Mobile elements in the human genome: implications for disease

It has been generally held that about half of the human genome is derived from mobile genomic elements, but according to a recent estimate over two-thirds of our genome may result from the presence or ancient activity of 'jumping genes' [1]. This massive amount of DNA includes domesticated elements with evolutionarily spectacular functions, such as the RAG (recombination activating) genes that form the basis of V(D)J recombination in our immune system [2,3], and the ERVWE1 (endogenous retrovirus group W, member 1) gene that plays a role in placental development [4]. Contrary to their evolutionary gifts, mobile elements are most notorious for being junk or for causing life-threatening human disorders by insertional mutagenesis and homologous recombination. As we usher in the era of genome-scale studies, it is clear that these elements have the potential to cause intra-individual and inter-individual variation and probably common disease through structural variation, deregulated transcriptional activity or epigenetic effects. Furthermore, large-scale studies have expanded the pool of human disorders resulting from retrotransposon-mediated insertional mutagenesis. Recent reviews have discussed the technical aspects of these new methods [5-8]. We focus here on the known, as well as inferred, potential health impact of their novel findings.Human mobile elements can be categorized as DNA transposons or retrotransposons. DNA transposons move by a cut-and-paste mechanism, while retrotransposons mobilize by a copy-and-paste mechanism via an RNA intermediate, a process called retrotransposition. Retrotransposons can be further subdivided into long terminal repeat (LTR) and non-LTR elements. LTR retrotransposons are human endogenous retroviruses (HERVs) that have an intracellular existence as a result of a non-functional envelope gene. Non-LTR elements are classified as long interspersed elements (LINEs; the prototype of which is the RNA polymerase II transcribed LINE-1 (L1)),