Biology subjects

Jackson, L.

Publications and source records attributed to Jackson, L..

At least 19 recordsLinked to original sources

bioRxiv2025

Whole-genome sequencing analysis of anthropometric traits in 672,976 individuals reveals convergence between rare and common genetic associations

Genetic association studies have mostly focussed on common variants from genotyping arrays or rare protein-coding variants from exome sequencing. Here, we used whole-genome sequence (WGS) data in 672,976 individuals of diverse ancestry to evaluate the contribution and architecture of rare non-coding variants to three commonly studied anthropometric traits: height, body mass index (BMI) and waist-hip ratio adjusted for BMI (WHRadjBMI). Analysing 447,461 individuals in UK Biobank for discovery and 225,515 individuals in All of Us for replication, we identified 90 novel rare and low-frequency single variant associations. This includes two independent rare variants upstream of IGF2BP2 that both substantially reduce WHRadjBMI, but have distinct effects on other adiposity traits. We identified 135 coding variant aggregates, several of which were missed by exome sequencing studies. For example, UBR3 protein-truncating variants were associated with a 2.7kg/m2 increase in BMI. We additionally identified 51 non-coding variant aggregate associations, including in the 5UTR of FGF18 (a highly constrained gene with no previously reported coding associations) associated with up to 6cm effects on height. We show that 97% of rare variant associations occur near GWAS loci demonstrating convergence of rare and common variant associations. Finally, we show that ultra rare variants (MAF<0.01%) explain a small fraction of heritability (<10%) compared to common variants for these traits, that heritability is largely shared across ancestries, and that this heritability is concentrated at or near common variant loci. Our work demonstrates the importance of large-scale WGS for fully understanding the genetic architecture of complex traits.

genetics↗

bioRxiv2024

Visualization of breast cancer using contrast-enhanced optical coherence elastography based on tissue heterogeneity

By mapping the mechanical properties of tissue, elastography can improve identification of breast cancer. On the macro-scale, ultrasound elastography and magnetic resonance elastography have emerged as effective clinical methods for the diagnosis of tumors. On the micro-scale, optical coherence elastography (OCE) shows promise for intraoperative tumor margin assessment during breast-conserving surgery. Whilst several OCE studies have demonstrated strong potential, the mechanical models used require the assumption of uniaxial stress throughout the sample. However, breast tissue is heterogeneous and contains compressible features (e.g., ducts and blood vessels) and collagen-rich fibrotic features (e.g., stroma). This heterogeneity can invalidate the assumption of uniaxial stress and reduce the accuracy of OCE, often making it challenging to interpret images. Here, we demonstrate a new variant of OCE based on mapping the Euler angle, i.e., the angle between the principal compression and the loading axis induced by tissue heterogeneity, which removes the assumption of uniaxial deformation. This is enabled by a hybrid three-dimensional (3-D) displacement estimation method that combines phase-sensitive detection and complex cross-correlation, providing access to the 3-D displacement and 3-D strain tensor on the micro-scale. We demonstrate this new OCE technique through experiments on phantoms and 10 fresh human breast specimens. Through close correspondence with histology, our results show that mapping the Euler angle provides additional contrast to both optical coherence tomography and a current OCE technique in identifying cancer. Mapping the Euler angle in breast tissue may provide a new biomarker for intraoperative tumor margin assessment.

bioengineering↗

bioRxiv2024

Sexually dimorphic control of aggression by androgen signaling in a cichlid

Innate social behaviors like aggression are modulated by sex steroid hormones such as androgens and estrogens. However, we know little about how the same hormone regulates similar behaviors in both sexes. We investigated the role of androgenic signaling in the regulation of aggression in Astatotilapia burtoni, a social fish in which males and females perform similar aggressive behaviors. We used AR knockout (KO) animals for this study, which was recently shown to be required for male-typical aggression and mating. Surprisingly, AR KO females did not show deficits in aggression. We also determined that females lacking the other AR, AR{beta} showed normal levels of aggression. Blocking both ARs pharmacologically confirmed that neither AR is necessary for aggression in females. However, AR KO males showed clear deficits in attacks. Thus, in A. burtoni there appears to be a sexual dimorphism in the role of AR in the control of aggression.

neuroscience↗

bioRxiv2023

Whole genome sequencing analysis identifies rare, large-effect non-coding variants and regions associated with circulating protein levels

The role of non-coding rare variation in common phenotypes is largely unknown, due to a lack of whole-genome sequence data, and the difficulty of categorising non-coding variants into biologically meaningful regulatory units. To begin addressing these challenges, we performed a cis association analysis using whole-genome sequence data, consisting of 391 million variants and 1,450 circulating protein levels in [~]20,000 UK Biobank participants. We identified 777 independent rare non-coding single variants associated with circulating protein levels (P<1x10-9), after conditioning on protein-coding and common associated variants. Rare non-coding aggregate testing identified 108 conditionally independent regulatory regions. Unlike protein-coding variation, rare non-coding genetic variation was almost as likely to increase as decrease protein levels. The regions we identified overlapped predicted tissue-specific enhancers more than promoters, suggesting they represent tissue-specific regulatory regions. Our results have important implications for the identification, and role, of rare non-coding variation associated with common human phenotypes.

genetics↗

bioRxiv2023

Female cichlids attack and avoid-but will still mate with-androgen receptor mutant males that lack male-typical body coloration

A key challenge in animal behavior is disentangling the social stimuli that drive conspecific behaviors. For behaviors like birdsong, insights can be made through the experimental isolation of relevant cues that affect behavior. However, for some species like teleost fish, putative sexual signaling cues are inextricably linked to others, making it difficult to parse the precise roles distinct signals play in driving conspecific behaviors. In the African cichlid Astatotilapia burtoni, males are dominant or subordinate, wherein bright coloration and territorial and courtship behavior inextricably correlate positively with rank. Here, we leveraged androgen receptor (AR) mutant male A. burtoni that lack dominance-typical coloration but not behavior to isolate the role of male coloration in driving female mating behaviors in this species. We found in independent behavioral assays that females behave aggressively towards AR mutant but not WT males but still mated with both types of males. Females showed enhanced activation of esr2b+ cells in the hypothalamus when housed with either mutant or WT males and this activation scaled with spawning activities. Therefore, there is not a simple relationship between male coloration and female mating behaviors in A. burtoni, suggesting independent sensory mechanisms converge on hypothalamic esr2b+ cells to coordinate behavioral output.

animal behavior and cognition↗

bioRxiv2023

Sex differences in aggression and its neural substrate in a cichlid fish

Aggression is ubiquitous among social species and functions to maintains social dominance hierarchies. The African cichlid fish Astatotilapia burtoni is an ideal study species for studying aggression due to their unique and flexible dominance hierarchy. However, female aggression in this species and the neural mechanisms of aggression in both sexes is not well understood. To further understand the potential sex differences in aggression in this species, we characterized aggression in male and female A. burtoni in a mirror assay. We then quantified neural activation patterns in brain regions of the social behavior network (SBN) to investigate if differences in behavior are reflected in the brain with immunohistochemistry by detecting the phosphorylated ribosome marker phospho-S6 ribosomal protein (pS6), a marker for neural activation. We found that A. burtoni perform both identical and sex-specific aggressive behaviors in response to a mirror assay. We observed sex differences in pS6 immunoreactivity in the Vv, a homolog of the lateral septum in mammals. Males but not females had higher ps6 immunoreactivity in the ATn after the aggression assay. The ATn is a homolog of the ventromedial hypothalamus in mammals, which is strongly implicated in the regulation of aggression in males. Several regions also have higher pS6 immunoreactivity in negative controls than fish exposed to a mirror, implicating a role for inhibitory neurons in suppressing aggression until a relevant stimulus is present. Male and female A. burtoni display both similar and sexually dimorphic behavioral patterns in aggression in response to a mirror assay. There are also sex differences in the corresponding neural activation patterns in the SBN. In mirror males but not females, the ATn clusters with the POA, revealing a functional connectivity of these regions that is triggered in an aggressive context in males. These findings suggest that distinct neural circuitry underlie aggressive behavior in male and female A. burtoni, serving as a foundation for future work investigating the molecular and neural underpinnings of sexually dimorphic behaviors in this species to reveal fundamental insights into understanding aggression.

neuroscience↗

bioRxiv2022

Diet Induced Obesity and Diabetes Enhance Mortality and Reduces Vaccine Efficacy for SARS-CoV-2

Severe Acute Respiratory Syndrome Coronavirus-2 (SARS-CoV-2), the causative agent of Coronavirus disease 2019 (COVID-19), emerged in Wuhan, China, in December 2019. As of October 2022, there have been over 625 million confirmed cases of COVID-19, including over 6.5 million deaths. Epidemiological studies have indicated that comorbidities of obesity and diabetes mellitus are associated with increased morbidity and mortality following SARS-CoV-2 infection. We determined how the comorbidities of obesity and diabetes affect morbidity and mortality following SARS-CoV-2 infection in unvaccinated and adjuvanted spike nanoparticle (NVX-CoV2373) vaccinated mice. We find that obese/diabetic mice infected with SARS-CoV-2 have increased morbidity and mortality compared to age matched normal mice. Mice fed a high-fat diet (HFD) then vaccinated with NVX-CoV2373 produce equivalent neutralizing antibody titers to those fed a normal diet (ND). However, the HFD mice have reduced viral clearance early in infection. Analysis of the inflammatory immune response in HFD mice demonstrates a recruitment of neutrophils that was correlated with increased mortality and reduced clearance of the virus. Depletion of neutrophils in diabetic/obese vaccinated mice reduced disease severity and protected mice from lethality. This model recapitulates the increased disease severity associated with obesity and diabetes in humans with COVID-19 and is an important comorbidity to study with increasing obesity and diabetes across the world. ImportanceSARS-CoV-2 has caused a wide spectrum of disease in the human population, from asymptomatic infections to death. It is important to study the host differences that may alter the pathogenesis of this virus. One clinical finding in COVID19 patients, is that people with obesity or diabetes are at increased risk of severe illness from SARS-CoV-2 infection. We used a high fat diet model in mice to study the effects of obesity and Type 2 diabetes on SARS-CoV-2 infection as well as how these comorbidities alter the response to vaccination. We find that diabetic/obese mice have increased disease after SARS-CoV-2 infection and they have slower clearance of virus. We find that the lungs of these mice have increased neutrophils and that removing these neutrophils protect diabetic/obese mice from disease. This demonstrates why these diseases have increased risk of severe disease and suggests specific interventions upon infection.

microbiology↗

bioRxiv2021

Insight into mammary gland development and tumor prevention in a newly developed metastatic mouse model of breast cancer

The development of breast cancer has been observed due to altered regulation of mammary gland developmental processes. Thus, a better understand of the normal mammary gland development can reveal possible mechanism in how normal cells are re-programmed to become malignant cells. E2F1-4 are part of the E2F transcription factor family with varied roles in mammary development. However, little is known about the role of E2F5 in mammary gland development. A combination of scRNAseq and predictive signature tools demonstrate the presence of E2F5 in the mammary gland and showed altered activity during the various phases of mammary gland development and function. Testing the hypothesis that E2F5 regulates mammary function, we generated a mammary-specific E2F5 knockout mouse model, resulting in modest mammary gland development changes. However, after a prolonged latency the E2F5 conditional knockout mice developed highly metastatic mammary tumors with metastases in both the lung and liver. Transplantation of the tumors revealed metastases to lymph nodes that was enriched through serial transplantation. Through whole genome sequencing and RNAseq analysis we identified, and then confirmed in vivo, that Cyclin D1 was dysregulated in E2F5 conditional knockout mammary glands and tumors. Based on these findings, we propose that loss of E2F5 leads altered regulation of Cyclin D1, which facilitates the development of mammary tumors.

cancer biology↗

bioRxiv2021

Novel Hendra virus variant detected by sentinel surveillance of Australian horses.

A novel Hendra virus (HeV) variant, not detected by routine testing, was identified and isolated from a Queensland horse that suffered acute, fatal disease consistent with HeV infection. Whole genome sequencing and phylogenetic analysis demonstrated the variant to have ~83% nucleotide identity to the prototype HeV strain. An updated RT-qPCR assay was designed for routine HeV surveillance. In silico and in vitro comparison of the receptor-binding protein with prototypic HeV showed that the human monoclonal antibody m102.4 used for post-exposure prophylaxis, as well as the current equine vaccine, should be effective against this variant. Genetic similarity of this virus to sequences detected from grey-headed flying-foxes suggests the variant circulates at-least in this species. Studies determining infection kinetics, pathogenicity, reservoir-species associations, viral-host co-evolution and spillover dynamics for this virus are urgently needed. Surveillance and biosecurity practices should be updated to appreciate HeV spillover risk across all regions frequented by flying foxes.

molecular biology↗

bioRxiv2021

SARS-CoV-2 cell-to-cell spread occurs rapidly and is insensitive to antibody neutralization

Viruses increase the efficiency of close-range transmission between cells by manipulating cellular physiology and behavior, and SARS-CoV-2 uses cell fusion as one mechanism for cell-to-cell spread. Here we visualized infection using time-lapse microscopy of a human lung cell line and used live virus neutralization to determine the sensitivity of SARS-CoV-2 cell-to-cell spread to neutralizing antibodies. SARS-CoV-2 infection rapidly led to cell fusion, forming multinucleated cells with clustered nuclei which started to be detected at 6h post-infection. To compare sensitivity of cell-to-cell spread to neutralization, we infected either with cell-free virus or with single infected cells expressing on their surface the SARS-CoV-2 spike protein. We tested two variants of SARS-CoV-2: B.1.117 containing only the D614G substitution, and the escape variant B.1.351. We used the much smaller area of single infected cells relative to infection foci to exclude any input infected cells which did not lead to transmission. The monoclonal antibody and convalescent plasma we tested neutralized cell-free SARS-CoV-2, with the exception of B.1.351 virus, which was poorly neutralized with plasma from non-B.1.351 infections. In contrast, cell-to-cell spread of SARS-CoV-2 showed no sensitivity to monoclonal antibody or convalescent plasma neutralization. These observations suggest that, once cells are infected, SARS-CoV-2 may be more difficult to neutralize in cell types and anatomical compartments permissive for cell-to-cell spread.

microbiology↗

bioRxiv2021

Durability of mRNA-1273-induced antibodies against SARS-CoV-2 variants

SARS-CoV-2 mutations may diminish vaccine-induced protective immune responses, and the durability of such responses has not been previously reported. Here, we present a comprehensive assessment of the impact of variants B.1.1.7, B.1.351, P.1, B.1.429, and B.1.526 on binding, neutralizing, and ACE2-blocking antibodies elicited by the vaccine mRNA-1273 over seven months. Cross-reactive neutralizing responses were rare after a single dose of mRNA-1273. At the peak of response to the second dose, all subjects had robust responses to all variants. Binding and functional antibodies against variants persisted in most subjects, albeit at low levels, for 6 months after the primary series of mRNA-1273. Across all assays, B.1.351 had the greatest impact on antibody recognition, and B.1.1.7 the least. These data complement ongoing studies of clinical protection to inform the potential need for additional boost vaccinations. One-Sentence SummaryMost mRNA-1273 vaccinated individuals maintained binding and functional antibodies against SARS-CoV-2 variants for 6 months.

immunology↗

bioRxiv2020

Perilipin2 down-regulation in beta cells impairs insulin secretion under nutritional stress and damages mitochondria

Perilipin 2 (PLIN2) is the lipid droplet (LD) protein in {beta} cells that increases under nutritional stress. Down-regulation of PLIN2 is often sufficient to reduce LD accumulation. To determine whether PLIN2 positively or negatively affects {beta} cell function under nutritional stress, PLIN2 was down-regulated in mouse {beta} cells, INS1 cells, and human islet cells. {beta} cell specific deletion of PLIN2 in mice on a high fat diet reduced glucose-stimulated insulin secretion (GSIS) in vivo and in vitro. Down-regulation of PLIN2 in INS1 cells blunted GSIS after 24 h incubation with 0.2 mM palmitic acids. Down-regulation of PLIN2 in human pseudoislets cultured at 5.6 mM glucose impaired both phases of GSIS, indicating that PLIN2 is critical for GSIS. Down-regulation of PLIN2 decreased specific OXPHOS proteins in all three models and reduced oxygen consumption rates in INS1 cells and mouse islets. Moreover, we found that PLIN2 deficient INS1 cells increased the distribution of a fluorescent oleic acid analog to mitochondria and showed signs of mitochondrial stress as indicated by susceptibility to fragmentation and alterations of acyl-carnitines and glucose metabolites. Collectively, PLIN2 in {beta} cells have an important role in preserving insulin secretion, {beta} cell metabolism and mitochondrial function under nutritional stress.

molecular biology↗

bioRxiv2020

HIV cell-to-cell spread slows evolution of drug resistance

Many enveloped viruses such as HIV have evolved to transmit by two infection modes: cell-free infection and cell-to-cell spread. Cell-to-cell spread is highly efficient as it involves directed viral transmission from the infected to the uninfected cell. In contrast, cell-free infection relies on chance encounters between the virion and cell. Despite the higher efficiency of cell-to-cell spread, there is substantial transmission by cell-free infection in conjunction with cell-to-cell spread. A possible reason is that cell-free infection offers a selective advantage by increasing sensitivity to factors interfering with infection, hence accelerating evolution of resistance relative to cell-to-cell spread alone. Here we investigated whether a combination of cell-free infection and cell-to-cell spread confers a selective advantage in experimental evolution to an antiretroviral drug. We maintained HIV infection using coculture of infected with uninfected cells in the face of moderate inhibition by the reverse transcriptase inhibitor efavirenz. We tested the effect on the rate of drug resistance evolution of replacing one coculture infection cycle with an infection cycle involving cell-free infection only, and observed earlier evolution of drug resistance mutations to efavirenz. When we increased selective pressure by adding a second reverse transcriptase inhibitor, emtricitabine, infection with the cell-free step consistently evolved multidrug resistance to both drugs and was able to replicate. In contrast, infection without a cell-free step mostly failed to evolve multidrug resistance. Therefore, HIV cell-to-cell spread decreases the ability of HIV to rapidly evolve resistance to inhibitors, which is conferred by cell-free infection. Author summaryCell-to-cell spread of HIV differs from cell-free, diffusion-based HIV infection in that viral transmission is directed from the infected to the uninfected cell through cellular interactions. Cell-to-cell spread has been recognized as a highly efficient infection mode that is able to surmount inhibition by antibodies and antiretroviral drugs. However, the effect of HIV cell-to-cell spread on the rate of evolution of viral resistance to infection inhibitors has not been studied. Here we used experimental evolution to investigate the effect of cell-to-cell spread versus cell-free infection on the emergence of drug resistance mutations to one or a combination of antiretroviral drugs. We found that replacing one infection cycle in experimental evolution with cell-free infection, where the filtered supernatant from infected cells, but not the cellular fraction, is used as the viral source, results in more rapid evolution of resistance. The consequences are that multidrug resistance consistently evolves with a cell-free viral cycle, but not when infection is solely by coculture of infected and uninfected cells. A possible consequence is that in environments where HIV cell-to-cell spread may predominate and some residual viral replication occurs in the face of ART, the emergence of drug resistance mutations would be delayed.

evolutionary biology↗

bioRxiv2020

Altered Thalamocortical Connectivity in Six-Week Old Infants at High Familial Risk for Autism Spectrum Disorder

Converging evidence from neuroimaging studies has revealed altered connectivity in cortical-subcortical networks in youth and adults with autism spectrum disorder (ASD). Comparatively little is known about the development of cortical-subcortical connectivity in infancy, before the emergence of overt ASD symptomatology. Here we examined early functional and structural connectivity of thalamocortical networks in infants at high familial risk for ASD (HR) and lowrisk controls (LR). Resting-state functional connectivity (rs-fcMRI) and diffusion tensor imaging (DTI) data were acquired 52 six-week-old infants. Functional connectivity was examined between six cortical seeds -prefrontal, motor, somatosensory, temporal, parietal, and occipital regions- and bilateral thalamus. We found significant thalamic-prefrontal underconnectivity, as well as thalamic-occipital and thalamic-motor overconnectivity in HR infants, relative to LR infants. Subsequent structural connectivity analyses also revealed atypical white matter integrity in thalamic-occipital tracts in HR infants, compared to LR infants. Notably, aberrant rs-fcMRI and DTI connectivity indices at 6 weeks predicted atypical social development between 6 and 36 months of age, as assessed with eye-tracking and diagnostic measures. These findings indicate that thalamocortical connectivity is disrupted at both the functional and structural level in HR infants as early as six weeks of age, providing a possible early marker of risk for ASD.

neuroscience↗

bioRxiv2020

Complementation can maintain a quasispecies of drug sensitive and resistant HIV

HIV exists as multiple genotypes in a single infected individual referred to as a quasispecies. Here we reproduced a quasispecies by moderate selective pressure using an HIV reverse transcriptase inhibitor. The drug resistant genotype never completely supplanted the drug sensitive genotype, which stabilized at about 20 percent of viral sequences. Single-cell sequencing showed that resistant genotype frequency plateaued when cells were co-infected with sensitive and resistant genotypes, suggesting a sharing of viral proteins in co-infected cells (complementation) which masks genotypic differences. To test if complementation can confer phenotypic drug resistance, we co-transfected fluorescently labelled molecular clones of sensitive and resistant HIV and observed that genotypically sensitive virus from co-transfected cells was drug resistant. Resistant virus preferentially infected cells in tandem with drug sensitive HIV, explaining how co-infections of sensitive and resistant genotypes were initiated. Modelling this effect, we observed that a stable quasispecies could form at the experimental multiplicities of infection for the drug resistant and drug sensitive virus, showing that complementation can lead to a quasispecies in an HIV evolution experiment.

evolutionary biology↗

bioRxiv2020

Simulation of the Gαq /Phospholipase Cβ1 Signaling Pathway Returns Differentiated PC12 Cells to a Stem-like State

Phospholipase C{beta}1 is activated by Gq to generate calcium signals in response to hormones and neurotransmitters, and is found at high levels in mammalian neuronal tissue. Besides carrying out this key plasma membrane function, PLC{beta}1 has a cytosolic population that helps, in part, to drive the differentiation of PC12 cells by inhibiting a nuclease that promotes RNA-induced silencing (C3PO). Here, we show that down-regulating PLC{beta}1 or reducing its cytosolic population by activating Gq to drive it to the plasma membrane, returns differentiated PC12 cells to an undifferentiated state. In this state, the cells return to a spherical morphology, resume proliferation and express the stem cell transcription factors nanog and Oct4. Similar changes are seen with C3PO down-regulation. This return to a stem-like state is accompanied by shifts in multiple miR populations, such as increased levels of rno-miR-21 and rno-miR-26a. Surprisingly, we find that de-differentiation can also be induced by extended stimulation of the Gq. In this case, the neurites completely retract over a 10-minute period, and while levels of nanog remain unchanged, the levels of some miRs begin to return to their undifferentiated values. In complementary studies, we followed the real time hydrolysis of a fluorescent-tagged miR in cells where PLC{beta}1 or C3PO were down-regulated. These samples showed substantial differences in miR processing in cells both the undifferentiated and differentiated states. Taken together, our studies suggest that PLC{beta}1, through its ability to regulate C3PO and endogenous miR populations, plays a key role in mediating PC12 cell differentiation.

biochemistry↗

bioRxiv2019

Very rare pathogenic genetic variants detected by SNP-chips are usually false positives: implications for direct-to-consumer genetic testing

ObjectivesTo determine the analytical validity of SNP-chips for genotyping very rare genetic variants. DesignRetrospective study using data from two publicly available resources, the UK Biobank and the Personal Genome Project. SettingResearch biobanks and direct-to-consumer genetic testing in the UK and USA. Participants49,908 individuals recruited to UK Biobank, and 21 individuals who purchased consumer genetic tests and shared their data online via the Personal Genomes Project. Main outcome measuresWe assessed the analytical validity of genotypes from SNP-chips (index test) with sequencing data (reference standard). We evaluated the genotyping accuracy of the SNP-chips and split the results by variant frequency. We went on to select rare pathogenic variants in the BRCA1 and BRCA2 genes as an exemplar for detailed analysis of clinically-actionable variants in UK Biobank, and assessed BRCA-related cancers (breast, ovarian, prostate and pancreatic) in participants using cancer registry data. ResultsSNP-chip genotype accuracy is high overall; sensitivity, specificity and precision are all >99% for 108,574 common variants directly genotyped by the UK Biobank SNP-chips. However, the likelihood of a true positive result reduces dramatically with decreasing variant frequency; for variants with a frequency <0.001% in UK Biobank the precision is very low and only 16% of 4,711 variants from the SNP-chips confirm with sequencing data. Results are similar for SNP-chip data from the Personal Genomes Project, and 20/21 individuals have at least one rare pathogenic variant that has been incorrectly genotyped. For pathogenic variants in the BRCA1 and BRCA2 genes, the overall performance metrics of the SNP-chips in UK Biobank are sensitivity 34.6%, specificity 98.3% and precision 4.2%. Rates of BRCA-related cancers in individuals in UK Biobank with a positive SNP-chip result are similar to age-matched controls (OR 1.28, P=0.07, 95% CI: 0.98 to 1.67), while sequence-positive individuals have a significantly increased risk (OR 3.73, P=3.5x10-12, 95% CI: 2.57 to 5.40). ConclusionSNP-chips are extremely unreliable for genotyping very rare pathogenic variants and should not be used to guide health decisions without validation. SUMMARY BOXO_ST_ABSSection 1: What is already known on this topicC_ST_ABSSNP-chips are an accurate and affordable method for genotyping common genetic variants across the genome. They are often used by direct-to-consumer (DTC) genetic testing companies and research studies, but there several case reports suggesting they perform poorly for genotyping rare genetic variants when compared with sequencing. Section 2: What this study addsOur study confirms that SNP-chips are highly inaccurate for genotyping rare, clinically-actionable variants. Using large-scale SNP-chip and sequencing data from UK Biobank, we show that SNP-chips have a very low precision of <16% for detecting very rare variants (i.e. the majority of variants with population frequency of <0.001% are false positives). We observed a similar performance in a small sample of raw SNP-chip data from DTC genetic tests. Very rare variants assayed using SNP-chips should not be used to guide health decisions without validation.

genetics↗

bioRxiv2019

Hemozoin produced by mammals confers heme tolerance

Free heme is cytotoxic as exemplified by hemolytic diseases and genetic deficiencies in heme recycling and detoxifying pathways. Thus, intracellular accumulation of heme has not been observed in mammalian cells to date. Here we show that mice deficient for the heme transporter HRG1 accumulate over ten-fold excess heme in reticuloendothelial macrophage lysosomes that are 10 to 100 times larger than normal. Macrophages tolerate these high concentrations of heme by polymerizing them into crystalline hemozoin, which heretofore has only been found in blood-feeding parasites. HRG1 deficiency results in impaired erythroid maturation and an inability to systemically respond to iron deficiency. Complete heme tolerance requires a fully-operational heme degradation pathway as haploinsufficiency of HMOX1 combined with HRG1 inactivation causes perinatal lethality demonstrating synthetic lethal interactions between heme transport and degradation. Our studies establish the formation of hemozoin by mammals as a previously unsuspected heme tolerance pathway.

pathology↗