T5: Imprinting and X-inactivation Flashcards
What is the genetic basis of a hydatidiform mole?
Results from androgenesis. These are masses of cystic tissue with no sign of a normal embryo. They represent an abnormal proliferation of trophoblastic tissue. Most of these are homozygous XX. These need careful clinic management and as there is a small but significant risk that they can process into a malignant trophoblastic tumour.
There is some evolutionary conservation. Androgenic embryos also die due to poor embryonic development despite having well-developed extra-embryonic membranes.
What is the genetic basis of ovarian teratomas?
This results from parthenogenesis. It is derived form oocytes which can completed first or both meiotic divisions. It results in a tumour called a ovarian teratomas located in the ovary. They are diploid and contain a wide spectrum of tissue types like a normal embryo: they are predominately epithelial (can find hair, skin and even teeth), but missing skeletal muscle and no membranes and placenta.
There is some evolutionary conservation. The parthenogenesis embryos die in mice models due to the failure of development of extraembryonic structure - trophoblasts and yolk sac.
Why do uniparental conceptions fail?
- Different roles of maternal and paternal genes in determining developmental fate
- The karyotype and gene dosage is missing
Genetic imprinting Mothers and fathers somehow “imprint” their genes with a memory of their paternal or maternal origin
- The karyotype and gene dosage is missing
What is genomic imprinting?
Genomic imprinting - A mechanism that ensures the functional non-equivalence of the maternal and paternal genomes. These genes are not encoded in the DNA nucleotide sequence, they are epigenetic. This means different modifications are laid down on the genome in spermatogenesis versus oogenesis. This affects a small subset of 100-200 genes and is evolutional conserved.
What is Angelman’s Syndrome and Prader-Willi’s Syndrome?
These disorders both are due to a deletion of chromosome 15. The same size and location of the deletion. It is always de novo and so the recurrence risk is very low.
The explanation is in the parental origin. In Angelman Syndrome it is the maternal chromosome that carriers the Deletion. A deletion in the paternal chromosome results in Pader-Willi Syndrome. There must be some genes in chromosome 15 that behave differently when inherited from a paternal chromosome compared to the maternal chromosome.
What is the role of DNA methylation in epigenetics?
DNA methylation occurs predominantly at the cytosine residues of CG dinucleotides. The methyl groups are put on by specific DNA methyltransferase after they have been newly synthesised. This is a prime example of an epigenetic modification and so it is reversible and regulated. There are also regions spared from methylation particularly around the promoter regions - CpG islands. These have a role in gene expression. This has to be maintained after replication.
The distribution of CG dinucleotide is not random around a gene. There is a lot around the promoter region on the first exon - CpG island. The also tend to be distinguishable by the fact they are not unmethylated compared to those in the gene. If they acquire methylation, this correlates with transcription silencing
In imprinting genes there is an observable difference in the paternal and maternal gene methylation status. If the paternal alleles is active we see this CpG island is not methylated compared to the methylated silenced maternal gene. There are many variations on this. This difference is the physical manifestation of memory of the imprinted gene as to whether it came from spermatogenesis and oogenesis.
What is the role of genetic imprinting in Beckwith-Wiedemann Syndrome and Russell-Silver Syndrome?
Looking at Beckwith-Wiedemann Syndrome - the syndrome shows foetal overgrowth. There is organomegaly. It is usually not an inherited gene but involves epigenetic changes at chromosome 11. We also see asymmetry and hypoglycaemia.
Russell-Silver Syndrome - Foetal growth problems and persistent perinatal growth failure. It results in a triangular face as the brain size is more conserved. It also shows asymmetry and sporadic occurrence.
These both result due to IGf2 (Insulin-like growth factor 2) gene in 11p15.5. The IGF2 gene is imprinted. We can also find a difference in methylation. The IGF2 gene is imprinted and expressed exclusively in the paternal allele. There is also a neighbouring H19 gene that shows the opposite. The methylated region is upstream of H19 methylated on the paternal allele and not on the maternal allele.
Extra: In the disease state:
In SRS - there is a change in methylation status so that both alleles epigenetically result the normal maternal allele. The H19 is then left unmethylated. The effect on IGF2 is to suppress it, switching off IGF2. There is less IGF2 production leading to growth impairment. Conversely in BWS, both alleles have assumed the configuration that resembles the paternal gene whereby H19 is switched off. There is hypermethylation of both H19 copies and an associated activation of the IGF2 gene on the normally silenced maternal allele.
What is the purpose for X-inactivation?
To ensure gene dosage:
The X and Y chromosome have psuedoautosomal regions. These are regions in which they share common sets of genes - these are at the telomeres. These pair up during meiosis and undergo crossover. Most of the rest of the Y chromosome is unique and mostly heterochromatin - composed of repeat non-coding DNA. There are very few Y specific genes that play important functions. In the unique region of the X chromosome is PGKI for example - the glycolytic enzyme. The gene has two copies in females and one in males. We need X-inactivation to ensure females do not create too much phosphoglycerate kinase.
What is the difference between X-inactivation and imprinting?
In X inactivation:
- A whole X chromosome is silences - There is random choice of parental chromosome - it is different in different cells and somatic cell clones remember which has been chosen - This occurs early in embryogenesis in the blastocyst stage
When does X-inactivation taken place?
Blastocyst stage
What is the role of X-inactivation in X-linked disorders?
Random variation in the proportion of genes activated shows variations in clinical manifestations.
In some clinical situations this can be seen particularly if the woman is a carrier of a X-linked disorder. In this example the female is a carrier of hyperhidrotic ectodermal dysplasia. In affected males this results in an inability to sweat due to failure of the sweat gland and skin to develop. You can detect sweat glands using starch/iodine. Where they generate moisture you can see a streaky distribution.
What are the consequences of X-inactivation?
Females are “epigenetic mosaics”
- Composed of “patches” of cells, working on one or other X chromosomes
- Carriers of x-linked mutations have some functionally defective and some normal cells
- The consequence of this “functional mosaicism” may be unpredictable, and may be also disease-specific
Define Parthenogenesis.
Parthenogenesis This is when you can get a diploid embryo without fertilisation. The second polar body is not extruded after the second miotic division. The embryo is therefore 46 XX.
Define Androgenesis.
Androgenesis This is when the female genetic material has been extruded and the male pronucleus finds itself in an empty egg. There can then be doubling up of the paternal genetic material after replication to give an androgenetic embryo. The zygote is 46 XX because if the sperm brought in a Y chromosome there would be no X at all and this would not be viable. You could also get 2 sperm fertilising an empty egg, again leading to 46,XX.
What is the purpose of genetic imprinting?
Imprinting does not happen on all genes. The fact we have recessive genes means that in not all cases both genes are knocked out - as being heterozygous means that you do not express the disorder. Both copies of the gene are functional.
Imprinted genes are different as they have something to do with growth control and foetal growth as it occurs in placental mammals but not in other species. There is a correlation between foetal growth and perinatal mortality - a poorly growth foetus is less likely to survive the neonatal period. This means evolution favours the genes that favour growth. However unrestrained foetal growth is detrimental to the mother. She then passes on genes to survive the pregnancy. These constraints do not apply to paternal genes. They are therefore likely to provide genes that promote foetal growth. For example IGF2 (insulin like growth factor 2) a major gene involved in foetal growth.
