Endogenous Retrovirus - Genome Evolution

Genome Evolution

Endogenous retroviral elements and their associated LTRs have been implicated in several forms of cancer and autoimmune disease. However, evidence has come about that shows, at least in human and mammalian models, that these elements have an active role in the shaping of the genome. The large proportion of research being done is in the HERV family, within the human genome, but some studies have been done in mice and sheep as well. The LTR sequences frequently act as alternate promoters and enhancers, often contributing to the transcriptome by producing tissue-specific variants. In addition, the retroviral proteins themselves have been co-opted to serve novel host functions, particularly in reproduction and development. Recombination between homologous retroviral sequences has also contributed to gene shuffling and the generation of genetic variation. Furthermore, in the instance of potentially antagonistic effects of retroviral sequences, repressor genes have co-evolved to combat them.

Solo LTRs and LTRs associated with complete retroviral sequences have been shown to act as transcriptional elements on host genes. Their range of action is mainly by insertion into the 5’ UTRs of protein coding genes, however, they have been know to act upon genes up to 70-100kb away. The majority of these elements are inserted in the sense direction to their corresponding genes, but there has been evidence of LTRs acting in the antisense direction and as a bidirectional promoter for neighboring genes. In a few cases, the LTR functions as the major promoter for the gene. For example, AMY1C has a complete HERV sequence in its promoter region; the associated LTR confers salivary specific expression of the digestive enzyme, amylase. Also, the primary promoter for BAAT, which codes for an enzyme that is integral in bile metabolism, is of HERV LTR origins. Interestingly, the insertion of a solo ERV-9 LTR may have produced a functional ORF causing the rebirth of the human immunity related GTPase gene, IGRM. ERV insertions have also been shown to generate alternative splice sites either by direct integration into the gene, as with the human leptin hormone receptor, or driven by the expression of an upstream LTR, as with the phospholipase A-2 like protein.

However, in the majority of cases the LTR functions as one of many alternate promoters, often conferring tissue-specific expression related to reproduction and development. In fact, 64% of known LTR-promoted transcription variants express in reproductive tissues. For example, CYP19 codes for aromatase P450, an important enzyme for estrogen synthesis, and is normally expressed in the brain and reproductive organs of most mammals. However, in primates an LTR-promoted transcriptional variant confers expression to the placenta and is responsible for controlling estrogen levels during pregnancy. Furthermore, NAIP the neuronal apoptosis inhibitory protein, normally wide spread, has a LTR of the HERV-P family acting as a promoter that confers expression to the testis and prostate Other proteins, such as nitric acid synthase 3 (NOS3), interleukin-2 receptor B (IL2RB), and another mediator of estrogen synthesis, HSD17B1, are also alternatively regulated by LTRs that confer placental expression, but their specific functions are not yet known. The high degree of reproductive expression is thought to be an aftereffect of the method by which they were endogenized, however, this also may be due to a lack of DNA methylation in germ-line tissues.

The most well characterized instance of placental protein expression comes not from an alternatively-promoted host gene, but a complete co-option of a retroviral protein. It is well documented that retroviral fusogenic env proteins, which play a role in the entry of the viroid into the host cell, have had an important impact on the development of mammalian placenta. In humans, and other mammals, intact env proteins called syncytins, are responsible for the formation and function of syncytiotrophoblasts. These multi-nucleated cells are mainly responsible for maintaining nutrient exchange and protecting the developing fetus from the mother’s immune system. It has been suggested that the selection and fixation of these proteins for this function have played a critical role in the evolution of viviparity.

In addition, the insertion of ERVs, and their respective LTRs, has the potential to induce chromosomal rearrangement due to recombination between viral sequences at inter-chromosomal loci. These rearrangements have been shown to induce gene duplications and deletions that largely contribute to genome plasticity and dramatically change the dynamic of gene function. Furthermore, retroelements in general are largely prevalent in rapidly evolving, mammal-specific gene families whose function is largely related to the response to stress and external stimuli. In particular, both human class I and class II MHC genes have a high density of HERV elements as compared to other multi-locus gene families. It has been shown that HERVs have contributed to the formation of extensively duplicated duplicon blocks that make up the HLA class 1 family of genes. More specifically, HERVs primarily occupy regions within and between the break points between these blocks, suggesting that considerable duplication and deletions events, typically associated with unequal crossover, facilitated their formation. The generation of these blocks, inherited as immunohaplotypes, act as a protective polymorphism against a wide range of antigens that may have imbued humans with an advantage over other primates.

Finally, the insertion of ERVs or ERV elements into genic regions of host DNA, or overexpression of their transcriptional variants, has a much higher potential to produce deleterious effects than positive ones. Their appearance into the genome has created a host-parasite co-evolutionary dynamic that proliferated the duplication and expansion of repressor genes. The most clear-cut example of this involves the rapid duplication and proliferation of tandem zinc-finger genes in mammal genomes. Zinc finger genes, particularly those that include a KRAB domain, exist in high copy number in vertebrate genomes and their range of functions are limited to transcriptional roles. However, it has been shown that in mammals that the diversification of these genes was due to multiple duplication and fixation events in response to new retroviral sequences or their endogenous copies to repress their transcription.