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Introduction to Mobile DNA

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Haig Kazazian reviews our current understanding of the substantial role mobile genetic elements play in genome and organism evolution and function.

Introduction to Mobile DNA

Charles Darwin would be surprised. Indeed, even present day scientists are surprised by the existence of mobile DNA. Consider the skepticism within the scientific community that greeted Barbara McClintock, already a highly-respected scientist, when she announced that she had found what appeared to be mobile DNA in maize plants (McClintock, 1950). DNA was the genetic material, so it must be static, stable, and immobile. The mutation rate had been determined to be ~10-8 per nucleotide, or building block, of DNA per generation—very low indeed. How and why would some DNA move from place to place in a genome? Scientists are still grappling with these questions. Two hundred years removed from Darwin’s birth, and we’re still wondering how mobile DNA with all its detrimental effects on organisms could have reached such high proportions in the genomes of mammals and plants. Yet mobile DNA is found in all forms of living things, including plants, animals, bacteria, and archea. The genome seems to cherish its ability to make rapid changes by rearranging some of its parts as opposed to the slow change afforded by the nucleotide mutation rate.

One theme of this book is that biological scientists have come to expect the unexpected. The study of living things is full of surprises. One of them is the prevalence of mobile DNA in genomes. Another is that most genes are broken up by sections of DNA called introns that need to be removed at the RNA stage in order for the genes to function. A third is that the protein-coding regions of genes make up a very small fraction of mammalian genomes. A fourth surprise is the importance of reverse transcriptase, the enzyme that synthesizes DNA from an RNA template. These are just a few examples of old surprises, or unexpected findings, that have now become hard facts in all biology textbooks. Many more will be highlighted in the research adventures outlined in this book. These “unexpected observations” provide excitement and anticipation for even the most experienced researchers. What finding will be the next to shatter our present view of the biological world? One can be sure that the future will bring many more surprises to delight the graduate student just beginning his or her studies.

Prior to 1970, scientists thought that the genome was composed mostly of genes lined up like balls on a string with some repetitive DNA in between the balls. Then in the late 1970s, introns were found to break up the regions of genes that encode proteins (Berget et al., 1977; Chow et al., 1977). Protein-coding regions were disrupted by intervening sequences (introns) that required removal from pre-messenger RNA before the intact protein could be synthesized. Soon, we knew that introns were much larger than protein-coding regions, then called exons. The DNA between the genes along with most of the intronic sequences of genes was thought to be functionless, and was called “junk DNA” (Orgel and Crick, 1980). However, now we know that introns make up about 30% of human and mammalian genomes, and exons encode only between 1 and 2% of the human genome (Lander et al., 2001). What a comedown for protein-coding regions! Thus, over 98% of human DNA had been dismissed as “junk.”

Transposable elements were then found in human DNA, and this active mobile DNA along with the remnants of many transposition events over hundreds of millions of years is now known to account for at least 50% of human genomic DNA. This transposable element DNA, both those relatively few sequences that are presently mobile, and the many remnants of old events are now demonstrating function. However, this function is evident only in the many ways mobile DNA can modify the genome over evolutionary time. It can be co-opted for useful purposes but has not yet been definitively shown to have a useful function in the individual organism. Moreover, DNA encoding small RNAs of different types and functions has been discovered amidst the “junk.” Enhancer sequences at great distances from the genes upon which they act are being found continually. Segmental duplications of hundreds to many thousands of nucleotide pairs of DNA are strewn around the genome and are further grist in the mill of genome plasticity and malleability. The bottom line is that “junk” DNA is gradually being eroded away as function is found for a greater and greater fraction of genomic DNA. In this book, I concentrate on the “junk” DNA that is mobile or has been over the millennia. This is the DNA that those of us in the mobile DNA field have come to treasure.

In the next several chapters, I provide details on important topics in the mobile DNA field as well as discuss a number of top scientists who have been pioneers in many areas involving mobile DNA. I then discuss the state of the human mobile DNA field prior to my involvement in it, what led to my fascination with mobile DNA, and why I jumped at the chance to work on it when the opportunity presented itself. Later, I discuss many of the people who worked in my lab up to the present time, their most important work, and the relationship of that work to what is known about L1 biology today. This is followed by important findings of other labs working on mammalian mobile DNA, ending with some thoughts about the future of the field. Yes, DNA as genetic material would have surprised Charles Darwin, but mobile DNA would have really made his head spin!

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