Non-Mendelian Inheritance I: Imprinting
(1) The process in which genetic material is expressed differently when inherited from the mother than when inherited from the father.
(2) The differential modification of the paternal and maternal contributions to the zygote, resulting in the differential expression of parental alleles; i.e. for some genes, paternal and maternal alleles function differently.
Mechanism of imprinting
The molecular basis if imprinting is still unclear. It is thought that there is an association between methylation and transcriptional inactivation. The attachment of methyl groups to DNA may inhibit the binding of proteins that promote transcription. Regardless, it is not clear if methylation is the primary imprinting signal or whether it serves to maintain the imprinting signal once it is established by other mechanisms (e.g., alteration in chromatin structure).
Studies of imprinting in the mouse
(A) Pro nuclear transplantation experiments
After the fertilization of a mouse egg the pronuclei (the genetic material in the sperm/egg before it combines with the other’s chromosomes) were separated and identified. One was removed and another replaced. This gave to the following:
(B) Analysis of translocation heterozygotes
A technique in which mice with identical translocations were mated was used to study which chromosomes got imprinted. As a result several mouse chromosomes are now known to be imprinted; however, most chromosomes show no imprinting effects.
(C) Studies of methylation/gene expression
Studies showed an imprinting effect on specific loci in the mouse genome. The imprint can be erased and re-established in each succeeding generation via methylation. Using this techinque several genes were shown to have imprinted patterns of expression: IGF2 repressed on maternal chromosome, and IGF2 Receptor and His repressed on paternal chromosome.
Studies of imprinting in humans
(A) Genome-wide imprinting abnormalities
- (1) Two maternal pronuclei: resulted in a poorly developed extraembryonic membrane.
- (2) Two paternal pronuclei: resulted in highly abnormal embryonic structures.
- (3) Pronuclei of both maternal and paternal origin: resulted in normal embryonic development.
Benign tumors derived from all three germ layers.
No extra-embryonic tissue. A mass of differentiated embryonic tissue (mature teeth, hair, etc).
Due to 2 maternally derived haploid chromosomes. (46, XX)
(B) Chromosome-specific imprinting effects
The best studied imprinting disorders in humans are the Prader-Willi and Angelman syndromes, which are both associated with uniparental disomy for chromosome 15.
Uniparental Disomy = condition in which two copies of one chromosome are derived from a single parent, and nocopies are derived from the other parent.
- Human placental tumors – usually malignant
- zygote does not develop to produce an embryo.
- Characterized by swollen, hyperplastic chorionic villi which have a propensity for malignancy.
- Due to 2 paternally derived haploid chromosomes. (46, YY)
Prader-Willi syndrome (PWS)
- Note: in some cases uniparental disomy can lead to recessive disorders, if the offspring gets two chromosomes with the recessive gene.
Angelman syndrome (AS)
- Clinical: hypogonadism, obesity, small hands and feet, short stature, and mental retardation.l
- Etiology: Due to a deletion on paternal chromosome 15 (15q11-15q13). Most likely caused by a defect in the gene for SNRPN (a gene that is only active on the paternal chromosome).
In both syndromes the same 15q segment is missing.
- "Happy Puppet Syndrome"
- Clinical: microcephaly, ataxia, seizures, inappropriate laughter, and severe mental retardation.
- Etiology: Due to a deletion on maternal chromosome 15 (15q11-15q13). Most likely caused by a mutation in the protein that degrades uBE3A (a gene that is only active on the maternal chromosome).
- Why are there more maternal than paternal ? – Because meiotic non-disjunction is much more common in women. (Lots of trisomy due to female nondisjunction).
The zygote initially has three chromosome 15’s (trisomy 15 is lethal).
Most likely the zygote has two from mom and one from dad.
Loss of one of the chromosome 15 may allow survival, but:
Þ Parder-Willi Syndrome
Loss of maternal 15 Þ Normal
The DNA sequence that apparently helps to set and reset the imprint.
A mutation in the imprinting center will lead to Prader-Willi or Angelman Syndrome.
In gametogenesis the imprinting center will reset the chromosomes as either maternal or paternal.
Clinical: large size for gestational age, large tongue, omphacele, predisposition to Wilhems tumor (a kidney tumor which is the most common childhood tumor).
Etiology: Several genes on chromosome 11 are imprinted. When get two paternal copies of chromosome 11 see this syndrome. Why? IGF2 (Insulin Growth Factor) is only active on the paternal chromosome 11. The disease is caused by the over-expression of the gene!