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Scientists Track 'Stealth' DNA Elements In Primate Evolution

 
  May, 3 2005 10:13
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BATON ROUGE, Monday, May 2, 2005 -- Louisiana State University scientists in the Department of Biological Sciences have unraveled the details of a 25-million-year-old evolutionary process in the human genome. Specific DNA sequences that appear to have persisted in a latent state for long periods of time may not be simply lying dormant. Instead, the researchers say that these elements have played a crucial role in human evolution by surreptitiously spawning hyperactive progeny copies, giving rise to the most abundant family of DNA elements in the human genome: Alu elements. The study, which was led by LSU scientist Dr. Mark A. Batzer, provides the first strong mechanistic evidence for the evolution of Alu elements to date. It appears in the May issue of the journal Genome Research.

Alu elements are short, 300-nucleotide-long DNA sequences capable of copying themselves, mobilizing through an RNA intermediate, and inserting into another location in the genome. Over evolutionary time, this retrotransposition activity has led to the generation of over one million copies of Alu elements in the human genome, making them the most abundant type of sequence present. Because Alu elements are so abundant, comprising approximately 10% of the total human genome, they have been thoroughly characterized in terms of their origin and sequence composition. What has remained elusive to scientists, however, are the actual mechanisms by which these elements persist and propagate over time to influence human evolution.

In an attempt to understand these mechanisms, Dr. Batzer and his colleagues examined a subfamily of Alu elements in the human genome known as the AluYb lineage, and compared these elements to those in the genomes of other primate species, including chimpanzees, bonobos, gorillas, orangutans, gibbons and siamangs. The AluYb subfamily accounts for approximately 40% of all human-specific Alu elements and is currently one of the most active Alu lineages in the human genome. Some AluYb elements are still actively mobilizing in the human genome, causing insertion mutations that have led to the development of a number of heritable diseases.

Dr. Batzer's team demonstrated that some AluYb subfamily members have orthologs in all primate genomes tested, which dates the AluYb linage to an origin approximately 18-25 million years ago. Their results also indicated that the AluYb subfamily underwent a major species-specific expansion in the human genome during the past 3-4 million years. This apparent 20-million-year stretch of retrotranspositional quiescence, followed by a sudden outburst of human-specific retrotransposition activity in the past few million years, led Dr. Batzer and colleagues to formulate a new theory for the evolution of Alu elements, termed the "stealth driver" model. In the "stealth driver" model, low-activity Alu elements are maintained in low-copy number for long periods of time and occasionally produce short-lived hyperactive progeny that contribute to the formation and expansion of Alu elements in the human genome.

To date, the most widely accepted theory of Alu retrotransposition is called the "master gene" theory, which asserts that the majority of Alu retrotransposition activity is driven by a small number of hyperactive "master" sequences. In this model, mutations occurring in the "master" copies have rendered themselves capable of substantial propagation and persistence over time. However, prior evidence from the Ya5 subfamily indicated that at least some "master" Alu elements may persist in low-copy numbers for long periods of evolutionary time without retrotranspositional activity, suggesting that the mechanisms of Alu expansion may be much more complex. These observations led Dr. Batzer and his co-workers to examine the Yb subfamily of Alu elements, to demonstrate that the Yb subfamily has a similar evolutionary pattern to that of AluYa5, and to formulate the "stealth driver" hypothesis for the evolution of these Alu elements.

"In contrast to 'master' genes, 'stealth drivers' are not responsible for generating the majority of new Alu copies, but rather for maintaining genomic retrotransposition capacity over extended periods of time," Batzer explains. "By generating new Alu copies at a slow rate, a 'stealth driver' may occasionally spawn progeny elements that are capable of much higher retrotransposition rates. These hyperactive progeny elements may act as 'master' genes for the amplification of Alu subfamilies and are responsible for producing the majority of the subfamily members. Due to their high retrotransposition levels, however, they are likely to be rapidly purged from human populations through natural selection."

Dr. Batzer, principal investigator on the study, is the George C. Kent Professor of Life Sciences in the Department of Biological Sciences at LSU. Co-first authors on the manuscript, Kyudong Han and Jinchuan Xing, are graduate students in the Department of Biological Sciences at LSU. LSU graduate students Hui Wang and Dale Hedges, along with postdoctoral fellows Drs. Randall Garber and Richard Cordaux, also share authorship on the paper.

(C) 2005 Cold Spring Harbor Laboratory

Kyudong Han, Jinchuan Xing, Hui Wang, Dale J. Hedges, Randall K. Garber, Richard Cordaux and Mark A. Batzer.
Under the genomic radar: The Stealth model of Alu amplification.
Genome Research 15:655-664, 2005


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