Abstract
Neuronal apoptosis inhibitory protein (NAIP, also known as BIRC1) is a member of the conserved inhibitor of apoptosis protein (IAP) family. Lineage-specific rearrangements and expansions of this locus have yielded different copy numbers among primates and rodents, with human retaining a single functional copy and mouse possessing several copies, depending on the strain. Roles for this gene in disease have been documented, but little is known about transcriptional regulation of NAIP. We show here that NAIP has multiple promoters sharing no similarity between human and rodents. Moreover, we demonstrate that multiple, domesticated long terminal repeats (LTRs) of endogenous retroviral elements provide NAIP promoter function in human, mouse, and rat. In human, an LTR serves as a tissue-specific promoter, active primarily in testis. However, in rodents, our evidence indicates that an ancestral LTR common to all rodent genes is the major, constitutive promoter for these genes, and that a second LTR found in two of the mouse genes is a minor promoter. Thus, independently acquired LTRs have assumed regulatory roles for orthologous genes, a remarkable evolutionary scenario. We also demonstrate that 5′ flanking regions of IAP family genes as a group, in both human and mouse are enriched for LTR insertions compared to average genes. We propose several potential explanations for these findings, including a hypothesis that recruitment of LTRs near NAIP or other IAP genes may represent a host-cell adaptation to modulate apoptotic responses.
Highlights
The prevalence of transposed elements (TEs) in mammalian genomes is well documented [1,2], and their inclusion within human and mouse transcription units is not uncommon
The viral DNA inserts into the cellular genome. If this happens in gametes, the viral DNA will be transmitted from parent to offspring, like all chromosomal DNA. Through evolutionary time, such infections of gametes have been so prevalent that 8%–10% of the normal human and mouse genomes are composed of ancient viral DNA, termed endogenous retroviruses (ERVs)
We demonstrate that both the human and rodent neuronal apoptosis inhibitory protein (NAIP) genes, involved in preventing cell death, use different ERV sequences to drive gene expression
Summary
The prevalence of transposed elements (TEs) in mammalian genomes is well documented [1,2], and their inclusion within human and mouse transcription units is not uncommon. While relatively few genes adopt TEs in their coding regions, primarily as alternative exons recruited from introns [3,4], ;25% of genes incorporate these sequences into their promoter [5] and UTRs [6]. Host recruitment of endogenous retrovirus (ERV) long terminal repeats (LTRs), as alternative gene promoters due to their strong RNA polymerase II regulatory signals, is becoming better recognized [7,8]. ERV proteins themselves can participate in important host functions. It appears that independently acquired ERV env genes in different mammals have assumed convergent roles in placental development [11,12]
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