TRANSPOSONS

Mobilizing diversity: transposable element

insertions in genetic variation and disease

Presented By : Narmeen Arshad

FUUAST

MS 2014

Outline

• Introduction

• Mechanism of TE regulation in germ line

• Mechanism of TE regulation in Somatic cells

• TE & Cancers

• Identification techniques

• Conclusion

Transposable element

Junk DNA

Jumping Genes

Mobile Genetic

Elements

Transposons

Selfish DNA

Transposable Elements

• A transposable element is a DNA sequence that can change its position within the genome, sometimes creating or reversing mutations and altering the cell's genome size.

• Barbara McClintock's discovery of these jumping genes earned her a Nobel prize in 1983.

Characteristics of TE• 45% of human chromosomal DNA is derived

fom TE.

• Contributes to genetic variation that leads to spontaneous mutation & genetic rearrangements.

• TE modify gene structure ---- hence alter gene expression.

• Mobilization , reshuffling, rearrangement occurs, that creates ---- “novel genes”.

• In Rare cases it causes mutations ---- disease.

Types of TE

• Reterotransposons ( Class I)

Copy & paste mechanism

• DNA transposons ( Class II)

Cut & paste mechanism

Imp. Characteristic of Retrotransposons

• Of all mobile elements family , RT remain actively mobile in human & primate genomes.

• Ongoing source of Genetic variation.

• By generating new transposons.

Effects of TE on host genome

• Little or no impact on gene function.

• Deleterious effect on host genome resulting in disease.

• 65 diseases causing TE insertions have been documented.

Mechanism of TE Regulation in Germ Line

• Expansion occurs when TE is transmitted into subsequent generations.

• Eg : DNA Methylation (There is also considerable evidence suggesting that DNA methylation suppresses proliferation of transposable elements.)

Consequences of TE insertions in the genome

• New insertions/passing through the germ line.

• Constitutional genetic diseases.

• Commonly involved TEs are ---- Alus, L1s, SVA’s.

Eg of diseases caused by insertions:

• Alu & L1 -----induce coagulopathies by disruption of coagulation factor VIII/IX

• Alu & SVA insertions causing -----immunodeficiency.

• Line 1 insertion ---- results in muscular dystrophies & cardiomyopathies.

• Intronic Alu insertion ---- disrupting function of NF1 tumour suppressor causing neurofibromatosis.

TE insertions in Somatic Cells

• Full length & processed L1 transcripts are detected in human somatic tissues but in low %.

• L1 somatic transposition have been discovered in blastocysts from transgenic mouse models expressing human L1 elements.

• This data suggests that L1 elements contribute to somatic cells.

• Gage & Colleagues detected an increase in copy # of L1 in some regions of adult human brain.

• Brain samples contain approx. 80 additional copies of L1 sequence per cell.

• Functional consequences are unknown.

• So the extent of genetic diversity due to TE remains largely unexplored.

TE & Cancers

• A hall mark of cancer proliferation is accumulation of somatic genetic changes.

• Eg : 1. Line1 reterotransposition ---- colon cancer.

2. L1 insertions ---- Human lung tumors.

• Thus it is possible that tmors provide environment where transposition events occur.

Strategies for identifying TE insertions

TE & human genetic diversity

• Sequencing of human genome revealed that single genome exhibits 0.1% variation.

• Bennet & colleagues tried to detect the degree of genetic variation caused by TE.

• They analyzed data from 36 people of diverse ancestry.

• They estimated human population have an average of 2000 common TE polymorphism.

Conclusion :

• Computational analysis & experimental validation suggests that roughly 700 novel transposable element insertion events takes place due to Alus, L1 & SVA in single diploid genome.

Future approach

• TE plays role in structural variance ?

• Characterization of TE --- to study potential functional consequences.

• Understanding of mechanism & regulation of TE is not fully understood.

Reference paper

Thank you

QS …..?