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Endogenous Retroviruses: With Us and against Us

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ABSTRACT

Mammalian genomes are scattered with thousands of copies of endogenous retroviruses (ERVs), mobile genetic elements that are relics of ancient retroviral infections. After inserting copies into the germ line of a host, most ERVs accumulate mutations that prevent the normal assembly of infectious viral particles, becoming trapped in host genomes and unable to leave to infect other cells. While most copies of ERVs are inactive, some are transcribed and encode the proteins needed to generate new insertions at novel loci. In some cases, old copies are removed via recombination and other mechanisms. This creates a shifting landscape of ERV copies within host genomes. New insertions can disrupt normal expression of nearby genes via directly inserting into key regulatory elements or by containing regulatory motifs within their sequences. Further, the transcriptional silencing of ERVs via epigenetic modification may result in changes to the epigenetic regulation of adjacent genes. In these ways, ERVs can be potent sources of regulatory disruption as well as genetic innovation. Here, we provide a brief review of the association between ERVs and gene expression, especially as observed in pre-implantation development and placentation. Moreover, we will describe how disruption of the regulated mechanisms of ERVs may impact somatic tissues, mostly in the context of human disease, including cancer, neurodegenerative disorders, and schizophrenia. Lastly, we discuss the recent discovery that some ERVs may have been pressed into the service of their host genomes to aid in the innate immune response to exogenous viral infections.

No MeSH data available.


Related in: MedlinePlus

Retroviral infection, horizontal transmission, endogenization, and vertical transmission. An exogenous retrovirus infects an individual in generation 1, resulting in their accruing provirus integrations in some somatic cells. Horizontal transmission of the virus from the first individual to the second results in the second accruing somatic integrations as well. However, the second individual subsequently receives germline integrations. The descendants of the first individual do not inherit any retroviral integrations, while any germline integrations in the second individual are transmitted vertically to half of its descendants as endogenous retrovirus insertions present in every cell. Only half of the descendants of this second individual in Generation 2 inherit any given germline integration locus because any cell receiving a new integration does so on only one copy of the affected chromosome. This results in a heterozygous pattern of inheritance.
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Figure 2: Retroviral infection, horizontal transmission, endogenization, and vertical transmission. An exogenous retrovirus infects an individual in generation 1, resulting in their accruing provirus integrations in some somatic cells. Horizontal transmission of the virus from the first individual to the second results in the second accruing somatic integrations as well. However, the second individual subsequently receives germline integrations. The descendants of the first individual do not inherit any retroviral integrations, while any germline integrations in the second individual are transmitted vertically to half of its descendants as endogenous retrovirus insertions present in every cell. Only half of the descendants of this second individual in Generation 2 inherit any given germline integration locus because any cell receiving a new integration does so on only one copy of the affected chromosome. This results in a heterozygous pattern of inheritance.

Mentions: A retroviral genome exists in different forms during its replication cycle. A viral particle, or virion, protects the RNA genome of the retrovirus during escape from the host cell and infection of new cells. A virion that enters a new host cell deploys its genomic payload, using its own reverse transcriptase to convert the RNA viral genome into a DNA copy which is integrated into the host genome, referred to as a provirus (Figure 1). Subsequently, a provirus can be transcribed into RNA again, and then translated by the host's ribosomal machinery to produce more virions. Ancient retroviral infections have occasionally resulted in such integrations into the germline of the host, becoming endogenous retroviruses (ERVs). While some ERVs have been shown to produce infectious particles (van der Laan et al., 2000), most ERV copies suffer mutations over evolutionary time that prevent the normal assembly of viral particles, preventing horizontal transmission of infections between individuals. However, while now trapped within the host genome, some of these provirus copies are still transcribed and can encode some if not all of the original viral proteins. Therefore, ERVs are classified as a family of autonomous retrotransposons. Further, offspring of the host can inherit any germline ERV insertions from their parents, resulting in a vertical transmission pattern with evolution (Figure 2). As much as 8% of the human genome consists of ERV sequences acquired through repeated endogenization events followed by subsequent retrotranspositional expansion of captured viral subfamilies.


Endogenous Retroviruses: With Us and against Us
Retroviral infection, horizontal transmission, endogenization, and vertical transmission. An exogenous retrovirus infects an individual in generation 1, resulting in their accruing provirus integrations in some somatic cells. Horizontal transmission of the virus from the first individual to the second results in the second accruing somatic integrations as well. However, the second individual subsequently receives germline integrations. The descendants of the first individual do not inherit any retroviral integrations, while any germline integrations in the second individual are transmitted vertically to half of its descendants as endogenous retrovirus insertions present in every cell. Only half of the descendants of this second individual in Generation 2 inherit any given germline integration locus because any cell receiving a new integration does so on only one copy of the affected chromosome. This results in a heterozygous pattern of inheritance.
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC5384584&req=5

Figure 2: Retroviral infection, horizontal transmission, endogenization, and vertical transmission. An exogenous retrovirus infects an individual in generation 1, resulting in their accruing provirus integrations in some somatic cells. Horizontal transmission of the virus from the first individual to the second results in the second accruing somatic integrations as well. However, the second individual subsequently receives germline integrations. The descendants of the first individual do not inherit any retroviral integrations, while any germline integrations in the second individual are transmitted vertically to half of its descendants as endogenous retrovirus insertions present in every cell. Only half of the descendants of this second individual in Generation 2 inherit any given germline integration locus because any cell receiving a new integration does so on only one copy of the affected chromosome. This results in a heterozygous pattern of inheritance.
Mentions: A retroviral genome exists in different forms during its replication cycle. A viral particle, or virion, protects the RNA genome of the retrovirus during escape from the host cell and infection of new cells. A virion that enters a new host cell deploys its genomic payload, using its own reverse transcriptase to convert the RNA viral genome into a DNA copy which is integrated into the host genome, referred to as a provirus (Figure 1). Subsequently, a provirus can be transcribed into RNA again, and then translated by the host's ribosomal machinery to produce more virions. Ancient retroviral infections have occasionally resulted in such integrations into the germline of the host, becoming endogenous retroviruses (ERVs). While some ERVs have been shown to produce infectious particles (van der Laan et al., 2000), most ERV copies suffer mutations over evolutionary time that prevent the normal assembly of viral particles, preventing horizontal transmission of infections between individuals. However, while now trapped within the host genome, some of these provirus copies are still transcribed and can encode some if not all of the original viral proteins. Therefore, ERVs are classified as a family of autonomous retrotransposons. Further, offspring of the host can inherit any germline ERV insertions from their parents, resulting in a vertical transmission pattern with evolution (Figure 2). As much as 8% of the human genome consists of ERV sequences acquired through repeated endogenization events followed by subsequent retrotranspositional expansion of captured viral subfamilies.

View Article: PubMed Central - PubMed

ABSTRACT

Mammalian genomes are scattered with thousands of copies of endogenous retroviruses (ERVs), mobile genetic elements that are relics of ancient retroviral infections. After inserting copies into the germ line of a host, most ERVs accumulate mutations that prevent the normal assembly of infectious viral particles, becoming trapped in host genomes and unable to leave to infect other cells. While most copies of ERVs are inactive, some are transcribed and encode the proteins needed to generate new insertions at novel loci. In some cases, old copies are removed via recombination and other mechanisms. This creates a shifting landscape of ERV copies within host genomes. New insertions can disrupt normal expression of nearby genes via directly inserting into key regulatory elements or by containing regulatory motifs within their sequences. Further, the transcriptional silencing of ERVs via epigenetic modification may result in changes to the epigenetic regulation of adjacent genes. In these ways, ERVs can be potent sources of regulatory disruption as well as genetic innovation. Here, we provide a brief review of the association between ERVs and gene expression, especially as observed in pre-implantation development and placentation. Moreover, we will describe how disruption of the regulated mechanisms of ERVs may impact somatic tissues, mostly in the context of human disease, including cancer, neurodegenerative disorders, and schizophrenia. Lastly, we discuss the recent discovery that some ERVs may have been pressed into the service of their host genomes to aid in the innate immune response to exogenous viral infections.

No MeSH data available.


Related in: MedlinePlus