Multiple effects govern endogenous retrovirus survival patterns in human gene introns

BACKGROUND: Endogenous retroviruses (ERVs) and solitary long terminal repeats (LTRs) have a significant antisense bias when located in gene introns, suggesting strong negative selective pressure on such elements oriented in the same transcriptional direction as the enclosing gene. It has been assumed that this bias reflects the presence of strong transcriptional regulatory signals within LTRs but little work has been done to investigate this phenomenon further. RESULTS: In the analysis reported here, we found significant differences between individual human ERV families in their prevalence within genes and degree of antisense bias and show that, regardless of orientation, ERVs of most families are less likely to be found in introns than in intergenic regions. Examination of density profiles of ERVs across transcriptional units and the transcription signals present in the consensus ERVs suggests the importance of splice acceptor sites, in conjunction with splice donor and polyadenylation signals, as the major targets for selection against most families of ERVs/LTRs. Furthermore, analysis of annotated human mRNA splicing events involving ERV sequence revealed that the relatively young human ERVs (HERVs), HERV9 and HERV-K (HML-2), are involved in no human mRNA splicing events at all when oriented antisense to gene transcription, while elements in the sense direction in transcribed regions show considerable bias for use of strong splice sites. CONCLUSION: Our observations suggest suppression of splicing among young intronic ERVs oriented antisense to gene transcription, which may account for their reduced mutagenicity and higher fixation rate in gene introns

Multiple effects govern endogenous retrovirus survival patterns in human gene introns

BACKGROUND: Endogenous retroviruses (ERVs) and solitary long terminal repeats (LTRs) have a significant antisense bias when located in gene introns, suggesting strong negative selective pressure on such elements oriented in the same transcriptional direction as the enclosing gene. It has been assumed that this bias reflects the presence of strong transcriptional regulatory signals within LTRs but little work has been done to investigate this phenomenon further. RESULTS: In the analysis reported here, we found significant differences between individual human ERV families in their prevalence within genes and degree of antisense bias and show that, regardless of orientation, ERVs of most families are less likely to be found in introns than in intergenic regions. Examination of density profiles of ERVs across transcriptional units and the transcription signals present in the consensus ERVs suggests the importance of splice acceptor sites, in conjunction with splice donor and polyadenylation signals, as the major targets for selection against most families of ERVs/LTRs. Furthermore, analysis of annotated human mRNA splicing events involving ERV sequence revealed that the relatively young human ERVs (HERVs), HERV9 and HERV-K (HML-2), are involved in no human mRNA splicing events at all when oriented antisense to gene transcription, while elements in the sense direction in transcribed regions show considerable bias for use of strong splice sites. CONCLUSION: Our observations suggest suppression of splicing among young intronic ERVs oriented antisense to gene transcription, which may account for their reduced mutagenicity and higher fixation rate in gene introns

Retroviral Elements and Their Hosts: Insertional Mutagenesis in the Mouse Germ Line

The inbred mouse is an invaluable model for human biology and disease. Nevertheless, when considering genetic mechanisms of variation and disease, it is important to appreciate the significant differences in the spectra of spontaneous mutations that distinguish these species. While insertions of transposable elements are responsible for only ~0.1% of de novo mutations in humans, the figure is 100-fold higher in the laboratory mouse. This striking difference is largely due to the ongoing activity of mouse endogenous retroviral elements. Here we briefly review mouse endogenous retroviruses (ERVs) and their influence on gene expression, analyze mechanisms of interaction between ERVs and the host cell, and summarize the variety of mutations caused by ERV insertions. The prevalence of mouse ERV activity indicates that the genome of the laboratory mouse is presently behind in the “arms race” against invasion

Comparative Study of Human and Mouse Postsynaptic Proteomes Finds High Compositional Conservation and Abundance Differences for Key Synaptic Proteins

Direct comparison of protein components from human and mouse excitatory synapses is important for determining the suitability of mice as models of human brain disease and to understand the evolution of the mammalian brain. The postsynaptic density is a highly complex set of proteins organized into molecular networks that play a central role in behavior and disease. We report the first direct comparison of the proteome of triplicate isolates of mouse and human cortical postsynaptic densities. The mouse postsynaptic density comprised 1556 proteins and the human one 1461. A large compositional overlap was observed; more than 70% of human postsynaptic density proteins were also observed in the mouse postsynaptic density. Quantitative analysis of postsynaptic density components in both species indicates a broadly similar profile of abundance but also shows that there is higher abundance variation between species than within species. Well known components of this synaptic structure are generally more abundant in the mouse postsynaptic density. Significant inter-species abundance differences exist in some families of key postsynaptic density proteins including glutamatergic neurotransmitter receptors and adaptor proteins. Furthermore, we have identified a closely interacting set of molecules enriched in the human postsynaptic density that could be involved in dendrite and spine structural plasticity. Understanding synapse proteome diversity within and between species will be important to further our understanding of brain complexity and disease

Characterization of the proteome, diseases and evolution of the human postsynaptic density

We isolated the postsynaptic density from human neocortex (hPSD) and identified 1,461 proteins. hPSD mutations cause 133 neurological and psychiatric diseases and were enriched in cognitive, affective and motor phenotypes underpinned by sets of genes. Strong protein sequence conservation in mammalian lineages, particularly in hub proteins, indicates conserved function and organization in primate and rodent models. The hPSD is an important structure for nervous system disease and behavior

NANOS2 is a sequence-specific mRNA-binding protein that promotes transcript degradation in spermatogonial stem cells

Summary: Spermatogonial stem cells (SSCs) sustain spermatogenesis and fertility throughout adult male life. The conserved RNA-binding protein NANOS2 is essential for the maintenance of SSCs, but its targets and mechanisms of function are not fully understood. Here, we generated a fully functional epitope-tagged Nanos2 mouse allele and applied the highly stringent cross-linking and analysis of cDNAs to define NANOS2 RNA occupancy in SSC lines. NANOS2 recognizes the AUKAAWU consensus motif, mostly found in the 3′ untranslated region of defined messenger RNAs (mRNAs). We find that NANOS2 is a regulator of key signaling and metabolic pathways whose dosage or activity are known to be critical for SSC maintenance. NANOS2 interacts with components of CCR4-NOT deadenylase complex in SSC lines, and consequently, NANOS2 binding reduces the half-lives of target transcripts. In summary, NANOS2 contributes to SSC maintenance through the regulation of target mRNA stability and key self-renewal pathways

Synaptopathies: Dysfunction of Synaptic Function Confirmed rare copy number variants implicate novel genes in schizophrenia

Abstract Understanding how cognitive processes including learning, memory, decision making and ideation are encoded by the genome is a key question in biology. Identification of sets of genes underlying human mental disorders is a path towards this objective. Schizophrenia is a common disease with cognitive symptoms, high heritability and complex genetics. We have identified genes involved with schizophrenia by measuring differences in DNA copy number across the entire genome in 91 schizophrenia cases and 92 controls in the Scottish population. Our data reproduce rare and common variants observed in public domain data from >3000 schizophrenia cases, confirming known disease loci as well as identifying novel loci. We found copy number variants in PDE10A (phosphodiesterase 10A), CYFIP1 [cytoplasmic FMR1 (Fragile X mental retardation 1)-interacting protein 1], K + channel genes KCNE1 and KCNE2, the Down's syndrome critical region 1 gene RCAN1 (regulator of calcineurin 1), cell-recognition protein CHL1 (cell adhesion molecule with homology with L1CAM), the transcription factor SP4 (specificity protein 4) and histone deacetylase HDAC9, among others (see http://www.genes2cognition.org/SCZ-CNV). Integrating the function of these many genes into a coherent model of schizophrenia and cognition is a major unanswered challenge

De novo CNV analysis implicates specific abnormalities of postsynaptic signalling complexes in the pathogenesis of schizophrenia

A small number of rare, recurrent genomic copy number variants (CNVs) are known to substantially increase susceptibility to schizophrenia. As a consequence of the low fecundity in people with schizophrenia and other neurodevelopmental phenotypes to which these CNVs contribute, CNVs with large effects on risk are likely to be rapidly removed from the population by natural selection. Accordingly, such CNVs must frequently occur as recurrent de novo mutations. In a sample of 662 schizophrenia proband–parent trios, we found that rare de novo CNV mutations were significantly more frequent in cases (5.1% all cases, 5.5% family history negative) compared with 2.2% among 2623 controls, confirming the involvement of de novo CNVs in the pathogenesis of schizophrenia. Eight de novo CNVs occurred at four known schizophrenia loci (3q29, 15q11.2, 15q13.3 and 16p11.2). De novo CNVs of known pathogenic significance in other genomic disorders were also observed, including deletion at the TAR (thrombocytopenia absent radius) region on 1q21.1 and duplication at the WBS (Williams–Beuren syndrome) region at 7q11.23. Multiple de novos spanned genes encoding members of the DLG (discs large) family of membrane-associated guanylate kinases (MAGUKs) that are components of the postsynaptic density (PSD). Two de novos also affected EHMT1, a histone methyl transferase known to directly regulate DLG family members. Using a systems biology approach and merging novel CNV and proteomics data sets, systematic analysis of synaptic protein complexes showed that, compared with control CNVs, case de novos were significantly enriched for the PSD proteome (P=1.72 × 10−6). This was largely explained by enrichment for members of the N-methyl-D-aspartate receptor (NMDAR) (P=4.24 × 10−6) and neuronal activity-regulated cytoskeleton-associated protein (ARC) (P=3.78 × 10−8) postsynaptic signalling complexes. In an analysis of 18 492 subjects (7907 cases and 10 585 controls), case CNVs were enriched for members of the NMDAR complex (P=0.0015) but not ARC (P=0.14). Our data indicate that defects in NMDAR postsynaptic signalling and, possibly, ARC complexes, which are known to be important in synaptic plasticity and cognition, play a significant role in the pathogenesis of schizophrenia

Synaptic scaffold evolution generated components of vertebrate cognitive complexity

The origins and evolution of higher cognitive functions, including complex forms of learning, attention and executive functions, are unknown. A potential mechanism driving the evolution of vertebrate cognition early in the vertebrate lineage (550 million years ago) was genome duplication and subsequent diversification of postsynaptic genes. Here we report, to our knowledge, the first genetic analysis of a vertebrate gene family in cognitive functions measured using computerized touchscreens. Comparison of mice carrying mutations in each of the four Dlg paralogs showed that simple associative learning required Dlg4, whereas Dlg2 and Dlg3 diversified to have opposing functions in complex cognitive processes. Exploiting the translational utility of touchscreens in humans and mice, testing Dlg2 mutations in both species showed that Dlg2\u27s role in complex learning, cognitive flexibility and attention has been highly conserved over 100 million years. Dlg-family mutations underlie psychiatric disorders, suggesting that genome evolution expanded the complexity of vertebrate cognition at the cost of susceptibility to mental illness

Genome-Wide Assessments Reveal Extremely High Levels of Polymorphism of Two Active Families of Mouse Endogenous Retroviral Elements

Endogenous retroviral elements (ERVs) in mice are significant genomic mutagens, causing ∼10% of all reported spontaneous germ line mutations in laboratory strains. The majority of these mutations are due to insertions of two high copy ERV families, the IAP and ETn/MusD elements. This significant level of ongoing retrotranspositional activity suggests that inbred mice are highly variable in content of these two ERV groups. However, no comprehensive genome-wide studies have been performed to assess their level of polymorphism. Here we compared three test strains, for which sufficient genomic sequence is available, to each other and to the reference C57BL/6J genome and detected very high levels of insertional polymorphism for both ERV families, with an estimated false discovery rate of only 0.4%. Specifically, we found that at least 60% of IAP and 25% of ETn/MusD elements detected in any strain are absent in one or more of the other three strains. The polymorphic nature of a set of 40 ETn/MusD elements found within gene introns was confirmed using genomic PCR on DNA from a panel of mouse strains. For some cases, we detected gene-splicing abnormalities involving the ERV and obtained additional evidence for decreased gene expression in strains carrying the insertion. In total, we identified nearly 700 polymorphic IAP or ETn/MusD ERVs or solitary LTRs that reside in gene introns, providing potential candidates that may contribute to gene expression differences among strains. These extreme levels of polymorphism suggest that ERV insertions play a significant role in genetic drift of mouse lines