Mammalian L1 elements (LINE-1) replicate (retrotranspose) by copying their RNA transcripts into DNA which is then integrated into the genome. L1 elements have been replicating and evolving in mammalian genomes since before the mammalian radiation 100 MYA and now account for as much as 20% of some genomes. In humans L1 retrotransposition causes up to 0.2% of the genetic defects. The ~7 kb L1 element has four regions: The 5' UTR (untranslated region) has a regulatory function; ORF I encodes an RNA binding protein; ORF II encodes the L1 cDNA replicase; the 3' UTR contains a conserved G-rich polypurine motif which can form complex intrastrand DNA and RNA structures. We found that both rodent and human L1 elements evolve rapidly with novel families continually replacing older ones. Since most of the copies of past L1 families are retained, modern genomes contain both ancestral and modern L1 families. Among other things, the relics of extinct L1 families can yield phylogenetic information about the host species and important genetic parameters such as its neutral mutation rate. L1 insertions generated by currently replicating families provide robust polymorphic genetic markers for analyzing population structure. Last year we reported on our analysis of the human Ta L1 family. This family arose ~4 MYA soon after the human and chimpanzee lineages split and has been amplifying rapidly, evolving into several subfamilies: Ta-0 and Ta-1. Overall, about 50% of Ta insertions are polymorphic across human populations and more than 90% of the inserts generated by Ta-1d, the youngest subset of Ta-1, are polymorphic. Indeed all 12 documented genetic defects caused by L1 insertions (some of which occurred in utero) are due to Ta, 10 by Ta-1d insertions. Thus novel Ta L1 insertions are increasing the genetic diversity of humans. We have since found that most of the genetic loci that once contained potentially active (i.e., full length, FL) ancestral L1 elements are no longer present in modern humans. These FL L1 elements represented four different L1 families that amplified from between 5 and 15 MYA. Thus, there has been continual purifying selection against these active L1 elements. This strongly implies that not only did the ancestral active L1 elements impose a significant genetic load on early humans, but that the currently active Ta family also does. The nature of this genetic load in now being investigated. We also compared sequence divergence within these four ancestral human L1 families. Our results provided the first unequivocal and statistically robust evidence that the human mutation rate is higher in males than in females. This was first proposed by Haldane over 50 years ago and despite considerable effort the results remained contradictory. Our results have profound implications for molecular evolution and speciation and provide a base line mutational rate for evaluating the rate of genetic change of given human loci. Given the importance of genetic polymorphisms for genetic mapping and population genetics we had initiated a special project to isolate all of the polymorphic loci in various human populations caused by the transpositional activity of the Ta-1 L1 subfamily. Phase I (the isolation of polymorphic loci from four different human populations) is now sufficiently advanced that we have initiated collaborations with several non-NIH institutions to use our presently identified loci to analyze the genetic composition of several human populations. We will soon implement the use of the L1 markers for mapping genetic traits related to disease states. We anticipate beginning phase II in about 6 months. Here we will use the information gained from phase I to identify additional polymorphic L1 loci from additional populations or individuals as well as to develop an assay for transposition rate.
| Boissinot, Stephane; Davis, Jerel; Entezam, Ali et al. (2006) Fitness cost of LINE-1 (L1) activity in humans. Proc Natl Acad Sci U S A 103:9590-4 |
| Boissinot, S; Furano, A V (2005) The recent evolution of human L1 retrotransposons. Cytogenet Genome Res 110:402-6 |
| Martin, S L; Li, W-L P; Furano, A V et al. (2005) The structures of mouse and human L1 elements reflect their insertion mechanism. Cytogenet Genome Res 110:223-8 |
| Boissinot, Stephane; Entezam, Ali; Young, Lynn et al. (2004) The insertional history of an active family of L1 retrotransposons in humans. Genome Res 14:1221-31 |
| Boissinot, Stephane; Roos, Christian; Furano, Anthony V (2004) Different rates of LINE-1 (L1) retrotransposon amplification and evolution in New World monkeys. J Mol Evol 58:122-30 |
| Furano, Anthony V; Duvernell, David D; Boissinot, Stephane (2004) L1 (LINE-1) retrotransposon diversity differs dramatically between mammals and fish. Trends Genet 20:9-14 |
| Boissinot, S; Entezam, A; Furano, A V (2001) Selection against deleterious LINE-1-containing loci in the human lineage. Mol Biol Evol 18:926-35 |
| Furano, A V (2000) The biological properties and evolutionary dynamics of mammalian LINE-1 retrotransposons. Prog Nucleic Acid Res Mol Biol 64:255-94 |
| Boissinot, S; Chevret, P; Furano, A V (2000) L1 (LINE-1) retrotransposon evolution and amplification in recent human history. Mol Biol Evol 17:915-28 |
