Our research focuses on mobile and invasive DNA, with an emphasis on the genomes of vertebrates, including humans. These include diverse genetic elements, such as transposons and endogenous viruses, able to integrate and often to propagate within and between genomes. Mobile elements are found in nearly all organisms and often account for the bulk of their genetic material. For example protein-coding sequences account for less than 2% of human DNA, while mobile elements occupy at least half. These elements have a tremendous impact on the structure and expression of the genome, for better or worse. For example, over a hundred human diseases, such as hemophilia A and several cancers, are directly linked to the mobility or rearrangement of mobile elements. On the other hand, there is growing evidence that a substantial fraction of human mobile elements are serving crucial cellular and developmental functions, although most remain unexplored.
My laboratory uses an integrative approach, combining bioinformatics, genetics and biochemistry, to investigate the contribution of mobile elements to genomic variation and to the emergence of biological novelty, including new genes and regulatory sequences, in a broad range of eukaryotic organisms. Another area of research activity falls within the emerging field of paleovirology. Here we capitalize on the fossil record left by viral sequences integrated in genomes to study the long-term co-evolution of viruses and their host. These studies have the power to yield critical insights into the biological and environmental factors facilitating cross-species transmission of viruses and other form of invasive DNA.
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MOBILE DNA: the dark matter of the genome
My research focuses on mobile DNA, a term that encompasses diverse genetic elements able to integrate and often propagate within the genome. In eukaryotes, these include transposons and endogenous viruses.
Mobile DNA is found in nearly all organisms and often account for a sizeable fraction of the genetic material. For example, transposons and their remnants make up at least 40 percent of the human genome and endogenous retroviruses account for another 8 percent. One may find it unsettling that half (or more) of our own genetic material is derived from genetic parasites and viruses!
Mobile DNA is often referred to as the ‘dark matter of the genome’ because we still poorly understand its functional significance. Yet the short-term, mutagenic effect of mobile elements on the structure and expression of the genome has been well documented. For example, over a hundred human diseases, such as hemophilia A and several cancers, are directly linked to de novo insertion or recombination of transposable elements. But much less is known about the long-term impact of mobile elements on the biology and evolution of species and on the mechanisms through which these parasitic elements persist over eons. These are the issues we are focusing on.
Research in my laboratory uses a combination of experimental and computational approaches to address three fundamental questions at a genome-wide scale:
(1) What are the mechanisms allowing for the persistence of transposons?
We have uncovered flagrant cases of horizontal transfers where transposons have crossed species boundaries on multiple occasions to invade the genome of widely diverged animals, including mammals. But how common are these ‘jumps’ across species and how do they happen?
(2) What is the biological significance of endogenous viruses and what do they tell us about host-virus evolution?
Endogenous viruses can be viewed as molecular fossils that have been deposited in the genome during past viral invasions. By excavating and analyzing such genomic relics we have the opportunity to explore viral evolution at a depth unreachable when studying modern viruses. This information has the power to yield critical insights and predictions relevant to pathogenic viruses circulating now as well as those threatening to trigger the next pandemics.
(3) What is the contribution of mobile DNA to the advent of new biological functions, and in particular regulatory evolution?
Although mobile elements are sometimes dismissed as merely ‘junk DNA’, there is now compelling evidence that they have profoundly influenced the evolution of genes and genomes. Currently we are studying the origin and function of genes and non-coding regulatory sequences that have emerged from mobile elements in human and Drosophila. We aim to assess the extent by which mobile elements have contributed to the advent of biological innovation.
Given the ubiquitous nature of mobile DNA and the ever-growing accessibility of whole genome sequencing, we do not restrict our research to a single model species or even a group of organisms. Instead, we are studying the genomes of a broad range of eukaryotic species, with a primary emphasis on vertebrates, including humans. Our research uses an integrative approach that hinges on a foundation of bioinformatics and comparative sequence analyses typically performed at the genome-wide level. The findings and patterns deciphered at the computer are then taken to the wet lab to test specific hypotheses in the most appropriate experimental systems, often in collaboration with other laboratories. These include functional analyses in vitro and ex vivo in mammalian cells, as well as genetic analyses in model organisms such as yeast, Arabidopsis and Drosophila.
Zhuo X, Rho M, Feschotte C. (2013) Genome-Wide Characterization of Endogenous Retroviruses in the Bat Reveals Recent and Diverse Infections. Journal of Virology (in press) Note: FEATURED AS JVI SPOTLIGHT ARTICLE
Kapusta A, Kronenberg Z, Lynch VJ, Zhuo X, Ramsay L, Bourque G, Yandell M & Feschotte C (2013) Transposable elements are major contributors to the origin, diversification, and regulation of vertebrate long noncoding RNAs. PLoS Genetics 9: e1003470
Li X., Mitra R., Kapusta A., Mayhew D., Mitra, R.D., Feschotte C. & Craig N.L. (2013) Functional characterization of piggyBat from the bat Myotis lucifugus unveils an active DNA transposon in a mammalian genome. Proc. Natl. Acad. Sci. USA 110: 234-239
Li X., Ewis H., Hice R.H., Malani N., Parker N., Zhou L., Feschotte C. Bushman F.D., Atkinson P.W., Craig N.L. (2012) A resurrected mammalian hAT transposable element and a closely related insect element are highly active in human cell culture. Proc. Natl. Acad. Sci. USA [in press, published online Oct 22]
Feschotte C. & Gilbert C. (2012) Endogenous viruses: insights into viral evolution and impact on host biology. Nature Reviews Genetics 13: 283-296
Gilbert C., Hernandez S.S., Flores J., Dao, T.M., Smith E.N. & Feschotte C. (2012) Rampant horizontal transfer of SPIN transposons in squamate reptiles. Molecular Biology and Evolution 29: 503-515
Castoe T.A., Hall K.A., Guibotsy M.L., Gu W., de Koning J.A.P., Fox S.E., Poole A.W., Vemulapalli V. Daza J.M., Mockler T. Smith E.N., Feschotte C. & Pollock D.D. (2011) Discovery of highly divergent repeat landscapes in snake genomes using high throughput sequencing. Genome Biology and Evolution 3: 641-653
Gilbert C. & Feschotte C. (2010) Genomic fossils calibrate the long-term evolution of Hepadnaviruses. PLoS Biology 8: e1000495
Schaack S., Gilbert C. & Feschotte C. (2010) Horizontal transfer of transposable elements and why it matters for eukaryotic evolution. Trends in Ecology and Evolution 25:537-546
Gilbert C., Schaack S., Pace J.K, II, Brindley P.J. & Feschotte C. (2010) A role for host-parasite interactions in the horizontal transfer of DNA transposons across animal phyla. Nature 464:1347-1350
Yang G., Holligan-Nagel D., Feschotte C., Hancock N.H. & Wessler S.R. (2009) Tuned for transposition: molecular determinants underlying the hyperactivity of a Stowaway MITE. Science 325: 1391-1394
Gilbert C., Maxfield D.G., Goodman S.M. & Feschotte C. (2009) Parallel germline infiltration of a lentivirus in two Malagasy lemurs. PLoS Genetics 5(3): e1000425
Pace J.K., II, Gilbert C., Clark M.S. & Feschotte C. (2008) Repeated horizontal transfer of a DNA transposon in mammals and other tetrapods. Proc. Natl. Acad. Sci. USA 105:17023-17028
Feschotte C (2008) Transposable elements and the evolution of regulatory networks. Nature Reviews Genetics 9:397-407
Ray DA, Feschotte C, Smith JD, Pagan HJT, Pritham EJ, Arensburger P, Atkinson PW & Craig NL (2008) Multiple waves of recent DNA transposon activity in the bat Myotis lucifugus. Genome Research 18:717-728
Lin R, Ding L, Casola C, Ripoll DR, Feschotte C & Wang H. (2007) Lin R, Ding L, Casola C, Ripoll DR, Feschotte C & Wang H. Transposase-derived transcription factors regulate light signaling in Arabidopsis. Science 318:1302-1305
Feschotte C. & Pritham E.J. (2007) DNA transposons and evolution of the eukaryotic genome. Annual Review of Genetics 41:331-338
Pace J.K, II & Feschotte C. (2007) The evolutionary history of human DNA transposons: evidence for intense activity in the primate lineage. Genome Research 17:422-432
Pritham E.J. & Feschotte C. (2007) Massive amplification of rolling-circle transposons in the lineage of the bat Myotis lucifugus. Proc. Natl. Acad. Sci. USA 104:1895-1900
Cordaux R, Udit S., Batzer MA & Feschotte C (2006) Birth of a chimeric primate gene by capture of the transposase gene from a mobile element. Proc. Natl. Acad. Sci. USA 103: 8101-8106
Department of Human Genetics
University of Utah
15 N 2030 E rm. 3410
Salt Lake City, Utah 84112-5330