Repeat Expansions

What are the features of the repetitive genome?

• Around 50% of the genome is repetitive  

• Likely significant contribution to human variability and disease risk  

What are interspersed repeats?

• Transposons - interspersed  

• Remnants of virus  

• 500,000 LINE-1 and 1 million Alu  

• Some are mobile and other's aren't  

What are the features of interspersed repeats?

• Moving sequences make it hard to sequence the genome and can unaligned  

• Chromosome rearrangement  

• Recombination between non-homologous loci  

• Insertion  

• Monogenic, into protein coding genes  

• Impact regulatory elements 

• Bring hypermethylation  

• Associated cancer  

• Loss of epigenetic control  

• Body defends against transposition  

• Cancer cause cancer  

• Hypermethylation can spread to other parts of the genome  

What are the features of tandem repeats?

• Over 1 million  

• Satellites  

• Chromosome structure and heterochromatin that are long  

• Variable number of tandem repeats  

• Micro/minisatellites which are 1-6bp  

What are the features of tandem repeats?

• Toxic gain of function 

• mRNA production  

• Polyglutamine disease (CAG/A) repeat expansions  

• Cause HD, SCA 9 conditions  

• Loss of function  

• Neurological and neuromuscular disease  

• Unstable – tissue mosaicism/ and on meiosis  

• Anticipation  

How do repeats cause problems in the lab?

• Slippage  

• Alignment  

• Some repetitive areas of the genome are still missing from reference sequence  

What are the lab tests for repetitive sequences?

• PCR  across  

• Triplet primed PCR 

• Southern blot 

• WGS  

• Long range sequencing  

What causes DMPK?

• Autosomal dominant condition  

• Affects 1 in 8500  

• Trinucleotide repeat disorder with classic anticipation  

What are the features of DMPK?

• Many only have cataracts, diabetes and balding  

• Facial/generalised weakness, ptosis, myotonia, cataracts, arrythmias, endocrine  

• Polyhydramnios, severe hypotonia, respiratory support, later LD, 20% infant mortality  

How do repeats cause DMPK?

• Triplet repeat expansion of non-coding part of myotonin gene  

• RNA toxicity  

• Toxicity increases with the size of the expansion  

How are repeats different in DMPK?

• Maternal anticipation  

• CTG<37 is normal  

• GTG>50 esp >200  

• >1000 congenital  

What are the features of Fragile X syndrome?

• Variable ID, autism, anxiety, macrocephaly, macroorchidism, hypermobility 

• Girls being less affected, sometimes mild to moderate learning delays and or anxiety  

• Tissue and methylation mosaicism overlap  

What are the features of Fragile X Premutation?

• Expand on full female transmission  

• Anchoring AGGs  

• Fragile X-associated tremor ataxia syndrome  

• TXTAS 40-45% of males>50 years and 8-16% females  

• Premature ovarian insufficiency – 20% females  

• Thyroid problems, anxiety  

What are the features of intermediate fragile X?

• Intermediate allele >44 relatively common in the population  

• 1 in 50  

• Have risk of expanding