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TRANSPOSONS, JUNK DNA
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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
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