27 Class Epigenetic inheritance, imprinting inheritance imprinting, and chromatin remodeling
Epigenetics refers to mitotically or meiotically inherited changes in gene function that cannot be explained by changes in DNA sequence. Three examples of epigenetic inheritance, which were mysterious until fairly recently: Maintenance of a determined or differentiated state through many cell divisions in development. X-inactivation in mammalian dosage compensation. Imprinting: parental effects on the next generation.
Genetics of mouse Igf2 gene deletions growth of the placenta, which allows embryos to grow larger. Mouse embryos homozygous for a deletion of the Igf2 gene (Igf2/Igf2) have very small placentas and the fetuses do not survive. When a heterozygous Igf2/+ male is mated to a normal female (Igf2+) mouse the resulting Igf2/+ embryos mouse, also die as above. From these data alone, you could conclude that Igf2 is a. a a dominant mutation b. a recessive mutation c. a gain-of-function mutation d. haploinsufficient mutation ( d a h l i ffi i t t ti (partial d i ti l dominance) ) e. none of the above
Igf2 encodes an insulin-like growth factor that stimulates
However, if a heterozygous Igf2/+ female mouse mates with an Igf2+ male, the resulting Igf2/+ embryos develop normally. This result together with the previous one suggest that: A) B) C) ) D) E)
Igf2 is not a dominant mutation. The Igf2 gene is imprinted in males. The Igf2 gene is imprinted in females. g g p
(A) and (B). (A) and (C).
Strange genetics of mouse Igf2 gene deletions
7
Normal
Inviable
* identical genotypes
This is the result of differential imprinting
Evidence for imprinting from pronuclear p g p transplantation experiments
In a newly fertilized mouse egg, the two pronuclei can be distinguished by their sizes. Either pronucleus can be removed with a pipette and replaced with a pronucleus from another embryo.
Results of mouse pronuclear transplantation experiments
enlarged placenta
late ^
" " arrested at somitogenesis
These pronuclei are from wild-type parents and are genetically identical. Yet neither two paternal nor two maternal genomes will support d ill t development. l t
Thinking about how imprinting works If 2 female pronuclei lead to a small placenta, what can we conclude about the genes that are generally imprinted in maternal germ line? Genes imprinted in the maternal germ line normally _______ growth. g a. Inhibit b. Activate
Let's draw it out with another example A gene closely linked to IGF2, called H19 has also been shown to be imprinted. Deletions () of H19 cause different phenotypes depending on whether the mutation is inherited from the mother or the father. When a heterozygous H19/+ female is mated to a normal male (H19+) mouse, the resulting H19/ embryos have an l (H19 th lti H19/+ b h overgrown placenta and the embryos die. However, However when an H19/+ male mates with an H19+ female H19/ H19 female, the resulting H19/+ embryos develop normally For each of the crosses described above, draw the two chromosomes from each parent with H19 marked, and indicate the site of the deletion with a box box. Now think about the imprinting. In which parental germ line must H19 be imprinted to get the data described?
These results indicate that the H19 gene is g imprinted a. a in females b. in males
How many copies of a parentally imprinted gene are functional in an embryo whose parents are both ild t b th wild-type? ? A) 0 B) 1 C) 2
The mouse Igfr gene encodes a receptor protein he that binds to IGF-2 and degrades it. What would you predict about imprinting of the Igfr gene? A) It is imprinted in females. B) It is imprinted in males. C) It is probably not imprinted.
One more thought experiment: The following Th f ll i gynogenetic mouse embryos (diploid, with 2 maternal ti b (di l id ith t l genomes) were constructed by injection of a second maternal pronucleus of the genotype shown into normal embryos from the which male pronucleus had been removed. One of these embryos removed developed normally. Which one would you predict? A) Igf2(+) H19(+) Igf2(+,imprinting bl k d) H19() I f2( i i ti blocked) B) Igf2(+) H19(+) Igf2(+, Igf2(+ imprinting blocked) H19(+) C) Igf2(+) Igf2() D) Igf2(+) Igf2(+) g ( ) H19(+) H19(+) H19(+) H19(+) ( )
Hint: Think about the states of these two genes in a normal embryo. Does one of these gynogenetic f th ti embryos mimic that state?
Evolution of imprinting? Control the regulation of nutrient exchange between the mother and the gestating fetus?
My genes encourage large and many offspring which can better y ff p g compete for food and mates and allow the production of more offspring. . . My genes encourage smaller and fewer offspring so the offspring survive and can produce more offspring
"Battle of the sexes" drives evolution of imprinted placental and embryonic growth genes?
How might imprinting have come about?
Interesting evolutionary story Imprinted genes are surrounded by transposable elements Transposable elements can hop around and cause damage, and are suppressed by a host defense mechanism, which mechanism targets them for inactivation. This can also silence nearby genes In the platypus (egg laying mammal), there is no imprinting. And in the genome, there are fewer transposable elements around those genes. A placental mammal may have had a better chance for survival if it imprinted placental growth genes
http://atlasgeneticsoncology.org/Deep/Images /GenomImprintFig15
Persistence of imprinting P i t f i i ti Imprints and the accompanying gene silencing persist throughout the lifetime of the animal in somatic tissues. Imprints are erased in the germline prior to meiosis. New imprints are applied during gametogenesis depending on the sex of the animal. What's the molecular mechanism?
Gene silencing by chromatin remodeling h G il i b h ti d li happens in: Maintenance of developmental states Maintenance of X-inactivation Imprinting Silencing of a gene is accompanied by methylation of cytosine bases in DNA of the promoter region in particular. p m g p .
Methylation of DNA accompanies gene silencing Only cytosines in CG dinucleotides become methylated State of methylation may be changed during development.
DNA methylation patterns are maintained when DNA replicates during cell division p g
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