Origin of the human L1 elements: Proposed progenitor genes deduced from a consensus DNA sequence

Abstract

A consensus sequence for the human long interspersed repeated DNA element, L1Hs (LINE or KpnI sequence), is presented. The sequence contains two open reading frames (ORFs) which are homologous to ORFs in corresponding regions of L1 elements in other species. The L1Hs ORFs are separated by a small evolutionarily nonconserved region. The 5' end of the consensus contains frequent terminators in all three reading frames and has a relatively high GC content with numerous stretches of weak homology with AluI repeats. The 5' ORF extends for a minimum of 723 bp (241 codons). The 3' ORF is 3843 bp (1281 codons) and predicts a protein of 149 kD which has regions of weak homology to the polymerase domain of various reverse transcriptases. The 3' end of the consensus has a 208-bp nonconserved region followed by an adenine-rich end. The organization of the L1Hs consensus sequence resembles the structure of eukaryotic mRNAs except for the noncoding region between ORFs. However, due to base substitutions or truncation most elements appear incapable of producing mRNA that can be translated. Our observation that individual elements cluster into subfamilies on the basis of the presence or absence of blocks of sequence, or by the linkage of alternative bases at multiple positions, suggests that most L1 sequences were derived from a small number of structural genes. An estimate of the mammalian L1 substitution rate was derived and used to predict the age of individual human elements. From this it follows that the majority of human L1 sequences have been generated within the last 30 million years. The human elements studied here differ from each other, yet overall the L1Hs sequences demonstrate a pattern of species-specificity when compared to the L1 families of other mammals. Possible mechanisms that may account for the origin and evolution of the L1 family are discussed. These include pseudogene formation (retroposition), transposition, gene conversion, and RNA recombination.

De novo Alu element insertions targeted to a sequence common to the BRCA1 and BRCA2 genes

“…Only a very small fraction of these repetitive sequences are still able to actively transpose. Full length L1 elements are about 6kb long and encode the proteins necessary for autonomous retrotransposition (Scott et al 1987). Alu elements are much smaller, 300-350bp long, and lack any protein-coding capacity.…”

LINE-1 ORF1 protein enhances Alu SINE retrotransposition

“…L1 contains two open reading frames (ORF1 and ORF2) that are translated from a single bicistronic transcript (Scott et al, 1987), though various splice products diversify the potential mechanisms of translation (Perepelitsa-Belancio and Deininger 2003;Belancio et al, 2006). Both proteins are necessary for L1 retrotransposition.…”

Selective inhibition of Alu retrotransposition by APOBEC3G

“…Although most L1s are immobile, it is estimated that the average human genome contains approximately 60-100 retrotransposition-competent L1s (RC-L1s) and their mobility can cause human disease (Sassaman et al, 1997, Brouha et al, 2003, Hulme et al, 2006, Kazazian et al, 1988. RC-L1s are composed of a 5' UTR that harbors an internal promoter, two non-overlapping open reading frames (ORF1 and ORF2), and a 3' UTR that ends in a poly (A) tail (Swergold, 1990, Scott et al, 1987, Dombroski et al, 1991, Minakami et al, 1992. The ORF2 encoded protein (ORF2p) contains both endonuclease and reverse transcriptase activities, which are required for retrotransposition , Feng et al, 1996.…”