X-inactivation 

• Overview
– lyonization
– inactivates # of X chromosomes - 1 in a Barr body
• triploid X will have 2 Barr bodies
• Mechanism
– mediated by XIST gene
– inactivation through methylation
– occurs at blastocyst stage in female embryos
– X copy chosen for inactivation is random
• after choosing every subsequent cell will have the same X copy inactivated
• Clinical relevance
– mosaicism
• non-homogenous X inactivation
• some cells express paternal X and some cells express maternal X
 Imprinting
• Describes differences in transcriptional activity based on
whether the chromosome is of maternal or paternal origin
• At a single locus
– 1 allele is active
– 1 allele is inactive
• Creates a hemizygous state
• Mechanism
– inactive ("imprinted") allele is methylated during gametogenesis
• creates transcriptional inactivity
– is maternal/paternal specific
• gene at one locus always methylated on a specific copy
– all cells of an individual have same imprinting level
 Prader-Willi syndrome
• Deletion of normally active paternal allele on 15q
• remember: Prader = paternal deletion
• Or Uniparental Disomy of mother’s chromosome
15
• Presentation
– mental retardation
– hyperphagia → obesity
– hypogonadism
– neonatal hypotonia
– behavior problems
 Angelman's syndrome
• disruption of the maternally expressed and paternally imprinted
gene UBE3A, which encodes an E3 ubiquitin ligase 
• Deletion of the normally active maternal allele on chromosome 15q
– same region of the genome as Prader-Willi syndrome deletion but opposite
chromosome (not the same gene)
• Or Uniparental Disomy of mother’s chromosome
• Presentation
– severe cognitive disability
– frequent seizures
– ataxia
– speech impairment
– hyperactivity
– inappropriate laughter
• "happy puppet"