SEARCH · bioRxiv Science

Results for “Genetics”

Search indexed bioRxiv preprints in genomics, neuroscience, cell biology and bioinformatics. Read source abstracts and check manuscript versions; preprints are not peer reviewed.

Quote a phrase for an exact phrase match. Source license links do not imply unrestricted reuse.

At least 1,639 records · Page 91Linked to original sources

bioRxiv2022

Robust genetic analysis of the X-linked anophthalmic (Ie) mouse

Anophthalmia (missing eye) describes a failure of early embryonic ocular development. Mutations in a relatively small set of genes account for 75% of bilateral anophthalmia cases, yet 25% of families currently are left without a molecular diagnosis. Here we report our experimental work that aimed to uncover the developmental and genetic basis of the anophthalmia characterising the X-linked Ie (eye-ear reduction) X-ray induced allele in mouse that was first identified in 1947. Histological analysis of the embryonic phenotype showed failure of normal eye development after the optic vesicle stage with particularly severe malformation of the ventral retina. Linkage analysis mapped this mutation to a [~] 6Mb region on the X chromosome. Short and long read whole-genome sequencing (WGS) of affected and unaffected male littermates confirmed the Ie linkage but identified no plausible causative variants or structural rearrangements. These analyses did reduce the critical candidate interval and revealed evidence of multiple variants within the ancestral DNA, although none were found that altered coding sequences or that were unique to Ie. To investigate early embryonic events at a genetic level, we then generated mouse ES cells derived from male Ie embryos and wild type littermates. RNA-seq and accessible chromatin sequencing (ATAC-seq) data generated from cultured optic vesicle organoids did not reveal any large differences in gene expression or accessibility of putative cis-regulatory elements between Ie and wild type. However, an unbiased TF-footprinting analysis of accessible chromatin regions did provide evidence of a genome-wide reduction in binding of transcription factors associated with ventral eye development in Ie, and evidence of an increase in binding of the Zic-family of transcription factors, including Zic3, which is located within the Ie-refined critical interval. We conclude that the refined Ie critical region at chrX: 56,145,000-58,385,000 contains multiple genetic variants that may be linked to altered cis regulation but does not contain a convincing causative mutation. Changes in the binding of key transcription factors to chromatin causing altered gene expression during development, possibly through a subtle mis-regulation of Zic3, presents a plausible cause for the anophthalmia phenotype observed in Ie, but further work is required to determine the precise causative allele and its genetic mechanism.

genetics↗

bioRxiv2022

Phenotype integration improves power and preserves specificity in biobank-based genetic studies of MDD

Biobanks often contain several phenotypes relevant to a given disorder, and researchers face complex tradeoffs between shallow phenotypes (high sample size, low specificity and sensitivity) and deep phenotypes (low sample size, high specificity and sensitivity). Here, we study an extreme case: Major Depressive Disorder (MDD) in UK Biobank. Previous studies found that shallow and deep MDD phenotypes have qualitatively distinct genetic architectures, but it remains unclear which are optimal for scientific study or clinical prediction. We propose a new framework to get the best of both worlds by integrating together information across hundreds of MDD-relevant phenotypes. First, we use phenotype imputation to increase sample size for the deepest available MDD phenotype, which dramatically improves GWAS power (increases #loci ~10 fold) and PRS accuracy (increases R2 ~2 fold). Further, we show the genetic architecture of the imputed phenotype remains specific to MDD using genetic correlation, PRS prediction in external clinical cohorts, and a novel PRS-based pleiotropy metric. We also develop a complementary approach to improve specificity of GWAS on shallow MDD phenotypes by adjusting for phenome-wide PCs. Finally, we study phenotype integration at the level of GWAS summary statistics, which can increase GWAS and PRS power but introduces non-MDD-specific signals. Our work provides a simple and scalable recipe to improve genetic studies in large biobanks by combining the sample size of shallow phenotypes with the sensitivity and specificity of deep phenotypes.

genetics↗

bioRxiv2022

Dispensing with unnecessary assumptions in population genetics analysis

Parametric assumptions in population genetics analysis - including linearity, sources of population stratification and additivity of variance as part of a Gaussian noise - are often made, yet their (approximate) validity depends on variant and traits of interest, as well as genetic ancestry and population dependence structure of the sample cohort. We present a unified statistical workflow, called TarGene, for targeted estimation of effect sizes, as well as two-point and higher-order epistatic interactions of genomic variants on polygenic traits, which dispenses with these unnecessary assumptions. Our approach is founded on Targeted Learning, a framework for estimation that integrates mathematical statistics, machine learning and causal inference. TarGene maximises power whilst simultaneously maximising control over false discoveries by: (i) guaranteeing optimal bias-variance trade-off, (ii) taking into account potential covariate non-linearities, sources of population stratification and dependence structure, and (iii) detecting genetic non-linearities. The necessity of this model-independent approach is demonstrated via extensive simulations. We validate the effectiveness of our method by reproducing previously verified effect sizes on UK Biobank data, whilst simultaneously discovering non-linear effect sizes of additional allelic copies on trait or disease, in a PheWAS study involving 781 traits. Specifically, we demonstrate genetic non-linearity at the FTO locus is significant for 54 traits in this study. We further find three pairs of epistatic loci associated with skin color that have been previously reported to be associated with hair color. Finally, we illustrate how TarGene can be used to investigate higher-order interactions using three variants linked to the vitamin D receptor complex. TarGene provides a platform for comparative analyses across biobanks, or integration of multiple biobanks and heterogeneous populations to simultaneously increase power and control for type I errors, whilst taking into account population stratification and complex dependence structures.

genetics↗

bioRxiv2022

Correction for participation bias in the UK Biobank reveals non-negligible impact on genetic associations and downstream analyses

While large-scale volunteer-based studies such as the UK Biobank (UKBB) have become the cornerstone of genetic epidemiology, the study participants are rarely representative of their target population. Here, we aim to evaluate the impact of non-random participation in the UKBB, and to pin down areas of research that are particularly susceptible to biases when using non-representative samples for genome-wide discovery. By comparing 14 harmonized characteristics of the UKBB participants to that of a representative sample, we derived a model for participation probability. We then conducted inverse probability weighted genome-wide association analyses (wGWA) on 19 UKBB traits. Comparing the output obtained from wGWA (Neffective=94,643 - 102,215) to standard GWA analyses (N=263,464 - 283,749), we assessed the impact of participation bias on three estimated quantities, namely 1) genotype-phenotype associations, 2) heritability and genetic correlation estimates and 3) exposure-outcome causal effect estimates obtained from Mendelian Randomization. Participation bias can lead to both overestimation (e.g., cancer, education) and underestimation (e.g., coffee intake, depression/anxiety) of SNP effects. Novel SNPs were identified in wGWA for 12 of the included traits, highlighting SNPs missed as a result of participation bias. While the impact of participation bias on heritability estimates was small (average change in h2: 1.5%, maximum: 5%), substantial distortions were present for genetic correlations (average absolute change in rg: 0.07, maximum: 0.31) and Mendelian Randomization estimates (average absolute change in standardized estimates: 0.04, maximum: 0.15), most markedly for socio-behavioural traits including education, smoking and BMI. Overall, the bias mainly affected the magnitude of effects, rather than direction. In contrast, genome-wide findings for more molecular/physical traits (e.g., LDL, SBP) exhibited less bias as a result of selective participation. Our results highlight that participation bias can distort genomic findings obtained in non-representative samples, and we propose a viable solution to reduce such bias. Moving forward, more efforts ensuring either sample representativeness or correcting for participation bias are paramount, especially when investigating the genetic underpinnings of behaviour, lifestyles and social outcomes.

genetics↗

bioRxiv2022

Cross-disorder genetic analysis of immune diseases reveals distinct disease groups and associated genes that converge on common pathogenic pathways

Genome-wide association studies (GWAS) have mapped thousands of susceptibility loci associated with immune-mediated diseases, many of which are shared across multiple diseases. To assess the extent of the genetic sharing across nine immune-mediated diseases we applied genomic structural equation modelling (genomic SEM) to GWAS data. By modelling the genetic covariance between these diseases, we identified three distinct groups: gastrointestinal tract diseases, rheumatic and systemic diseases, and allergic diseases. We identified 92, 103 and 91 genetic loci that predispose to each of these disease groups, with only 12 of them being shared across groups. Although loci associated with each of these disease groups were highly specific, they converged on perturbing the same pathways, primarily T cell activation and cytokine signalling. Finally, to assess whether variants associated with each disease group modulate gene expression in immune cells, we tested for colocalization between loci and single-cell eQTLs derived from peripheral blood mononuclear cells. We identified the causal route by which 47 loci contribute to predisposition to these three disease groups. In addition, given that the assessed variants are pleiotropic, we found evidence for eight of these genes being strong candidates for drug repurposing. Taken together, our data suggest that different constellations of diseases have distinct patterns of genetic association, but that associated loci converge on perturbing different nodes in a common set of T cell activation and signalling pathways.

genetics↗

bioRxiv2022

A meta-analysis of genome-wide association studies identifies new genetic loci associated with all-cause and vascular dementia

Dementia is multifactorial with Alzheimer (AD) and vascular (VaD) pathologies making the largest contributions. Genome-wide association studies (GWAS) have identified over 70 genetic risk loci for AD but the genomic determinants of other dementias, including VaD remain understudied. We hypothesize that common forms of dementia will share genetic risk factors and conducted the largest GWAS to date of "all-cause dementia" (ACD) and examined the genetic overlap with VaD. Our dataset includes 809,299 individuals from European, African, Asian, and Hispanic ancestries with 46,902 and 8,702 cases of ACD and VaD, respectively. We replicated known AD loci at genome-wide significance for both ACD and VaD and conducted bioinformatic analyses to prioritize genes that are likely functionally relevant, and shared with closely related traits and risk factors. For ACD, novel loci identified were associated with energy transport (SEMA4D), neuronal excitability (ANO3), amyloid deposition in the brain (RBFOX1), and MRI markers of small vessel disease (HBEGF). Novel VaD loci were associated with hypertension, diabetes, and neuron maintenance (SPRY2, FOXA2, AJAP1, and PSMA3). Our study identified genetic risks underlying all-cause dementia, demonstrating overlap with neurodegenerative processes, vascular risk factors (Type-II diabetes, blood pressure, lipid) and cerebral small vessel disease. These novel insights could lead to new prevention and treatment strategies for all dementias.

genetics↗

bioRxiv2022

Detection of adaptation to light environment in myopia-associated loci: Diversity of the myopia genetic background

The time spent outdoors and exposure to bright sunlight have been reported to play important roles in preventing myopia progression. Myopia prevalence is generally low in Europe, and we hypothesized that local adaptation of ancestors in insufficient sunlight regions might underlie this low prevalence in Europeans. To verify this conjecture and understand how ancestry adaptation influenced on the diversity of myopia genetic background, polygenic risk scores (PRS) was calculated and revealed that the genetic risk of myopia increased as latitude decreased in the 1000 genome projects (1KGP) EUR, and we further determined selection signatures near the rhodopsin (RHO) coding region in 1KGP Finnish. The derived allele frequencies of identified loci correlated with sunshine duration worldwide, and the allele age was estimated to be [~]20,000 years, coincidently after the divergence of Europeans and East Asians. TSPAN10 (rs9747347) is significantly associated with both myopia and pigmentation in Europeans, and we found selection favored the myopia risk allele in EUR. Haplotype comparison highlighted the divergence between EAS and EUR in RHO and pigmentation-associated loci, and the frequency diversity in Admixed American (AMR) of these loci was found to originate from recent admixture and local adaptation. We concluded that local adaptation played a role in myopia prevalence deviation, and selective pressure in the myopia-associated loci may originate from adaptation to sunlight environments rather than myopia itself. These findings reveal traces of evolution history of myopias genetic background, providing a new aspect of understanding the patterns and diversity of myopia prevalence. Author SummaryThe explanation for the distinct bias of myopia prevalence among ethnicities remains controversial, we took an evolutionary approach to understanding the history and diversity of the genetic background of myopia. We detected selection signatures of myopia-associated loci near the rhodopsin gene (RHO) in the 1000 Genome Project Europeans. Ambient light exposure is crucial for myopia; RHO is mainly expressed in rod cells and is extremely sensitive to light, indicating that local adaptation might contribute to myopia prevalence bias. Parallel geographical disposition of allele frequencies of myopia-associated loci in RHO and pigmentation-associated markers was observed, implying that selective pressure in myopia-associated loci may originate from adaptation events involved in sunlight exposure rather than myopia itself.

genetics↗

bioRxiv2022

The power of geohistorical boundaries for modeling the genetic background of human populations: the case of the rural Catalan Pyrenees

The genetic variation of the European population at a macro-geographic scale follows genetic gradients which reflect main migration events. However, less is known about factors affecting mating choices at a micro-geographic scale. In this study we have analyzed 726,718 autosomal SNPs in 435 individuals from the Catalan Pyrenees covering around 200 km of a vast and abrupt region in the north of the Iberian Peninsula, for which we have information about the geographic origin of all grand-parents and parents. At a macro-geographic scale, our analyses recapitulate the genetic gradient observed in Spain. However, we also identified the presence of micro-population substructure among the sampled individuals. Such micro-population substructure does not correlate with geographic barriers such as the expected by the orography of the considered region, but by the bishoprics present in the covered geographic area. These results support that, on top of main human migrations, long ongoing socio-cultural factors have also shaped the genetic diversity observed at rural populations.

genetics↗

bioRxiv2022

Leveraging the Genetic Correlation between Traits Improves the Detection of Epistasis in Genome-wide Association Studies

Epistasis, commonly defined as the interaction between genetic loci, is known to play an important role in the phenotypic variation of complex traits. As a result, many statistical methods have been developed to identify genetic variants that are involved in epistasis, and nearly all of these approaches carry out this task by focusing on analyzing one trait at a time. Previous studies have shown that jointly modeling multiple phenotypes can often dramatically increase statistical power for association mapping. In this study, we present the "multivariate MArginal ePIstasis Test" (mvMAPIT) -- a multi-outcome generalization of a recently proposed epistatic detection method which seeks to detect marginal epistasis or the combined pairwise interaction effects between a given variant and all other variants. By searching for marginal epistatic effects, one can identify genetic variants that are involved in epistasis without the need to identify the exact partners with which the variants interact -- thus, potentially alleviating much of the statistical and computational burden associated with conventional explicit search-based methods. Our proposed mvMAPIT builds upon this strategy by taking advantage of correlation structure between traits to improve the identification of variants involved in epistasis. We formulate mvMAPIT as a multivariate linear mixed model and develop a multi-trait variance component estimation algorithm for efficient parameter inference and P-value computation. Together with reasonable model approximations, our proposed approach is scalable to moderately sized GWA studies. With simulations, we illustrate the benefits of mvMAPIT over univariate (or single-trait) epistatic mapping strategies. We also apply mvMAPIT framework to protein sequence data from two broadly neutralizing anti-influenza antibodies and approximately 2,000 heterogenous stock of mice from the Wellcome Trust Centre for Human Genetics. The mvMAPIT R package can be downloaded at https://github.com/lcrawlab/mvMAPIT.

genetics↗

bioRxiv2022

Genetic estimates of the initial peopling of Polynesian islands actually reflect later inter-island contacts

The timing of the initial peopling of the Polynesian islands remains highly debated. Suggested dates are primarily based on archaeological evidence and differ by several hundred years. Ioannidis et al. [2021] used genome-wide data from 430 modern individuals from 21 Pacific islands to obtain genetic estimates. Their results supported late settlement dates, e.g. approximately 1200 CE for Rapa Nui. However, when investigating the underlying model we found that the genetic estimator used by Ioannidis et al. [2021] is biased to be about 300 years too old. Correcting for this bias gives genetic settlement dates that are more recent than any dates consistent with archaeological records, as radiocarbon dating of human-modified artifacts shows settlement definitively earlier than the bias-corrected genetic estimates. These too-recent estimates can only be explained by substantial gene flow between islands after their initial settlements. Therefore, contacts attested by archaeological and linguistic evidence [Kirch, 2021] must have been accompanied also by demographically significant movement of people. This gene flow well after the initial settlements was not modelled by Ioannidis et al. [2021] and challenges their interpretation that carving anthropomorphic stone statues was spread during initial settlements of islands. Instead, the distribution of this cultural practice likely reflects later inter-island exchanges, as suggested earlier [Kirch, 2017].

genetics↗

bioRxiv2022

The association between transcriptional regulation of macrophage differentiation and activation and genetic susceptibility to inflammatory bowel disease

The abundant macrophage population of the intestinal lamina propria turns over rapidly and is replaced by blood monocytes. The differentiation and survival of resident intestinal macrophages depends upon signals from the macrophage colony-stimulating factor receptor (CSF1R). The response of human monocyte-derived macrophages (MDM) grown in macrophage colony-stimulating factor (CSF1) to bacterial lipopolysaccharide (LPS) has been proposed as a model for the differentiation and adaptation of monocytes entering the intestinal lamina propria. We hypothesized that dysregulation of this response leads to susceptibility to chronic inflammatory bowel disease (IBD). To address this hypothesis we analyzed transcriptomic variation in MDM from affected and unaffected sib pairs/trios from 22 IBD families and 6 healthy controls. There was no overall or inter-sib distinction between affected and unaffected individuals in basal gene expression or the stereotypical time course of the response to LPS. However, the basal or LPS-inducible expression of individual genes including inflammatory cytokines and many associated with IBD susceptibility in genome-wide association studies (GWAS) varied by as much as 100-fold between subjects. Extreme independent variation in the expression of pairs of HLA-associated transcripts (HLA-B/C, HLA-A/F and HLA-DRB1/DRB5) was associated with HLA genotype providing a novel explanation for the HLA association with disease susceptibility. The relationship between single nucleotide variant (SNV) genotype and gene expression at other loci was weaker and inconsistent suggesting that much of the variation arises from the integration of multiple trans-acting effects. For example, expression of IL1B at 2 hrs of LPS treatment was significantly associated with local SNV genotype and with peak expression of IL23A at 7 hrs. By contrast, there was no evidence of association between peak IL6 mRNA at 7hrs, IL6-associated SNV genotype or IL1B at 2 hrs. Our results support the view that gene-specific dysregulation in macrophage adaptation to the intestinal milieu provides a plausible explanation for genetic susceptibility to IBD. The analysis also suggests that the molecular basis of susceptibility is unique to each individual which may contribute to variation in the precise environmental trigger, the consequent pathology and response to treatment. Author summaryCells of the innate immune system called macrophages are abundant in the wall of the gut, providing a first line of defense against potential pathogens. These cells must also avoid an inappropriate or excessive response to the abundant microbial population (the microbiome) of the intestine. We have previously proposed that genetic differences between individuals in macrophage adaptation to the unique environment of the intestine underlie genetic susceptibility to inflammatory bowel disease (IBD). In this study we developed a model of the adaptation of macrophages and used that model to identify surprisingly extreme variation in the response amongst a cohort of affected and unaffected siblings in families with IBD. The response did not distinguish affected individuals from their unaffected siblings. Our results support the view that each individual within IBD-susceptible families carries a unique set of genetic variants of large effect that together predispose to uncontrolled gut inflammation in the face of an environmental trigger.

genetics↗

bioRxiv2023

Genetic mapping reveals new loci and alleles for flowering time and plant height using the double round-robin population of barley

Flowering time and plant height are two critical determinants of yield potential in barley (Hordeum vulgare). Although their role as key traits, a comprehensive understanding of the genetic complexity of flowering time and plant height regulation in barley is still lacking. Through a double round-robin population originated from the crossings of 23 diverse parental inbred lines, we aimed to determine the variance components in the regulation of flowering time and plant height in barley as well as identify new genetic variants by single and multi-population quantitative trait loci (QTL) analyses and allele mining. Despite similar genotypic variance, we observed higher environmental variance components for plant height than flowering time. Furthermore, we detected one new QTL for flowering time and two new QTL for plant height. Finally, we identified a new functional allelic variant of the main regulatory gene Ppd-H1. Our results show that the genetic architecture of flowering time and plant height might be more complex than reported earlier and that a number of undetected, small effect or low frequency, genetic variants underlie the control of these two traits.

genetics↗

bioRxiv2023

Genetics of continuous colour variation in a pair of sympatric sulphur butterflies

Continuous colour polymorphisms can serve as a tractable model for the genetic and developmental architecture of traits, but identification of the causative genetic loci is complex due to the number of individuals needed, and the challenges of scoring continuously varying traits. Here we investigated continuous colour variation in Colias eurytheme and C. philodice, two sister species of sulphur butterflies that hybridise in sympatry. Using Quantitative Trait Locus (QTL) analysis of 483 individuals from interspecific crosses and an high-throughput method of colour quantification, we found that two interacting large effect loci explain around 70% of the heritable variation in orange-to-yellow chromaticity. Knockouts of red Malphighian tubules (red), a candidate gene at the primary QTL likely involved in endosomal maturation, resulted in depigmented wing scales showing disorganised pterin granules. The Z sex chromosome contains a large secondary colour QTL that includes the transcription factor bric-a-brac (bab), which we show can act as a modulator of orange pigmentation in addition to its previously-described role in specifying UV-iridescence. We also describe the QTL architecture of other continuously varying traits, and that wing size maps to the Z chromosome, supporting a Large-X effect model where the genetic control of species-defining traits is enriched on sex chromosomes. This study sheds light on the genetic architecture of a continuously varying trait, and illustrates the power of using automated measurement to score phenotypes that are not always conspicuous to the human eye. ForewordThe colour phenotypes in this article involve nuanced gradations of yellow and orange that may be difficult to perceive for people who are colour vision deficient. Hue-shifted versions of all main figures are accessible online for dichromat readers (BioRxiv preprint: Supplementary Material).

genetics↗

bioRxiv2023

Genetic timeline of human brain and cognitive traits

Human evolution is characterised by extensive changes of body and brain, with perhaps one of the core developments being the fast increase in cranial capacity and brain volume. Paleontological records are the most direct method to study such changes, but they can unfortunately provide a limited view of how soft traits such as brain function and cognitive abilities have evolved in humans. A potential complementary approach is to identify when particular genetic variants associated with human phenotypes (such as height, body mass index, intelligence, and also disease) have emerged in the 6-7 million years since we diverged from chimpanzees. In this study, we combine data from genome-wide association studies on human brain and cognitive traits with estimates of human genome dating. We systematically analyse the temporal emergence of genetic variants associated with modern-day human brain and cognitive phenotypes over the last five million years. Our analysis provides evidence that genetic variants related to neocortex structure (e.g., area, thickness; median evolutionary age = 400,170 years old), cognition (e.g., fluid intelligence; median age = 459,465), education (median age = 637,646), and psychiatric disorders (median age = 412,639) have emerged more recently in human evolution than expected by chance. In contrast, variants related to other physical traits, such as height (median age = 811,305) and body mass index (median age = 794,265), emerged relatively later. We further show that genes containing recent evolutionary modifications (from around 54,000 to 4,000 years ago) are linked to intelligence (P = 2 x 10-6) and neocortical surface area (P = 6.7 x 10-4), and that these genes tend to be highly expressed in cortical areas involved in language and speech (pars triangularis, P = 6.2 x 10-4). Elucidating the temporal dynamics of genetic variants associated with brain and cognition is another source of evidence to advance our understanding of human evolution.

genetics↗

bioRxiv2023

Nuclear genetic background influences the phenotype of the Drosophila tko25t mitochondrial protein-synthesis mutant

The Drosophila tko25t point mutation in the gene encoding mitoribosomal protein S12 produces a complex phenotype of multiple respiratory chain deficiency, developmental delay, bang-sensitivity, impaired hearing, sugar and antibiotic sensitivity and impaired male courtship. Its phenotypic severity was previously shown to be alleviated by inbreeding, and to vary with mitochondrial genetic background. Here we show similarly profound effects conferred by nuclear genetic background. We backcrossed tko25t into each of two standard nuclear backgrounds, Oregon R and w1118, the latter used as recipient line in many transgenic applications requiring selection for the white minigene marker. In the w1118 background, tko25t flies showed a moderate developmental delay and modest bang-sensitivity. In the Oregon R background, males showed longer developmental delay and more severe bang-sensitivity, and we were initially unable to produce homozygous tko25t females in sufficient numbers to conduct a meaningful analysis. When maintained as a balanced stock over 2 years, tko25tflies in the Oregon R background showed clear phenotypic improvement though were still more severely affected than in the w1118 background. Phenotypic severity did not correlate with the expression level of the tko gene. Analysis of tko25t hybrids between the two backgrounds indicated that phenotypic severity was conferred by autosomal, X-chromosomal and parent-of-origin dependent determinants. Although some of these effects may be tko25t-specific, we recommend that, in order to minimize genetic drift and confounding background effects, the genetic background of non-lethal mutants should be controlled by regular backcrossing, even if stocks are usually maintained over a balancer chromosome.

genetics↗

bioRxiv2023

WNT activity reveals context-specific genetic effects on gene regulation in neural progenitors

Gene regulatory effects in bulk-post mortem brain tissues are undetected at many non-coding brain trait-associated loci. We hypothesized that context-specific genetic variant function during stimulation of a developmental signaling pathway would explain additional regulatory mechanisms. We measured chromatin accessibility and gene expression following activation of the canonical Wnt pathway in primary human neural progenitors from 82 donors. TCF/LEF motifs, brain structure-, and neuropsychiatric disorder-associated variants were enriched within Wnt-responsive regulatory elements (REs). Genetically influenced REs were enriched in genomic regions under positive selection along the human lineage. Stimulation of the Wnt pathway increased the detection of genetically influenced REs/genes by 66.2%/52.7%, and led to the identification of 397 REs primed for effects on gene expression. Context-specific molecular quantitative trait loci increased brain-trait colocalizations by up to 70%, suggesting that genetic variant effects during early neurodevelopmental patterning lead to differences in adult brain and behavioral traits.

genetics↗

bioRxiv2023

Genetic manipulation of betta fish

Betta splendens, also known as Siamese fighting fish or betta, are renowned for their astonishing morphological diversity and extreme aggressive behavior. Despite recent advances in our understanding of the genetics and neurobiology of betta, the lack of tools to manipulate their genome has hindered progress at functional and mechanistic levels. In this study, we outline the use of three genetic manipulation technologies, which we have optimized for use in betta: CRISPR/Cas9-mediated knockout, CRISPR/Cas9-mediated knockin, and Tol2-mediated transgenesis. We knocked out three genes: alkal2l, bco1l, and mitfa, and analyzed their effects on viability and pigmentation. Furthermore, we successfully knocked in a fluorescent protein into the mitfa locus, a proof-of-principle experiment of this powerful technology in betta. Finally, we used Tol2-mediated transgenesis to create fish with ubiquitous expression of GFP, and then developed a bicistronic plasmid with heart-specific expression of a red fluorescent protein to serve as a visible marker of successful transgenesis. Our work highlights the potential for the genetic manipulation of betta, providing valuable resources for the effective use of genetic tools in this animal model.

genetics↗

bioRxiv2023

GenBank genomics highlight the genomic features, genetic diversity and regulation of morphological, metabolic and disease-resistance traits in Nicotiana tabacum

Nicotiana tabacum is a model organism in plant molecular and pathogenic research and has significant potential in the production of biofuels and active pharmaceutical compounds in synthetic biology. Because of the large allotetraploid genome of tobacco, its genomic features, genetic diversity and genetic regulation of many complex traits remain unknown. In this study, we present a nearly complete chromosome-scale assembly of N. tabacum and provide evidence that homoeologous exchange between subgenomes and epigenetic remodelling are likely mechanisms of genome stabilization and subgenome coordination following polyploidization. By leveraging GenBank-scale sequencing and phenotyping data from 5196 lines, geography at the continent scale, rather than types assigned on the basis of curing crop practices, was found to be the most important correlate of genetic structure. Using 178 marker{square}trait associations detected in genome-wide association analysis, a reference genotype-to-phenotype map was built for 39 morphological, developmental, and disease-resistance traits. A novel gene, auxin response factor 9 (Arf9), associated with wider leaves after being knocked out, was fine-mapped to a single nucleotide polymorphism (SNP). This point mutation alters the translated amino acid from Ala203 to Pro203, likely preventing homodimer formation during DNA binding. Our analysis also revealed signatures of positive and polygenic selection for multiple traits during the process of selective breeding. Overall, this study demonstrated the power of leveraging GenBank genomics to gain insights into the genomic features, genetic diversity, and regulation of complex traits in N. tabacum, laying a foundation for future research on plant functional genomics, crop breeding, and the production of biopharmaceuticals and biofuels.

genetics↗