Genetic imprinting Flashcards
(lec 5 ) SF
Genetic imprinting
Monoallelic expression of autosomal genes depending on the sex of transmitting parent.
How does a gene get silenced in genetic imprinting?
epigenetic modification such as DNA methylation
or any other changes in proteins that bind to DNA (cytosine methylation and histone modifications.)
androgenetic
Fertilized egg (zygote) with all paternal chromosomes
gynogenetic
Fertilized egg (zygote) with all maternal chromosomes
Why do androgenetic and gynogenetic embryos fail to complete development?
because of imprinted genes, which are expressed differently during development depending on their parental origin. Even though they are autosomal and present in two copies, one maternal and one paternal, only one of the two alleles is expressed.
Are the same paternal imprint kept on the offsrpting and passed down?
no, imprints are erased and reapplied in the germline so that only maternal imprints are seen in oocytes and only paternal imprints are seen in sperm
Disorders caused by disruption of imprinted genes
Prader-Willi
Angelman
How do gynogenones develop?
They have poorly developed extraembryonic tissues, differentiated fetal tissues (Like ovarian teratoma)
How do Androgenones develop?
They have poorly developed embryonic tissue but extensive extraembryonic tissue (hydatidiform mole
Examples of imprinted genes
Examples include IGF2, IGF2R, H19, Insulin, Some G proteins
How are imprinted genes positioned on the DNA
Imprinted genes oftentimes cluster but different genes within the same cluster may be imprinted in opposite direction (Mat vs Pat)
Prader-Willi
Cause: deletion (5-6 Megabases) at 15q11-q13 (paternal allele deleted) Symptoms: Initial feeding problems Later hyperphagia Obesity Short stature Small hands and feet Mild-moderate MR Hypogonadism
Angelman
Cause: deletion (5-6 Megabases) at 15q11-q13 (maternal allele deleted) symptoms: Ataxic gait (unsteady walking) Absent speech Prominent jaw Inappropriate laughter Moderate-severe MR ( mental retardation)
What can cause imprinting disorders?
Deletion point mutation Unnniparental disomy (innheritance of two copies from one parents -> caused by trisomy rescue)
Beckwith Wiedemann syndrome
Cause:
Mutations in one of 11p15.5 alleles
(IGF2 is a fetal growth factor and is paternally expressed
H19 is an untranslated RNA that is maternally expressed
Only one of the 2 genes can be expressed at any given time from the same chromosome)
Clinical phenotype: overgrowth Large for gestational age Macroglossia Nephromegaly and adrenomegaly Omphalocoele Some predisposition to kidney/liver/adrenal tumors
Waht are histones?
Histones are globular proteins with a flexible N terminus tail that bind to DNA to form nucleosomes
How are histone modification implemented?
acetylation of specific lysine residues by histone acetyltransferases and deacetylation by histone deacetylase
The methylation of lysine and arginine residues by histone methytransferases and the demethylation of lysine residues by histone demethylases
What kind of DNA configureation does trimethylation cause?
Generally, tri-methylation at H3-K4, H3-K36, or H3-K79 results in an open chromatin configuration and is therefore characteristic of euchromatin.
What are some types of histone modification?
Methylation
Acetylation
phosphorylation of specific serine groups by histone kinases
attachment of ubiquitin, small ubiquitin-like modifiers, and poly ADP-ribose (PAR) units
How do you read H3K27me3?
histone 3
aminno acid lysine, 27th position from the N terminus
trimethylation
What type of disease does mutation in many of the histone modification and chromatin configuration genes result in?
ntellectual disability syndromes such as Weaver syndrome, Sotos syndrome, Kabuki syndrome
