Jumping Genes Discovery Challenges Current Assumptions

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Jumping Genes Discovery " Challenges Current Assumptions "

http://www.medicalnewstoday.com/articles/153699.php

Jumping genes do most of their jumping, not during the development of sperm and

egg cells, but during the development of the embryo itself. The research,

published this month in Genes and Development, " challenges standard assumptions

on the timing of when mobile DNA, so-called jumping genes, insert into the human

genome, " says senior author Haig H. Kazazian Jr., MD, Seymour Gray Professor of

Molecular Medicine in Genetics at the University of Pennsylvania School of

Medicine.

Jumping genes also called transposons are sequences of DNA that can move or jump

to different areas of the genome within the same cell. Jumping gene insertions

do cause disease; however, it's not known how frequently diseases due to

insertions can be inherited in the next generation. They are a rare cause of

several genetic diseases, such as hemophilia and Duchenne muscular dystrophy. In

addition, transposon insertion into the genome could play a role in the

development of cancer.

The current work alters thinking in the field of jumping genes, challenging

standard assumptions that mobile DNA inserts only in eggs and sperm during their

respective early development. In this study, the researchers found that

insertions took place during embryogenesis after fertilization, at a time when

nearly all of the changes can't be inherited. The researchers now purport, based

on the study's findings, that many of those insertions occur in the early

embryo, perhaps in the 4- or 8-cell stage.

The study looked at retrotransposons, one class of jumping genes, with the L1

family the most abundant type of retrotransposon in the human genome.

Retrotransposons move by having their DNA sequence transcribed or copied to RNA,

and then instead of the genetic code being translated directly into a protein

sequence, the RNA is copied back to DNA by the retrotransposon's own enzyme

called reverse transcriptase. This new DNA is then inserted back into the

genome. The process of copying is similar to that of retroviruses, such as HIV,

leading scientists to speculate that retroviruses were derived from

retrotransposons.

The L1 family of retrotransposons comprises about 17 percent of the human

genome. Eventually, continuous jumping by retrotransposons expands the size of

the human genome and may cause shuffling of genome content. For example, when

retrotransposons jump, they may take portions of nearby gene sequences with

them, inserting these where they land, and thereby allowing for the creation of

new genes. Even otherwise unremarkable insertions of L1 may cause significant

effects on nearby genes, such as lowering their expression.

Insertions can come from an L1 retrotransposon that is in the genome of the

embryo or it can arise from an L1 that was in a parent and is not in the embryo.

In the latter case, the L1 RNA from that parent is carried over through

fertilization and inserts in the embryo. Insertions in the latter case are much

less frequent than when the L1 itself is present in the genome of the embryo.

Despite L1 abundance in the genomes of mammals, relatively little is understood

about L1 retrotransposition outside of the test tube. Using transgenic mice and

rats containing human or mouse L1 elements, the team demonstrated abundant L1

RNA in both egg and sperm cells and embryos. However, the integration events

usually occur during the development of the embryo rather than in egg or sperm

cells and are not heritable.

They also demonstrated that L1 RNA transcribed in egg or sperm cells can be

carried over through fertilization and integrate during embryogenesis, an

interesting example of heritability of RNA independent of its encoding DNA,

creating somatic mosaicism during mammalian development. Soma are all cells

other than egg or sperm cells. A cell mosaic is an insertion that occurs after

fertilization in which some cells have the insertion and others don't within the

same tissue type. The mosaicism suggests a role for L1 in carcinogenesis and

other diseases; for example cancerous growth may be initiated if insertions

happen near an oncogene.

This work was funded by the National Institute for General Medical Sciences and

the National Center for Research Resources. Co-authors in addition to Kazazian

are first author Hiroki Kano, a former postdoctoral fellow in the Kazazian lab

now at the University of Osaka, Irene Godoy, and , along with

R. Vetter and L. Gerton, all from Penn, and co-senior author

M. Ostertag, Transposagen Biopharmaceuticals Inc, (Lexington, KY).