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Imprinting: Angelman, Prader-Willi, and Other Syndromes: Advanced Human Genetics Jonathan Wolfe

Imprinting is an epigenetic phenomenon where genes are expressed differently depending on whether they are inherited from the mother or father. Certain genetic syndromes like Angelman syndrome and Prader-Willi syndrome are caused by deletions on chromosome 15 that remove imprinted genes. The Callipyge phenotype in sheep is an example of polar overdominance where only paternal inheritance of a mutation causes a muscle hypertrophy trait. Beckwith-Wiedemann syndrome in humans involves epigenetic changes and loss of imprinting in an imprinted gene cluster on chromosome 11p15.5 that regulates growth.

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Boppani Ram Manohar
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74 views22 pages

Imprinting: Angelman, Prader-Willi, and Other Syndromes: Advanced Human Genetics Jonathan Wolfe

Imprinting is an epigenetic phenomenon where genes are expressed differently depending on whether they are inherited from the mother or father. Certain genetic syndromes like Angelman syndrome and Prader-Willi syndrome are caused by deletions on chromosome 15 that remove imprinted genes. The Callipyge phenotype in sheep is an example of polar overdominance where only paternal inheritance of a mutation causes a muscle hypertrophy trait. Beckwith-Wiedemann syndrome in humans involves epigenetic changes and loss of imprinting in an imprinted gene cluster on chromosome 11p15.5 that regulates growth.

Uploaded by

Boppani Ram Manohar
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© © All Rights Reserved
We take content rights seriously. If you suspect this is your content, claim it here.
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Imprinting: Angelman, Prader-Willi, and other syndromes

Advanced Human Genetics Jonathan Wolfe

androgenetic embryos

gynogentic and androgenetic embryos


Experimental ... gynogenetic (two female pronuclei) androgenetic (two male pronuclei) and see also the naturally occurring ... ovarian teratoma
- 46,XX karyotype, benign tumour, many differentiated tissues

hydatidiform mole
- 46, XX karyotype, - hyperplasia of trophoblast - choriocarcinoma (50% 0f cases)

uniparental isodisomy

Robertsonian translocations
Fusion of two chromosomes with the loss of the short arms

Mouse maps

sites
http://www.mgu.har.mrc.ac.uk/research/imprinting/ http://www.geneimprint.com/

references
Tilghman, 1999 Cell, 96, 185193, The Sins of the Fathers and Mothers: Genomic Imprinting in Mammalian Development Vu, and Hoffman, 2000 Genome Research, 10, 1660-1663, Comparative Genomics Sheds Light on Mechanisms of Genomic Imprinting Freking et al., 2002 Genome Research 12, 1496-1506, Identification of the Single Base Change Causing the Callipyge Muscle Hypertrophy Phenotype, the Only Known Example of Polar Overdominance in Mammals Ferguson-Smith and Surani, 2001, Science, 293, 1086-1089 Imprinting and the Epigenetic Asymmetry Between Parental Genomes Nicholls and Knepper, 2001, Ann. Rev. Genomics and Hum. Genet., 2, 153175 Genome organization, function and imprinting in Prader-Willi and Angelman syndromes. David A. F. Loebel and Patrick P. L. Tam, 2004, Mice without a father, Nature 428, 810-811

Beckwith Wiedeman Syndrome


frequency in the general population is about 1/14,000 characterized by somatic overgrowth, congenital malformations and a predisposition to embryonic neoplasia. The majority of cases occur sporadically. In up to 60% of sporadic cases, the epigenetic changes occur at differentially methylated regions within 11p15.5 in a region of approximately 1 Mb. This region contains an imprinted cluster of at least 12 genes, including paternally expressed genes IGF2 and KCNQ1OT1 maternally expressed genes H19, CDKN1C and KCNQ1

Transcription regulation in the BWS region

Approximately 25 to 50% of BWS patients have biallelic expression of the IGF2 gene some of these cases exhibit loss of imprinting (LOI) of IGF2 which is dependent on hypermethylation changes of H19 Approximately 50% of sporadic BWS have a loss of methylation associated to a LOI at KCNQ1OT1, an untranslated RNA within the KCNQ1 gene Some BWS cases exhibit LOI for KCNQ1OT1 as well as LOI for IGF2

aberrant methylation of KCNQ1OT1 is specifically associated with overgrowth and congenital defects
aberrant methylation of H19 is specifically associated with an increased risk of developing tumors.

Angelman, Prader-Willi syndromes


Usually caused by large (megabase+) deletions of 15q11-q13 Delete maternal chromosome = AS Delete paternal chromosome = PWS

Paternally expressed genes are imprinted in all tissues UBE3A, is only differentially expressed in parts of the brain

Callipyge
Beautiful buttocks A mutation which arose in a Dorset Ram Polar Overdominance

Polar overdominance
Heterozygote expresses the phenotype but neither homozygote does Heterozygote only expresses the phenotype if the mutant gene is inherited from the father

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