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LMG Fellows Host Talk on Endogenous Mutagenesis

By Stephanie Nick McElhinny
January 2009

Boeke opened his lecture
Boeke opened his lecture with kind words for his colleagues at NIEHS. "One of my formative experiences as a graduate student was attending a Gordon Conference on Mutagenesis where I heard talks by Jan Drake and Tom Kunkel. That meeting was such an exciting experience, and I knew then that I had found my niche in science." (Photo courtesy of Steve McCaw)

DNA Replication Fidelity Group Postdoctoral Fellows Andreas Larrea, Ph.D., and Scott Lujan, Ph.D.
The near-capacity audience failed to keep DNA Replication Fidelity Group Postdoctoral Fellows Andreas Larrea, Ph.D., and Scott Lujan, Ph.D., from finding a place to sit during the presentation. (Photo courtesy of Steve McCaw)

Boeke and lecture host Yong Yang, right
Boeke and lecture host Yong Yang, right, fielded questions from fellows and senior investigators following the lecture. (Photo courtesy of Steve McCaw)

On December 8 in Rodbell Auditorium, the NIEHS Trainee Action Committee (TAC) of the Laboratory of Molecular Genetics (LMG) welcomed the most recent researcher in its trainee-invited speaker series. The guest lecturer, Jef Boeke, Ph.D., of the Johns Hopkins University School of Medicine, presented his group's latest research results and diagnostic advances in a seminar titled "Retrotransposons in Humans and Other Mammals." Yong Yang, Ph.D., a visiting fellow in the LMG Chromosome Stability Group, was the seminar host.

A professor of Molecular Biology and Genetics and the founder and director of the High Throughput Biology (HiT) Center at Johns Hopkins, Boeke investigates the mechanism and regulation of retrotransposons - mobile genetic elements that insert copies of themselves at new locations in the genome. "Transposable elements are the endogenous mutagen of every organism," Boeke stressed, "and are very important for the ongoing evolution and molding of genome structure and content."

In his talk, Boeke focused on the most abundant transposon in the human genome, the LINE-1 element (L1). L1 insertions have the potential to alter gene expression and cause human disease via several different mechanisms, such as insertion into the coding or functional sequences of a gene, which is predicted to disrupt gene function. Boeke explained, however, that the outcomes of insertion can be much more subtle, and he noted that "many of the alleles believed to be normal, because they have normal exon sequences, might actually contain mutations that are not appreciated."

According to Boeke, most L1 insertions occur in introns or between genes, and his group has recently shown that L1 insertion into the intron of a gene can attenuate transcription of that gene, leading to a decrease in protein levels. He emphasized that such intronic insertions are likely to have a significant impact on gene function and human disease but, because of their genomic location, are often overlooked.

To investigate whether L1 insertions in non-coding sequences contribute to human disease, Boeke's group has developed a transposon insertion-site profiling chip (TIP-chip) to map the location of L1 insertions throughout the human genome. The goal of these efforts is to identify new candidate disease genes by mapping novel L1 insertions in clinical samples.

The preliminary results from this work with the TIP-chip are promising. Novel L1 insertions were detected in samples from patients affected by X-linked familial disorders, but Boeke noted that identical L1 insertions were also detected in samples from healthy individuals. Thus, while these L1 insertions may be contributing to the disease phenotype, they alone are not sufficient to cause disease.

Boeke believes the TIP-chip will prove particularly important for identifying genes linked to diseases with complex traits, such as cancer susceptibility and schizophrenia. These diseases are likely to be enriched for mutations that cause only a partial loss in gene function, which is the anticipated consequence of most L1 insertions.

Boeke is also investigating L1 retrotransposition using a synthetic biology approach. Boeke's group has created a synthetic L1 element, ORFeus, which is 200-fold more active in transposition than the original element. When inserted into a mouse model, an inducible version of ORFeus transposed randomly and generated a high frequency of both heritable and non-heritable mutations, producing the first evidence of regulated retrotransposition from a single integrated donor copy of L1 in cells. Boeke hopes to use the inducible ORFeus mouse as a tool to identify novel modifier genes of human disease, with current efforts focused on liver cancer.

(Stephanie Nick McElhinny, Ph.D., is a postdoctoral fellow in the LMG DNA Replication Fidelity Group.)

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