Phylogenetic analysis reveals that ERVs "Die Young" but HERV-H Is unusually conserved

About 8% of the human genome is made up of endogenous retroviruses (ERVs). Though most human endogenous retroviruses (HERVs) are thought to be irrelevant to our biology notable exceptions include members of the HERV-H family that are necessary for the correct functioning of stem cells. ERVs are commonly found in two forms, the full-length proviral form, and the more numerous solo-LTR form, thought to result from homologous recombination events. Here we introduce a phylogenetic framework to study ERV insertion and solo-LTR formation. We then apply the framework to site patterns sampled from a set of long alignments covering six primate genomes. Studying six categories of ERVs we quantitatively recapitulate patterns of insertional activity that are usually described in qualitative terms in the literature. A slowdown in most ERV groups is observed but we suggest that HERV-K activity may have increased in humans since they diverged from chimpanzees. We find that the rate of solo-LTR formation decreases rapidly as a function of ERV age and that an age dependent model of solo-LTR formation describes the history of ERVs more accurately than the commonly used exponential decay model. We also demonstrate that HERV-H loci are markedly less likely to form solo-LTRs than ERVs from other families. We conclude that the slower dynamics of HERV-H suggest a host role for the internal regions of these exapted elements and posit that in future it will be possible to use the relationship between full-length proviruses and solo-LTRs to help identify large scale co-options in distant vertebrate genomes

Phylogenetic analysis reveals that ERVs "die young" but HERV-H is unusually conserved

About 8% of the human genome is made up of endogenous retroviruses (ERVs). Though most human endogenous retroviruses (HERVs) are thought to be irrelevant to our biology notable exceptions include members of the HERV-H family that are necessary for the correct functioning of stem cells. ERVs are commonly found in two forms, the full-length proviral form, and the more numerous solo-LTR form, thought to result from homologous recombination events. Here we introduce a phylogenetic framework to study ERV insertion and solo-LTR formation. We then apply the framework to site patterns sampled from a set of long alignments covering six primate genomes. Studying six categories of ERVs we quantitatively recapitulate patterns of insertional activity that are usually described in qualitative terms in the literature. A slowdown in most ERV groups is observed but we suggest that HERV-K activity may have increased in humans since they diverged from chimpanzees. We find that the rate of solo-LTR formation decreases rapidly as a function of ERV age and that an age dependent model of solo-LTR formation describes the history of ERVs more accurately than the commonly used exponential decay model. We also demonstrate that HERV-H loci are markedly less likely to form solo-LTRs than ERVs from other families. We conclude that the slower dynamics of HERV-H suggest a host role for the internal regions of these exapted elements and posit that in future it will be possible to use the relationship between full-length proviruses and solo-LTRs to help identify large scale co-options in distant vertebrate genomes.Author summary: Animal genomes contain ancient pathogens known as endogenous retroviruses (ERVs). Though the widespread abundance of ERVs is due to their ability to self replicate, some ERVs are known to have become important to host processes including placentation, and in the case of HERV-H, the functioning of human stem cells. In our study we place the insertion and deletion activity of primate ERV families in direct quantitative comparison. In particular, we show that ERV deletion is an age dependent process, so that as an ERV ages it becomes less likely to be deleted at any given instant. We also find that ERVs from the HERV-H family are unusually slowly deleted, an interesting result that suggests that the exaptation of HERV-H may have involved internal regions of the virus and not just its terminal promoters. Assuming the behaviour of primate ERVs is not unusual, our study suggests that future bioinformatics screening for ERVs with slow deletion dynamics could help identify large-scale exaptations in distant species. Furthermore, as we demonstrate that ERVs are deleted rapidly, we think that such screening could be performed using ratios of conserved to deleted elements and could therefore be applied to single genomes.</p

Phylogenetic analysis reveals that ERVs "Die Young" but HERV-H Is unusually conserved

About 8% of the human genome is made up of endogenous retroviruses (ERVs). Though most human endogenous retroviruses (HERVs) are thought to be irrelevant to our biology notable exceptions include members of the HERV-H family that are necessary for the correct functioning of stem cells. ERVs are commonly found in two forms, the full-length proviral form, and the more numerous solo-LTR form, thought to result from homologous recombination events. Here we introduce a phylogenetic framework to study ERV insertion and solo-LTR formation. We then apply the framework to site patterns sampled from a set of long alignments covering six primate genomes. Studying six categories of ERVs we quantitatively recapitulate patterns of insertional activity that are usually described in qualitative terms in the literature. A slowdown in most ERV groups is observed but we suggest that HERV-K activity may have increased in humans since they diverged from chimpanzees. We find that the rate of solo-LTR formation decreases rapidly as a function of ERV age and that an age dependent model of solo-LTR formation describes the history of ERVs more accurately than the commonly used exponential decay model. We also demonstrate that HERV-H loci are markedly less likely to form solo-LTRs than ERVs from other families. We conclude that the slower dynamics of HERV-H suggest a host role for the internal regions of these exapted elements and posit that in future it will be possible to use the relationship between full-length proviruses and solo-LTRs to help identify large scale co-options in distant vertebrate genomes

Phylogenetic analysis reveals that ERVs “die young” but HERV-H is unusually conserved

About 8% of the human genome is made up of endogenous retroviruses (ERVs). Though most human endogenous retroviruses (HERVs) are thought to be irrelevant to our biology notable exceptions include members of the HERV-H family that are necessary for the correct functioning of stem cells. ERVs are commonly found in two forms, the full-length proviral form, and the more numerous solo-LTR form, thought to result from homologous recombination events. Here we introduce a phylogenetic framework to study ERV insertion and solo-LTR formation. We then apply the framework to site patterns sampled from a set of long alignments covering six primate genomes. Studying six categories of ERVs we quantitatively recapitulate patterns of insertional activity that are usually described in qualitative terms in the literature. A slowdown in most ERV groups is observed but we suggest that HERV-K activity may have increased in humans since they diverged from chimpanzees. We find that the rate of solo-LTR formation decreases rapidly as a function of ERV age and that an age dependent model of solo-LTR formation describes the history of ERVs more accurately than the commonly used exponential decay model. We also demonstrate that HERV-H loci are markedly less likely to form solo-LTRs than ERVs from other families. We conclude that the slower dynamics of HERV-H suggest a host role for the internal regions of these exapted elements and posit that in future it will be possible to use the relationship between full-length proviruses and solo-LTRs to help identify large scale co-options in distant vertebrate genomes.Author summary: Animal genomes contain ancient pathogens known as endogenous retroviruses (ERVs). Though the widespread abundance of ERVs is due to their ability to self replicate, some ERVs are known to have become important to host processes including placentation, and in the case of HERV-H, the functioning of human stem cells. In our study we place the insertion and deletion activity of primate ERV families in direct quantitative comparison. In particular, we show that ERV deletion is an age dependent process, so that as an ERV ages it becomes less likely to be deleted at any given instant. We also find that ERVs from the HERV-H family are unusually slowly deleted, an interesting result that suggests that the exaptation of HERV-H may have involved internal regions of the virus and not just its terminal promoters. Assuming the behaviour of primate ERVs is not unusual, our study suggests that future bioinformatics screening for ERVs with slow deletion dynamics could help identify large-scale exaptations in distant species. Furthermore, as we demonstrate that ERVs are deleted rapidly, we think that such screening could be performed using ratios of conserved to deleted elements and could therefore be applied to single genomes

Human Endogenous Retroviruses in Autism Spectrum Disorders: Recent Advances and New Perspectives at the Gene-Environment Interface

Human endogenous retroviruses (HERVs) are genetic elements, derived from their exogenous retroviral counterpart by a process of germline infection and proliferation within the human genome, and their integration as proviruses led to the fixation and the vertical transmission, following Mendelian laws. HERVs currently make up ~8% of the genetic material, and some of them have been cooped for physiological functions. Otherwise, their activation in response to environmental factors has been associated with human pathological conditions. In the setting of neurodevelopmental disorders, HERVs have been proposed as contributing factors involved in Autism Spectrum Disorders (ASD), spanning the bridge between genetic susceptibility, environmental risk factors and immune response. We described a distinct expression profile of some HERV families and cytokines in lymphocytes from autistic children and in their mothers suggesting a close mother-child association in ASD. Moreover, in vitro treatment with an antiretroviral drug was able to restore the expression level of HERVs and cytokines providing new insights into the potential role of HERVs as biomarkers of ASD and raising the possibility of using HERVs expression as a therapeutic target for a tailored approach to patient care