Jumping Genes Challenge Assumptions About Genetic Diseases Such As Cancer
The study was conducted by senior author Dr Haig H. Kazazian Jr, Seymour Gray Professor of Molecular Medicine in Genetics at the University of Pennsylvania School of Medicine in Philadelphia, and colleagues, and is published this month in the journal Genes and Development.
Transposons, or "jumping genes", are DNA sequences that jump to different parts of the genome within a cell.
Transposons cause disease but we don't know the extent to which the diseases they cause, such as hemophilia and Duchenne muscular dystrophy, are passed onto offspring. They also play a role in the development of cancer.
Kazazian Jr and colleagues found that transposons insertion can occur after fertilization, when the embryo is developing, which is after the point at which genetic changes can be inherited: ie they happen once the individual is formed from the egg and sperm of the bioligical parents.
Based on their findings, the researchers propose that many of the insertions occur in the early embryo, while it comprises just 4 or 8 cells.
This is a dramatic challenge to current assumptions about mobile DNA, which until now scientists assumed could only be inserted in the genome prior to fertlization, in egg and sperm of the parents.
For the study, Kazazian Jr and colleagues looked at the L1 family of retrotransposons, the most common type of retrotransposon in the human genome.
A retrotransposon is a type of jumping gene that moves in a distinct way: its DNA sequence is copied to RNA as with other genes, but instead of being used directly to code a protein, it is then copied back into DNA under the control of its own reverse transcriptase enzyme. This new DNA sequence is then put back into the genome.
The process is similar to the way that HIV and other retroviruses behave, leading scientists to suggest that retroviruses came from retrotransposons.
About 17 per cent of the human genome is made up of the L1 family of retrotransposons, so they are no small matter and they have an impact that is even larger than this. For example, when they "jump" they take parts of nearby DNA sequences with them, causing new genes to be created where they eventually "land".
Eventually, as one can imagine, the more that retrotransposons jump around the genome, the longer it gets and the more its content gets shuffled. As well as this, an otherwise unremarkable jump of L1 can have a significant impact such as lowering the ability of nearby genes to express themselves.
L1 insertions come about in two ways: one is where the L1 RNA is carried over from the parent through fertilization and then gets inserted in the embryo's genome. The other and more frequent way, is when the L1 itself arises in the embryonic genome.
Using mice and rats bred to have elements of human L1, the researchers showed there was lots of L1 RNA in egg, sperm and embryos. But they also showed that integration into the genome occured primarily at the embryo development stage and not within egg and sperm cells and were therefore not inheritable.
Kazazian Jr and colleagues also showed that L1 RNA transcribed in egg and sperm cells carry over through fertilization and insert during embryo development, which is a curious example of RNA being heriditary independently of the DNA that encodes it. This creates what the authors called "somatic mosaicism" with some cells having the insertion and others not, leading to cell populations with different genotypes developing within the same organism.
This mosaicism could suggest that L1 plays an important role in the development of cancer and other diseases, for instance if the insertion happens near a cancer gene, it could trigger cancer growth.
"L1 retrotransposition occurs mainly in embryogenesis and creates somatic mosaicism."
Hiroki Kano, Irene Godoy, Christine Courtney, Melissa R. Vetter, George L. Gerton, Eric M. Ostertag, and Haig H. Kazazian, Jr.
Genes Dev. June 1, 2009 23: 1303- 1312.
Additional sources: PENN Medicine.
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