Endogenous retroviruses in the human genome sequence

Abstract

The human genome contains many endogenous retroviral sequences, and these have been suggested to play important roles in a number of physiological and pathological processes. Can the draft human genome sequences help us to define the role of these elements more closely?

Figure 1

Structure of retroviral proviruses. (a) Infectious retroviruses have at least three genes: gag, which encodes the structural proteins of the viral core; pol, which encodes the viral enzymes, including reverse transcriptase; and env, which encodes the surface glycoproteins of the viral envelope. Viral protein expression is controlled by promoter and enhancer elements and polyadenylation signals in the long terminal repeats (LTRs), which are generated during reverse transcription. Other regulatory elements are also present in the viral genome, including splice donor (SD) and acceptor (SA) sites (for env expression) and a primer-binding site (PBS) for a specific tRNA molecule used to initiate reverse transcription. The tRNA specificity varies among different retroviruses and has been used to classify endogenous retroviruses in the human genome. (b) Human endogenous retroviruses (HERVs) have a similar structure to the proviruses of infectious retroviruses but typically contain many inactivating mutations including point mutations (dark bands), frameshifts and deletions (particularly in env). Frequently, the entire central portion has been lost by homologous recombination, leaving behind a 'solitary LTR'. Although almost all HERVs are defective, the LTRs may still be active, and transcription of HERVs is common particularly in fetal tissue and in inflammatory disease and cancer. In a few cases, coding competence has been retained for env even when adjacent viral genes are heavily mutated, suggesting that selective pressures have maintained these open reading frames because they serve a cellular function.

Figure 2

HERVs as regulators of host gene expression. HERV LTRs can influence expression of flanking host genes (host exons are indicated by black boxes and HERV is indicated in grey). (a) The normal transcript from the cellular promoter. (b) An alternative transcript from the HERV LTR (for example, see [21]). Either the 5' or the 3' LTR can be used, but transcripts from the 5' LTR may use the HERV splice donor site and could potentially generate alternative transcripts. Expression of the cellular gene may be either activated or silenced by this mechanism. (c) The activity of the HERV LTR may be modulated by other factors such as methylation [22], polymorphisms [23] and the activation state of the cell.