Lecture 11 'SVAs and their contribution to human disease'

Question 1

Non-autonomous

Answer 1

SVAs are non-autonomous since they do not have the ability to move or replicate on their own (do not
encode own endonuclease and reverse transcriptase). Instead, they depend on other transposable elements, such as L1 LINE elements,
for their movement and proliferation within the genome.

Question 2

Human polymorphic SVAs

Answer 2

• Some human SVA insertions are
  polymorphic, meaning the
  insertion is only present in a
  subset of humans.
• Lots of human polymorphic SVA
  insertions have been identified.
• Some of these polymorphic SVA
  insertions can lead to diseases

Question 3

Definition and structure of SVA

Answer 3

SVAs are repetitive DNA sequences found in the human genome.
- SVA is a composite element. They are composed of three main repetitive DNA elements: an Alu element, a Variable number tandem repeat (VNTR) region, and a Sine element.
- SVA also includes a hexameric repeat (CCCTCT)n at the 5’ end and a Poly(A) at the 3’ end.
- SVA replicate through an RNA intermediate via “copy and paste” mechanism

Question 4

SVA insertions

Answer 4

Some of these polymorphic SVA insertions can lead to diseases. SVA insertions can impact the genome in various ways. SVAs are rich in G-quadruplex (G4) forming sequences. SVAs containing strong gene regulatory potential. SVA are bound and repressed by KRAB Zinc finger 91 (ZNF91)

Question 5

Evolution of SVAs

Answer 5

• SVAs arose and have been active very recent in hominoid (great apes) evolution.
• The distribution and prevalence of SVAs vary among different hominoid species.
• Approximately half of SVAs in the human genome are unique to humans (human-specific)

Question 6

The potential mechanisms of SVA to mediated diseases are

Answer 6

having impact on genome structure & having impact on gene expression
Genome structure: insetional mutagenesis, creation of hexamer and or VNTR, insertion mediated deletion and non-canonical DNA structures like G4s
Gene expression: Aberrant splicing, premature transcripiton, carry TF binding sites that can modulate gene expression, contain promotors that can initiate transcription, and epigenetic changes

Question 7

Pathogenic SVA insertions

Answer 7

can cause mis-splicing, truncated proteins, and abberrant protein localization. The first human disease found to result from a SVA insertion is FCMD

Question 8

Case study about X-linked Dystonia Parkinsonism (XDP)

Answer 8

X-linked Dystonia Parkinsonism (XDP) is a severe neurodegenerative diseases associated with the insertion of a Sin-VNTR-Alu (SVA), retrotransposon in exon 32 of the TAF1 gene. XDP-SVA dysregulates TAF1 transcription.
- Loss of ZNF91 further aggravates TAF1 dysregulation
* ZNF91 is an endogenous repressor of the XDP molecular phenotype