Network intervention analysis indicates that roluperidone achieves its effect on negative symptoms of schizophrenia by targeting avolition.

Roluperidone, a 5-HT2A, sigma2, and ɑ1A-adrenergic receptor antagonist, has proven efficacious for treating negative symptoms of schizophrenia in phase 2b and phase 3 clinical trials. Using network analysis, we demonstrated that the improvements observed in the phase 2b trial resulted from targeting avolition which was highly central and spurred a cascading effect of global negative symptom reductions when successfully treated. The current study aims to replicate these network findings using the phase 3 roluperidone clinical trial data. Participants included 496 schizophrenia patients with moderate to severe negative symptoms who were randomized to either roluperidone 32 mg/day (n =167), 64 mg/day (n = 162), or placebo (n = 167). Negative symptoms were assessed at baseline and weeks 2,4,8, and 12. Network intervention analysis (NIA) evaluated treatment-induced symptom changes over time to identify direct and indirect treatment effects. This analytic approach extends prior work by determining whether the symptoms with highest centrality have causal effects on the entire negative symptom construct and directly lead to symptom improvement. NIA indicated that the efficacious 64 mg/day dose of roluperidone had a direct effect on avolition, suggesting that changes in avolition propels treatment effects across the entire negative symptom constellation. These phase 3 findings replicated the phase 2b findings, indicating that from a network perspective, roluperidone achieves its effect by influencing the extent to which avolition drives other negative symptoms. These findings are relevant for understanding negative symptoms and how to treat them in neuropsychiatric disorders.

Repeated co-option of HMG-box genes for sex determination in brown algae and animals.

In many eukaryotes, genetic sex determination is not governed by XX/XY or ZW/ZZ systems but by a specialized region on the poorly studied U (female) or V (male) sex chromosomes. Previous studies have hinted at the existence of a dominant male-sex factor on the V chromosome in brown algae, a group of multicellular eukaryotes distantly related to animals and plants. The nature of this factor has remained elusive. Here, we demonstrate that an HMG-box gene acts as the male-determining factor in brown algae, mirroring the role HMG-box genes play in sex determination in animals. Over a billion-year evolutionary timeline, these lineages have independently co-opted the HMG box for male determination, representing a paradigm for evolution's ability to recurrently use the same genetic "toolkit" to accomplish similar tasks.

Long-term effects of Roluperidone on negative symptoms of schizophrenia.

Roluperidone has antagonist properties for 5-HT2A, sigma2, α1A- and α1B-adrenergic receptors, but no dopaminergic binding affinities. In 2 randomized controlled trials (RCT), treatment improved negative symptoms of schizophrenia and social functioning among patients with moderate to severe negative symptoms. We report results of the protocol specified analysis of 2 open-label extension studies of 24 and 40 weeks investigating whether improvement of negative symptoms was sustained without significant adverse effects or worsening of psychosis. Following 12-week double-blind phase of both RCTs, patients were eligible to receive monotherapy roluperidone 32 mg/day or 64 mg/day for 24 weeks (trial 1) or 40 weeks (trial 2) in open-label extension study. Trial 1 included 244 patients of whom 142 entered 24-week open-label extension and trial 2 included 513 patients of whom 341 entered 40-week open-label extension. Trial 1 had PANSS negative factor score of Pentagonal Structure Model as primary outcome. Trial 2 had Marder Negative Symptoms Factor Score as primary outcome measure and Personal and Social Performance (PSP) Total score as secondary outcome. During open-label extensions, continued improvements in negative symptoms and on PSP were observed. Overall rate of symptomatic worsening requiring discontinuation of roluperidone and treatment with an antipsychotic was <10 %. Roluperidone was well tolerated with no meaningful changes in vital signs, laboratory values, weight gain, metabolic indices, or extrapyramidal symptoms. Results of 2 open-label extension trials support roluperidone as a treatment of negative symptoms and social functioning deficits in patients with moderate to severe negative symptoms of schizophrenia.

Efficacy and Safety of Roluperidone for the Treatment of Negative Symptoms of Schizophrenia.

BACKGROUND: This is a placebo-controlled multi-national trial of roluperidone, a compound with antagonist properties for 5-HT2A, sigma2, and α1A-adrenergic receptors, targeting negative symptoms in patients with schizophrenia. This trial follows a previous trial that demonstrated roluperidone superiority over placebo in a similar patient population. METHODS: Roluperidone 32 mg/day, roluperidone 64 mg/day, or placebo was administered for 12 weeks to 513 patients with schizophrenia with moderate to severe negative symptoms. The primary endpoint was the PANSS-derived Negative Symptom Factor Score (NSFS) and the key secondary endpoint was Personal and Social Performance scale (PSP) total score. RESULTS: NSFS scores were lower (improved) for roluperidone 64 mg compared to placebo and marginally missing statistical significance for the intent-to-treat (ITT) analysis data set (P ≤ .064), but reached nominal significance (P ≤ .044) for the modified-ITT (m-ITT) data set. Changes in PSP total score were statistically significantly better on roluperidone 64 mg compared to placebo for both ITT and m-ITT (P ≤ .021 and P ≤ .017, respectively). CONCLUSIONS: Results of this trial confirm the potential of roluperidone as a treatment of negative symptoms and improving everyday functioning in patients with schizophrenia. Study registration: Eudra-CT: 2017-003333-29; NCT03397134.

Evolution of life cycles and reproductive traits: Insights from the brown algae.

A vast diversity of types of life cycles exists in nature, and several theories have been advanced to explain how this diversity has evolved and how each type of life cycle is retained over evolutionary time. Here, we exploited the diversity of life cycles and reproductive traits of the brown algae (Phaeophyceae) to test several hypotheses on the evolution of life cycles. We investigated the evolutionary dynamics of four life-history traits: life cycle, sexual system, level of gamete dimorphism and gamete parthenogenetic capacity. We assigned states to up to 77 representative species of the taxonomic diversity of the brown algal group, in a multi-gene phylogeny. We used maximum likelihood and Bayesian analyses of correlated evolution, while taking the phylogeny into account, to test for correlations between traits and to investigate the chronological sequence of trait acquisition. Our analyses are consistent with the prediction that diploid growth evolves when sexual reproduction is preferred over asexual reproduction, possibly because it allows the complementation of deleterious mutations. We also found that haploid sex determination is ancestral in relation to diploid sex determination. However, our results could not address whether increased zygotic and diploid growth are associated with increased sexual dimorphism. Our analyses suggest that in the brown algae, isogamous species evolved from anisogamous ancestors, contrary to the commonly reported pattern where evolution proceeds from isogamy to anisogamy.

Do Patterns of Instability or Severity of Psychopathology During Screening Predict Relapse in Schizophrenic Outpatient Subjects with Moderate to Severe Negative Symptoms Assigned to Placebo?

Background: Patients with schizophrenia who, prior to inclusion in placebo-controlled trials, experience the most severe and/or unstable symptoms might be more likely to manifest symptomatic worsening upon antipsychotic discontinuation. Methods: This retrospective analysis included all randomized patients assigned to placebo (n=83) in a 12-week, double-blind, placebo-controlled outpatient trial of MIN-101 (roluperidone) for the treatment of negative symptoms in schizophrenia. The following risk factors were defined for exacerbation: instability between screening and baseline defined operationally as patients with the highest 10 percent of absolute change from the screening visit to baseline in the Positive and Negative Syndrome Scale (PANSS) total or one of the five PANSS Marder factors; screening or baseline severity in PANSS total or one of the five PANSS Marder factors; and gender and age. We used two operational criteria of relapse and the odds ratios of meeting the relapse criteria were calculated for each risk factor. Results: The odds of meeting one of the operational thresholds for relapse after antipsychotic discontinuation were not statistically significantly increased in the subjects who were unstable on the PANSS total or on one of the five PANSS Marder factors before antipsychotic discontinuation. Further, the severity of PANSS total and Marder factor scores at screening and baseline were not statistically significantly associated with odds of relapse. Neither age nor gender had any effect on relapse rates. Conclusion: Mild to moderate symptomatic variations in the severity of symptoms during screening and more severe symptomology at baseline as measured by the PANSS were not predictive of increased risk of subsequent relapse in schizophrenic patients.

Network Analysis Indicates That Avolition Is the Most Central Domain for the Successful Treatment of Negative Symptoms: Evidence From the Roluperidone Randomized Clinical Trial.

A recent conceptual development in schizophrenia is to view its manifestations as interactive networks rather than individual symptoms. Negative symptoms, which are associated with poor functional outcome and reduced rates of recovery, represent a critical need in schizophrenia therapeutics. MIN101 (roluperidone), a compound in development, demonstrated efficacy in the treatment of negative symptoms in schizophrenia. However, it is unclear how the drug achieved its effect from a network perspective. The current study evaluated the efficacy of roluperidone from a network perspective. In this randomized clinical trial, participants with schizophrenia and moderate to severe negative symptoms were randomly assigned to roluperidone 32 mg (n = 78), 64 mg (n = 83), or placebo (N = 83). Macroscopic network properties were evaluated to determine whether roluperidone altered the overall density of the interconnections among symptoms. Microscopic properties were evaluated to examine which individual symptoms were most influential (ie, interconnected) on other symptoms in the network and are responsible for successful treatment effects. Participants receiving roluperidone did not differ from those randomized to placebo on macroscopic properties. However, microscopic properties (degree and closeness centrality) indicated that avolition was highly central in patients receiving placebo and that roluperidone reduced this level of centrality. These findings suggest that decoupling the influence of motivational processes from other negative symptom domains is essential for producing global improvements. The search for pathophysiological mechanisms and targeted treatment development should be focused on avolition, with the expectation of improvement in the entire constellation of negative symptoms if avolition is effectively treated.

Effects of Roluperidone (MIN-101) on two dimensions of the negative symptoms factor score: Reduced emotional experience and reduced emotional expression.

BACKGROUND: Recent research has suggested that negative symptoms (NS) can be considered in terms of two different dimensions: reduced expression (expressive deficit) and reduced experience (experiential deficit). Roluperidone, a compound with high affinities for 5 HT2A and sigma2 receptors, has previously shown superiority over placebo on improving NS in a prospective study in patients with schizophrenia. The objective here is to explore the effect of roluperidone compared to placebo, on the 2 domains of the Negative Symptoms. METHODS: This was a multi-national Phase 2b trial that enrolled 244 symptomatically stable patients with schizophrenia who had baseline scores ≥20 on the NS subscale of the PANSS. Patients were randomized to daily monotherapy with roluperidone 32 mg, roluperidone 64 mg, or placebo in a 1:1:1 ratio. All enrolled patients were Caucasian, and 137 (56%) were male. The 3 treatment groups were balanced on all demographic and illness-related baseline characteristics. RESULTS: Both doses of roluperidone were superior to placebo on both domains: Reduced Experience (p ≤ .006 for the 32 mg; p ≤ .001 for the 64 mg) with persistent superiority from Week 2 for the 64 mg dose and Week 8 for the 32 mg dose; Reduced Expression (p ≤ .003 for 32 mg; p ≤ .001 for 64 mg) with similar persistence. IMPLICATIONS: Both doses of roluperidone previously improved PANSS negative symptoms in general and demonstrated tolerability in stable schizophrenia patients. The post hoc analysis reported here found the drug to work on both the reduced emotional experience and reduced emotional expression sub-scales empirically derived from the PANSS.

Correction to: The selective orexin-2 antagonist seltorexant (JNJ-42847922/MIN-202) shows antidepressant and sleep-promoting effects in patients with major depressive disorder.

In the original Article, Tables two and three had formatting issues which affected their clarity. This has been corrected in the PDF and HTML versions of this Article.

The selective orexin-2 antagonist seltorexant (JNJ-42847922/MIN-202) shows antidepressant and sleep-promoting effects in patients with major depressive disorder.

Excessive arousal has a role in the pathophysiology of major depressive disorder (MDD). Seltorexant (JNJ-42847922/MIN-202) is a selective antagonist of the human orexin-2 receptor (OX2R) that may normalize excessive arousal and thereby attenuate depressive symptoms. In this study, the effects of night-time arousal suppression on depressive symptoms were investigated. 47 MDD patients with a total Inventory of Depressive Symptomatology (IDS) score of ≥30 at screening were included in a randomized, double-blind, diphenhydramine-, and placebo-controlled multicentre study. Symptoms of depression were rated using the 17-item Hamilton Depression Rating Scale (HDRS17). Effects on sleep were evaluated by polysomnography and by the Leeds Sleep Evaluation Questionnaire (LSEQ). To investigate the safety and tolerability of seltorexant, vital signs, suicidal ideation and adverse events were monitored. At baseline the severity of depressive symptoms correlated with sleep efficiency (SE), wake after sleep onset (WASO), duration of stage 2 sleep, and ruminations. Ten days of treatment with seltorexant (and not diphenhydramine) resulted in a significant improvement of core depressive symptoms compared to placebo; the antidepressant efficacy of seltorexant was maintained with continued treatment up to 28 days. Compared to placebo, the antidepressant efficacy of seltorexant coincided with an overall increase in (left posterior) EEG power and a relative increase in delta- and decrease in theta-, alpha- and beta power during stage 2 sleep. Treatment with seltorexant was associated with mild, self-limiting adverse drug reactions. Seltorexant affected core symptoms of depression in the absence of overt changes in the hypnogram; in contrast, diphenhydramine was not efficacious.

A key role for sex chromosomes in the regulation of parthenogenesis in the brown alga Ectocarpus.

Although evolutionary transitions from sexual to asexual reproduction are frequent in eukaryotes, the genetic bases of these shifts remain largely elusive. Here, we used classic quantitative trait analysis, combined with genomic and transcriptomic information to dissect the genetic basis of asexual, parthenogenetic reproduction in the brown alga Ectocarpus. We found that parthenogenesis is controlled by the sex locus, together with two additional autosomal loci, highlighting the key role of the sex chromosome as a major regulator of asexual reproduction. We identify several negative effects of parthenogenesis on male fitness, and different fitness effects of parthenogenetic capacity depending on the life cycle generation. Although allele frequencies in natural populations are currently unknown, we discuss the possibility that parthenogenesis may be under both sex-specific selection and generation/ploidally-antagonistic selection, and/or that the action of fluctuating selection on this trait may contribute to the maintenance of polymorphisms in populations. Importantly, our data provide the first empirical illustration, to our knowledge, of a trade-off between the haploid and diploid stages of the life cycle, where distinct parthenogenesis alleles have opposing effects on sexual and asexual reproduction and may help maintain genetic variation. These types of fitness trade-offs have profound evolutionary implications in natural populations and may structure life history evolution in organisms with haploid-diploid life cycles.

The selective orexin-2 receptor antagonist seltorexant improves sleep: An exploratory double-blind, placebo controlled, crossover study in antidepressant-treated major depressive disorder patients with persistent insomnia.

BACKGROUND: Insomnia is common in patients with major depressive disorder. Although antidepressants improve mood, insomnia often persists as a result of physiological hyperarousal. The orexin-2 receptor is increasingly being recognized as a new target for the treatment of persistent insomnia in major depressive disorder . AIM: This exploratory study investigated the effects of seltorexant on objective sleep parameters and subjective depressive symptoms in antidepressant treated major depressive disorder patients with persistent insomnia. METHODS: Twenty male and female patients received a single dose of 10, 20, 40 mg seltorexant and placebo with a washout period of seven days in a double-blind four-way crossover study. Effects on latency to persistent sleep, total sleep time and sleep efficiency were assessed with polysomnography. Subjective changes in mood were explored by the Quick Inventory of Depressive Symptomatology Self-Report. Safety was recorded and suicidal ideation and behavior were assessed with the Columbia Suicide Severity Rating Scale. RESULTS: Latency to persistent sleep was significantly shorter for all doses of seltorexant compared to placebo. Placebo least square mean was 61.05 min with least square mean ratios treatment/placebo (80% confidence interval) of 0.32 (0.24-0.44), 0.15 (0.11-0.2) and 0.17 (0.12-0.23) 19.69, 9.2, 10.15 for 10, 20 and 40 mg seltorexant respectively, (all p<0.001). Total sleep time was significantly longer for all doses of seltorexant compared to placebo. Sleep efficiency was significantly improved. The Quick Inventory of Depressive Symptomatology Self-Report demonstrated a trend to mood-improvement for the 40 mg group. CONCLUSIONS: Seltorexant showed a statistically significant, dose-dependent decrease in latency to persistent sleep, and increase in total sleep time and sleep efficiency combined with a tendency toward subjectively improved mood.

A randomized Phase 2 study to evaluate the orexin-2 receptor antagonist seltorexant in individuals with insomnia without psychiatric comorbidity.

BACKGROUND: Seltorexant is a potent and selective antagonist of the orexin-2 receptor that is being developed for the treatment of insomnia and major depressive disorder. AIMS: The primary objective was to investigate the effect of seltorexant on sleep efficiency after single and multiple dose administration in subjects with insomnia disorder without psychiatric comorbidity. Secondary objectives included evaluation of total sleep time, latency to persistent sleep, and wake after sleep onset. Subjects received 40 mg of seltorexant for five days during Period 1 and placebo during Period 2 or vice versa in this randomized, two-way crossover study. Objective sleep parameters were evaluated by polysomnography over 8 h on Day 1/2 (single dose) and on Day 5/6 (multiple doses). Subjective sleep parameters were assessed by questionnaires. RESULTS: Twenty-seven subjects completed the study. The mean changes in sleep efficiency (% (SD)) of seltorexant from placebo at Day 1/2 were 5.8 (9.2), and 7.9 (9.8) at Day 5/6 ( p < 0.001 at both time points); in total sleep time (min (SD)) 27.7 (44.3) and 37.9 (47.1), respectively; in latency to persistent sleep (min (SD)) -18.8 (21.3) and -29.9 (27.7), respectively; and in wake after sleep onset (min (SD)) -11.1 (36.4) and -11.3 (46.5). The most common adverse events were headache and somnolence. CONCLUSIONS: Sleep efficiency was increased with seltorexant treatment compared with placebo. Treatment with seltorexant resulted in a prolonged total sleep time, shorter latency to persistent sleep and wake after sleep onset. There were no unexpected safety findings.

Cognitive Effects of MIN-101 in Patients With Schizophrenia and Negative Symptoms: Results From a Randomized Controlled Trial.

OBJECTIVE: Current dopamine-blocking antipsychotic drugs have little impact on the cognitive deficits associated with schizophrenia. We evaluated whether MIN-101, a molecule that combines sigma-2 antagonism and 5-HT2A antagonism, might improve cognitive deficits in individuals with moderate to severe negative symptoms in schizophrenia. METHODS: Individuals (N = 244) aged 18 to 60 years with stable symptoms of DSM-5-defined schizophrenia and moderate to severe negative symptoms were randomized to placebo (n = 83), MIN-101 32 mg (n = 78), or MIN-101 64 mg (n = 83) in a 12-week, phase 2b, prospective, double-blind, placebo-controlled, parallel-group trial between May 2015 and December 2015. In a post hoc analysis, mean z and T score changes from baseline at 12 weeks of treatment in the cognitive composite score and individual tests on the Brief Assessment of Cognition in Schizophrenia (BACS) Battery were compared between MIN-101 and placebo. RESULTS: A total of 79 patients (95.2%) from the placebo group, 76 (97.4%) from the MIN-101 32 mg group, and 79 (95.2%) from the MIN-101 64 mg group completed the BACS at baseline. The BACS token motor (P = .04), verbal fluency (P = .01), and composite z scores (P = .05) showed significant improvements in the MIN-101 32 mg group compared to the placebo group. At week 4, the clinical improvements from baseline in the Positive and Negative Syndrome Scale (PANSS) negative factor showed a significant correlation with improvements from baseline on the BACS composite in the 64 mg group (r = -0.292, P = .020). At week 12, improvement in the PANSS negative factor showed significant correlations with improvements in the BACS composite (r = -0.408, P = .002), Trail Making Test (r = -0.394, P = .003), and verbal memory (r = -0.322, P = .017) for the 64 mg group. CONCLUSIONS: Results suggest a possible benefit of MIN-101 on cognitive performance in individuals with schizophrenia with stable positive symptoms and concurrent clinically significant negative symptoms. TRIAL REGISTRATION: EU Clinical Trials Register identifier: 2014-004878-42​.

The brief negative symptom scale (BNSS): Sensitivity to treatment effects.

The Brief Negative Symptom Scale (BNSS) grew out of a recommendation by the NIMH-sponsored Consensus Development Conference on Negative Symptoms that a scale based on contemporary concepts be developed. We assessed sensitivity to change of the BNSS in a trial of MIN-101, which showed efficacy for negative symptoms (PANSS pentagonal model) at daily doses of 32 and 64mg/day. Using mixed-effects model for repeated measures, we examined change in BNSS total score and in the BNSS factors of anhedonia/avolition/asociality (AAA), and expressivity (EXP). Compared to placebo, the 64mg group (N=83) showed a significant decrease in BNSS total score (effect size d [ES] 0.56, p<0.01) and both factor scores (AAA ES=0.48, EXP ES=0.46, p<0.02 for both). Patients in the trial had minimal depression and positive symptom scores; covarying for disorganization, positive symptoms, or anxiety/depression did not cause a meaningful change in the significance of the BNSS total or factor scores in this group. The 32mg group (N=78) did not differ significantly from placebo (N=83) on BNSS total score (ES=0.33, p<0.09), AAA (ES=0.25, p<0.20) or EXP (ES=0.30, p<0.12) scores. These results demonstrate the BNSS is sensitive to change.

Efficacy and Safety of MIN-101: A 12-Week Randomized, Double-Blind, Placebo-Controlled Trial of a New Drug in Development for the Treatment of Negative Symptoms in Schizophrenia.

OBJECTIVE: The authors assessed the efficacy, safety, and tolerability of MIN-101, a compound with affinities for sigma-2 and 5-HT2A receptors and no direct dopamine affinities, in comparison with placebo in treating negative symptoms in stabilized patients with schizophrenia. METHOD: The trial enrolled 244 patients who had been symptomatically stable for at least 3 months and had scores of at least 20 on the negative subscale of the Positive and Negative Syndrome Scale (PANSS). After at least 5 days' withdrawal from all antipsychotic medication, patients were randomly assigned to receive placebo or 32 mg/day or 64 mg/day of MIN-101 for 12 weeks. The primary outcome measure was the PANSS negative factor score (pentagonal structure model). Secondary outcome measures were PANSS total score and scores on the Clinical Global Impressions Scale (CGI), the Brief Negative Symptom Scale, the Brief Assessment of Cognition in Schizophrenia, and the Calgary Depression Scale for Schizophrenia. RESULTS: A statistically significant difference in PANSS negative factor score was observed, with lower scores for the MIN-101 32 mg/day and 64 mg/day groups compared with the placebo group (effect sizes, d=0.45 and d=0.57, respectively). Supporting these findings were similar effects on several of the secondary outcome measures, such as the PANSS negative symptom, total, and activation factor scores, the CGI severity item, and the Brief Negative Symptom Scale. There were no statistically significant differences in PANSS positive scale score between the MIN-101 and placebo groups. No clinically significant changes were observed in vital signs, routine laboratory values, weight, metabolic indices, and Abnormal Involuntary Movement Scale score. CONCLUSIONS: MIN-101 demonstrated statistically significant efficacy in reducing negative symptoms and good tolerability in stable schizophrenia patients.

Assessing sleep architecture and continuity measures through the analysis of heart rate and wrist movement recordings in healthy subjects: comparison with results based on polysomnography.

OBJECTIVE: The objective of the study was to evaluate the reliability of a new methodology for assessing sleep architecture descriptors based on heart rate and body movement recordings. METHODS: Twelve healthy male and female subjects between 18 and 40 years of age, without sleep disorders and not taking any drug or medication that could affect sleep, were recorded continuously during five consecutive nights. Together with the standard polysomnography, heart rate was recorded with a Holter and wrist movements by actimetry. Of the 60 recorded nights, 48 artifact-free nights were analyzed by two independent and well-trained visual scorers according to the rules of the American Academy of Sleep Medicine. Sleep stages were assigned to every 30-s epoch. In parallel, the same nights were analyzed by the new methodology using only heart rate and actimetry data, allowing a 1-s epoch sleep stage classification. Sleep architecture was measured for 48 nights, independently for the two manual scorings and the automatic analysis. RESULTS: Over 42 nights, the intra-class correlation coefficient, used to assess the consistency or reproducibility of quantitative measurements made by different observers, was classified as excellent when all 12 descriptors were combined. Analyses of the individual descriptors showed excellent interclass correlation for eight and good for four of the 12. CONCLUSION: The automatic analysis of heart rate and body movement during sleep allows for the evaluation of sleep architecture and continuity that is equivalent to those obtained by manual scoring of polysomnography. The technique used here is simple and robust to allow for home sleep monitoring.

The Pseudoautosomal Regions of the U/V Sex Chromosomes of the Brown Alga Ectocarpus Exhibit Unusual Features.

The recombining regions of sex chromosomes (pseudoautosomal regions, PARs) are predicted to exhibit unusual features due to their being genetically linked to the nonrecombining, sex-determining region. This phenomenon is expected to occur in both diploid (XY, ZW) and haploid (UV) sexual systems, with slightly different consequences for UV sexual systems because of the absence of masking during the haploid phase (when sex is expressed) and because there is no homozygous sex in these systems. Despite a considerable amount of theoretical work on PAR genetics and evolution, these genomic regions have remained poorly characterized empirically. We show here that although the PARs of the U/V sex chromosomes of the brown alga Ectocarpus recombine at a similar rate to autosomal regions of the genome, they exhibit many genomic features typical of nonrecombining regions. The PARs were enriched in clusters of genes that are preferentially, and often exclusively, expressed during the sporophyte generation of the life cycle, and many of these genes appear to have evolved since the Ectocarpales diverged from other brown algal lineages. A modeling-based approach was used to investigate possible evolutionary mechanisms underlying this enrichment in sporophyte-biased genes. Our results are consistent with the evolution of the PAR in haploid systems being influenced by differential selection pressures in males and females acting on alleles that are advantageous during the sporophyte generation of the life cycle.

Sexual dimorphism and the evolution of sex-biased gene expression in the brown alga ectocarpus.

Males and females often have marked phenotypic differences, and the expression of these dissimilarities invariably involves sex differences in gene expression. Sex-biased gene expression has been well characterized in animal species, where a high proportion of the genome may be differentially regulated in males and females during development. Male-biased genes tend to evolve more rapidly than female-biased genes, implying differences in the strength of the selective forces acting on the two sexes. Analyses of sex-biased gene expression have focused on organisms that exhibit separate sexes during the diploid phase of the life cycle (diploid sexual systems), but the genetic nature of the sexual system is expected to influence the evolutionary trajectories of sex-biased genes. We analyze here the patterns of sex-biased gene expression in Ectocarpus, a brown alga with haploid sex determination (dioicy) and a low level of phenotypic sexual dimorphism. In Ectocarpus, female-biased genes were found to be evolving as rapidly as male-biased genes. Moreover, genes expressed at fertility showed faster rates of evolution than genes expressed in immature gametophytes. Both male- and female-biased genes had a greater proportion of sites experiencing positive selection, suggesting that their accelerated evolution is at least partly driven by adaptive evolution. Gene duplication appears to have played a significant role in the generation of sex-biased genes in Ectocarpus, expanding previous models that propose this mechanism for the resolution of sexual antagonism in diploid systems. The patterns of sex-biased gene expression in Ectocarpus are consistent both with predicted characteristics of UV (haploid) sexual systems and with the distinctive aspects of this organism's reproductive biology.