Genet 302 lec 43 & 44
What 2 imprinting disorders were used as examples from chromosome 15?
Prader-Willi syndrome and Angelman syndrome
How can the same chromosome region cause different syndromes depending on parental origin?
Because different genes in the imprinted cluster are active on the maternal versus paternal chromosome
What is a common cause of Prader-Willi syndrome or Angelman syndrome in this lecture?
A germline deletion caused by NAHR
Are the common 15q11 deletions usually inherited or new germline events in this lecture?
New germline events
If the 15q11 deletion is on the paternal chromosome, what syndrome results?
Prader-Willi syndrome
If the 15q11 deletion is on the maternal chromosome, what syndrome results?
Angelman syndrome
What is the general mechanism behind deletion-based imprinting disorders?
Deletion removes the only active parental copy of an imprinted gene or gene cluster
About what fraction of human genes are in imprinted gene clusters?
About 1%
What is an imprinting control region, or ICR?
A regulatory region whose parent-specific methylation helps control expression of genes in an imprinted cluster
At 15q11, is the ICR methylated on the maternal or paternal chromosome?
Maternal
Is maternal ICR methylation at 15q11 typical or unusual in this lecture?
Typical
What happens if SNRPN is mutated on the paternal chromosome?
Prader-Willi syndrome
What is the general mechanism behind key-gene mutation causing an imprinting disorder?
Mutation hits the only active parental copy of an imprinted gene
What happens if the ICR is mutated on the maternal chromosome in the 15q11 example?
Angelman syndrome
What is the general mechanism behind ICR mutation causing an imprinting disorder?
The regulatory methylation pattern is disrupted, so parent-specific gene expression is lost
What happens with upd(15)mat in the lecture example?
Prader-Willi syndrome
Can either maternal isodisomy or maternal heterodisomy cause the same imprinting disorder?
Yes, because both remove the paternal contribution
What is the general mechanism behind UPD causing an imprinting disorder?
Both chromosomes come from one parent, so the child lacks the normal maternal-paternal imprinting balance
What is the purpose of genomic imprinting in mammals according to lecture 44?
To regulate parent-specific expression of genes involved especially in placental and embryonic growth
What mouse chromosome example was emphasized for genomic imprinting?
The imprinted gene cluster on mouse chromosome 7
What general effect does maternal H19 have in the lecture example?
It decreases embryo and placenta size
What general effect does paternal Igf2 have in the lecture example?
It increases embryo and placenta size
What is a major cost of genomic imprinting?
It eliminates one advantage of diploidy because only one parental copy is expressed
Why is genomic imprinting thought to have evolved mainly in placental mammals?
Because it is associated with live birth and competition over maternal resources in utero
How does the lecture connect imprinting with monotremes, marsupials, and placentals?
Monotremes lay eggs, while marsupials and placentals have live birth, and imprinting is associated with the live-birth lineages
Where are most imprinted genes active according to the mouse lecture?
In the placenta rather than the embryo
What theory for the evolution of imprinting was emphasized?
The kinship theory
What does the kinship theory say in one sentence?
Maternal and paternal genes have conflicting interests over fetal growth and maternal resource use
According to the kinship theory, what is in the father’s best interest?
Increase embryo size
According to the kinship theory, what is in the mother’s best interest?
Decrease embryo size
Why would paternal genes favor increased embryo size?
Because other embryos may not share the same father, so paternal genes benefit from extracting more maternal resources
Why would maternal genes favor decreased embryo size?
Because all embryos share the mother, so she benefits from distributing resources more evenly
What marsupial fact supports the kinship theory in this lecture?
Marsupials spend less time in utero and have fewer imprinted genes
What classic experiment showed both maternal and paternal genomes are needed for normal mouse development?
Pronuclear transplantation by McGrath and Solter
What happens when a mouse embryo has one maternal and one paternal pronucleus?
The placenta is the correct size and the embryo is healthy
What happens when a mouse embryo has two maternal pronuclei?
The placenta is too small and the embryo starves
What happens when a mouse embryo has two paternal pronuclei?
The placenta is too large and the embryo starves
What do the two-mother and two-father mouse experiments show about the purpose of imprinting?
Maternal and paternal genomes are not functionally equivalent because they make different contributions to growth regulation
How was a parthenogenetic mouse made viable in the later Kono experiment?
One maternal chromosome 7 had a deletion that altered the imprinting balance
Why did deleting one maternal MMU7 help rescue development?
It reduced the excess maternal-growth-restraining effect and restored a more normal balance of imprinted gene activity
How is genomic imprinting achieved in mammals overall?
By parent-specific DNA methylation at ICRs that controls expression of imprinted gene clusters and makes some genes maternally expressed and others paternally expressed