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The observation of genetic correlations between disparate human traits has been interpreted as evidence of widespread pleiotropy. Here, we introduce cross-trait assortative mating (xAM) as an alternative explanation. We observe that xAM affects many phenotypes and that phenotypic cross-mate correlation estimates are strongly associated with genetic correlation estimates (R2=74%). We demonstrate that existing xAM plausibly accounts for substantial fractions of genetic correlation estimates and that previously reported genetic correlation estimates between some pairs of psychiatric disorders are congruent with xAM alone. Finally, we provide evidence for a history of xAM at the genetic level using cross-trait even/odd chromosome polygenic score correlations. Together, our results demonstrate that previous reports have likely overestimated the true genetic similarity between many phenotypes.

In this paper, a data augmentation method is proposed for depression detection from speech signals. Samples for data augmentation were created by changing the frame-width and the frame-shift parameters during the feature extraction process. Unlike other data augmentation methods (such as VTLP, pitch perturbation, or speed perturbation), the proposed method does not explicitly change acoustic parameters but rather the time-frequency resolution of frame-level features. The proposed method was evaluated using two different datasets, models, and input acoustic features. For the DAIC-WOZ (English) dataset when using the DepAudioNet model and mel-Spectrograms as input, the proposed method resulted in an improvement of 5.97% (validation) and 25.13% (test) when compared to the baseline. The improvements for the CONVERGE (Mandarin) dataset when using the x-vector embeddings with CNN as the backend and MFCCs as input features were 9.32% (validation) and 12.99% (test). Baseline systems do not incorporate any data augmentation. Further, the proposed method outperformed commonly used data-augmentation methods such as noise augmentation, VTLP, Speed, and Pitch Perturbation. All improvements were statistically significant., Comment: Accepted to ICASSP 2022. copyright 2022 IEEE. Personal use of this material is permitted

Additional file 6: Figure S1. Contrasting QC metrics between V-seq and meta-transcriptomics. A) Coverage of the SARS2-CoV-2 genome at >=3x compared to the cycling threshold (Ct). The horizontal line in black represents the cut-off for determining whether genomes passed quality-control. B) Proportion of reads mapping confidently to SARS-CoV-2 before removing PCR duplicates compared to the Ct. C) Read duplication rate for reads mapped to SARS-CoV-2 for both NEB and V-seq libraries. D) Proportion of reads mapping confidently to SARS-CoV-2 after removing PCR duplicates. Figure S2. Summary of samples collected for sequencing using both V-seq and NEB approaches. A) Histogram of collection dates colored by whether they were sequenced using NEB or V-seq methods. B) Histogram of collection dates colored by whether the genome passed QC. C) Ct values for genomes passing and not passing QC sequencing using NEB and V-seq. Figure S3. Collection dates of high-quality Los Angeles County SARS-CoV-2 genomes from UCLA Health. Figure S4. Multiple introductions of SARS-CoV-2 into LA county. A) Phylogenetic tree of 286 LA County SARS-CoV-2 together with 3,809 genomes sampled from across the world. Branches are colored according to the region of origin. Tip triangles (black) indicate the position of LA county sequences on the tree. In B) is the same tree with different annotations. We zoomed in and highlighted four regions (blue, orange, purple, and green) of the tree where a single introduction was related to a cluster containing LA County genomes indicating community transmission. Nodes shown with a red star indicate a LA County introduction related to a cluster with more than one LA County genome. The x-axis is in units of mutations away from the root (NC_045512). Figure S5. Phylogenetic tree of 247 B.1.43 and 987 other SARS-CoV-2 genomes from around the world built using Nextstrain. We have zoomed in on the clade containing all B.1.43 sequences and highlighted the tips according to the county of origin. 6 branches are labelled according to their ancestral mutation. The x-axis shows the sampling dates.

Additional file 7.

Additional file 6: Figure S1. Contrasting QC metrics between V-seq and meta-transcriptomics. A) Coverage of the SARS2-CoV-2 genome at >=3x compared to the cycling threshold (Ct). The horizontal line in black represents the cut-off for determining whether genomes passed quality-control. B) Proportion of reads mapping confidently to SARS-CoV-2 before removing PCR duplicates compared to the Ct. C) Read duplication rate for reads mapped to SARS-CoV-2 for both NEB and V-seq libraries. D) Proportion of reads mapping confidently to SARS-CoV-2 after removing PCR duplicates. Figure S2. Summary of samples collected for sequencing using both V-seq and NEB approaches. A) Histogram of collection dates colored by whether they were sequenced using NEB or V-seq methods. B) Histogram of collection dates colored by whether the genome passed QC. C) Ct values for genomes passing and not passing QC sequencing using NEB and V-seq. Figure S3. Collection dates of high-quality Los Angeles County SARS-CoV-2 genomes from UCLA Health. Figure S4. Multiple introductions of SARS-CoV-2 into LA county. A) Phylogenetic tree of 286 LA County SARS-CoV-2 together with 3,809 genomes sampled from across the world. Branches are colored according to the region of origin. Tip triangles (black) indicate the position of LA county sequences on the tree. In B) is the same tree with different annotations. We zoomed in and highlighted four regions (blue, orange, purple, and green) of the tree where a single introduction was related to a cluster containing LA County genomes indicating community transmission. Nodes shown with a red star indicate a LA County introduction related to a cluster with more than one LA County genome. The x-axis is in units of mutations away from the root (NC_045512). Figure S5. Phylogenetic tree of 247 B.1.43 and 987 other SARS-CoV-2 genomes from around the world built using Nextstrain. We have zoomed in on the clade containing all B.1.43 sequences and highlighted the tips according to the county of origin. 6 branches are labelled according to their ancestral mutation. The x-axis shows the sampling dates.

Additional file 7.

Conventional methods for viral genome sequencing largely use metatranscriptomic approaches or, alternatively, enrich for viral genomes by amplicon sequencing with virus-specific PCR or hybridization-based capture. These existing methods are costly, require extensive sample handling time, and have limited throughput. Here, we describe V-seq, an inexpensive, fast, and scalable method that performs targeted viral genome sequencing by multiplexing virus-specific primers at the cDNA synthesis step. We designed densely tiled reverse transcription (RT) primers across the SARS-CoV-2 genome, with a subset of hexamers at the 3’ end to minimize mis-priming from the abundant human rRNA repeats and human RNA PolII transcriptome. We found that overlapping RT primers do not interfere, but rather act in concert to improve viral genome coverage in samples with low viral load. We provide a path to optimize V-seq with SARS-CoV-2 as an example. We anticipate that V-seq can be applied to investigate genome evolution and track outbreaks of RNA viruses in a cost-effective manner. More broadly, the multiplexed RT approach by V-seq can be generalized to other applications of targeted RNA sequencing.

Computational omics methods packaged as software have become essential to modern biological research. The increasing dependence of scientists on these powerful software tools creates a need for systematic assessment of these methods, known as benchmarking. Adopting a standardized benchmarking practice could help researchers who use omics data to better leverage recent technological innovations. Our review summarizes benchmarking practices from 25 recent studies and discusses the challenges, advantages, and limitations of benchmarking across various domains of biology. We also propose principles that can make computational biology benchmarking studies more sustainable and reproducible, ultimately increasing the transparency of biomedical data and results., Benchmarking studies are important for comprehensively understanding and evaluating different computational omics methods. Here, the authors review practices from 25 recent studies and propose principles to improve the quality of benchmarking studies.

Rapid technological advances, such as the development of next-generation sequencing, are driving the need for comprehensive computational tools to analyse the wealth of generated genomic data. Systematic benchmarking has been successful in many research disciplines to help non-computational researchers evaluate the accuracy and applicability of new computational tools. Adopting a standardized benchmarking practice and following established principles for the design of new benchmarking studies could help researchers using omics data to better leverage technological innovation. In this Review, we propose step-by-step instructions for increasing reusability, transparency, and reproducibility of benchmarking studies by using containerization, common data representation, open data, and systematic parameter description.

SummaryControl over the number of mtDNA molecules per cell appears to be tightly regulated, but the mechanisms involved are largely unknown. Reversible alterations in the amount of mtDNA occur in response to stress suggesting that control over the amount of mtDNA is involved in stress-related diseases including major depressive disorder (MDD). Using low-coverage sequence data from 10,442 Chinese women to compute the normalized numbers of reads mapping to the mitochondrial genome as a proxy for the amount of mtDNA, we identified two loci that contribute to mtDNA levels: one within the TFAM gene on chromosome 10 (rs11006126, p value = 8.73 × 10−28, variance explained = 1.90%) and one over the CDK6 gene on chromosome 7 (rs445, p value = 6.03 × 10−16, variance explained = 0.50%). Both loci replicated in an independent cohort. CDK6 is thus a new molecule involved in the control of mtDNA. We identify increased rates of heteroplasmy in women with MDD, and show from an experimental paradigm using mice that the increase is likely due to stress. Furthermore, at least one heteroplasmic variant is significantly associated with changes in the amount of mtDNA (position 513, p value = 3.27 × 10−9, variance explained = 0.48%) suggesting site-specific heteroplasmy as a possible link between stress and increase in amount of mtDNA. These findings indicate the involvement of mitochondrial genome copy number and sequence in an organism’s response to stress.

Supplemental tables. Supplemental tables S1â S5. (PDF 109 kb)

SNP, indel and SV density plots for all strains. SNP, indel and SV (deletions and insertions) density plots for all chromosomes (1â 19, X and Y) for each strain. (PDF 3421 kb)

Summary Adversity, particularly in early life, can cause illness. Clues to the responsible mechanisms may lie with the discovery of molecular signatures of stress, some of which include alterations to an individual’s somatic genome. Here, using genome sequences from 11,670 women, we observed a highly significant association between a stress-related disease, major depression, and the amount of mtDNA (p = 9.00 × 10−42, odds ratio 1.33 [95% confidence interval [CI] = 1.29–1.37]) and telomere length (p = 2.84 × 10−14, odds ratio 0.85 [95% CI = 0.81–0.89]). While both telomere length and mtDNA amount were associated with adverse life events, conditional regression analyses showed the molecular changes were contingent on the depressed state. We tested this hypothesis with experiments in mice, demonstrating that stress causes both molecular changes, which are partly reversible and can be elicited by the administration of corticosterone. Together, these results demonstrate that changes in the amount of mtDNA and telomere length are consequences of stress and entering a depressed state. These findings identify increased amounts of mtDNA as a molecular marker of MD and have important implications for understanding how stress causes the disease., Highlights • Amount of mtDNA is increased, and telomeric DNA is shortened in major depression • Both changes can be induced with stress but are contingent on the depressed state • Changes are tissue specific and in part due to glucocorticoid secretion • Changes are in part reversible and represent switches in metabolic strategy, Cai et al. found increases in mtDNA and a reduction in telomeric DNA in cases of major depression using whole-genome sequencing. Both changes are depression state dependent. Mice exposed to chronic stress or glucorticoids showed that these changes reflect switches in metabolic strategy and are tissue specific and partial reversible.

International audience; Structural variation is variation in structure of DNA regions affecting DNA sequence length and/or orientation. It generally includes deletions, insertions, copy-number gains, inversions, and transposable elements. Traditionally, the identification of structural variation in genomes has been challenging. However, with the recent advances in high-throughput DNA sequencing and paired-end mapping (PEM) methods, the ability to identify structural variation and their respective association to human diseases has improved considerably. In this review, we describe our current knowledge of structural variation in the mouse, one of the prime model systems for studying human diseases and mammalian biology. We further present the evolutionary implications of structural variation on transposable elements. We conclude with future directions on the study of structural variation in mouse genomes that will increase our understanding of molecular architecture and functional consequences of structural variation.

El uso de roedores genéticamente heterogéneos constituye una estrategia única para la identificación y el 'mapeo fino' a alta resolución de locus genéticos (QTL) con influencia sobre fenotipos cuantitativos biológicos y conductuales, permitiendo la identificación de genes individuales (genes cuantitativos) con acción sobre aquéllos. Presentamos el primer estudio de este tipo con ratas genéticamente heterogéneas (N/Nih-HS; derivadas de ocho cepas de ratas consanguíneas), que se evalúan en varias pruebas conductuales que miden ansiedad/miedo no aprendidos ('Caja blanca/negra', 'Laberinto en 'cero' elevado') o aprendidos (conducta de petrificación en contexto condicionado, adquisición de la evitación activa en dos sentidos en la caja de vaivén). Las ratas N/Nih-HS presentan una conducta más parecida a la de la cepa consanguínea RLA-I (ansiosas) que a la de la RHA-I (poco ansiosas). Se hallan correlaciones significativas entre variables incondicionadas de ansiedad y de la adquisición de la evitación activa en dos sentidos, confirmadas parcialmente por análisis de regresión múltiple. Las ratas N/Nih-HS relativamente 'evitadoras' exhiben niveles más bajos de ansiedad no aprendida que las poco 'evitadoras'. Los resultados de esta evaluación del comportamiento de las ratas N/Nih-HS son discutidos en términos de su potencial utilidad para la investigación neurogenética de la ansiedad y el miedo The use of genetically heterogeneous (outbred) rodents is a unique resource for the identification and fine mapping of genetic loci (QTL) influencing biological and behavioural quantitative phenotypes, allowing the identification of quantitative genes. We present the first study of this kind carried out with genetically heterogeneous rats (N/Nih-HS; derivated from an eight-way cross of inbred strains), whose behaviour is assessed in tests evoking unlearned (Black/white box, Elevated 'zero' maze) or learned (context conditioned freezing, two-way active avoidance acquisition in the shuttlebox) anxious/fearful responses. The behavioural profile of N/Nih-HS rats is more similar to that of RLA-I (anxious) rats rather than to RHA-I (low anxious) rats. Significant correlations are found among unconditioned anxiety variables and two-way active avoidance acquisition in the shuttlebox; these are partially confirmed by multiple regression analysis. 'High avoider' N/Nih-HS rats show lower unlearned anxiety levels than 'low avoiders'. Results of this behavioural assessment of the N/Nih-HS rats are discussed in terms of their potential usefulness for present and future neurobehavioural and genetic studies of fearfulness and anxiety

The unintended consequences of gene targeting in mouse models have not been thoroughly studied and a more systematic analysis is needed to understand the frequency and characteristics of off-target effects. Using RNA-seq, we evaluated targeted and neighboring gene expression in tissues from 44 homozygous mutants compared with C57BL/6N control mice. Two allele types were evaluated: 15 targeted trap mutations (TRAP); and 29 deletion alleles (DEL), usually a deletion between the translational start and the 3’ UTR. Both targeting strategies insert a bacterial beta-galactosidase reporter (LacZ) and a neomycin resistance selection cassette. Evaluating transcription of genes in +/- 500 kb of flanking DNA around the targeted gene, we found up-regulated genes more frequently around DEL compared with TRAP alleles, however the frequency of alleles with local down-regulated genes flanking DEL and TRAP targets was similar. Down-regulated genes around both DEL and TRAP targets were found at a higher frequency than expected from a genome-wide survey. However, only around DEL targets were up-regulated genes found with a significantly higher frequency compared with genome-wide sampling. Transcriptome analysis confirms targeting in 97% of DEL alleles, but in only 47% of TRAP alleles probably due to non-functional splice variants, and some splicing around the gene trap. Local effects on gene expression are likely due to a number of factors including compensatory regulation, loss or disruption of intragenic regulatory elements, the exogenous promoter in the neo selection cassette, removal of insulating DNA in the DEL mutants, and local silencing due to disruption of normal chromatin organization or presence of exogenous DNA. An understanding of local position effects is important for understanding and interpreting any phenotype attributed to targeted gene mutations, or to spontaneous indels., Author Summary Insertion of foreign DNA into mammalian genomes, and the deletion of DNA, may have unintended consequences extending beyond the site of the mutation. In the mouse, the insertion of foreign DNA, including foreign regulatory DNA, combined with the deletion of part of the targeted gene, had striking effects on the regulation of neighboring genes. And this ectopic local gene dysregulation occurred at high frequency in regions of high gene density. These findings emphasize the importance of evaluating the local effects on gene regulation following spontaneous insertions and deletions, and after engineering mutations, in mammalian systems. Phenotypes associated with mutations in a specific gene may be partially or entirely due to effects on neighboring genes.

Aquest treball doctoral explora dues aproximacions a l’estudi de la conducta a través de la genètica. La primera és una aproximació de caire intervencionista l'objectiu de la qual és estudiar la funció conductual de la regió del Cornus Ammonis (CA) a l’hipocamp utilitzant un model transgènic. La tesi descriu els processos per a validar aquesta aproximació mitjançant un model d’ablació cel.lular induïda per la toxina diftèrica, i els nostres resultats demostren la inserció del constructe i una expressió parcial. Describim els resultats tot analitzant la viabilitat d’aquest model per a l’estudi de la conducta. La segona aproximació és un estudi observacional de l’heretabilitat dels trets complexos com el comportament ansiós mitjançant l’anàlisi de dades genotípiques i fenotípiques. Analitzant una llarga mostra de rates heterogènies describim com l’heretabilitat dels trets complexos té un efecte lligat al parent d’origen (parent-of-origin effect) en rates, i centrem l’anàlisi en les conductes i estratègies d’enfrontament davant d’estímuls estressants (coping style)., The present work explores two approaches to the study of behaviour through genetics. The first approach is an interventional transgenic model that aims to study the behavioral function of the Cornus Ammonis (CA) sub region in the hippocampus. I describe the steps to validate an interventional model using a diphtheria-induced cell knockout rat, and our results confirm the insertion of the transgenic construct and a partial expression. We report the results and discuss the feasibility of the model. The second approach is an observational study of the heritability of complex traits such as anxious behaviour analysing phenotypic and genotypic data. Using a large sample of outbred heterogeneous stock rats, I describe how the heritability of complex traits has a parent-of-origin effect in rats, and focus the analysis on coping style behaviour.

Significant advances have been made in the discovery of genes affecting bone mineral density (BMD); however, our understanding of its genetic basis remains incomplete. In the current study, genome-wide association (GWA) and co-expression network analysis were used in the recently described Hybrid Mouse Diversity Panel (HMDP) to identify and functionally characterize novel BMD genes. In the HMDP, a GWA of total body, spinal, and femoral BMD revealed four significant associations (−log10P>5.39) affecting at least one BMD trait on chromosomes (Chrs.) 7, 11, 12, and 17. The associations implicated a total of 163 genes with each association harboring between 14 and 112 genes. This list was reduced to 26 functional candidates by identifying those genes that were regulated by local eQTL in bone or harbored potentially functional non-synonymous (NS) SNPs. This analysis revealed that the most significant BMD SNP on Chr. 12 was a NS SNP in the additional sex combs like-2 (Asxl2) gene that was predicted to be functional. The involvement of Asxl2 in the regulation of bone mass was confirmed by the observation that Asxl2 knockout mice had reduced BMD. To begin to unravel the mechanism through which Asxl2 influenced BMD, a gene co-expression network was created using cortical bone gene expression microarray data from the HMDP strains. Asxl2 was identified as a member of a co-expression module enriched for genes involved in the differentiation of myeloid cells. In bone, osteoclasts are bone-resorbing cells of myeloid origin, suggesting that Asxl2 may play a role in osteoclast differentiation. In agreement, the knockdown of Asxl2 in bone marrow macrophages impaired their ability to form osteoclasts. This study identifies a new regulator of BMD and osteoclastogenesis and highlights the power of GWA and systems genetics in the mouse for dissecting complex genetic traits., Author Summary Osteoporosis is a disease of weak and fracture-prone bones. The characteristic of bone that is most predictive of fractures is low bone mineral density (BMD), a trait primarily controlled by genetics. In recent years, significant advances have been made in the discovery of genes affecting BMD; however, our understanding of its genetic basis is still primitive. In this study, we used genome-wide association in the mouse to identify additional sex combs like-2 (Asxl2) as a novel BMD gene. In confirmation of our genetic analysis, mice deficient in Asxl2 had reduced BMD. To evaluate its function in bone, the expression levels of Asxl2 and tens of thousands of other genes were measured in bone in a large number of inbred mouse strains. Asxl2 demonstrated a pattern of expression indicative of genes that play a critical role in osteoclasts, the cells that are responsible for bone resorption. Further study of Asxl2 may reveal novel therapeutic targets for the treatment and prevention of osteoporosis.