Human Genome Was Shaped by an Evolutionary Arms Race with Itself

New study of primate genomes reveals an ongoing battle to control 'jumping genes,' driving the evolution of greater genomic complexity

Sunday, 28 September 2014

New findings by scientists at the University of California, Santa Cruz, suggest that an evolutionary arms race between rival elements within the genomes of primates drove the evolution of complex regulatory networks that orchestrate the activity of genes in every cell of our bodies.

The arms race is between mobile DNA sequences known as "retrotransposons" (a.k.a. "jumping genes") and the genes that have evolved to control them. The UC Santa Cruz researchers have, for the first time, identified genes in humans that make repressor proteins to shut down specific jumping genes. The researchers also traced the rapid evolution of the repressor genes in the primate lineage.

Their findings, published September 28 in Nature, show that over evolutionary time, primate genomes have undergone repeated episodes in which mutations in jumping genes allowed them to escape repression, which drove the evolution of new repressor genes, and so on. Furthermore, their findings suggest that repressor genes that originally evolved to shut down jumping genes have since come to play other regulatory roles in the genome.

"We have basically the same 20,000 protein-coding genes as a frog, yet our genome is much more complicated, with more layers of gene regulation. This study helps explain how that came about," said Sofie Salama, a research associate at the UC Santa Cruz Genomics Institute who led the study.

Retrotransposons are thought to be remnants of ancient viruses that infected early animals and inserted their genes into the genome long before humans evolved. Now they can only replicate themselves within the genome. Depending on where a new copy gets inserted into the genome, a jumping event can disrupt normal genes and cause disease. Often the effect is neutral, simply adding to the overall size of the genome. Very rarely the effect might be advantageous, because the added DNA can itself be a source of new regulatory elements that enhance gene expression. But the high probability of deleterious effects means natural selection favours the evolution of mechanisms to prevent jumping events.

Scientists estimate that jumping genes or "transposable elements" account for at least 50 percent of the human genome, and retrotransposons are by far the most common type.

"There have been successive waves of retrotransposon activity in primate evolution, when a transposable element changed to become expressed and replicated itself throughout the genome until something turned it off," Salama said.

"We've discovered a major mechanism by which the genome is able to shut down these mobile DNA elements."

The repressors identified in the new study belong to a large family of proteins known as "KRAB zinc finger proteins." These are DNA-binding proteins that repress gene activity, and they constitute the largest family of gene-regulating proteins in mammals. The human genome has over 400 genes for KRAB zinc finger proteins, and about 170 of them have emerged since primates diverged from other mammals.

According to Salama, her team's findings support the idea that expansion of this family of repressor genes occurred in response to waves of retrotransposon activity. Because repression of a jumping gene also affects genes located near it on the chromosome, the researchers suspect that these repressors have been co-opted for other gene-regulatory functions, and that those other functions have persisted and evolved long after the jumping genes the repressors originally turned off have degraded due to the accumulation of random mutations.

"The way this type of repressor works, part of it binds to a specific DNA sequence and part of it binds other proteins to recruit a whole complex of proteins that creates a repressive landscape in the genome. This affects other nearby genes, so now you have a potential new layer of regulation available for further evolution," Salama said.

KRAB zinc finger proteins are the subject of intensive research as scientists try to sort out their many regulatory roles within the genome. The idea that they are involved in repression of jumping genes is not new – previous studies by other researchers have shown that these proteins silence jumping genes in mouse embryonic stem cells. But until now, no one had been able to demonstrate that the same thing occurs in human cells.

The UC Santa Cruz team developed a novel assay to test whether a particular KRAB zinc finger protein could shut down certain jumping genes. The first authors of the paper, postdoctoral researcher Frank Jacobs and graduate student David Greenberg, came up with the strategy of testing primate retrotransposons in non-primate cells by using mouse embryonic stem cells that contain a single human chromosome. In the environment of a mouse cell, jumping genes that were repressed in primate cells became active. Greenberg then developed an assay for testing individual zinc finger proteins for their ability to turn off a primate jumping gene in the mouse cell environment.

"We did all our tests in mouse cells because they lack all of the primate zinc finger proteins, so when you put primate retrotransposons into a mouse cell they're all active," Salama explained.

The results demonstrated that two human proteins called ZNF91 and ZNF93 bind and repress two major classes of retrotransposons (known as SVA and L1PA) that are currently or recently active in primates. Assistant research scientist Benedict Paten directed graduate student Ngan Nguyen in a painstaking analysis of primate genomes, including the reconstruction of ancestral genomes, which showed that ZNF91 underwent structural changes 8 to 12 million years ago that enabled it to repress SVA elements.

Experiments with ZNF 93, which shuts down L1PA retrotransposons, provided a striking illustration of the arms race between jumping genes and repressors. The researchers found that, while it is good at shutting down many L1PA elements, there is one subset of a recently evolved lineage of L1PA that has lost a short section of DNA that includes the ZNF93 binding site. Without the binding site, these jumping genes evade repression by ZNF93. Interestingly, when the researchers put the missing sequence back into one of these genes and put it in a mouse cell without ZNF93, they found that it was better at jumping. So even though the sequence helps with jumping activity, losing it gives the jumping gene an advantage in primates by allowing it to escape repression by ZNF93.

"That's kind of the icing on the cake for aficionados of molecular evolution, because it demonstrates that this is a never-ending race," Salama said.

"KRAB zinc finger proteins are a rare class of proteins that is rapidly expanding and evolving in mammalian genomes, which makes sense because the transposable elements are themselves continually evolving to escape repression."

Corresponding author David Haussler, professor of biomolecular engineering and director of the UC Santa Cruz Genomics Institute, said the study involved close collaboration between his group's "wet lab," directed by Salama, and the "dry lab" where researchers under Paten's direction used the computational tools of genome bioinformatics to reconstruct the evolutionary history of primate genomes. Haussler, a Howard Hughes Medical Institute investigator who has used his background in computer science to do pioneering work in genomics, said he established the wet lab to enable just this kind of collaboration.

"Both parts were integral to this study, and there was a lot of back and forth between them. This paper shows how important it is to integrate computational and experimental approaches to fundamental scientific problems, such as how and why we continuously evolve to be more complex," Haussler said.

Source: University of California - Santa Cruz

Contact: Tim Stephens

Reference:

An evolutionary arms race between KRAB zinc-finger genes ZNF91/93 and SVA/L1 retrotransposons

Frank M. J. Jacobs, David Greenberg, Ngan Nguyen, Maximilian Haeussler, Adam D. Ewing, Sol Katzman, Benedict Paten, Sofie R. Salama & David Haussler

Nature, 28 September  2014, doi:10.1038/nature13760

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Induced Pluripotent Stem Cells Reveal Differences between Humans and Great Apes

Key differences in the regulation of jumping genes may have arisen relatively recently in evolution

Thursday, 24 October 2013

Researchers at the Salk Institute for Biological Studies have, for the first time, taken chimpanzee and bonobo skin cells and turned them into induced pluripotent stem cells (iPSCs), a type of cell that has the ability to form any other cell or tissue in the body.

This microscope image shows induced pluripotent

stem cells (iPSC) from our closest living relatives.

Skin cells from bonobos (pigmy chimps) were

reprogrammed to pluripotent stem cells, an

advance that allows scientists to study the

differences between the neurons of humans and

chimps. The colours show different aspects of the

cells' molecular components. Credit: Courtesy of

Carol Marchetto, Salk Institute for Biological

Studies. 

Mouse iPSCs were created in 2006 by Kazutoshi Takahashi and Shinya Yamanaka at Kyoto University in Japan, and human iPSCs soon followed – feats which earned Yamanaka the Nobel Prize in Physiology or Medicine last year. Now scientists regularly use iPSCs to model diseases using cells that would be otherwise difficult to obtain from a living person or animal. By adding a combination of four key factors, a skin cell can be made into an iPSC, which can then be coaxed into forming liver, lung and brain cells in a culture dish.

It's now possible to not only model disease using the cells, but also to compare iPSCs from humans to those of our closest living relatives – great apes, with which we share a majority of genes – for insight into what molecular and cellular features make us human.

"Comparing human, chimpanzee and bonobo cells can give us clues to understand biological processes, such as infection, diseases, brain evolution, adaptation or genetic diversity," says senior research associate Iñigo Narvaiza, who led the study with senior staff scientist Carol Marchetto at the Salk Institute in La Jolla.

"Until now, the sources for chimpanzee and bonobo cells were limited to post-mortem tissue or blood. Now you could generate neurons, for example, from the three different species and compare them to test hypotheses."

In the new study, published online October 23 in the journal Nature, scientists found disparities in the regulation of jumping genes or transposons – DNA elements that can copy and paste themselves into spots throughout the genome – between humans and non-human primate cells. Jumping genes provide a means to rapidly shuffle DNA and might be shaping the evolution of our genomes, the scientists say.

From left are Salk scientists Ahmet Denli, Carol

Marchetto, Iñigo Narvaiza and Fred Gage.

Credit: Courtesy of the Salk Institute for
Biological Studies.

Working in the lab of Salk's Fred Gage, the Vi and John Adler Chair for Research on Age-Related Neurodegenerative Disease, Narvaiza, Marchetto and their colleagues identified genes that are differentially expressed between iPSCs from humans and both chimpanzees and bonobos.

To the group's surprise, two of those genes code for proteins that restrict a jumping gene called long interspersed element-1or L1, for short. Compared with non-human primate cells, human iPSCs expressed higher levels of these restrictors, called APOBEC3B and PIWIL2.

"We weren't expecting that," Marchetto says.

"Those genes caught our eyes, so they were the first targets we focused on."

L1 and a handful of other jumping genes are abundant throughout our genomes. Where these bits of DNA insert themselves is hard to predict, and they can produce variable effects. For example, they might completely disrupt genes, modulate them, or cause them to be processed into entirely new proteins.

Using L1 tagged with a fluorescent marker, the group observed higher numbers of fluorescent iPSCs from non-human primates compared with humans. In separate experiments, they produced iPSCs with too much or too little APOBEC3B and PIWIL2, finding – as expected – that an excess of the two proteins dampened the mobility and reduced the appearance of newly inserted DNA in the non-human primate cells.

These results suggested that L1 elements insert themselves less often throughout our genomes. Indeed, looking at genomes of humans and chimpanzees that had already been sequenced, the researchers found that the primates had more copies of L1 sequences than did humans.

The question that remains is what would be the impact of differences in L1 regulation?

"It could mean that we have gone, as humans, through one or more bottlenecks in evolution, that decrease the variability present in our genome," says Marchetto, though the hypothesis is admittedly hard to prove. It is known, however, that humans' genomes are less variable than chimpanzees'.

The new study provides proof of concept that the iPSC technology can be used to understand some of the evolutionary differences between humans and non-human primates, says Narvaiza. The group plans to make technology, and all the data, available to the broader research community – which is especially helpful now that great ape research is severely restricted in the United States and abroad – so that other scientists can learn about primates using non-invasive, ethically sound methods.

The team plans to differentiate the stem cells into other tissues, such as neurons, and comparing how the cells from different species behave. They will also use the iPSC technology to investigate how chimpanzees might differ from people in susceptibility to cancer, genetic diseases and viral infection.

Source: Salk Institute for Biological Studies

Contact: Kat Kearney

Reference:

Differential L1 regulation in pluripotent stem cells of humans and apes

Maria C. N. Marchetto, Iñigo Narvaiza, Ahmet M. Denli, Christopher Benner, Thomas A. Lazzarini, Jason L. Nathanson, Apuã C. M. Paquola, Keval N. Desai, Roberto H. Herai, Matthew D. Weitzman, Gene W. Yeo, Alysson R. Muotri, Fred H. Gage 

Nature (2013), doi:10.1038/nature12686

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What Can the Axolotl Teach Us About Tissue Regeneration In Humans?

Understanding how salamanders grow new limbs provides insights into the potential of human regenerative medicine

Tuesday, 25 September 2012

Based on two new studies by researchers at the Salk Institute for Biological Studies, regeneration of a new limb or organ in a human will be much more difficult than the mad scientist and super villain, Dr. Curt Connors, made it seem in the Amazing Spider-man comics and films.

As those who saw the recent "The Amazing Spiderman" movie will know, Dr. Connors injected himself with a serum made from lizard DNA to successfully regrow his missing lower right arm - that is, before the formula transformed him into a reptilian humanoid.

Salk research shows that in the axolotl, a Mexican salamander, jumping genes 

have to be shackled or they might move around in the genomes of cells in the 

tissue destined to become a new limb, and disrupt the process of regeneration. 

Credit: the Salk Institute for Biological Studies. 

But by studying a real lizard-like amphibian, which can regenerate missing limbs, the Salk researchers discovered that it isn't enough to activate genes that kick starts the regenerative process. In fact, one of the first steps is to halt the activity of so-called jumping genes.

In research published August 23 in Development, Growth & Differentiation, and July 27 in Developmental Biology, the researchers show that in the Mexican axolotl, jumping genes have to be shackled or they might move around in the genomes of cells in the tissue destined to become a new limb, and disrupt the process of regeneration.

They found that two proteins, piwi-like 1 (PL1) and piwi-like 2 (PL2), perform the job of quieting down jumping genes in this immature tadpole-like form of a salamander, known as an axolotl - a creature whose name means water monster and who can regenerate everything from parts of its brain to eyes, spinal cord, and tail.

Salk researchers Gerald M. Pao, Wei 

Zhu, and Tony Hunter. Credit: the 

Salk Institute for Biological Studies. 

"What our work suggests is that jumping genes would be an issue in any situation where you wanted to turn on regeneration," says the studies' senior author, Tony Hunter, a professor in the Molecular and Cell Biology Laboratory and director of the Salk Institute Cancer Center.

"As complex as it already seems, it might seem a hopeless task to try to regenerate a limb or body part in humans, especially since we don't know if humans even have all the genes necessary for regeneration," says Hunter.

"For this reason, it is important to understand how regeneration works at a molecular level in a vertebrate that can regenerate as a first step. What we learn may eventually lead to new methods for treating human conditions, such as wound healing and regeneration of simple tissues."

The research team, which included investigators from other universities around the country, sought to characterize the transcriptional fingerprint emerging from the early phase of axolotl regeneration. They specifically looked at the blastema, a structure that forms at a limb's stump.

There the scientists found transcriptional activation of some genes, usually found only in germ line cells, which indicated cellular reprogramming of differentiated cells into a germ line state.

In the Development, Growth & Differentiation study, the research team, led by Wei Zhu, then a postdoctoral researcher in Hunter's laboratory, focused on one of these genes, the long interspersed nucleotide element-1 (LINE-1) retrotransposon.

LINE-1 elements are jumping genes that arose early in vertebrate evolution. They are pieces of DNA that copy themselves in two stages - first from DNA to RNA by transcription, and then from RNA to DNA by reverse transcription. These DNA copies can then insert themselves into the cell's genome at new positions.

A few years ago, Fred Gage, professor in the Laboratory of Genetics at the Salk Institute, discovered that LINE-1 elements move around during neuronal development, and may program the identities of individual neurons.

"Most of these copies appear to be 'junk' DNA, because they are defective and can never jump again," says Hunter. But all mammals, including humans, still have active LINE-1 genes, and the salamander, whose genome is 10 times larger than a human's, contains many more.

Active LINE-1 retrotransposons can keep jumping, and that was true in the developing blastema where LINE-1 jumping was dramatically switched on. But in the researchers' companion study, in Developmental Biology, they found that PL1 and PL2 switch off transcription of repeat elements, such as LINE-1.

"The idea is that in the development of germ cells, you definitely don't want these things hopping around," says Hunter.

"The mobilization of these jumping genes can introduce harmful genomic rearrangements or even abort the regeneration process."

In fact, when the researchers inhibited PL1 and PL2 activity in the axolotl limb blastema, regeneration was significantly slowed down.

"The need to switch on one set of genes to stop other genes from jumping just illustrates how amazingly difficult it would be to regenerate something as complex as a limb in humans," Hunter says.

"But that doesn't mean we won't learn valuable lessons about how to treat degenerative diseases."

Source: Salk Institute for Biological Studies

Contact: Andy Hoang

References:

Retrotransposon long interspersed nucleotide element-1 (LINE-1) is activated during salamander limb regeneration

Wei Zhu, Dwight Kuo, Jason Nathanson, Akira Satoh, Gerald M. Pao, Gene W. Yeo, Susan V. Bryant, S. Randal Voss, David M. Gardiner and Tony Hunter

Development, Growth & Differentiation, Volume 54, Issue 7, pages 673–685, September 2012, DOI: 10.1111/j.1440-169X.2012.01368.x

Activation of germline-specific genesis required for limb regeneration in the Mexican axolotl

Wei Zhu, Gerald M. Pao, Akira Satoh, Gillian Cummings, James R. Monaghan, Timothy T. Harkins, Susan V. Bryant, S. Randal Voss, David M. Gardiner, Tony Hunter

Developmental Biology, 2012 Oct 1;370(1):42-51. Epub 2012 Jul 27

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Transposons: DNA that May Contribute to Each Person's Uniqueness

Transposons: DNA that May Contribute to Each Person's Uniqueness
Thursday, 12 August 2010

Building on a tool that they developed in yeast four years ago, researchers at the Johns Hopkins University School of Medicine scanned the human genome and discovered what they believe is the reason people have such a variety of physical traits and disease risks.

In a report published in the June 25 issue of Cell, the team identified a near complete catalogue of the DNA segments that copy themselves, move around in, and insert themselves here and there in our genome. The insertion locations of these moveable segments — transposons — in each individual's genome helps determine why some are short or tall, blond or brunette, and more likely or less likely to have cancer or heart disease. The Johns Hopkins researchers say that tracking the locations of transposons in people with specific diseases might lead to the discovery of new disease genes or mutations.

Using their specialized "chip" with DNA spots that contain all of the DNA sequences that appear in the genome, researchers applied human DNA from 15 unrelated people. The research team compared transposon sites first identified in the original published human "index" genome and found approximately 100 new transposon sites in each person screened.

"We were surprised by how many novel insertions we were able to find," says Jef Boeke, Ph.D., Sc.D., an author on the article, a professor of molecular biology and genetics, and co-director of the High Throughput Biology Center of the Institute for Basic Biomedical Sciences at Johns Hopkins.

"A single microarray experiment was able to reveal such a large number of new insertions that no one had ever reported before. The discovery taught us that these transposons are much more active than we had guessed."

Each of the 15 different DNA samples used in the study was purified from blood cells before it was applied to a DNA chip. Transposons stick to spots on the DNA chip corresponding to where they are normally found in the genome, letting the researchers locate new ones.

Boeke's group first invented the transposon chip in 2006 for use in yeast. However, it was Kathleen Burns, M.D., Ph.D., now an assistant professor of pathology at Johns Hopkins, who first got the chip to work with human DNA.

"The human genome is much larger and more complex, and there are lots of look-a-like DNA’s that are not actively moving but are similar to the transposons that we were interested in," says Burns.

The trick was to modify how they copied the DNA before it was applied over the chip. The team was able to copy DNA from the transposons of interest, which have just three different genetic code letters than other look-alike DNA segments.

"We've known that genomes aren't static places, but we didn't know how many transposons there are in each one of us; we didn't know how often a child is born with a new one that isn't found in either parent and we didn't know if these DNA’s were moving around in diseases like cancer," says Burns.

"Now we have a tool for answering these questions. This adds a whole dimension to how we look at our DNA."

Source: Johns Hopkins Medical Institutions
Contact: Vanessa McMains

Reference:
Mobile Interspersed Repeats Are Major Structural Variants in the Human Genome
Cheng Ran Lisa Huang, Anna M. Schneider, Yunqi Lu, Tejasvi Niranjan, Peilin Shen, Matoya A. Robinson, Jared P. Steranka, David Valle, Curt I. Civin, Tao Wang, Sarah J. Wheelan, Hongkai Ji, Jef D. Boeke, Kathleen H. Burns
Cell, Volume 141, Issue 7, 1171-1182, 25 June 2010, 10.1016/j.cell.2010.05.026
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Ancient Viral Invasion Shaped the Human Genome

Ancient Viral Invasion Shaped the Human Genome
Monday, 07 June 2010

Scientists at the Genome Institute of Singapore (GIS), and their colleagues from the National University of Singapore, Nanyang Technological University, Duke-NUS Graduate Medical School and Princeton University have recently discovered that viruses that 'invaded' the human genome millions of years ago have changed the way genes get turned on and off in human embryonic stem (ES) cells.

The study provides definitive proof of a theory that was first proposed in the 1950s by Nobel Laureate in physiology and medicine, Barbara McClintock, who hypothesized that transposable elements, mobile pieces of the genetic material (DNA), such as viral sequences, could be "control elements" that affect gene regulation once inserted in the genome.

This finding is an important contribution to the advancement of stem cell research and to its potential for regenerative medicine. Led by GIS Senior Group Leader Dr Guillaume Bourque, the study was published in Nature Genetics on June 6, 2010.

Through the use of new sequencing technologies, the scientists studied the genomic locations of three regulatory proteins (OCT4, NANOG and CTCF) in human and mouse embryonic stem (ES) cells. Interestingly, while the scientists found a lot of similarities, they also found many differences in the methods and the types of genes that are being regulated in humans. In particular, it was discovered that specific types of viruses that inserted themselves in the human genomes millions of years ago have dramatically changed the gene regulatory network in human stem cells.

"This study is a computational and experimental tour de force. It provides undeniable evidence that some transposable elements, which are too often dismissed as merely junk DNA, are key components of a regulatory code underlying human development," said Dr Cedric Feschotte, Associate Professor of the University of Texas Arlington.

The comparisons between the human and mouse model system in the study of gene regulatory networks help to advance the understanding of how stem cells differentiate into various cell types of the body.

"This understanding is crucial in the improved development of regenerative medicine for diseases such as Parkinson's disease and leukaemia," said Dr Bourque.

"Despite the advantages of using mouse ES cells in the study of gene regulatory networks, further research must focus more directly on human stem cells. This is due to the inherent challenges of converting the results of studies done from one species to that of the next. More research will need to be done in both human and non-human primate stem cells for findings on stem cells to be used in clinical application."

Prof Raymond L. White, PhD, Rudi Schmid Distinguished Professor of Neurology, University of California said:

"The paper reports very exciting new findings that establish a new and fundamentally distinct mechanism for the regulation of gene expression. By comparing the genomes of mouse with human, the scientists were able to show that the binding sites for gene regulatory factors are very often not in the same place between the two species. This by itself would be very surprising, but the investigators go further and demonstrate that many of the sites are imbedded within a class of DNA sequences called "transposable" elements because of their ability to move to new places in the genome. There are a number of such elements believed to be the evolutionary remnants of viral genomes, but it was very surprising to learn that they were carrying binding sites for regulatory elements to new locations. These changes in regulation would be expected to create major changes in the organisms, which carry them. Indeed, many think that regulatory changes are at the heart of speciation and may have played a large role in the evolution of humans from their predecessors. This is likely to be a landmark paper in the field."

Dr Eddy Rubin, Director of the U.S. Department of Energy Joint Genome Institute and Director of the Genomics Division at Lawrence Berkeley National Laboratory in Berkeley added:

"This study using a comparative genomics strategy discovered important human specific properties of the regulatory network in human ES cells. This information is significant and should contribute to helping move the regenerative medicine field forward."

Reference:
Transposable elements have rewired the core regulatory network of human embryonic stem cells
Galih Kunarso, Na-Yu Chia, Justin Jeyakani, Catalina Hwang, Xinyi Lu, Yun-Shen Chan, Huck-Hui Ng & Guillaume Bourque
Nature Genetics, Published online: 06 June 2010, doi:10.1038/ng.600
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Jumping Genes Provide Extensive 'Raw Material' for Evolution

Jumping Genes Provide Extensive 'Raw Material' for Evolution
Wednesday, 02 June 2010

Using high-throughput sequencing to map the locations of a common type of jumping gene within a person's entire genome, researchers at the University of Pennsylvania School of Medicine found extensive variation in these locations among the individuals they studied, further underscoring the role of these errant genes in maintaining genetic diversity.

The investigators determined that any two peoples' genomes differ at roughly 285 sites out of the 1139 sites studied. These results were found by scanning the genomes of 25 individuals, 15 of which were unrelated. They report their findings online in Genome Research.

Jumping genes – also called transposons – are sequences of DNA that move to different areas of the genome within the same cell.

"The significance of this work is that there is much more diversity in our genome due to insertions by this family of transposons than previously thought," said co-author Haig Kazazian, MD, Seymour Gray Professor of Molecular Medicine, in the Penn Department of Genetics.

"This movement of genetic material provides the raw material of genetic evolution, and it doesn't take into account the insertions that we believe occur outside of the sperm and egg cells studied in this project."

Transposons are a source of diversity within a species' gene pool, with implications on many levels. For example, slight changes in genes help organisms adapt and survive in new environments, and populations with genetic diversity are less vulnerable to disease and problems with reproduction.

Insertions into certain spots in the genome can also cause cell function to go awry, so understanding their placement and variation in the human genome is important for a fundamental understanding of disease. Insertions can cause many genetic diseases, such as haemophilia and Duchenne muscular dystrophy, and may play a role in the development of cancer.

Retrotransposons are the major class of jumping genes, with the L1 family the most abundant type of retrotransposon in the human genome. L1s comprise about 17 percent of the human genome and were the subject of this study.

Eventually, continuous jumping by retrotransposons expands the size of the human genome and may cause shuffling of genetic 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 L1s may cause significant effects on nearby genes, such as lowering their expression.

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 team also found that on average 1 in 140 individuals have obtained a new L1 insertion from their parents. When all retrotransposon insertions, including L1 and others, are considered about 1 in 40 individuals have received a new insertion from their parents.

The current study counted insertions in the heritable germ cell line, which is in egg and sperm cells.

"The real elephant in the room is the question of the incidence of somatic insertions, insertions in cells that aren't eggs or sperm" says Kazazian.

"We don't yet know the incidence of those somatic insertions."

Because the insertions detected in this study and others like it are present in some individuals and not others, there is the possibility of association with genetic disease. Future studies in the Kazazian lab funded by an ARRA stimulus grant through the National Institutes of Health will develop techniques to uncover such associations using these retrotransposon insertions as genetic markers.
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Transposable Elements in Human Genetic Diseases and Human Development

Jumping elements, some of which cause genetic diseases, become incorporated in the genome at different stages of human development 
Friday, 30 April 2010

The density of transposable (jumping) elements between sex chromosomes in primates may have important consequences for the studies of human genetic diseases, say Penn State University researchers. Erika Kvikstad, a 2009 Penn State Ph.D. graduate in genetics, and Kateryna Makova, an associate professor of biology at Penn State, used a statistical regression method to study the genomes of the human, chimpanzee, macaque, and orang-utans. They concluded that there is a strong sex-chromosome bias in the distribution of transposable elements, and providing insights about whether these non-coding, but important, DNA elements integrate themselves specifically into the male germline or female germline, or integrate themselves into the genome during the early stages of embryogenesis. Their study will be published in the May 2010 issue of the scientific journal Genome Research.

According to Kvikstad, now a postdoctoral scholar at the Université Claude Bernard Lyon 1 in Lyon, France, the team chose to study primates because of the importance of human evolution, human disease, and the "unique availability of a very detailed description of the human genome – more so than any other mammalian genome." The strides made in sequencing the human and other primate genomes have made this research possible only in the last decade. Makova, one of the researchers who contributed to the analysis of the macaque and chimpanzee genomes, notes that the sequence of the orang-utan genome used in the Penn State study has not yet been published. Makova received special permission to use the orang-utan data set in her study.

The team looked specifically at the densities of transposable elements, which are snippets of DNA capable of moving about, replicating themselves, and inserting copies within the genome. The classes of transposable elements are further distinguished by being short or long interspersed nuclear elements – SINEs and LINEs. Kvikstad and Makova looked at one SINE family – Alu sequences, which are about 300 base pairs long, – and one LINE family – L1 sequences, which can be thousands of bases long.

"The transposable elements that we chose to study, Alus and L1s, are significant because they are abundant," says Kvikstad.

"They comprise about a third of the primate genome. They are actively moving around in the genome via a copy-and-paste retro-transposition mechanism, so they can create new variation; for example, human diseases and cancers."

Even more importantly, Kvikstad points out:

"These transposable elements are highly abundant on the sex chromosomes – X and Y – which mean they could be evolving uniquely because of the unusual nature of sex-chromosome transmission. The Y is paternally inherited, so it resides in the male germline only; the X spends two-thirds of its time in the female germline and one-third in the male germline. If there are germline-specific differences in the activity of transposable elements, for example, we should see clues to these differences in their sex-chromosome distributions."

The team's findings surprised Kvikstad and Makova.

"Even after we corrected for regional genomic effects, we still observed a very strong sex-chromosome bias in distributions of transposable elements," says Makova.

"This finding clearly indicates that there are biases according to which elements integrate into the genome. There also are differences between these two classes of elements. Our study suggests that Alus probably integrate mostly in the male germline, while L1s integrate in both male and female germ lines, or they might integrate in early embryogenesis."

This bias has implications for understanding and perhaps someday even preventing and treating genetic diseases.

"For us to really understand how the genetic diseases occur, we need to know when the elements integrate – at what point in human development this occurs," says Makova.

"We are studying evolution mostly, but our results are relevant to genetic diseases caused by insertions of transposable elements in the genome. For instance, Alu insertions are known to cause some types of neurofibromatosis, haemophilia, breast cancer, Apert syndrome, cholinesterase deficiency, and complement deficiency."

When transposable elements were first discovered in the 1940s, many in the scientific community labelled them as "junk" DNA.

"I don't think many people agree that they are 'junk' DNA any longer. Many of these elements have function. Alu elements frequently possess the regulatory elements. Both the Alu and L1 elements are often involved in recombination, the phenomenon under which the genome can undergo rearrangement and reshuffling," says Makova.

Kvikstad and Makova spent a year analyzing the primate data. Previously, together with Francesca Chiaromonte, associate professor of statistics at Penn State, they had worked together on a project looking at primate insertions and deletions of a much smaller size, under 30 base pairs.

"We are the first team to look into this much detail at the distribution of transposable elements on human sex chromosomes," Makova says.

Kvikstad points out other important implications of this study.

"In particular, we noted that gene density was not a significant predictor of either Alu or L1 element density, at any evolutionary time point," she says.

"By contrast, density of conserved non-coding DNA or 'most conserved elements' was a strong negative predictor of L1 density – so L1 elements are scarce in regions of the genome that might contain many of these potentially functional non-coding DNAs. This is an important distinction, since previous studies inferring the action of natural selection in shaping the densities of transposable elements relied on gene density as a proxy for natural selection. Our results suggest that the potentially functional DNA residing in these most-conserved elements may be an additional hallmark of natural selection."

Source: The Pennsylvania State University
Contact: Barbara K. Kennedy

Reference:

The (r)evolution of SINE versus LINE distributions in primate genomes: Sex chromosomes are important
Erika M. Kvikstad and Kateryna D. Makova
Genome Res. 2010, 20: 600-613
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Moving Gene Therapy Forward

Mobile DNA elements that can integrate into 'foreign' DNA Monday, 04 May 2009 Gene therapy Gene therapy is the introduction of genetic material into a patient's cells resulting in a cure or a therapeutic effect. In recent years, it has been shown that gene therapy is a promising technology to treat or even cure several fatal diseases for which there is no attractive alternative therapy. Gene therapy can be used for hereditary diseases, but also for other diseases that affect heart, brain and even for cancer. Indeed, recent results suggest that gene therapy can be beneficial for patients suffering from aggressive brain cancer that would otherwise be lethal. A safe delivery of the genes? Despite the overall progress, there is still a need to develop improved and safer approaches to deliver genes into cells. The success of gene therapy ultimately depends on these gene delivery vehicles or vectors. Most vectors have been derived from viruses that can be tailor-made to deliver therapeutic genes into the patients' cells. However, some of these viral vectors can induce side-effects, including cancer and inflammation. Marinee Chuah, Thierry VandenDriessche, Eyayu Belay and their fellow VIB researchers at K.U. Leuven in collaboration with Zsuzsanna Iszvak and Zoltan Ivics and colleagues at the Max Delbrück Center in Berlin (Germany) have now developed a new non-viral approach that overcomes some of the limitations associated with viral vectors. Lessons from evolution Using the principles of evolution and natural selection, that were initially conceived by Charles Darwin, they have now developed an efficient and safe gene delivery approach based on non-viral genetic elements, called transposons. Transposons are mobile DNA elements that can integrate into 'foreign' DNA via a 'cut-and-paste' mechanism. In a way they are natural gene delivery vehicles. The researchers constructed the transposons in such a way that they can carry the therapeutic gene into the target cell DNA. Doing so, they obviate the need to rely on viral vectors. “We show for the first time that it is now possible to efficiently deliver genes into stem cells, particularly those of the immune system, using non-viral gene delivery,” says Marinee Chuah. “Many groups have tried this for many years but without success. We are glad that we could now overcome this hurdle,” claims Thierry VandenDriessche. Zsuzsanna Izsvak and Zoltan Ivics concur: “This transposon technology may greatly simplify the way gene therapy is conducted, improve its overall safety and reduce the costs.” The VIB researchers are further testing this technology to treat specific diseases including cancer and genetic disorders, in anticipation of moving forward and treat patients suffering from these diseases. ......... ZenMaster

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Researchers Piggyback to Safer Reprogrammed Stem Cells

Researchers Piggyback to Safer Reprogrammed Stem Cells Saturday, 28 February 2009 Austin Smith and his research team at the Centre for Stem Cell Research in Cambridge have just published in the journal Development a new and safer way of generating pluripotent stem cells – the stem cells that can give rise to every tissue of the body. Rapid developments in stem cell research in recent years have provided a way for stem cell scientists to convert specialised cells, such as skin cells, into stem cells that can form numerous cell types of the body. Research into the creation of these 'reprogrammed' cells – so-called induced pluripotent stem (iPS) cells – is of vital importance because it could lead to new ways of creating human stem cells from adult tissues for the study and treatment of disease. But there is one key problem with the techniques currently used to generate such stem cells: they rely on potentially harmful viruses to deliver the reprogramming factors that change specialised cells into iPS cells. Now Austin Smith and his team report in the journal Development an approach that avoids the use of such viruses. They successfully persuaded partly specialised mouse cells, called Epi-stem cells, to reprogram into iPS cells using a single reprogramming factor called Klf4. Instead of relying on viruses to introduce Klf4 into the Epi-stem cells, they turned to a special type of DNA, called a transposable element, which can insert itself into an organism's DNA and carry a cargo with it, in this case Klf4. The transposable element Smith and colleagues used in their study is called Piggybac, which delivered a single copy of Klf4 into the Epi-stem cells, causing them to reprogram into iPS cells. The researchers then used an enzyme to cut the Klf4 out of Piggybac. In doing so, they discovered that the iPS cells could maintain themselves using their own Klf4 gene, which had been switched on during the reprogramming process. Once the Piggybac Klf4 is removed, they report, iPS cells can go on to create normal mice when introduced into newly developing mouse embryos and can give rise to the offspring of these mice by contributing to their reproductive cells. This is the most stringent test of the normality of iPS cells. As Professor Smith explains below, this is a significant advance in the field. "The paper we've published in Development, together with two other publications in Nature”, says Professor Smith, “is a significant technical development in the field as together these papers present a more reliable and precise method for generating iPS cells. The method allows for greater control over the genetic modification process and this is fully reversible once reprogramming is complete. Therefore, the final iPS cells carry no potentially damaging foreign DNA. Our findings published in Development show that this approach produces perfectly reprogrammed mouse cells. The Nature papers show that it can also work in human cells. These studies provide a new tool to help advance basic research into reprogramming and pave the way to the creation of human iPS cells suitable for biomedical applications." Reference: Klf4 reverts developmentally programmed restriction of ground state pluripotency Ge Guo, Jian Yang, Jennifer Nichols, John Simon Hall, Isobel Eyres, William Mansfield, and Austin Smith Development, 18 Feb 2009, doi: 10.1242/dev.030957 ......... ZenMaster

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Parasites in the Genome

A molecular parasite could play an important role in human evolution Monday, 19 January 2009 Researchers at the Max Planck Institute for Developmental Biology in Tübingen, Germany, determined the structure of a protein (L1ORF1p), which is encoded by a parasitic genetic element and which is responsible for its mobility. The so-called LINE-1 retrotransposon is a mobile genetic element that can multiply and insert itself into chromosomal DNA at many different locations. This disturbs the genetic code at the site of integration, which can have serious consequences for the organism. On the other hand, this leads to genetic variation, an absolute prerequisite for the evolution of species. The structure of the L1ORF1p protein now allows a much more precise investigation of the mechanism of LINE-1 mobilization. This provides new insight into the relation between retrotransposons and retroviruses and probably also into certain evolutionary processes in humans and animals. Moreover, the researchers assume that the mechanism of LINE-1 retrotransposition can be exploited one day to precisely insert genetic information into specific locations. This would be an alternative to contemporary, less location-specific methods that are based on a retroviral mechanism. (PNAS, January 20th, 2009) The LINE-1 retrotransposon is a mobile gene that has multiplied massively in the history of the human genome. Presently, approximately 17 per cent of our DNA consists of LINE-1 sequences. This is an enormous proportion if one considers that the roughly 30.000 human proteins are encoded by less that 5 per cent of the DNA. The LINE-1 retrotransposon not only propagates itself, but also is responsible for the genomic integration of approximately one million Alu-sequences (another parasitic gene). Alu-sequences are only present in higher primates and occupy another 10 per cent of our genome. The insertion of LINE-1 and Alu-sequences is a continuous process and roughly every twentieth newborn is estimated to contain at least one new insertion of such an element. Consequently, there rarely is a human gene that has not been affected in the past by the integration of a LINE-1 or Alu element.

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Retrotransposition cycle of the human LINE-1 element. LINE-1-RNA is transcribed in the nucleus from genomic DNA. Subsequently, in the cytosol, it gets translated into two proteins (L1ORF1p and L1ORF2p) by the ribosome. Both proteins then bind LINE-1 RNA and form an RNA-protein complex. Back in the nucleus the L1ORF2p protein nicks chromosomal DNA and begins with the reverse transcription of LINE-1 RNA into DNA, which gets integrated into the genome at the place of the nick. L1ORF1p likely supports this process. Credit: Elena Khazina and Oliver Weichenrieder, Max Planck Institute for Developmental Biology.

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“It is difficult to believe that the massive integration of LINE-1 and Alu sequences remained without consequences on human evolution. Thus it is surprising how little we know so far about the mechanism of retrotransposition and about the proteins and nucleic acids involved in this process“, says Oliver Weichenrieder, leading scientists at the Max Planck Institute for Developmental Biology. The researchers therefore try to gain new insights via the biochemical characterisation of the involved molecules and via the determination of their molecular structures. This provides the basis for a detailed functional analysis and reveals similarities to already known proteins, especially similarities that are not obvious from a simple comparison of the respective amino acid sequences. In the present work Elena Khazina und Oliver Weichenrieder characterize one of two proteins that are encoded by the human LINE-1 retrotransposon. This so-called L1ORF1p protein binds to LINE-1 RNA, which was transcribed from a LINE-1 element in the genomic DNA. Subsequently, L1ORF1p likely supports the following reverse transcription of LINE-1 RNA into DNA. This process happens directly at the genomic integration site of the new LINE-1 element. The researchers show that the L1ORF1p protein consists of three parts. The first part causes a self-association such that always three molecules come together to form a trimer. The other two parts are necessary for binding LINE-1 RNA. “Especially surprising was the identification of a so-called RRM domain in the middle part of the protein, since this part was believed so far to be rather unstructured”, says Elena Khazina. “Our crystal structure clearly proves the existence of this domain. Meanwhile we identified RRM-domains also in other retrotransposons, in a variety of animal and plant species“, adds the structural biologist.

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A. Scheme of the L1ORF1p trimer. B. Crystal structure of the RRM-domain of the human L1ORF1p protein. Credit: Elena Khazina and Oliver Weichenrieder, Max Planck Institute for Developmental Biology.

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RRM-domains (RNA Recognition Motif) occur frequently in the cell, particularly in RNA-binding proteins. The existence of an RRM-domain in L1ORF1p now explains why L1ORF1p binds LINE-1 RNA and how this could happen in detail. The insight into the structure of the L1ORF1p protein provides a new perspective and a good basis for future investigations of those cellular processes that are exploited by the LINE-1 element for its own propagation, and also for those mechanisms that are available to the cell to prevent the excessive propagation of retrotransposons. Reference: Non-LTR retrotransposons encode noncanonical RRM domains in their first open-reading frame. Elena Khazina, Oliver Weichenrieder PNAS, 12 January 2009, vol. 106 (3), 731-736, doi: 10.1073/pnas0809964106 ......... ZenMaster

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More 'Junk' DNA Proves Functional

Helps explain human differences from other species Tuesday, 04 November 2008 In a paper published in Genome Research on Nov. 4, scientists at the Genome Institute of Singapore (GIS) report that what was previously believed to be "junk" DNA is one of the important ingredients distinguishing humans from other species. More than 50 percent of human DNA has been referred to as "junk" because it consists of copies of nearly identical sequences. A major source of these repeats is internal viruses that have inserted themselves throughout the genome at various times during mammalian evolution. Using the latest sequencing technologies, GIS researchers showed that many transcription factors, the master proteins that control the expression of other genes, bind specific repeat elements. The researchers showed that from 18 to 33% of the binding sites of five key transcription factors with important roles in cancer and stem cell biology are embedded in distinctive repeat families. Over evolutionary time, these repeats were dispersed within different species, creating new regulatory sites throughout these genomes. Thus, the set of genes controlled by these transcription factors is likely to significantly differ from species to species and may be a major driver for evolution. This research also shows that these repeats are anything but "junk DNA," since they provide a great source of evolutionary variability and might hold the key to some of the important physical differences that distinguish humans from all other species. The GIS study also highlighted the functional importance of portions of the genome that are rich in repetitive sequences. "Because a lot of the biomedical research use model organisms such as mice and primates, it is important to have a detailed understanding of the differences between these model organisms and humans in order to explain our findings," said Guillaume Bourque, Ph.D., GIS Senior Group Leader and lead author of the Genome Research paper. "Our research findings imply that these surveys must also include repeats, as they are likely to be the source of important differences between model organisms and humans," added Dr. Bourque. "The better our understanding of the particularities of the human genome, the better our understanding will be of diseases and their treatments." "The findings by Dr. Bourque and his colleagues at the GIS are very exciting and represent what may be one of the major discoveries in the biology of evolution and gene regulation of the decade," said Raymond White, Ph.D., Rudi Schmid Distinguished Professor at the Department of Neurology at the University of California, San Francisco, and chair of the GIS Scientific Advisory Board. "We have suspected for some time that one of the major ways species differ from one another – for instance, why rats differ from monkeys – is in the regulation of the expression of their genes: where are the genes expressed in the body, when during development, and how much do they respond to environmental stimuli," he added. "What the researchers have demonstrated is that DNA segments carrying binding sites for regulatory proteins can, at times, be explosively distributed to new sites around the genome, possibly altering the activities of genes near where they locate. The means of distribution seem to be a class of genetic components called 'transposable elements' that are able to jump from one site to another at certain times in the history of the organism. The families of these transposable elements vary from species to species, as do the distributed DNA segments which bind the regulatory proteins." Dr. White also added: "This hypothesis for formation of new species through episodic distributions of families of gene regulatory DNA sequences is a powerful one that will now guide a wealth of experiments to determine the functional relationships of these regulatory DNA sequences to the genes that are near their landing sites. I anticipate that as our knowledge of these events grows, we will begin to understand much more how and why the rat differs so dramatically from the monkey, even though they share essentially the same complement of genes and proteins." Genome Institute of Singapore: The Genome Institute of Singapore (GIS) is a member of the Agency for Science, Technology and Research (A*STAR). It is a national initiative with a global vision that seeks to use genomic sciences to improve public health and public prosperity. Established in 2001 as a centre for genomic discovery, the GIS will pursue the integration of technology, genetics and biology towards the goal of individualized medicine. The key research areas at the GIS include Systems Biology, Stem Cell & Developmental Biology, Cancer Biology & Pharmacology, Human Genetics, Infectious Diseases, Genomic Technologies, and Computational & Mathematical Biology. The genomics infrastructure at the GIS is utilized to train new scientific talent, to function as a bridge for academic and industrial research, and to explore scientific questions of high impact. Agency for Science, Technology and Research (A*STAR): A*STAR is Singapore's lead agency for fostering world-class scientific research and talent for a vibrant knowledge-based Singapore. A*STAR actively nurtures public sector research and development in Biomedical Sciences, Physical Sciences and Engineering, with a particular focus on fields essential to Singapore's manufacturing industry and new growth industries. It oversees 22 research institutes, consortia and centres, and supports extramural research with the universities, hospital research centres and other local and international partners. At the heart of this knowledge intensive work is human capital. Top local and international scientific talent drive knowledge creation at A*STAR research institutes. The agency also sends scholars for undergraduate, graduate and post-doctoral training in the best universities, a reflection of the high priority A*STAR places on nurturing the next generation of scientific talent. Reference: Evolution of the mammalian transcription factor binding repertoire via transposable elements Guillaume Bourque, Bernard Leong, Vinsensius B. Vega, Xi Chen, Yen Ling Lee, Kandhadayar G. Srinivasan, Joon-Lin Chew, Yijun Ruan, Chia-Lin Wei, Huck Hui Ng, and Edison T. Liu Genome Research, Nov. 4, 2008 See also: Study Finds Value in 'Junk' DNA CellNEWS - Friday, 17 October 2008 ......... ZenMaster

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Study Finds Value in 'Junk' DNA

Significant number of exons created from junk DNA seem to play a role in gene regulation Friday, 17 October 2008 For about 15 years, scientists have known that certain "junk" DNA — repetitive DNA segments previously thought to have no function — could evolve into exons, which are the building blocks for protein-coding genes in higher organisms like animals and plants. Now, a University of Iowa study has found evidence that a significant number of exons created from junk DNA seem to play a role in gene regulation. The findings, which increase understanding of how humans differ from other animals, including non-human primates, appear Oct. 17 in the open-access journal PLoS Genetics. Nearly half of human DNA consists of repetitive DNA, including transposons, which can "transpose" or move around to different positions within the genome. A type of transposon called retrotransposons are transcribed into RNA and then reintegrated into the genomic DNA. The most common form of retrotransposons in the human genome are Alu elements, which have more than one million copies and occupy approximately 10 percent of the human genome. "Alu elements are a major source of new exons. Because Alu is a primate-specific retrotransposon, creation of new exons from Alu may contribute to unique traits of primates. We want to better understand this process," said the study's senior author Yi Xing, Ph.D., assistant professor of internal medicine and biomedical engineering, who holds a joint appointment in the University of Iowa Carver College of Medicine and the UI College of Engineering. To study the impact of Alu-derived exons on human gene expression, the researchers used a high-density exon microarray. The technology has nearly six million probes for monitoring the expression patterns of all human exons. Using data generated by these microarrays, the scientists analyzed 330 Alu-derived exons in 11 human tissues. The team then identified a number of exons with interesting expression and functional characteristics. "Hundreds of exons in the human genome were created from Alu elements. The whole-genome exon microarray allowed us to quickly identify exons that most likely contribute to the regulation of gene expression and function," said Lan Lin, Ph.D., University of Iowa postdoctoral fellow in internal medicine and the lead author of this study. Analysis of one human gene, SEPN1, which is known to be involved in a type of muscular dystrophy, along with comparative data from chimpanzee and macaque tissues, suggested that the presence of a muscle-specific Alu-derived exon resulted from a human-specific change that occurred after humans and chimpanzees diverged evolutionarily. "In this case, this exon is only expressed at a high level in the human muscle but not in any other human or non-human primate tissue, so this implies that the exon plays a functional role in muscle, and this role is human-specific," said Xing, who is also affiliated with University of Iowa Center for Bioinformatics and Computational Biology. Reference: Diverse Splicing Patterns of Exonized Alu Elements in Human Tissues Lan Lin, Shihao Shen, Anne Tye, James J. Cai, Peng Jiang, Beverly L. Davidson, Yi Xing PLoS Genet 4(10): e1000225. doi:10.1371/journal.pgen.1000225 See also: More 'Junk' DNA Proves Functional CellNEWS - Tuesday, 04 November 2008 ......... ZenMaster

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