The National Institute of Diabetes & Digestive & Kidney Diseases

The mammalian L1 (LINE-1) retrotransposon

The L1 retrotransposon is an autonomous genetic element that replicates (retrotransposes) by copying its RNA transcript into genomic DNA. It can also copy other RNAs (e.g., SINE and processed nuclear gene transcripts) into genomic DNA. L1 and SINE insertions can inactivate or alter gene activity, and cause genetic rearrangements by participating in non-allelic homologous recombination.

L1 retrotransposons have been replicating and evolving in mammalian species since >= 80 million years ago, and have generated about 40% of mammalian DNA. Novel L1 families repeatedly arose, only to go extinct coincident with the emergence of another novel L1 family. This pattern has persisted to the present despite the fact that L1 activity is deleterious to its host, including present day humans.

The pattern of mammalian L1 evolution resembles that of the influenza virus HA antigen in humans. The latter is explained by the successive emergence of viral variants that bypass existing host defenses (immunity) followed by the reestablishment of host immunity. We suggest that an analogous adversarial interaction between L1 and its host could explain the pattern of L1 evolution.

Despite its dominance in mammalian genomes, little is known about the regulation of L1 activity or how it interacts with its host. Our ignorance of such basic parameters represents a major gap in our understanding of mammalian biology. Our approach to examining these issues is framed by the statement of the eminent geneticist Theodosius Dobzhansky that "Nothing in biology makes sense except in the light of evolution".

Our premise is that the evolutionary history of L1 elements holds clues to both their replicative success and the nature of L1 / host interaction. We address these inferences experimentally using a variety of approaches including molecular & structural biology, biochemistry, bioinformatics, genomics, and population genetics. We also use the fossils of extinct L1 families to examine basic genetic parameters such as the factors that influence mutation rate.

1. Walser JC, Ponger L, Furano AV CpG dinucleotides and the mutation rate of non-CpG DNA. Genome Res(18): 1403-14, 2008. [Full Text/Abstract]

2. Boissinot S, Davis J, Entezam A, Petrov D, Furano AV Fitness cost of LINE-1 (L1) activity in humans. Proc Natl Acad Sci U S A (103): 9590-9594, 2006. [Full Text/Abstract]

3. Martin SL, Li WL, Furano AV, Boissinot S The structures of mouse and human L1 elements reflect their insertion mechanism. Cytogenet Genome Res (110): 223-8, 2005. [Full Text/Abstract]

4. Boissinot S Roos C Furano AV Different rates of LINE-1 (L1) retrotransposon amplification and evolution in New World monkeys. J Mol Evol (58): 122-30, 2004. [Full Text/Abstract]

5. Furano AV Duvernell DD Boissinot S L1 (LINE-1) retrotransposon diversity differs dramatically between mammals and fish. Trends Genet (20): 9-14, 2004. [Full Text/Abstract]

6. Boissinot S Entezam A Young L Munson PJ Furano AV The insertional history of an active family of L1 retrotransposons in humans. Genome Res (14): 1221-31, 2004. [Full Text/Abstract]

7. Eickbush TH Furano AV Fruit flies and humans respond differently to retrotransposons. Curr Opin Genet Dev (12): 669-74, 2002. [Full Text/Abstract]

8. Boissinot S Furano AV Adaptive evolution in LINE-1 retrotransposons. Mol Biol Evol (18): 2186-94, 2001. [Full Text/Abstract]

9. Boissinot S Entezam A Furano AV Selection against deleterious LINE-1-containing loci in the human lineage. Mol Biol Evol (18): 926-35, 2001. [Full Text/Abstract]

10. Boissinot S Chevret P Furano AV L1 (LINE-1) retrotransposon evolution and amplification in recent human history. Mol Biol Evol (17): 915-28, 2000. [Full Text/Abstract]

11. Furano AV The biological properties and evolutionary dynamics of mammalian LINE-1 retrotransposons. Prog Nucleic Acid Res Mol Biol (64): 255-94, 2000. [Full Text/Abstract]