Transposable element-mediated rearrangements are prevalent in human genomes.

Transposable elements constitute about half of human genomes, and their role in generating human variation through retrotransposition is broadly studied and appreciated. Structural variants mediated by transposons, which we call transposable element-mediated rearrangements (TEMRs), are less well studied, and the mechanisms leading to their formation as well as their broader impact on human diversity are poorly understood. Here, we identify 493 unique TEMRs across the genomes of three individuals. While homology directed repair is the dominant driver of TEMRs, our sequence-resolved TEMR resource allows us to identify complex inversion breakpoints, triplications or other high copy number polymorphisms, and additional complexities. TEMRs are enriched in genic loci and can create potentially important risk alleles such as a deletion in TRIM65, a known cancer biomarker and therapeutic target. These findings expand our understanding of this important class of structural variation, the mechanisms responsible for their formation, and establish them as an important driver of human diversity

Inter-Strain Epigenomic Profiling Reveals a Candidate IAP Master Copy in C3H Mice.

Insertions of endogenous retroviruses cause a significant fraction of mutations in inbred mice but not all strains are equally susceptible. Notably, most new Intracisternal A particle (IAP) ERV mutagenic insertions have occurred in C3H mice. We show here that strain-specific insertional polymorphic IAPs accumulate faster in C3H/HeJ mice, relative to other sequenced strains, and that IAP transcript levels are higher in C3H/HeJ embryonic stem (ES) cells compared to other ES cells. To investigate the mechanism for high IAP activity in C3H mice, we identified 61 IAP copies in C3H/HeJ ES cells enriched with H3K4me3 (a mark of active promoters) and, among those tested, all are unmethylated in C3H/HeJ ES cells. Notably, 13 of the 61 are specific to C3H/HeJ and are members of the non-autonomous 1Δ1 IAP subfamily that is responsible for nearly all new insertions in C3H. One copy is full length with intact open reading frames and hence potentially capable of providing proteins i

LINE-1 Retrotransposition Activity in Human Genomes

SummaryHighly active (i.e., “hot”) long interspersed element-1 (LINE-1 or L1) sequences comprise the bulk of retrotransposition activity in the human genome; however, the abundance of hot L1s in the human population remains largely unexplored. Here, we used a fosmid-based, paired-end DNA sequencing strategy to identify 68 full-length L1s that are differentially present among individuals but are absent from the human genome reference sequence. The majority of these L1s were highly active in a cultured cell retrotransposition assay. Genotyping 26 elements revealed that two L1s are only found in Africa and that two more are absent from the H952 subset of the Human Genome Diversity Panel. Therefore, these results suggest that hot L1s are more abundant in the human population than previously appreciated, and that ongoing L1 retrotransposition continues to be a major source of interindividual genetic variation

Transduction‐Specific ATLAS Reveals a Cohort of Highly Active L 1 Retrotransposons in Human Populations

L ong IN terspersed E lement‐1 ( LINE ‐1 or L 1) retrotransposons are the only autonomously active transposable elements in the human genome. The average human genome contains ∼80–100 active L1s, but only a subset of these L1s are highly active or ‘hot’. Human L1s are closely related in sequence, making it difficult to decipher progenitor/offspring relationships using traditional phylogenetic methods. However, L1 m RNA s can sometimes bypass their own polyadenylation signal and instead utilize fortuitous polyadenylation signals in 3′ flanking genomic DNA . Retrotransposition of the resultant m RNA s then results in lineage specific sequence “tags” (i.e., 3′ transductions) that mark the descendants of active L1 progenitors. Here, we developed a method (Transduction‐Specific Amplification Typing of L1 Active Subfamilies or TS ‐ ATLAS ) that exploits L1 3′ transductions to identify active L1 lineages in a genome‐wide context. TS ‐ ATLAS enabled the characterization of a putative active progenitor of one L1 lineage that includes the disease causing L1 insertion L1 RP , and the identification of new retrotransposition events within two other “hot” L1 lineages. Intriguingly, the analysis of the newly discovered transduction lineage members suggests that L1 polyadenylation, even within a lineage, is highly stochastic. Thus, TS ‐ ATLAS provides a new tool to explore the dynamics of L1 lineage evolution and retrotransposon biology. Long INterspersed Element‐1 (L1) retrotransposons are the only independently mobile elements in the human genome. We developed Transduction‐Specific Amplification Typing of L1 Active Subfamilies (TS‐ATLAS), which utilizes L1‐transduced genomic sequences, to identify a subset of highly active L1s genome‐wide. TS‐ATLAS enabled the characterization of the putative progenitor of an active disease‐causing L1 lineage, and identified new retrotransposition events within two other “hot” L1 lineages.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/98809/1/humu22327.pdfhttp://deepblue.lib.umich.edu/bitstream/2027.42/98809/2/humu22327-sup-0001-si.pd

Age-stratified heritability estimation in the Framingham Heart Study families

The Framingham Heart Study provides a unique source of longitudinal family data related to CVD risk factors. Age-stratified heritability estimates were obtained over three age groups (31–49 years, 50–60 years, and 61–79 years), reflecting the longitudinal nature of the data, for four quantitative traits. Age-adjusted heritability estimates were obtained at a single common time point for the same four quantitative traits. The importance of these groups is that they consist of the same individuals. The highest age-stratified heritability estimate (h(2 )= 0.88 (± 0.06)) was for height in the model adjusting for gender over all three age groups. SBP gave the lowest heritability estimate (h(2 )= 0.15 (± 0.11)) for the 70 age group in the model adjusting for gender, height, BMI, smoker, and drinker. BMI had slightly higher estimates (h(2 )= 0.64 (± 0.11)) in the 40 age group than previously published. The highest age-adjusted heritability estimate (h(2 )= 0.90 (± 0.06)) was for height in the model adjusting for gender. SBP gave the lowest heritability estimate (h(2 )= 0.38 (± 0.09)) for unadjusted model. These results indicate that some common, complex traits may vary little in their genetic architecture over time and suggest that a common set of genes may be contributing to observed variation for these longitudinally collected phenotypes

Co-option of endogenous retroviruses through genetic escape from TRIM28 repression

Endogenous retroviruses (ERVs) have rewired host gene networks. To explore the origins of co-option, we employed an active murine ERV, IAPEz, and an embryonic stem cell (ESC) to neural progenitor cell (NPC) differentiation model. Transcriptional silencing via TRIM28 maps to a 190 bp sequence encoding the intracisternal A-type particle (IAP) signal peptide, which confers retrotransposition activity. A subset of "escapee" IAPs (∼15%) exhibits significant genetic divergence from this sequence. Canonical repressed IAPs succumb to a previously undocumented demarcation by H3K9me3 and H3K27me3 in NPCs. Escapee IAPs, in contrast, evade repression in both cell types, resulting in their transcriptional derepression, particularly in NPCs. We validate the enhancer function of a 47 bp sequence within the U3 region of the long terminal repeat (LTR) and show that escapee IAPs convey an activating effect on nearby neural genes. In sum, co-opted ERVs stem from genetic escapees that have lost vital sequences required for both TRIM28 restriction and autonomous retrotransposition

IntCal09 and Marine09 radiocarbon age calibration curves, 0-50,000yeats cal BP

The IntCal04 and Marine04 radiocarbon calibration curves have been updated from 12 cal kBP (cal kBP is here defined as thousands of calibrated years before AD 1950), and extended to 50 cal kBP, utilizing newly available data sets that meet the IntCal Working Group criteria for pristine corals and other carbonates and for quantification of uncertainty in both the 14C and calendar timescales as established in 2002. No change was made to the curves from 0–12 cal kBP. The curves were constructed using a Markov chain Monte Carlo (MCMC) implementation of the random walk model used for IntCal04 and Marine04. The new curves were ratified at the 20th International Radiocarbon Conference in June 2009 and are available in the Supplemental Material at www.radiocarbon.org

Resolution of structural variation in diverse mouse genomes reveals chromatin remodeling due to transposable elements.

Diverse inbred mouse strains are important biomedical research models, yet genome characterization of many strains is fundamentally lacking in comparison with humans. In particular, catalogs of structural vari- ants (SVs) (variants R 50 bp) are incomplete, limiting the discovery of causative alleles for phenotypic vari- ation. Here, we resolve genome-wide SVs in 20 genetically distinct inbred mice with long-read sequencing. We report 413,758 site-specific SVs affecting 13% (356 Mbp) of the mouse reference assembly, including 510 previously unannotated coding variants. We substantially improve the Mus musculus transposable element (TE) callset, and we find that TEs comprise 39% of SVs and account for 75% of altered bases. We further utilize this callset to investigate how TE heterogeneity affects mouse embryonic stem cells and find multiple TE classes that influence chromatin accessibility. Our work provides a comprehensive analysis of SVs found in diverse mouse genomes and illustrates the role of TEs in epigenetic differences

SvAnna: efficient and accurate pathogenicity prediction of coding and regulatory structural variants in long-read genome sequencing.

Structural variants (SVs) are implicated in the etiology of Mendelian diseases but have been systematically underascertained owing to sequencing technology limitations. Long-read sequencing enables comprehensive detection of SVs, but approaches for prioritization of candidate SVs are needed. Structural variant Annotation and analysis (SvAnna) assesses all classes of SVs and their intersection with transcripts and regulatory sequences, relating predicted effects on gene function with clinical phenotype data. SvAnna places 87% of deleterious SVs in the top ten ranks. The interpretable prioritizations offered by SvAnna will facilitate the widespread adoption of long-read sequencing in diagnostic genomics. SvAnna is available at https://github.com/TheJacksonLaboratory/SvAnn a

Social recovery therapy: a treatment manual

Social Recovery Therapy is an individual psychosocial therapy developed for people with psychosis. The therapy aims to improve social recovery through increasing the amount of time individuals spend in meaningful structured activity. Social Recovery Therapy draws on our model of social disability arising as functional patterns of withdrawal in response to early socio-emotional difficulties and compounded by low hopefulness, self-agency and motivation. The core components of Social Recovery Therapy include using an assertive outreach approach to promote a positive therapeutic relationship, with the focus of the intervention on using active behavioural work conducted outside the clinical room and promoting hope, values, meaning, and positive schema. The therapy draws on traditional Cognitive Behavioural Therapy techniques but differs with respect to the increased use of behavioural and multi-systemic work, the focus on the development of hopefulness and positive self, and the inclusion of elements of case management and supported employment. Our treatment trials provide evidence for the therapy leading to clinically meaningful increases in structured activity for individuals experiencing first episode and longer-term psychosis. In this paper, we present the core intervention components with examples in order to facilitate evaluation and implementation of the approach