LSU Scientists Develop New Theory About Human Genome Evolution By Tracking 'Stealth' DNA Elements

"Effectively, we've devised a theory that allows us to explain the origin of about half of all of the human genome," said Batzer.

Batzer was the principal investigator on the study, while LSU biological sciences graduate students Kyudong Han and Jinchuan Xing were the co-authors of the Genome Research paper on the discoveries. Other contributors to the research included graduate students Hui Wang and Dale Hedges, along with postdoctoral fellows Randall Garber and Richard Cordaux. Their findings were recently published in the journal Genome Research.

Batzer, the George C. Kent Professor of Life Sciences in the Department of Biological Sciences at LSU, and his group found that specific DNA sequences that appear to be in an inactive state for long periods of time may not be simply lying dormant after all. Instead, Batzer and his team have discovered that these elements played a crucial role in human evolution by secretly spawning hyperactive copies, giving rise to the most abundant family of transposable elements in the human genome, known as Alu elements. The study provides the first strong evidence for the evolution of Alu elements to date.

Alu elements are short DNA sequences capable of copying themselves, mobilizing through an RNA intermediate and inserting into another location in the genome. Over evolutionary time, this activity, known as "retrotransposition," has led to the generation of more than 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 percent of the total human genome, they have been thoroughly examined and characterized in terms of their origin and sequence composition. What has remained elusive to scientists, however, is how these elements persist and propagate over time and influence human evolution. In an attempt to understand this process, Batzer and his colleagues examined a sub-family 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 sub-family accounts for approximately 40 percent 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 inherited diseases.

"These elements have contributed quite a bit to the diversity of human and non-human primate genomes, so it is very important to understand their origin and spread," said Batzer. "They cause about half a percent of all human genetic disorders."

According to Batzer, some of the genetic disorders related to these elements include hemophilia and some cancers. These disorders are caused by insertional mutation or by recombination between these elements, which is when elements that are near each other undergo a "recombination" and part of the genome is deleted in the process.

Batzer's team demonstrated that the AluYb linage dates back approximately 18-25 million years. Their results also indicated that the AluYb sub-family underwent a major species-specific expansion in the human genome during the past 3-4 million years. This apparent 20-million-year stretch of general inactivity, followed by a sudden outburst of human-specific retrotransposition activity in the past few million years, led 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.

Batzer explained that the exact purpose or function of these elements is still debated, but understanding their basic behavior and history could be crucial to finding answers in the future.

"Mobile elements make up a huge proportion of the human genome and understanding how these elements spread through the genome and how they contribute to genetic diversity is critical," said Batzer. "This research provides a fundamental insight into their spread and it has changed our opinion about what it takes to successfully spread through the genome."