Regulation and Expression of Sexual Differentiation Factors in Embryonic and Extragonadal Tissues of Atlantic salmon

Background: The products of cyp19, dax, foxl2, mis, sf1 and sox9 have each been associated with sex-determiningprocesses among vertebrates. We provide evidence for expression of these regulators very early in salmoniddevelopment and in tissues outside of the hypothalamic-pituitary-adrenal/gonadal (HPAG) axis. Although thefunction of these factors in sexual differentiation have been defined, their roles in early development before sexualfate decisions and in tissues beyond the brain or gonad are essentially unknown.Results: Bacterial artificial chromosomes containing salmon dax1 and dax2, foxl2b and mis were isolated and theregulatory regions that control their expression were characterized. Transposon integrations are implicated in theshaping of the dax and foxl2 loci. Splice variants for cyp19b1 and mis in both embryonic and adult tissues weredetected and characterized. We found that cyp19b1 transcripts are generated that contain 5’-untranslated regionsof different lengths due to cryptic splicing of the 3’-end of intron 1. We also demonstrate that salmon mistranscripts can encode prodomain products that present different C-termini and terminate before translation of theMIS hormone. Regulatory differences in the expression of two distinct aromatases cyp19a and cyp19b1 are exerted,despite transcription of their transactivators (ie; dax1, foxl2, sf1) occurring much earlier during embryonicdevelopment.Conclusions: We report the embryonic and extragonadal expression of dax, foxl2, mis and other differentiationfactors that indicate that they have functions that are more general and not restricted to steroidogenesis andgonadogenesis. Spliced cyp19b1 and mis transcripts are generated that may provide regulatory controls for tissueordevelopment-specific activities. Selection of cyp19b1 transcripts may be regulated by DAX-1, FOXL2 and SF-1complexes that bind motifs in intron 1, or by signals within exon 2 that recruit splicing factors, or both. Thepotential translation of proteins bearing only the N-terminal MIS prodomain may modulate the functions of otherTGF b family members in different tissues. The expression patterns of dax1 early in salmon embryogenesisimplicate its role as a lineage determination factor. Other roles for these factors during embryogenesis and outsidethe HPAG axis are discussed

Evolution of duplicated IgH loci in Atlantic salmon, Salmo salar

<p>Abstract</p> <p>Background</p> <p>The Atlantic salmon (<it>Salmo salar</it>) immunoglobulin heavy chain (<it>IgH</it>) locus possesses two parallel <it>IgH </it>isoloci (<it>IGH-A </it>and <it>IGH-B</it>), that are related to the genomic duplication event in the family Salmonidae. These duplicated <it>IgH </it>loci in Atlantic salmon provide a unique opportunity to examine the mechanisms of genome diversity and genome evolution of the <it>IgH </it>loci in vertebrates. In this study, we defined the structure of these loci in Atlantic salmon, and sequenced 24 bacterial artificial chromosome (BAC) clones that were assembled into the <it>IGH-A </it>(1.1 Mb) and <it>IGH-B </it>(0.9 Mb) loci. In addition, over 7,000 cDNA clones from the <it>IgH </it>variable (V<smcaps>H</smcaps>) region have been sequenced and analyzed.</p> <p>Results</p> <p>The present study shows that the genomic organization of the duplicated <it>IgH </it>loci in Atlantic salmon differs from that in other teleosts and other vertebrates. The loci possess multiple Cτ genes upstream of the Cμ region, with three of the Cτ genes being functional. Moreover, the duplicated loci possess over 300 V<smcaps>H</smcaps> segments which could be classified into 18 families. This is the largest number of V<smcaps>H</smcaps> families currently defined in any vertebrate. There were significant structural differences between the two loci, indicating that both <it>IGH-A </it>and <it>-B </it>loci have evolved independently in the short time after the recent genome duplication approximately 60 mya.</p> <p>Conclusions</p> <p>Our results indicate that the duplication of the <it>IgH </it>loci in Atlantic salmon significantly contributes to the increased diversity of the antibody repertoire, as compared with the single <it>IgH </it>locus in other vertebrates.</p

Individual participant data meta-analysis of LR-5 in LI-RADS version 2018 versus revised LI-RADS for hepatocellular carcinoma diagnosis

Background A simplification of the Liver Imaging Reporting and Data System (LI-RADS) version 2018 (v2018), revised LI-RADS (rLI-RADS), has been proposed for imaging-based diagnosis of hepatocellular carcinoma (HCC). Single-site data suggest that rLI-RADS category 5 (rLR-5) improves sensitivity while maintaining positive predictive value (PPV) of the LI-RADS v2018 category 5 (LR-5), which indicates definite HCC. Purpose To compare the diagnostic performance of LI-RADS v2018 and rLI-RADS in a multicenter data set of patients at risk for HCC by performing an individual patient data meta-analysis. Materials and Methods Multiple databases were searched for studies published from January 2014 to January 2022 that evaluated the diagnostic performance of any version of LI-RADS at CT or MRI for diagnosing HCC. An individual patient data meta-analysis method was applied to observations from the identified studies. Quality Assessment of Diagnostic Accuracy Studies version 2 was applied to determine study risk of bias. Observations were categorized according to major features and either LI-RADS v2018 or rLI-RADS assignments. Diagnostic accuracies of category 5 for each system were calculated using generalized linear mixed models and compared using the likelihood ratio test for sensitivity and the Wald test for PPV. Results Twenty-four studies, including 3840 patients and 4727 observations, were analyzed. The median observation size was 19 mm (IQR, 11–30 mm). rLR-5 showed higher sensitivity compared with LR-5 (70.6% [95% CI: 60.7, 78.9] vs 61.3% [95% CI: 45.9, 74.7]; P < .001), with similar PPV (90.7% vs 92.3%; P = .55). In studies with low risk of bias (n = 4; 1031 observations), rLR-5 also achieved a higher sensitivity than LR-5 (72.3% [95% CI: 63.9, 80.1] vs 66.9% [95% CI: 58.2, 74.5]; P = .02), with similar PPV (83.1% vs 88.7%; P = .47). Conclusion rLR-5 achieved a higher sensitivity for identifying HCC than LR-5 while maintaining a comparable PPV at 90% or more, matching the results presented in the original rLI-RADS study

A large genome-wide association study of age-related macular degeneration highlights contributions of rare and common variants.

This is the author accepted manuscript. The final version is available from Nature Publishing Group via http://dx.doi.org/10.1038/ng.3448Advanced age-related macular degeneration (AMD) is the leading cause of blindness in the elderly, with limited therapeutic options. Here we report on a study of >12 million variants, including 163,714 directly genotyped, mostly rare, protein-altering variants. Analyzing 16,144 patients and 17,832 controls, we identify 52 independently associated common and rare variants (P < 5 × 10(-8)) distributed across 34 loci. Although wet and dry AMD subtypes exhibit predominantly shared genetics, we identify the first genetic association signal specific to wet AMD, near MMP9 (difference P value = 4.1 × 10(-10)). Very rare coding variants (frequency <0.1%) in CFH, CFI and TIMP3 suggest causal roles for these genes, as does a splice variant in SLC16A8. Our results support the hypothesis that rare coding variants can pinpoint causal genes within known genetic loci and illustrate that applying the approach systematically to detect new loci requires extremely large sample sizes.We thank all participants of all the studies included for enabling this research by their participation in these studies. Computer resources for this project have been provided by the high-performance computing centers of the University of Michigan and the University of Regensburg. Group-specific acknowledgments can be found in the Supplementary Note. The Center for Inherited Diseases Research (CIDR) Program contract number is HHSN268201200008I. This and the main consortium work were predominantly funded by 1X01HG006934-01 to G.R.A. and R01 EY022310 to J.L.H

Evaluation of the cost and effectiveness of diverse recruitment methods for a genetic screening study

Purpose: Recruitment of participants from diverse backgrounds is crucial to the generalizability of genetic research, but has proven challenging. We retrospectively evaluated recruitment methods used for a study on return of genetic results. Methods: The costs of study design, development, and participant enrollment were calculated, and the characteristics of the participants enrolled through the seven recruitment methods were examined. Results: A total of 1118 participants provided consent, a blood sample, and questionnaire data. The estimated cost across recruitment methods ranged from $579 to$1666 per participant and required a large recruitment team. Recruitment methods using flyers and staff networks were the most cost-efficient and resulted in the highest completion rate. Targeted sampling that emphasized the importance of Latino/a participation, utilization of translated materials, and in-person recruitments contributed to enrolling a demographically diverse sample. Conclusions: Although all methods were deployed in the same hospital or neighborhood and shared the same staff, each recruitment method was different in terms of cost and characteristics of the enrolled participants, suggesting the importance of carefully choosing the recruitment methods based on the desired composition of the final study sample. This analysis provides information about the effectiveness and cost of different methods to recruit adults for genetic research

No Reliable Association between Runs of Homozygosity and Schizophrenia in a Well-Powered Replication Study

It is well known that inbreeding increases the risk of recessive monogenic diseases, but it is less certain whether it contributes to the etiology of complex diseases such as schizophrenia. One way to estimate the effects of inbreeding is to examine the association between disease diagnosis and genome-wide autozygosity estimated using runs of homozygosity (ROH) in genome-wide single nucleotide polymorphism arrays. Using data for schizophrenia from the Psychiatric Genomics Consortium (n = 21,868), Keller et al. (2012) estimated that the odds of developing schizophrenia increased by approximately 17% for every additional percent of the genome that is autozygous (β = 16.1, CI(β) = [6.93, 25.7], Z = 3.44, p = 0.0006). Here we describe replication results from 22 independent schizophrenia case-control datasets from the Psychiatric Genomics Consortium (n = 39,830). Using the same ROH calling thresholds and procedures as Keller et al. (2012), we were unable to replicate the significant association between ROH burden and schizophrenia in the independent PGC phase II data, although the effect was in the predicted direction, and the combined (original + replication) dataset yielded an attenuated but significant relationship between Froh and schizophrenia (β = 4.86,CI(β) = [0.90,8.83],Z = 2.40,p = 0.02). Since Keller et al. (2012), several studies reported inconsistent association of ROH burden with complex traits, particularly in case-control data. These conflicting results might suggest that the effects of autozygosity are confounded by various factors, such as socioeconomic status, education, urbanicity, and religiosity, which may be associated with both real inbreeding and the outcome measures of interest

Gene expression imputation across multiple brain regions provides insights into schizophrenia risk

Transcriptomic imputation approaches combine eQTL reference panels with large-scale genotype data in order to test associations between disease and gene expression. These genic associations could elucidate signals in complex genome-wide association study (GWAS) loci and may disentangle the role of different tissues in disease development. We used the largest eQTL reference panel for the dorso-lateral prefrontal cortex (DLPFC) to create a set of gene expression predictors and demonstrate their utility. We applied DLPFC and 12 GTEx-brain predictors to 40,299 schizophrenia cases and 65,264 matched controls for a large transcriptomic imputation study of schizophrenia. We identified 413 genic associations across 13 brain regions. Stepwise conditioning identified 67 non-MHC genes, of which 14 did not fall within previous GWAS loci. We identified 36 significantly enriched pathways, including hexosaminidase-A deficiency, and multiple porphyric disorder pathways. We investigated developmental expression patterns among the 67 non-MHC genes and identified specific groups of pre- and postnatal expression

Age at first birth in women is genetically associated with increased risk of schizophrenia

Prof. Paunio on PGC:n jäsenPrevious studies have shown an increased risk for mental health problems in children born to both younger and older parents compared to children of average-aged parents. We previously used a novel design to reveal a latent mechanism of genetic association between schizophrenia and age at first birth in women (AFB). Here, we use independent data from the UK Biobank (N = 38,892) to replicate the finding of an association between predicted genetic risk of schizophrenia and AFB in women, and to estimate the genetic correlation between schizophrenia and AFB in women stratified into younger and older groups. We find evidence for an association between predicted genetic risk of schizophrenia and AFB in women (P-value = 1.12E-05), and we show genetic heterogeneity between younger and older AFB groups (P-value = 3.45E-03). The genetic correlation between schizophrenia and AFB in the younger AFB group is -0.16 (SE = 0.04) while that between schizophrenia and AFB in the older AFB group is 0.14 (SE = 0.08). Our results suggest that early, and perhaps also late, age at first birth in women is associated with increased genetic risk for schizophrenia in the UK Biobank sample. These findings contribute new insights into factors contributing to the complex bio-social risk architecture underpinning the association between parental age and offspring mental health.Peer reviewe