Genetic Sex Research Articles

Oryzias curvinotus in Sanya Does Not Contain the Male Sex-Determining Gene dmy.

Simple Summarydmy is considered to be the male-determining gene in Japanese medaka (Oryzias latipes) and Hainan medaka (Oryzias. curvinotus), both of which have the XX/XY sex-determination system. Here, we found a group of medaka in the Sanya River (named SY-medaka) and confirmed that SY-medaka belongs to O. curvinotus by morphological characteristics and mitochondrial phylogenetic analysis. Through genetic sex identification, genome re-sequencing and gonadal transcriptome analysis, it was preliminary confirmed that SY-medaka did not contain dmy. Our results provide a basis for further studies of the mechanism underlying sex determination in Oryzias and functional genomics and reproduction biology in O. curvinotus.Hainan medaka (Oryzias curvinotus) is distributed in the coastal waters of the South China Sea and is able to adapt to a wide range of salinities. In this study, we characterized O. curvinotus in Sanya River (SY-medaka), which lacks dmy (a male sex-determining gene in O. latipes and O. curvinotus). In a comparison of SY-medaka and Gaoqiao medaka (GQ-medaka), the morphological difference between the two populations does not reach the subspecies level and they can be considered two geographic populations of O. curvinotus. A mitochondrial cytochrome oxidase subunit I (CoI) sequence alignment showed that the sequence identities between SY-medaka and other geographic populations of O. curvinotus are as high as 95%. A phylogenetic analysis of the mitochondrial genome also indicated that SY-medaka belongs to O. curvinotus. Molecular marker-based genetic sex assays and whole genome re-sequencing showed that SY-medaka does not contain dmy. Further, in RNA-Seq analyses of the testis and ovaries of sexually mature SY-medaka, dmy expression was not detected. We speculate that high temperatures resulted in the loss of dmy in SY-medaka during evolution, or the lineage has another sex-determining gene. This study provides a valuable dataset for elucidating the mechanism underlying sex determination in Oryzias genus and advances research on functional genomics or reproduction biology in O. curvinotus.

Differential accumulation of tau pathology between reciprocal F1 hybrids of rTg4510 mice

Tau, a family of microtubule-associated proteins, forms abnormal intracellular inclusions, so-called tau pathology, in a range of neurodegenerative diseases collectively known as tauopathies. The rTg4510 mouse model is a well-characterized bitransgenic F1 hybrid mouse model of tauopathy, which was obtained by crossing a Camk2α-tTA mouse line (on a C57BL/6 J background) with a tetO-MAPT*P301L mouse line (on a FVB/NJ background). The aim of this study was to investigate the effects of the genetic background and sex on the accumulation of tau pathology in reciprocal F1 hybrids of rTg4510 mice, i.e., rTg4510 on the (C57BL/6 J × FVB/NJ)F1 background (rTg4510_CxF) and on the (FVB/NJ × C57BL/6 J)F1 background (rTg4510_FxC). As compared with rTg4510_CxF mice, the rTg4510_FxC mice showed marked levels of tau pathology in the forebrain. Biochemical analyses indicated that the accumulation of abnormal tau species was accelerated in rTg4510_FxC mice. There were strong effects of the genetic background on the differential accumulation of tau pathology in rTg4510 mice, while sex had no apparent effect. Interestingly, midline-1 (Mid1) was identified as a candidate gene associated with this difference and exhibited significant up/downregulation according to the genetic background. Mid1 silencing with siRNA induced pathological phosphorylation of tau in HEK293T cells that stably expressed human tau with the P301L mutation, suggesting the role of Mid1 in pathological alterations of tau. Elucidation of the underlying mechanisms will provide novel insights into the accumulation of tau pathology and is expected to be especially informative to researchers for the continued development of therapeutic interventions for tauopathies.

Paternalism in DSD Management: A Real and Present Threat

In 1965, a botched circumcision left Bruce Reimer, a healthy, 8-month old XY male, with a disfigured penis. At the recommendation of Dr. John Money and physicians at Johns Hopkins, the infant was reassigned to female sex and underwent an orchiectomy and vaginoplasty. The family renamed the child “Brenda.” Unaware of her history, Brenda struggled with significant gender identity, psychological, and behavioral issues throughout her childhood and adolescence. When made aware of this history, she transitioned to male gender and assumed the name “David.” After years of psychological distress, David Reimer committed suicide in 2004. Despite the myriad lessons gleaned from this tragic story, medical and surgical management of children with atypical genitalia still remains often misguided, as providers continue to assume paternalistic roles in determining sex assignment and surgical interventions. A fifteen year old XY male with Robinow Syndrome presented for evaluation of hypogonadism and urinary incontinence. At birth, the patient was discovered to have a micropenis and perineal hypospadias and was diagnosed with hypogonadotropic hypogonadism. At the recommendation of the medical team, the infant underwent bilateral orchiectomy at eight months of age followed by urethroplasty and vaginoplasty at six years of age. The child was then given a female sex assignment. At twelve years of age, the child felt discordant from the sex of rearing and wished to be identified as male—his natal, genetic sex. He transitioned to male gender and began testosterone injections. He had history of recurrent UTIs and severe incontinence requiring diaper use. He strongly desired neophallus and urethral reconstruction for improved quality of life. The patient endorsed prior depression and desires to self-harm. He had significant concerns regarding his gender presentation and transition. He shared his difficulties in continuing in the same school system with peers who knew him as a female prior to transition and was concerned about peers knowing his medical history. In the years since the famous David Reimer case, the medical system has made tremendous strides in recognizing the need for patient autonomy and shared decision-making in patients with Differences of Sex Development and genital atypia. However, the paternalistic history of this field continues to leave its indelible mark more than 20 years since David Reimer’s case made headlines, as physicians continue to recommend definitive sex assignments and surgical interventions. As with the David Reimer case, the bodily integrity of this XY infant was altered in a permanent fashion with inadequate education of his family and little to no credence given to the autonomy of the child himself. We, as physicians, cannot continue to paternalistically apply John Money’s concept of gender neutrality and rigidly mandate sex assignments and early surgical interventions.

Genetic Sex Effects of Polycystic Ovary Syndrome Reveal Distinct Metabolic Etiology

Females with polycystic ovary syndrome (PCOS) have an increased risk of developing metabolic disorders such as insulin resistance, obesity, and type 2 diabetes (T2D). High-risk groups or individuals with a family history are more likely to have a greater genetic susceptibility to these diseases, which drastically increases their risk of developing other chronic health conditions. In this study, we systematically evaluated the bidirectional genetic burden of PCOS and its comorbidities among females and males. First, we analyzed the pleiotropic effects of the PCOS polygenic risk score (PRS), a measurement of genetic liability to PCOS, across 1,857 medical conditions recorded in the Vanderbilt University Medical Center electronic health record. We conducted a phenome-wide association study (PheWAS) adjusted for median age, sex, and genetic ancestry. In the European sex-combined model (n = 72,824), we observed that PCOS PRS was significantly (Bonferroni corrected p < 7.86e-06) associated with T2D (OR = 1.11, p = 8.75e-08) and hypertension (OR = 1.06, p = 1.13e-07) in addition to polycystic ovaries (OR = 1.11, p = 1.91e-07). In the sex-stratified model, we found that males (n = 32,022) with a higher PRS for PCOS were more likely to develop cardiovascular diseases (CVD) compared to females (n = 40,802) who had higher odds of developing T2D. Although we were underpowered to detect any phenome-wide significant effects in our African descent sample (n=15,283), uterine leiomyoma (OR = 1.24, p = 3.79e-03), osteoarthritis (OR = 1.21, p = 3.94e-03), and benign neoplasm of uterus (OR = 1.24, p = 4.00e-03) were the top three nominal significant results (p < 0.05) in females (n = 9,418). To understand the genetic relationships observed in the PheWAS, we used LD score regression to determine the genetic correlation between the phenotypes. We found that PCOS was positively correlated with T2D (rg = 31%), systolic blood pressure (rg = 12%), and pulse pressure (rg = 15%). However, we found no significant associations between the genetic risk of CVD and PCOS diagnosis in the European or African descent samples. Our findings show that the genetic architecture of PCOS has distinct metabolic sex differences, but the genetic risk of those comorbidities is not predictive of a PCOS diagnosis. This suggests that other drivers are contributing to the endocrine and cardiovascular comorbid signatures that underlie PCOS.

The embryonic ontogeny of the gonadal somatic cells in mice and monkeys.

In the early fetal stage, the gonads are bipotent and only later become the ovary or testis, depending on the genetic sex. Despite many studies examining how sex determination occurs from biopotential gonads, the spatial and temporal organization of bipotential gonads and their progenitors is poorly understood. Here, using lineage tracing in mice, we find that the gonads originate from a T+ primitive streak through WT1+ posterior intermediate mesoderm and appear to share origins anteriorly with the adrenal glands and posteriorly with the metanephric mesenchyme. Comparative single-cell transcriptomic analyses in mouse and cynomolgus monkey embryos reveal the convergence of the lineage trajectory and genetic programs accompanying the specification of biopotential gonadal progenitor cells. This process involves sustained expression of epithelial genes and upregulation of mesenchymal genes, thereby conferring an epithelial-mesenchymal hybrid state. Our study provides key resources for understanding early gonadogenesis in mice and primates.

Sex‐Specific Genetic Regulation of Adipose Mitochondria and Their Relationship to Metabolic Syndrome

Background and Objectives Mitochondria plays a major role in the pathophysiology of complex metabolic traits such as obesity, insulin resistance and fatty liver disease. However, the exact causal relationship between mitochondrial function and these traits is not completely understood. Similarly, sex differences in susceptibility to metabolic phenotypes have been amply described in mice, humans and other species, with females generally exhibiting a beneficial metabolic profile. Yet, the vast majority of previous studies examined sex differences in phenotypes or gene expression in isolation, generating trait or tissue specific results without putting them in context of genetic variation. Methods To understand the nature of the sex differences and causal relationships, we examined genetic factors contributing to mitochondrial function using a mouse reference population that were extensively phenotyped called hybrid mouse diversity panel. Results We identified a genetic locus on mouse chromosome 17 that controls mitochondria levels and function in adipose tissue in a sex- and tissue-specific manner. It regulates the expression of at least 89 mitochondrial genes, many of them related to oxidative phosphorylation, as well as mitochondrial DNA levels, in female but not male mice. Overexpression studies indicate that the effects of the locus are mediated by the Ndufv2 gene that encodes a subunit of the mitochondrial complex-I. The gene is activated by gonadal hormones and is regulated in cis only in females. Conclusion We report that adipose mitochondria are regulated by both genetic variation and sex hormones and that high levels are an important determinant of metabolic syndrome traits.

Pattern of Alcohol Consumption in Patients of Alcoholic Liver Disease in India

Background: Alcohol-related chronic liver disease (ALD) and its complications are major causes of morbidity and mortality. Predisposing factors for ALD include the amount, type, duration of alcohol consumption, patient’s genetic predisposition, race, sex, and other comorbid conditions. Â

A Nonlethal Genetic Assay for Discriminating Sex in Brook Trout

AbstractIdentifying sex in salmonids using nonlethal methods is valuable for controlled breeding in aquaculture and understanding behavior and dispersal for conservation. Although salmonids are male heterogametic, genetic sex identification has been problematic because a specific sex determination locus has been elusive. We implemented a blind analysis to identify sex in Brook Trout Salvelinus fontinalis using genetic primers (sdY) developed for Brown Trout Salmo trutta along with cytochrome c oxidase subunit I (COI_BT1) as an internal control. Fin clips were taken from 35 Brook Trout and analyzed via PCR and gel electrophoresis, and fish were simultaneously sacrificed and dissected to identify sex via gonads. The genetic and phenotypic analysis matched in 97% of the Brook Trout that were sampled, suggesting that this primer combination is successful in genetic sex determination. The ability to sex Brook Trout genetically will allow scientists to observe the difference in male and female Brook Trout behavior in the lab and natural stream ecosystems without using lethal methods.

Male-specific markers developed by next-generation sequencing confirmed an XX/XY sex-determination system in farmed ayu (Plecoglossus altivelis)

Ayu (Plecoglossus altivelis) is a commercially important common osmeroid fish for freshwater fisheries. But little is known about the sex-determination (SD) mechanisms. Type IIB endonucleases restriction-site associated DNA sequencing (2b-RAD-seq) is a popular reduced representation method and shown to be an efficient and valuable way for identifying the sex-specific DNA fragments and SD systems. In this study, one male and one female were first whole-genome sequenced. The total size of high-quality genome assembly of the male was 434 Mb (14,900 scaffolds) and of the female 424 Mb (15,340 scaffolds). And ten males and ten females were then subjected to 2b-RAD-seq and isolated 124 candidate male-specific tags and no female-specific tags. The candidate male-specific tags were mapped to 14 male scaffolds, nine of which were aligned to the female allelic scaffolds, and the other five belonged to the candidate male-specific scaffolds. Thereinto, scaf162525, scaf184183, scaf192610 encoded 45 candidate genes in all, 9 of which had functional descriptions. Furthermore, the anti-Müllerian hormone type-2 receptor on scaf192610 was tentatively identified as a Y-linked duplicate copy (Amhr2by) of the autosomal counterpart (Amhr2a), demonstrating the potential role in the SD system of ayu. Based on the four selected male-specific loci, four sets of primers were designed to develop the multiplex-PCR assay. Results showed that the four male-specific markers could identify the genetic sex with 100% accuracy in 126 farmed mature ayu of the different source populations. In conclusion, the genome sequences from both sexes combined with 2b-RAD sequencing analyses from other males and females led to the isolation of male-specific scaffolds, supporting an XX/XY SD system in ayu. The multiplex-PCR assay based on male-specific markers can be applied to perform molecular sexing in ayu culture.

Psychiatric Resilience and Alcohol Resistance: A Twin Study of Genetic Correlation and Sex Differences.

Variability in psychiatric response following stressful/traumatic life events is frequently observed. There is also variability in propensity for alcohol use disorder (AUD) such that some can consume substantial amounts and not develop AUD symptoms whereas others develop an AUD. Our group has applied discrepancy-based approaches to capture psychiatric resilience (PR) and alcohol resistance (AR), both moderately heritable. This study sought to (1) examine the genetic and environmental correlation of these constructs and (2) model qualitative and quantitative sex effects. Data came from a large twin sample (N = 4501 twin pairs) with self-report measures and interviewsassessing distress symptoms, stressful life events, alcohol use, and AUD. Correlated liability model results suggested a moderate degree of genetic correlation between PR and AR (0.54) due to the same genetic factors in males and females. Findings highlight the shared genetic predisposition of these resilience/resistance constructs while emphasizing the impact of unique environmental experiences.

Sex disparities matter in cancer development and therapy.

Curing cancer through precision medicine is the paramount aim of the new wave of molecular and genomic therapies. Currently, whether patients with non-reproductive cancers are male or female according to their sex chromosomes is not adequately considered in patient standard of care. This is a matter of consequence because there is growing evidence that these cancer types generally initiate earlier and are associated with higher overall incidence and rates of death in males compared with females. Gender, in contrast to sex, refers to a chosen sexual identity. Hazardous lifestyle choices (notably tobacco smoking) differ in prevalence between genders, aligned with disproportionate cancer risk. These add to underlying genetic predisposition and influences of sex steroid hormones. Together, these factors affect metabolism, immunity and inflammation, and ultimately the fidelity of the genetic code. To accurately understand how human defences against cancer erode, it is crucial to establish the influence of sex. Our Perspective highlights evidence from basic and translational research indicating that including genetic sex considerations in treatments for patients with cancer will improve outcomes. It is now time to adopt the challenge of overhauling cancer medicine based on optimized treatment strategies for females and males.

Two transcriptionally distinct pathways drive female development in a reptile with both genetic and temperature dependent sex determination.

How temperature determines sex remains unknown. A recent hypothesis proposes that conserved cellular mechanisms (calcium and redox; ‘CaRe’ status) sense temperature and identify genes and regulatory pathways likely to be involved in driving sexual development. We take advantage of the unique sex determining system of the model organism, Pogona vitticeps, to assess predictions of this hypothesis. P. vitticeps has ZZ male: ZW female sex chromosomes whose influence can be overridden in genetic males by high temperatures, causing male-to-female sex reversal. We compare a developmental transcriptome series of ZWf females and temperature sex reversed ZZf females. We demonstrate that early developmental cascades differ dramatically between genetically driven and thermally driven females, later converging to produce a common outcome (ovaries). We show that genes proposed as regulators of thermosensitive sex determination play a role in temperature sex reversal. Our study greatly advances the search for the mechanisms by which temperature determines sex.

Molecular sexing of degraded DNA from elephants and mammoths: a genotyping assay relevant both to conservation biology and to paleogenetics

It is important to determine the sex of elephants from their samples—faeces from the field or seized ivory—for forensic reasons or to understand population demography and genetic structure. Molecular sexing methods developed in the last two decades have often shown limited efficiency, particularly in terms of sensitivity and specificity, due to the degradation of DNA in these samples. These limitations have also prevented their use with ancient DNA samples of elephants or mammoths. Here we propose a novel TaqMan-MGB qPCR assay to address these difficulties. We designed it specifically to allow the characterization of the genetic sex for highly degraded samples of all elephantine taxa (elephants and mammoths). In vitro experiments demonstrated a high level of sensitivity and low contamination risks. We applied this assay in two actual case studies where it consistently recovered the right genotype for specimens of known sex a priori. In the context of a modern conservation survey of African elephants, it allowed determining the sex for over 99% of fecal samples. In a paleogenetic analysis of woolly mammoths, it produced a robust hypothesis of the sex for over 65% of the specimens out of three PCR replicates. This simple, rapid, and cost-effective procedure makes it readily applicable to large sample sizes.

With or Without W? Molecular and Cytogenetic Markers are Not Sufficient for Identification of Environmentally-Induced Sex Reversal in the Bearded Dragon

Transitions from environmental sex determination (ESD) to genotypic sex determination (GSD) require an intermediate step of sex reversal, i.e., the production of individuals with a mismatch between the ancestral genotypic and the phenotypic sex. Among amniotes, the sole well-documented transition in this direction was shown in the laboratory in the central bearded dragon, Pogona vitticeps, where very high incubation temperatures led to the production of females with the male-typical (ZZ) genotype. These sex-reversed females then produced offspring whose sex depended on the incubation temperature. Sex-reversed animals identified by molecular and cytogenetic markers were also reported in the field, and their increasing incidence was speculated as a climate warming-driven transition in sex determination. We show that the molecular and cytogenetic markers normally sex-linked in P. vitticeps are also sex-linked in P. henrylawsoni and P. minor, which points to quite ancient sex chromosomes in this lineage. Nevertheless, we demonstrate, based on a crossing experiment with a male bearded dragon who possesses a mismatch between phenotypic sex and genotype, that the used cytogenetic and molecular markers might not be reliable for the identification of sex reversal. Sex reversal should not be considered as the only mechanism causing a mismatch between genetic sex-linked markers and phenotypic sex, which can emerge also by other processes, here most likely by a rare recombination between regions of sex chromosomes which are normally sex-linked. We warn that sex-linked, even apparently for a long evolutionary time, and sex-specific molecular and cytogenetic markers are not a reliable tool for the identification of sex-reversed individuals in a population and that sex reversal has to be verified by other approaches, particularly by observation of the sex ratio of the progeny.

Sex-Dependent Shared and Nonshared Genetic Architecture Across Mood and Psychotic Disorders

BackgroundSex differences in incidence and/or presentation of schizophrenia (SCZ), major depressive disorder (MDD), and bipolar disorder (BIP) are pervasive. Previous evidence for shared genetic risk and sex differences in brain abnormalities across disorders suggest possible shared sex-dependent genetic risk. MethodsWe conducted the largest to date genome-wide genotype-by-sex (G×S) interaction of risk for these disorders using 85,735 cases (33,403 SCZ, 19,924 BIP, and 32,408 MDD) and 109,946 controls from the PGC (Psychiatric Genomics Consortium) and iPSYCH. ResultsAcross disorders, genome-wide significant single nucleotide polymorphism–by-sex interaction was detected for a locus encompassing NKAIN2 (rs117780815, p = 3.2 × 10−8), which interacts with sodium/potassium-transporting ATPase (adenosine triphosphatase) enzymes, implicating neuronal excitability. Three additional loci showed evidence (p < 1 × 10−6) for cross-disorder G×S interaction (rs7302529, p = 1.6 × 10−7; rs73033497, p = 8.8 × 10−7; rs7914279, p = 6.4 × 10−7), implicating various functions. Gene-based analyses identified G×S interaction across disorders (p = 8.97 × 10−7) with transcriptional inhibitor SLTM. Most significant in SCZ was a MOCOS gene locus (rs11665282, p = 1.5 × 10−7), implicating vascular endothelial cells. Secondary analysis of the PGC-SCZ dataset detected an interaction (rs13265509, p = 1.1 × 10−7) in a locus containing IDO2, a kynurenine pathway enzyme with immunoregulatory functions implicated in SCZ, BIP, and MDD. Pathway enrichment analysis detected significant G×S interaction of genes regulating vascular endothelial growth factor receptor signaling in MDD (false discovery rate-corrected p < .05). ConclusionsIn the largest genome-wide G×S analysis of mood and psychotic disorders to date, there was substantial genetic overlap between the sexes. However, significant sex-dependent effects were enriched for genes related to neuronal development and immune and vascular functions across and within SCZ, BIP, and MDD at the variant, gene, and pathway levels.

Maternal Psychological Problems During Pregnancy and Child Externalizing Problems: Moderated Mediation Model with Child Self-regulated Compliance and Polygenic Risk Scores for Aggression

A potential pathway underlying the association between prenatal exposure to maternal psychological problems and childhood externalizing problems is child self-regulation. This prospective study (N = 687) examined whether self-regulated compliance mediates the relation between maternal affective problems and hostility during pregnancy and childhood externalizing problems, and explored moderation by child polygenic risk scores for aggression and sex. Self-regulated compliance at age 3 was observed in mother–child interactions, and externalizing problems at age 6 were reported by mothers and teachers. Polygenic risk scores were calculated based on a genome-wide association study of aggressive behavior. Self-regulated compliance mediated the associations between maternal psychological problems and externalizing problems. Aggression PRS was associated with higher externalizing problems reported by mothers. No evidence was found of moderation by aggression PRS or sex. These findings support the hypothesis that maternal psychological problems during pregnancy might influence externalizing problems through early self-regulation, regardless of child genetic susceptibility or sex.

Genetic Parameters of Effort and Recovery in Sport Horses Assessed with Infrared Thermography.

Simple SummaryThe way a horse activates (effort phase-EP) and recovers (recovery phase-RP) during a sport event can affect its sport performance. The aim of this manuscript was to test horses’ adaptation to sport performance and its genetic basis, using eye temperature assessed with infrared thermography. EP and RP were measured in 495 Spanish Sport Horses, during a performance test, considering sex (2) and genetic lines (5) as fixed effects. The ranking position obtained on the official sport competition celebrated the day after the performance test was also collected. Differences in variables due to genetic line and sex effects were found, showing that, regardless of the genetic line, stallions tended to recover better than mares after the sport test developed. High positive correlations were found between EP and RP for both fixed effects, so that, the higher the EP, the higher the RP. However, for the ranking position, a low negative correlation was found, so that the higher the eye temperature increase, the better the position. Heritabilities showed medium–high values with a medium positive genetic correlation between them. Thus, breed origins and sex influence horses’ effort and recovery during sport performance, showing a genetic basis adequate for selection.The way a horse activates (effort phase-EP) and recovers (recovery phase-RP) during a sport event can affect its sport performance. The aim of this manuscript was to test horses’ adaptation to sport performance and its genetic basis, using eye temperature assessed with infrared thermography. EP and RP were measured in 495 Spanish Sport Horses, during a performance test, considering sex (2) and genetic lines (5) as fixed effects. The ranking position obtained on an official sport competition was also collected. Differences in variables due to genetic line and sex effects were found, showing that, regardless of the genetic line, stallions tended to recover better than mares after the sport test developed. High positive intra-class correlations (p < 0.001) were found between EP and RP for both fixed effects, so that the higher the EP, the higher the RP. However, for the ranking position, a low negative correlation (p < 0.01) was found, so that the higher the eye temperature increase, the better the position. Heritabilities showed medium–high values with a medium positive genetic correlation between them. Thus, breed origins and sex influence horses’ effort and recovery during sport performance, showing a genetic basis adequate for selection.

Sex-specific genetic architecture in response to American and ketogenic diets

Background/objectivesThere is a growing appreciation for individual responses to diet. In a previous study, mouse strain-specific responses to American and ketogenic diets were observed. In this study, we searched for genetic variants underlying differences in the responses to American and ketogenic diets between C57BL/6J (B6) and FVB/NJ (FVB) mouse strains.ResultsGenetic mapping of fat and lean mass gain revealed QTLs on Chromosome (Chr) 1 at 191.6 Mb (Fmgq1) (P < 0.001, CI = 180.2–194.4 Mb), Chr5 at 73.7 Mb (Fmgq2, Lmgq1) (P < 0.001, CI = 66.1–76.6 Mb), and Chr7 at 40.5 Mb (Fmgq3) (P < 0.01, CI = 36.6–44.5 Mb). Analysis of serum HDL cholesterol concentration identified a significant (P < 0.001, CI = 160.6–176.1 Mb) QTL on Chr1 at 168.6 Mb (Hdlq1). Causal network inference suggests that HDL cholesterol and fat mass gain are both linked to Fmgq1.ConclusionsStrong sex effects were identified at both Fmgq2 and Lmgq1, which are also diet-dependent. Interestingly, Fmgq2 and Fmgq3 affect fat gain directly, while Fmgq1 influences fat gain directly and via an intermediate change in serum cholesterol. These results demonstrate how precision nutrition will be advanced through the integration of genetic variation and sex in physiological responses to diets varied in carbohydrate composition.

Identification of a novel sex determining chromosome in cichlid fishes that acts as XY or ZW in different lineages

Sex determination systems are highly conserved among most vertebrates with genetic sex determination, but can be variable and evolve rapidly in some. Here, we study sex determination in a clade with exceptionally high sex chromosome turnover rates. We identify the sex determining chromosomes in three interspecific crosses of haplochromine cichlid fishes from Lakes Victoria and Malawi. We find evidence for different sex determiners in each cross. In the Malawi cross and one Victoria cross the same chromosome is sex-linked but while females are the heterogametic sex in the Malawi species, males are the heterogametic sex in the Victoria species. This chromosome has not previously been reported to be sex determining in cichlids, increasing the number of different chromosomes shown to be sex determining in cichlids to 12. All Lake Victoria species of our crosses are less than 15,000 years divergent, and we identified different sex determiners among them. Our study provides further evidence for the diversity and evolutionary flexibility of sex determination in cichlids, factors which might contribute to their rapid adaptive radiations.

The comparative effect of exposure to various risk factors on the risk of hyperuricaemia: diet has a weak causal effect

BackgroundPrevention of hyperuricaemia (HU) is critical to the prevention of gout. Understanding causal relationships and relative contributions of various risk factors to hyperuricemia is therefore important in the prevention of gout. Here, we use attributable fraction to compare the relative contribution of genetic, dietary, urate-lowering therapy (ULT) and other exposures to HU. We use Mendelian randomisation to test for the causality of diet in urate levels.MethodsFour European-ancestry sample sets, three from the general population (n = 419,060) and one of people with gout (n = 6781) were derived from the Database of Genotypes and Phenotypes (ARIC, FHS, CARDIA, CHS) and UK Biobank. Dichotomised exposures to diet, genetic risk variants, BMI, alcohol, diuretic treatment, sex and age were used to calculate adjusted population and average attributable fractions (PAF/AAF) for HU (≥0.42 mmol/L [≥7 mg/dL]). Exposure to ULT was also assessed in the gout cohort. Two sample Mendelian randomisation was done in the UK Biobank using dietary pattern-associated genetic variants as exposure and serum urate levels as outcome.ResultsAdherence to dietary recommendations, BMI (< 25 kg/m2), and absence of the SLC2A9 rs12498742 urate-raising allele produced PAFs for HU of 20 to 24%, 59 to 69%, and 57 to 64%, respectively, in the three non-gout cohorts. In the gout cohort, diet, BMI, SLC2A9 rs12498742 and ULT PAFs for HU were 12%, 49%, 48%, and 63%, respectively. Mendelian randomisation demonstrated weak causal effects of four dietary habits on serum urate levels (e.g. preferentially drinking skim milk increased urate, β = 0.047 mmol/L, P = 3.78 × 10−8). These effects were mediated by BMI, and they were not significant (P ≥ 0.06) in multivariable models assessing the BMI-independent effect of diet on urate.ConclusionsDiet has a relatively minor role in determining serum urate levels and HU. In gout, the use of ULT was the largest attributable fraction tested for HU.