWITH WIEDMANN SYNDROME
also, known as EMG syndrome (Exomphalos-Macroglossia-Gigantism)
-symptoms may include abdominal wall defects, macroglossia, gigantism, enlargement of organs, neonatal hypoglycaemia and increased risk of tumours – e.g. Wilms tumour
- Reciprocally imprinted genes are next to teach other on 11p15 IGF2 (expression of paternal allele) and H19 (expression
of maternal allele)
- Same problem as in PWS and AS -> duplication, deletion, uniparental disomy (UDP), translocation or faulty imprinting
can lead to a different state than the normal physiological one (1 active allele IGF2 and 1 active allele H19) and every abnormality of this type causes Beckwith-Wiedmann syndrome
EXPLAIN PROTO ONCOGENES
for expression need both alleles active, if one allele is imprinted, the whole gene is disabled
-> if an inactive allele becomes demethylated (loss of imprinting), the proto-oncogene is turned into an oncogene and tumor form
EXPLAIN TUMOR SUPPRESSOR GENES
if accidental imprinting of one tumor suppressor gene occurs, the loss of the second healthy allele will cause tumor development
-> imprinting of tumor suppressor genes means high predisposition to tumors
EG: WT1 (11p13)
-> IGF2R (6q26) – gene of receptor for IGF2 (insulin-like growth factor 2), marks IGF2 for degradation, however if there is no receptor, IGF2 is not degraded and cell continues to receive signals to grow
- methylation is however reversible - methylation and demethylation is studied as one of the possible cures in cancers
EXPLAIN WILMS TUMOR
malignant tumour of kidneys/kidneys of small children (max. 3 years old)
- locus 11p13 – associated with WAGR
o WAGR = genetic syndrome, predisposition for Wilms tumour, Aniridia (absence of iris), Genital anomalies and
mental Retardation
o WT1 – tumour suppressor gene, if imprinting occurs – predisposition to tumours
- locus 11p15 – associated with BWS -> high no. copies of growth gene IGF2
o gene IGF2 (from father) codes for IGF2 (insulin-like growth factor 2), if there are more genes -> more IGF2 ->
more growth -> BWS
o deletion or translocation of maternal alleles H19 causes activation of maternal allele IGF2 -> more growth -> BWS
WHICH MECHAMISM DOES IMPRINTING USUALLY OCCUR THROUGH?
imprinting occurs mainly through methylation, but acetylation of histones also plays a role, as well as any process
which causes the reconstruction of chromatin into inactive state
IS IMPRINTING A REVERSIBLE PROCESS?
imprinting is reversible and reprogrammed in gametogenesis
HOW CAN IMPRINTING BE A MECHANISM FOR REGULATING GENE EXPRESSION?
play a role in the regulation of growth, cell proliferation and differentiation, code for growth factors, receptors of growth factors, regulatory proteins, transcription factors, proteins involved in splicing
EXPLAIN THE POLYMORPHISM OF IMPRINTING
some people have monoallelic expression of genes, but the vast majority has biallelic expression
WHAT IS UNIPARENTAL DISOMY?
inheritance of 2 homologous chromosomes from one parent
-results of UPD - abnormality in the case that chromosomes contain imprinted genes
EXPLAIN THE EVIDENCE FOR UNIPARENTAL DISOMY
inheritance of haemophilia from father to son (zygote XXY and loss of maternal X chromosome)
- maternal UPD in PWS / paternal UPD in AS (increased age of parents)
- placental mosaic trisomy 15 in CVS (chorionic villus sampling)
- transfer of balanced translocation 22/22 in balanced form onto child and zygotic loss of free 22
- presence of homozygotic inversion on chromosome 4 in daughter of a mother who is a heterozygote for this inversion
WHAT ARE THE MECHANISMS OF UPD ORIGIN?
loss of chromosome in trisomic gamete
- gametic complementation – fertilization between nullisomic and disomic gametes
- duplication of single chromosome in monosomic gamete
- postzygotic nondisjunction and duplication or mitotic recombination
DYNAMIC MUTATIONS
