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Results for “genetics”

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bioRxiv2022

Variation in anthelmintic responses are driven by genetic differences among diverse C. elegans strains

Treatment of parasitic nematode infections in humans and livestock relies on a small arsenal of anthelmintic drugs that have historically reduced parasite burdens. However, anthelmintic resistance (AR) is increasing, and little is known about the molecular and genetic causes of resistance for most drugs. The free-living roundworm Caenorhabditis elegans has proven to be a tractable model to understand AR, where studies have led to the identification of molecular targets of all major anthelmintic drug classes. Here, we used genetically diverse C. elegans strains to perform dose-response analyses across 26 anthelmintic drugs that represent the three major anthelmintic drug classes (benzimidazoles, macrocyclic lactones, and nicotinic acetylcholine receptor agonists) in addition to seven other anthelmintic classes. First, we found that C. elegans strains displayed significant variation in anthelmintic responses across drug classes. Dose-response trends within a drug class showed that the C. elegans strains elicited similar responses within the benzimidazoles but variable responses in the macrocyclic lactones and nicotinic acetylcholine receptor agonists. Next, we compared the effective concentration estimates to induce a 10% maximal response (EC10) and slope estimates of each dose-response curve of each strain to the reference strain, N2, which enabled the identification of anthelmintics with population-wide differences to understand how genetics contribute to AR. Because genetically diverse strains displayed differential susceptibilities within and across anthelmintics, we show that C. elegans is a useful model for screening potential nematicides. Third, we quantified the heritability of responses to each anthelmintic and observed a significant correlation between exposure closest to the EC10 and the exposure that exhibited the most heritable responses. Heritable genetic variation can be explained by strain-specific anthelmintic responses within and across drug classes. These results suggest drugs to prioritize in genome-wide association studies, which will enable the identification of AR genes. AUTHOR SUMMARYParasitic nematodes infect most animal species and significantly impact human and animal health. Control of parasitic nematodes in host species relies on a limited collection of anthelmintic drugs. However, anthelmintic resistance is widespread, which threatens our ability to control parasitic nematode populations. Here, we used the non-parasitic roundworm Caenorhabditis elegans as a model to study anthelmintic resistance across 26 anthelmintics that span ten drug classes. We leveraged the genetic diversity of C. elegans to quantify anthelmintic responses across a range of doses, estimate dose-response curves, fit strain-specific model parameters, and calculate the contributions of genetics to these parameters. We found that genetic variation within a species plays a considerable role in anthelmintic responses within and across drug classes. Our results emphasize how the incorporation of genetically diverse C. elegans strains is necessary to understand anthelmintic response variation found in natural populations. These results highlight drugs to prioritize in future mapping studies to identify genes involved in anthelmintic resistance. GRAPHICAL ABSTRACT O_FIG O_LINKSMALLFIG WIDTH=125 HEIGHT=200 SRC="FIGDIR/small/518036v1_ufig1.gif" ALT="Figure 1"> View larger version (31K): org.highwire.dtl.DTLVardef@6222bborg.highwire.dtl.DTLVardef@d635a6org.highwire.dtl.DTLVardef@15c3935org.highwire.dtl.DTLVardef@1afe3fe_HPS_FORMAT_FIGEXP M_FIG C_FIG

genetics↗

bioRxiv2023

Genome-wide association study of occupational status and prestige identifies 106 genetic variants and defines their role for intergenerational status transmission and the life course

Socioeconomic status (SES) impacts health and the life course. This GWAS on sociologically informed occupational status measures (ISEI, SIOPS, and CAMSIS) using the UKBiobank (N=273,157) identified 106 genetic variants of which 8 are novel to the study of SES. Genetic correlation analyses point to a common genetic factor for SES. Within-family prediction and its reduction was attributable in equal parts to genetic nurture and assortative mating. Using polygenic scores from population predictions of 5-8%, we, firstly, showed that cognitive and non-cognitive traits - including scholastic and occupational motivation and aspiration - link genetic scores to occupational status. Second, 62% of the intergenerational transmission of occupational status can be ascribed to non-genetic inheritance (e.g., family environment). Third, the link between genetics, occupation, and health are interrelated with parental occupational status confounding the genetic prediction of general health. Finally, across careers, genetic prediction compresses during mid-career with divergence in status at later stages.

genetics↗

bioRxiv2023

A data-driven approach for enhancing forest productivity by accounting for indirect genetic effects

Maintaining the past decades current genetic gains for tree species is a challenging task for foresters and tree breeders due to biotic and abiotic factors. Planting a mixture of genotypes or clonal composites can be an alternative to increase the phytosanitary security and yield of forest plantations. These clonal composites are more complex than monocultures due to inter-genotypic competition and indirect genetic effects that can affect the total heritable variation. This study aims to understand how indirect genetic effects can impact the response to selection and how the stand composition can be used to explore these effects and enhance forest yield. We used a clonally trial of Eucalyptus urophylla x Eucalyptus grandis hybrids in a randomized complete block design with 24 replications, containing a single tree per plot evaluated for mean annual increment at 3 and 6 years. We focus on partitioning the genetic variation of trees into direct and indirect genetic effects based on competition intensity factors. We identified clones as aggressive, homeostatic, and sensitive based on the magnitude of indirect genetic effects. By accounting for indirect genetic effects, for mean annual increment, the total heritability decreased 39 and 44% for 3 and 6 years, respectively. We proposed a workflow that uses the direct and indirect genetic effect to predict the mean value of clonal composite combinations and to select the one with highest yield. Our methodology accounted for spatial variability and interplot competition that can contribute to the total heritable variance and response to selection in forest trials. Based on the models evaluated, the clones are easily classified according to their deviation from the indirect genetic effects mean. Also, we extract useful information to predict different clonal composites compositions, their expected average performance, and define the best recommended combination to be planted in large scale.

genetics↗

bioRxiv2023

CRISPRi-TnSeq: A genome-wide high-throughput tool for bacterial essential-nonessential genetic interaction mapping

Genetic interaction networks can help identify functional connections between genes and pathways, which can be leveraged to establish (new) gene function, drug targets, and fill pathway gaps. Since there is no optimal tool that can map genetic interactions across many different bacterial strains and species, we develop CRISPRi-TnSeq, a genome-wide tool that maps genetic interactions between essential genes and nonessential genes through the knockdown of a targeted essential gene (CRISPRi) and the simultaneous knockout of individual nonessential genes (Tn-Seq). CRISPRi-TnSeq thereby identifies, on a genome-wide scale, synthetic and suppressor-type relationships between essential and nonessential genes, enabling the construction of essential-nonessential genetic interaction networks. To develop and optimize CRISPRi-TnSeq, CRISPRi strains were obtained for 13 essential genes in Streptococcus pneumoniae, involved in different biological processes including metabolism, DNA replication, transcription, cell division and cell envelope synthesis. Transposon-mutant libraries were constructed in each strain enabling screening of [~]24,000 gene-gene pairs, which led to the identification of 1,334 genetic interactions, including 754 negative and 580 positive genetic interactions. Through extensive network analyses and validation experiments we identify a set of 17 pleiotropic genes, of which a subset tentatively functions as genetic capacitors, dampening phenotypic outcomes and protecting against perturbations. Furthermore, we focus on the relationships between cell wall synthesis, integrity and cell division and highlight: 1) how essential gene knockdown can be compensated by rerouting flux through nonessential genes in a pathway; 2) the existence of a delicate balance between Z-ring formation and localization, and septal and peripheral peptidoglycan (PG) synthesis to successfully accomplish cell division; 3) the control of c-di-AMP over intracellular K+ and turgor, and thereby modulation of the cell wall synthesis machinery; 4) the dynamic nature of cell wall protein CozEb and its effect on PG synthesis, cell shape morphology and envelope integrity; 5) functional dependency between chromosome decatenation and segregation, and the critical link with cell division, and cell wall synthesis. Overall, we show that CRISPRi-TnSeq uncovers genetic interactions between closely functionally linked genes and pathways, as well as disparate genes and pathways, highlighting pathway dependencies and valuable leads for gene function. Importantly, since both CRISPRi and Tn-Seq are widely used tools, CRISPRi-TnSeq should be relatively easy to implement to construct genetic interaction networks across many different microbial strains and species.

genetics↗

bioRxiv2024

A genetic perspective on the recent demographic history of Ireland and Britain

BackgroundWhile subtle yet discrete clusters of genetic identity across Ireland and Britain have been identified, their demographic history is unclear. MethodsUsing genotype data from 6,574 individuals with associated regional Irish or British ancestry, we identified Irish-like and British-like genetic communities using network community detection. We segregated Identity-by-Descent (IBD) and Runs-of-Homozygosity (ROH) segments by length and approximated their corresponding time periods. Through this, we inferred the regional Irish and British demographic histories in these time periods by (1) estimating genetic relatedness between communities, (2) estimating changes in effective population sizes, (3) inferring recent migration rates across Ireland and Britain, and (4) estimating changing affinities to regional European populations. For a subset of the Irish communities, we determined the enrichment/depletion of surnames within the genetic communities. ResultsThrough patterns of IBD-sharing and ROH, we find evidence of recent population bottlenecks in the Orcadian, Manx and Welsh communities. While the structure in Ireland is subtler, the communities share relatively more IBD segments that are shorter in length, and the genetic differences between the Irish communities are more subtle on average, when compared to the British communities. Regional effective population size trajectories indicate a similar demographic history throughout the island of Ireland. Further, we observe a stable migration corridor between north-east Ireland and south-west Scotland while there is a recent migration barrier between South-Eastern Ireland and Western Ireland. We observed an enrichment of Anglo-Norman and English surnames in the Wexford community while within the West Ulster-Argyll community, we saw an enrichment of Gallowglass and Scottish surnames. ConclusionsUsing well-annotated Irish and British reference genotypes, we observed temporal changes in genetic affinities within and between genetic communities in Ireland and Britain. In addition, using effective population size estimates and levels of haplotype-sharing, we detected varying degrees of genetic isolation in some Irish and British genetic communities across time. Using these new insights into the regional demographic history of Ireland and Britain across different time periods, we hope to understand the driving forces of rare allele frequencies and disease risk association within these populations.

genetics↗

bioRxiv2024

Optimizing the use of cryopreserved genetic resources for the selection and conservation of animal populations

AO_SCPLOWBSTRACTC_SCPLOWO_ST_ABSBackgroundC_ST_ABSGenetic diversity is essential for the sustainability and adaptability of populations, and is thus a central pillar of the agro-ecological transition. However, within a population it is inevitable that some amount of genetic variability is lost, and efforts must be made to limit this as much as possible. A valuable tool in this endeavor could be the use of cryopreserved genetic resources in cryobanks, which could assist in the management of various animal populations in the contexts of both selection and conservation. ResultsWe performed simulations that revealed that the most appropriate use of ex situ genetic resources differs radically depending on characteristics of the target population and its management objectives. With populations under conservation, the aim is the management of genetic diversity, which was optimized by the regular use of cryopreserved genetic resources at each generation. For populations under selection, instead, the concern is the addition of additive genetic variability, which benefited from the use of cryopreserved collections over only a few generations based primarily on the genetic values of donors. In both cases, the use of cryopreserved individuals in animal populations requires a large amount of material: for breeds under selection because the number of offspring is high, and for breeds under conservation because the frozen semen is used repeatedly over a long period. ConclusionsThe use of cryopreserved material appears to be an effective means of managing the genetic variability of an animal population, either by slowing down the erosion of variability or by helping to redirect a selection objective. However, care must be taken with populations under selection to limit the disadvantages associated with the reintroduction of old genetic material, in particular the gap in breeding values for traits of interest. Finally, our study highlights the need for a sufficiently large stock of cryopreserved material in collections (e.g., number of doses, straws) to ensure the most efficient use.

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bioRxiv2025

A multipurpose microhaplotype panel for genetic analysis of California Chinook salmon

Genetic methods have become an essential component of ecological investigation and conservation planning for fish and wildlife. Among these methods is the use of genetic marker data to identify individuals to populations, or stocks, of origin. More recently, methods that involve genetic pedigree reconstruction to identify relationships between individuals within populations have also become common. We present, here, a novel set of multi-allelic microhaplotype genetic markers for Chinook salmon which provide unprecedented resolution for population discrimination and relationship identification from a rapidly and economically assayed panel of markers. We show how this set of microhaplotypes provides definitive power to identify all known lineages of Chinook salmon in California. The inclusion of genetic loci that have known associations with phenotype and that were identified as outliers in examination of whole genome sequence data, allows resolution of stocks that are not highly genetically differentiated but are phenotypically distinct and managed as such. This same set of multiallelic genetic markers have ample variation to accurately identify parent-offspring and full-sibling pairs in all California populations, including the genetically depauperate winter-run lineage. Validation of this marker panel in coastal salmon populations not previously studied with modern genetic methods, also reveals novel biological insights, including the presence of a single copy of a haplotype for a phenotype that has not been documented in that part of the species range, and a clear signal of mixed ancestry for a salmon population that is on the geographic margins of the primary evolutionary lineages present in California.

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bioRxiv2025

Genetic Correlates of Host Use in Scotland's Pearl Mussels

The freshwater pearl mussel (Margaritifera margaritifera) is an ecologically important and highly endangered bivalve native to running freshwaters across Europe and eastern North America. Its life cycle includes an obligate parasite stage in which newly emerged larvae attach to the gills of juvenile salmonid fishes. In northern Europe, populations specialize on one of two hosts: Atlantic salmon (Salmo salar) or brown trout (S. trutta). Previous microsatellite studies of pearl mussels in the Nordic region have shown an association between host specialization and population genetic characteristics. Scotland is considered a remaining stronghold for freshwater pearl mussel, however current knowledge of genetic characteristics and host association of Scottish M. margaritifera populations is limited. We combined minimally-invasive viscera swabbing with reduced-representation sequencing (nextRAD) to examine genetic diversity of pearl mussels at 5,486 genome-wide SNP markers across 18 populations in Scotland. Our results revealed a substantial variation among populations in genetic diversity and interpopulation differentiation which was strongly related to known host. Populations known to specialize on Atlantic salmon exhibited high genetic diversity (mean He = 0.24) and low inter-population differentiation (Fst = 0.026), even between rivers draining to opposite coasts. In contrast, populations known to specialize on brown trout or occurring where only trout are available consistently showed lower genetic diversity (mean He = 0.15 /0.14) and much higher inter-population differentiation (Fst = 0.160 /0.271), with many populations being highly genetically distinct even when geographically proximate. Principal component analysis and neighbor-joining trees confirmed this pattern, with salmon-specialist populations clustering together while trout-associated populations formed discrete, population-specific clusters. These findings mirror previously observed patterns in other parts of the M. margaritifera range and indicate that population sizes and migratory behavior of hosts may drive contrasting evolutionary trajectories in pearl mussel populations. The striking genetic differences between salmon- and trout-specialist populations have important implications for conservation planning, as they indicate differential capacity for local adaptation and vulnerability to reduced population sizes. Our results suggest that population genetic characteristics could be used to predict host associations for unstudied populations, providing a valuable tool for conservation management. The study emphasizes the importance of considering both direct impacts on pearl mussel populations and the status of their salmonid hosts when developing conservation strategies for this rapidly declining species.

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bioRxiv2025

Population genetic assessment of marine megafauna using seawater environmental DNA: a case study of whale sharks from the Ningaloo Coast World Heritage Area.

There is a growing need for scalable and cost-effective genetic monitoring tools to support the management of species and populations of conservation importance, driven by the increasing biodiversity loss, need for long-term population data and limitations of invasive genetic sampling. Whale sharks (Rhincodon typus), along with other Endangered, elusive and highly migratory species, spend the majority of their lives in offshore ocean waters. This behaviour poses logistical and ethical challenges to invasive genetic sampling of the species, which is traditionally done via tissue biopsy. Here, we develop a genetic toolkit to study populations of whale sharks from seawater environmental DNA using short segments of nuclear DNA (100-300bp) containing two or more SNPs called "microhaplotypes". Amplifying these markers from seawater collected in 1L bottles behind sharks showed that we can reliably genotype sharks from water samples taken immediately behind the animal. Moreover, we observed a strong relationship between population-level allele frequencies and estimates of genetic diversity between eDNA and tissue-derived samples, demonstrating the capability of eDNA in capturing population-level genetic information with high fidelity. We also analysed a tissue dataset of 72 sharks that attended the Ningaloo Coast World Heritage Area over six-years to showcase the utility of our SNP panel to study temporal processes in these populations. Our data revealed patterns of genetic variation through time that were consistent with whole genome techniques. Contributor estimation from mock environmental samples using various combinations of tissue-derived sequence data to estimate abundance of animals in a mixed DNA sample was shown to accurately identify the number of contributors in mixtures containing [≤] 10 individuals, beyond which biases were too large. Our findings illustrate the viability of using microhaplotype markers from seawater eDNA as a tool to study conservation genetics of whale sharks, with the potential for broader expansion of eDNA-based genetic assessments to other marine megafauna and aquatic species.

genetics↗

bioRxiv2025

Urbanization drives genetic erosion and population structure in a historically connected carnivore population

Urbanization is a dominant driver of habitat fragmentation globally, creating small, isolated wildlife populations vulnerable to accelerated genetic drift, reduced genetic diversity, and increased population differentiation. We investigated how urban development affects the genetic composition and structure of caracals (Caracal caracal) in Cape Town, South Africa using microsatellites and mitochondrial DNA sequence data. Sampling across four geographically disparate urban and rural populations revealed contrasting temporal patterns: mitochondrial markers indicated historical genetic connectivity among populations, while microsatellite data demonstrated recent genetic structuring driven primarily by urbanization. An extensively isolated urban population showed reduced allelic richness and pronounced genetic differentiation, reflecting urbanization as a strong barrier to gene flow. Within the isolated urban population, GPS-collared caracals demonstrated a degree of spatial genetic organization, with related individuals maintaining significantly higher home range overlap despite inhabiting a severely fragmented urban landscape. This kin-structured space use occurred despite caracals in the system having large home ranges compressed within a relatively small, isolated environment. Our findings reveal that urbanization has rapidly disrupted gene flow in this otherwise geographically widespread and adaptable carnivore, imposing a sufficient barrier to generate detectable genetic consequences within contemporary timeframes. The contrasting signals from historical versus contemporary molecular markers highlight urbanizations role in fragmenting previously connected populations and demonstrates the value of multi-marker approaches for detecting anthropogenic impacts on wildlife populations. These results underscore urbanizations capacity to rapidly alter population genetic dynamics, even in a highly mobile and adaptable carnivore.

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bioRxiv2025

Host genetics and diet jointly shape the microbiome of Drosophila melanogaster but do not predict lifespan or age-related traits

The microbiome is a key determinant of organismal health, yet inter-individual variability and heterogeneous responses to environmental conditions complicates the understanding of its effects on hosts. Here, we present a comprehensive analysis using the Drosophila Genetic Reference Panel (DGRP) to investigate how the interplay between host genetic variation and diet influences microbiome composition, and to assess whether microbiome features in young flies can be used to predict lifespan and age-related traits. Our findings show that adult flies reared on a nutritionally rich control diet exhibited higher microbial richness but lower evenness compared to those on a nutritionally poor restricted diet. Principal component analysis (PCA) highlighted substantial diversity among lines reared on the same diet, and this variation was heritable supported by high heritability estimates for all measured -diversity metrics, including Unique OTU counts, Shannon and Simpson indices, as well as the relative abundances of genera and species with relative abundances exceeding 1%. These results underscore the critical roles of both environmental factors and genetic variation in shaping microbiome composition under different dietary conditions. Moreover, we identified widespread genotype-by-diet interactions, suggesting that the genetic regulation of the microbiome is highly complex. Finally, we found that the microbiome features of young flies including diversity indices, taxonomic abundances, or ordination scores cannot predict age-associated phenotypes (lifespan, locomotor activity, dry weight, and heat knockdown time). Our findings offer valuable insights into the genetic architecture that governs microbiome composition, dietary responses, and aging in Drosophila melanogaster. Author SummaryThe community of microbes living on or inside animals - the microbiome - plays an important role in health and aging, but its composition varies greatly between individuals and across environments, making it challenging to fully understand its importance. In this study, we examined how host genetics and diet shape the microbiome of the fruit fly, Drosophila melanogaster, using a large panel of genetically diverse lines. We found that the microbiome of flies on a restricted nutritionally poor diet were relatively evenly distributed, while the microbiome of flies on a nutritionally rich diet had a higher species diversity. Many features of the microbiome were strongly influenced by the flies genes, and these genetic effects often depended on diet. Finally, we tested whether microbiome features obtained from young flies could predict age-related traits such as lifespan and activity at similar aged flies or later in life, but found no evidence for such links. These results highlight how genetic variation and diet interact to shape the microbiome and its role in aging.

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bioRxiv2025

Diversity and genetic structure within a Mexican maize race reveal consistent biocultural processes across geographic scales.

Understanding how genetic diversity is distributed within maize races is critical for conserving maize genetic diversity. While maize races are traditionally treated as homogeneous units to be targeted by conservation, each race may encompass genetically distinct populations of landraces, shaped by environmental conditions and farmer selection. In this study, the genetic diversity and population structure of the Olotillo race were examined using 89,810 SNPs from 158 samples collected across local, regional, and national scales in Mexico. Additional samples from other races Dzit-bacal, Tuxpeno, and a Mix, group combining Olotillo with other varieties, brought the total to 171 individuals. Population structure analyses (ADMIXTURE, PCA) revealed that genetic clusters do not align with race identity, but instead reflect geographic origin. Inbreeding depression was evident within Olotillo populations, with mean FIS = 0.746 {+/-} 0.066. A heterozygote deficiency was observed: mean HeOB = 0.075 {+/-} 0.020, compared to a higher expected heterozygosity (HeEX = 0.295 {+/-} 0.002). Expected homozygosity (HOEX) of 0.705{+/-} 0.002 was observed, reflecting reduced effective genetic variation. The above is reflected in the population contraction signal (e.g., positive Tajimas D), and no significant differences between scales in HeEX, HOEX, and nucleotide diversity ({pi}), suggesting that similar evolutionary forces act across regions with a strong directional selection. These findings underscore the need to ascertain the genetic background among races and to recognize meaningful within-race differentiation. Conservation actions should reflect this structure, promoting targeted seed exchange to counteract genetic erosion while respecting farmer preferences. Olotillo exemplifies how maize diversity is structured not only by genetics, but by cultural and management systems that shape evolution in situ.

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bioRxiv2018

Required marker properties for unbiased estimates of the genetic correlation between populations

Populations generally differ in environmental and genetic factors, which can create differences in allele substitution effects between populations. Therefore, a single genotype may have different additive genetic values in different populations. The correlation between the two additive genetic values of a single genotype in both populations is known as the additive genetic correlation between populations and can differ from one. Our objective was to investigate whether differences in linkage disequilibrium (LD) and allele frequencies of markers and causal loci between populations affect bias of the estimated genetic correlation. We simulated two populations that were separated for 50 generations. Markers and causal loci were selected to either have similar or different allele frequencies in the two populations. Differences in consistency of LD between populations were obtained by using different marker density panels. Results showed that when the difference in allele frequencies of causal loci between populations was reflected by the markers, genetic correlations were only slightly underestimated using markers. This was even the case when LD patterns, measured by LD statistic r, were different between populations. When the difference in allele frequencies of causal loci between populations was not reflected by the markers, genetic correlations were severely underestimated. We conclude that for an unbiased estimate of the genetic correlation between populations, marker allele frequencies should reflect allele frequencies of causal loci so that marker-based relationships can accurately predict the relationships at causal loci, i.e. E(Gcausal loci|Gmarkers) = Gmarkers. Differences in LD between populations have little effect on the estimated genetic correlation.

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bioRxiv2018

Maternal and fetal genetic effects on birth weight and their relevance to cardio-metabolic risk factors

Birth weight (BW) variation is influenced by fetal and maternal genetic and non-genetic factors, and has been reproducibly associated with future cardio-metabolic health outcomes. These associations have been proposed to reflect the lifelong consequences of an adverse intrauterine environment. In earlier work, we demonstrated that much of the negative correlation between BW and adult cardio-metabolic traits could instead be attributable to shared genetic effects. However, that work and other previous studies did not systematically distinguish the direct effects of an individuals own genotype on BW and subsequent disease risk from indirect effects of their mothers correlated genotype, mediated by the intrauterine environment. Here, we describe expanded genome-wide association analyses of own BW (n=321,223) and offspring BW (n=230,069 mothers), which identified 278 independent association signals influencing BW (214 novel). We used structural equation modelling to decompose the contributions of direct fetal and indirect maternal genetic influences on BW, implicating fetal- and maternal-specific mechanisms. We used Mendelian randomization to explore the causal relationships between factors influencing BW through fetal or maternal routes, for example, glycemic traits and blood pressure. Direct fetal genotype effects dominate the shared genetic contribution to the association between lower BW and higher type 2 diabetes risk, whereas the relationship between lower BW and higher later blood pressure (BP) is driven by a combination of indirect maternal and direct fetal genetic effects: indirect effects of maternal BP-raising genotypes act to reduce offspring BW, but only direct fetal genotype effects (once inherited) increase the offsprings later BP. Instrumental variable analysis using maternal BW-lowering genotypes to proxy for an adverse intrauterine environment provided no evidence that it causally raises offspring BP. In successfully separating fetal from maternal genetic effects, this work represents an important advance in genetic studies of perinatal outcomes, and shows that the association between lower BW and higher adult BP is attributable to genetic effects, and not to intrauterine programming.

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bioRxiv2018

Six percent loss of genetic variation in wild populations since the industrial revolution

Genetic variation underpins population fitness and adaptive potential1,2. Thus it plays a key role in any species probability of long-term persistence, particularly under global climate change. Genetic variation can be lost in a single generation but its replenishment may take hundreds of generations3. For that reason safeguarding genetic variation is considered fundamental to maintaining biodiversity, and is an Aichi Target for 20204. As human activities are driving declines in many wild populations5, genetic variation is also likely declining. However the magnitude of ongoing genetic variation loss has not been assessed, despite its importance. Here we show a 6% decline in within-population genetic variation of wild organisms since the industrial revolution. The erosion of genetic variation has been most severe for island species, with an 18% average decline. We also identified several key taxonomic and geographic information gaps that must be urgently addressed. Our results are consistent with single time-point meta-analyses that indicated genetic variation is likely declining 6,7. However, our results represent the first confirmation of a global decline, and estimate of the magnitude of the genetic variation lost from wild populations.

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bioRxiv2018

Nationwide population genetic screening improves outcomes of newborn screening for hearing loss in China

PurposeConcurrent newborn hearing and genetic screening has been reported, but its benefits have not been statistically proven due to limited sample sizes and outcome data. To fill this gap, we analyzed outcomes of a large number of newborns with genetic screening results.\n\nMethodsNewborns in China were screened for 20 hearing-loss-related genetic variants from 2012-2017. Genetic results were categorized as positive, at-risk, inconclusive, or negative. Hearing screening results, risk factors, and up-to-date hearing status were followed-up via phone interviews.\n\nResultsWe completed genetic screening on one million newborns and followed up 12,778. We found that a positive genetic result significantly indicated a higher positive predictive value of the initial hearing screening (60% vs. 5.0%, P<0.001) and a lower rate of loss-to-follow-up (5% vs. 22%, P<0.001) than an inconclusive one. Importantly, 42% of subjects in the positive group with reported or presymptomatic hearing loss were \"missed\" by conventional hearing screening. Furthermore, genetic screening identified 0.23% of subjects predisposed to preventable ototoxicity.\n\nConclusionOur results demonstrate that limited genetic screening identified additional cases, reduced loss-to-follow-up, and informed families of ototoxicity risks, providing convincing evidence to support integrating genetic screening into universal newborn hearing screening programs.

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bioRxiv2019

Genetic association study of psychotic experiences in UK Biobank

Psychotic experiences, such as hallucinations and delusions, are reported by approximately 5%-10% of the general population, though only a small proportion of individuals develop psychotic disorders such as schizophrenia or bipolar disorder. Studying the genetic aetiology of psychotic experiences in the general population, and its relationship with the genetic aetiology of other disorders, may increase our understanding of their pathological significance. Using the population-based UK Biobank sample, we performed the largest genetic association study of psychotic experiences in individuals without a psychotic disorder. We conducted three genome-wide association studies (GWAS) for (i) any psychotic experience (6123 cases vs. 121,843 controls), (ii) distressing psychotic experiences (2143 cases vs. 121,843 controls), and (iii) multiple occurrence psychotic experiences (3337 cases vs. 121,843 controls). Analyses of polygenic risk scores (PRS), genetic correlation, and copy number variation (CNV) were conducted to assess whether genetic liability to psychotic experiences is shared with schizophrenia and/or other neuropsychiatric disorders and traits. GWAS analyses identified four loci associated with psychotic experiences including a locus in Ankyrin-3 (ANK3, OR=1.16, p=3.06 x 10-8) with any psychotic experience and a locus in cannabinoid receptor 2 gene (CNR2, OR=0.66, p=3.78x10-8) with distressing psychotic experiences. PRS analyses identified associations between psychotic experiences and genetic liability for schizophrenia, major depressive disorder, and bipolar disorder, and these associations were stronger for distressing psychotic experiences. Genetic correlation analysis identified significant genetic correlations between psychotic experiences and major depressive disorder, schizophrenia, autism spectrum disorder and a cross-disorder GWAS. Individuals reporting psychotic experiences had an increased burden of CNVs previously associated with schizophrenia (OR=2.04, p=2.49x10-4) and of those associated with neurodevelopmental disorders more widely (OR=1.75, p=1.41x10-3). In conclusion, we identified four genome-wide significant loci in the largest GWAS of psychotic experiences from the population-based UK Biobank sample and found support for a shared genetic aetiology between psychotic experiences and schizophrenia, but also major depressive disorder, bipolar disorder and neurodevelopmental disorders.

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bioRxiv2019

The p factor: Genetic analyses support a general dimension of psychopathology in childhood and adolescence

BackgroundDiverse behaviour problems in childhood correlate phenotypically, suggesting a general dimension of psychopathology that has been called the p factor. The shared genetic architecture between childhood psychopathology traits also supports a genetic p. This study systematically investigates the manifestation of this common dimension across self-, parent- and teacher-rated measures in childhood and adolescence.\n\nMethodsThe sample included 7,026 twin pairs from the Twins Early Development Study (TEDS). First, we employed multivariate twin models to estimate common genetic and environmental influences on p based on diverse measures of behaviour problems rated by children, parents and teachers at ages 7, 9, 12 and 16 (depressive symptoms, emotional problems, peer problems, autistic symptoms, hyperactivity, antisocial, conduct and psychopathic symptoms). Second, to assess the stability of genetic and environmental influences on p across time, we conducted longitudinal twin modelling of the first phenotypic principal components of childhood psychopathological measures across each of the four ages. Third, we created a genetic p factor in 7,026 unrelated genotyped individuals based on eight polygenic scores for adult psychiatric disorders to estimate how a general polygenic predisposition to adult psychiatric disorders relates to childhood p.\n\nResultsBehaviour problems were consistently correlated phenotypically and genetically across ages and raters. The p factor is substantially heritable (50-60%), and manifests consistently across diverse ages and raters. Genetic correlations of p components across childhood and adolescence suggest stability over time (49-78%). A polygenic general psychopathology factor, derived from studies of adult psychiatric disorders consistently predicted a general phenotypic p factor across development.\n\nConclusionsDiverse forms of psychopathology consistently load on a common p factor, which is highly heritable. There are substantial genetic influences on the stability of p across childhood. Our analyses indicate genetic overlap between general risk for psychiatric disorders in adulthood and p in childhood, even as young as age 7. The p factor has far-reaching implications for genomic research and, eventually, for diagnosis and treatment of behaviour problems.

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