Biology subjects

Clark, A. G.

Publications and source records attributed to Clark, A. G..

At least 37 records · Page 2Linked to original sources

bioRxiv2023

High quality genome assemblies reveal evolutionary dynamics of repetitive DNA and structural rearrangements in the Drosophila virilis sub-group

High-quality genome assemblies across a range of non-traditional model organisms can accelerate the discovery of novel aspects of genome evolution. The Drosophila virilis group has several attributes that distinguish it from more highly studied species in the Drosophila genus, such as an unusual abundance of repetitive elements and extensive karyotype evolution, in addition to being an attractive model for speciation genetics. Here we used long-read sequencing to assemble five genomes of three virilis group species and characterized sequence and structural divergence and repetitive DNA evolution. We find that our contiguous genome assemblies allow characterization of chromosomal arrangements with ease and can facilitate analysis of inversion breakpoints. We also leverage a small panel of resequenced strains to explore the genomic pattern of divergence and polymorphism in this species and show that known demographic histories largely predicts the extent of genome-wide segregating polymorphism. We further find that a neo-X chromosome in D. americana displays X-like levels of nucleotide diversity. We also found that unusual repetitive elements were responsible for much of the divergence in genome composition among species. Helitron-derived tandem repeats tripled in abundance on the Y chromosome in D. americana compared to D. novamexicana, accounting for most of the difference in repeat content between these sister species. Repeats with characteristics of both transposable elements and satellite DNAs expanded by three-fold, mostly in euchromatin, in both D. americana and D. novamexicana compared to D. virilis. Our results represent a major advance in our understanding of genome biology in this emerging model clade. Significance statementThe Drosophila virilis sub-group is an emerging model with an enticing combination of attributes, including abundant and diverse repetitive DNA content, structural rearrangements, and hybridization capability. The lack of high-quality genome assemblies for this group have prevented detailed understanding of genome evolution. Here, we present five new long-read genome assemblies of three virilis sub-group species along with analyses of structural variants, polymorphisms, repetitive DNAs, and Y chromosome genes and repeats. We find that the expansion and mobilization of non-canonical repetitive elements accounts for most of the divergence in assembled genome sequence between these species, with an especially striking takeover of the Y chromosome by a single type of element in one of the three species. Overall, our study positions the virilis sub-group as a model for a variety of future studies.

genomics↗

bioRxiv2023

The structure of simple satellite variation in the human genome and its correlation with centromere ancestry

Although repetitive DNA forms much of the human genome, its study is challenging due to limitations in assembly and alignment of repetitive short-reads. We have deployed k-Seek, software that detects tandem repeats embedded in single reads, on 2,504 human genomes from the 1,000 Genomes Project to quantify the variation and abundance of simple satellites (repeat units < 20 bp). We find that homopolymers and the Human Satellite 3 monomer make up the largest portions of simple satellite content in humans (mean of [~]19 Mb combined). We discovered[~]50,000 rare tandem repeats that are not detected in the T2T-CHM13v2.0 assembly, including undescribed variants of telomeric- and centromeric repeats. We find broad homogeneity of the most abundant repeats across populations, except for AG-rich repeats that are more abundant in African individuals. We also find cliques of highly similar AG- and AT-rich satellites that are interspersed and form higher-order structures that covary in copy number across individuals, likely through concerted amplification via unequal exchange. Finally, we use centromere-linked polymorphisms to estimate centromeric genetic relatedness between individuals and find a strong predictive relationship between centromeric lineages and centromeric simple satellite abundances. In particular, Human Satellite 2 and Human Satellite 3 abundances correlate with clusters of centromeric ancestry on chromosome 16 and chromosome 9, with some clusters structured by population. These results provide new descriptions of the population dynamics that underlie the evolution of simple satellites in humans.

genomics↗

bioRxiv2023

The seminal odorant binding protein Obp56g is required for mating plug formation and male fertility in Drosophila melanogaster

In Drosophila melanogaster and other insects, the seminal fluid proteins (SFPs) and male sex pheromones that enter the female with sperm during mating are essential for fertility and induce profound post-mating effects on female physiology and behavior. The SFPs in D. melanogaster and other taxa include several members of the large gene family known as odorant binding proteins (Obps). Previous work in Drosophila has shown that some Obp genes are highly expressed in the antennae and can mediate behavioral responses to odorants, potentially by binding and carrying these molecules to odorant receptors. These observations have led to the hypothesis that the seminal Obps might act as molecular carriers for pheromones or other compounds important for male fertility in the ejaculate, though functional evidence in any species is lacking. Here, we used RNAi and CRISPR/Cas9 generated mutants to test the role of the seven seminal Obps in D. melanogaster fertility and the post-mating response (PMR). We found that Obp56g is required for male fertility and the induction of the PMR, whereas the other six genes had no effect on fertility when mutated individually. Obp56g is expressed in the males ejaculatory bulb, an important tissue in the reproductive tract that synthesizes components of the mating plug. We found males lacking Obp56g fail to form a mating plug in the mated females reproductive tract, leading to ejaculate loss and reduced sperm storage. We also examined the evolutionary history of these seminal Obp genes, as several studies have documented rapid evolution and turnover of SFP genes across taxa. We found extensive lability in gene copy number and evidence of positive selection acting on two genes, Obp22a and Obp51a. Comparative RNAseq data from the male reproductive tract of multiple Drosophila species revealed that Obp56g shows high male reproductive tract expression only in species of the melanogaster and obscura groups, though conserved head expression in all species tested. Together, these functional and expression data suggest that Obp56g may have been co-opted for a reproductive function over evolutionary time.

genetics↗

bioRxiv2023

The Drosophila melanogaster Y-linked gene, WDY, is required for sperm to swim in the female reproductive tract.

Unique patterns of inheritance and selection on Y chromosomes lead to the evolution of specialized gene functions. Yet characterizing the function of genes on Y chromosomes is notoriously difficult. We report CRISPR mutants in Drosophila of the Y-linked gene, WDY, which is required for male fertility. WDY mutants produce mature sperm with beating tails that can be transferred to females but fail to enter the female sperm storage organs. We demonstrate that the sperm tails of WDY mutants beat approximately half as fast as wild-type sperms and that the mutant sperm do not propel themselves within the male ejaculatory duct or female reproductive tract (RT). These specific motility defects likely cause the sperm storage defect and sterility of the mutants. Regional and genotype-dependent differences in sperm motility suggest that sperm tail beating and propulsion do not always correlate. Furthermore, we find significant differences in the hydrophobicity of key residues of a putative calcium-binding domain between orthologs of WDY that are Y-linked and those that are autosomal. Given that WDY appears to be evolving under positive selection, our results suggest that WDYs functional evolution coincides with its transition from autosomal to Y-linked in Drosophila melanogaster and its most closely related species. Finally, we show that mutants for another Y-linked gene, PRY, also show a sperm storage defect that may explain their subfertility. In contrast to WDY, PRY mutants do swim in the female RT, suggesting they are defective in yet another mode of motility, navigation, or a necessary interaction with the female RT. Overall, we provide direct evidence for the long-held presumption that protein-coding genes on the Drosophila Y regulate sperm motility.

genetics↗

bioRxiv2022

Inference of selective sweep parameters through supervised learning

A selective sweep occurs when positive selection drives an initially rare allele to high population frequency. In nature, the precise parameters of a sweep are seldom known: How strong was positive selection? Did the sweep involve only a single adaptive allele (hard sweep) or were multiple adaptive alleles at the locus sweeping at the same time (soft sweep)? If the sweep was soft, did these alleles originate from recurrent new mutations (RNM) or from standing genetic variation (SGV)? Here, we present a method based on supervised machine learning to infer such parameters from the patterns of genetic variation observed around a given sweep locus. Our method is trained on sweep data simulated with SLiM, a fast and flexible framework that allows us to generate training data across a wide spectrum of evolutionary scenarios and can be tailored towards the specific population of interest. Inferences are based on summary statistics describing patterns of nucleotide diversity, haplotype structure, and linkage disequilibrium, which are estimated across systematically varying genomic window sizes to capture sweeps across a wide range of selection strengths. We show that our method can accurately infer selection coefficients in the range 0.01 < s < 100 and classify sweep types between hard sweeps, RNM soft sweeps, and SGV soft sweeps with accuracy 69 % to 95 % depending on sweep strength. We also show that the method infers the correct sweep types at three empirical loci known to be associated with the recent evolution of pesticide resistance in Drosophila melanogaster. Our study demonstrates the power of machine learning for inferring sweep parameters from present-day genotyping samples, opening the door to a better understanding of the modes of adaptive evolution in nature. Author summaryAdaptation often involves the rapid spread of a beneficial genetic variant through the population in a process called a selective sweep. Here, we develop a method based on machine learning that can infer the strength of selection driving such a sweep, and distinguish whether it involved only a single adaptive variant (a so-called hard sweep) or several adaptive variants of independent origin that were simultaneously rising in frequency at the same genomic position (a so-called soft selective sweep). Our machine learning method is trained on simulated data and only requires data sampled from a single population at a single point in time. To address the challenge of simulating realistic datasets for training, we explore the behavior of the method under a variety of testing scenarios, including scenarios where the history of the population of interest was misspecified. Finally, to illustrate the accuracy of our method, we apply it to three known sweep loci that have contributed to the evolution of pesticide resistance in Drosophila melanogaster.

evolutionary biology↗

bioRxiv2022

Time series transcriptome analysis uncovers regulatory networks and a role for the circadian clock in the Drosophila melanogaster female's response to Sex Peptide

Sex Peptide, a seminal fluid protein of D. melanogaster males, has been described as driving a virgin-to-mated switch in females, through eliciting an array of responses, including increased egg laying, activity and food intake and a decreased re-mating rate. While it is known that Sex Peptide achieves this, at least in part, by altering neuronal signaling in females, the identity of key molecular regulators that act downstream of Sex Peptide is not known. Here, we used a high-resolution time series RNA-sequencing dataset of female heads at 10 time points within the first 24 hours after mating to investigate the genetic architecture, at the gene- and exon-level, of the females response to Sex Peptide. We find that Sex Peptide is not essential to trigger a virgin-to-mated transcriptional switch, which involves changes in a metabolic gene regulatory network. However, Sex Peptide is needed to maintain and diversify metabolic changes and to trigger changes in a neuronal gene regulatory network. We further find that Sex Peptide might interact with the females circadian clock to orchestrate transcriptional changes across different regulatory networks. That a male seminal fluid protein can alter a females rhythmic gene expression has implications for our understanding of both reproductive and circadian behaviors.

genomics↗

bioRxiv2022

Finding the strongest gene drive: Simulations reveal unexpected performance differences between Anopheles homing suppression drive candidates

Recent experiments have produced several Anopheles gambiae homing gene drives that disrupt female fertility genes, thereby eventually inducing population collapse. Such drives may be highly effective tools to combat malaria. One such homing drive, based on the zpg promoter driving CRISPR/Cas9, was able to eliminate a cage population of mosquitoes. A second version, purportedly improved upon the first by incorporating an X-shredder element (which biases inheritance towards male offspring), was similarly successful. Here, we re-analyze the data of each of these gene drives and suggest an alternative interpretation of their performance. We assess each suppression drive within an individual-based simulation framework that models mosquito population dynamics in continuous space. We find that the combined homing/X-shredder drive is actually less effective at population suppression within the context of our mosquito population model. In particular, the combined drive often fails to completely suppress the population, instead resulting in an unstable equilibrium between drive and wild-type alleles. By contrast, otherwise similar drives based on the nos promoter may prove to be more promising candidates for future development due to potentially superior performance.

genetics↗

bioRxiv2022

Octopaminergic/tyraminergic Tdc2 neurons regulate biased sperm usage in female Drosophila melanogaster

In polyandrous internally fertilizing species, a multiply-mated female can use stored sperm from different males in a biased manner to fertilize her eggs. The females ability to assess sperm quality and compatibility is essential for her reproductive success, and represents an important aspect of postcopulatory sexual selection. In Drosophila melanogaster, previous studies demonstrated that the female nervous system plays an active role in influencing progeny paternity proportion, and suggested a role for octopaminergic/tyraminergic Tdc2 neurons in this process. Here, we report that inhibiting Tdc2 neuronal activity causes females to produce a higher-than-normal proportion of first-male progeny. This difference is not due to differences in sperm storage or release, but instead is attributable to the suppression of second-male sperm usage bias that normally occurs in control females. We further show that a subset of Tdc2 neurons innervating the female reproductive tract is largely responsible for the progeny proportion phenotype that is observed when Tdc2 neurons are inhibited globally. On the contrary, overactivation of Tdc2 neurons does not further affect sperm storage and release or progeny proportion. These results suggest that octopaminergic/tyraminergic signaling allows a multiply-mated female to bias sperm usage, and identify a new role for the female nervous system in postcopulatory sexual selection.

evolutionary biology↗

bioRxiv2021

An Empirical Bayes Approach to Estimating Dynamic Models of Co-regulated Gene Expression

Time-course gene expression datasets provide insight into the dynamics of complex biological processes, such as immune response and organ development. It is of interest to identify genes with similar temporal expression patterns because such genes are often biologically related. However, this task is challenging due to the high dimensionality of these datasets and the nonlinearity of gene expression time dynamics. We propose an empirical Bayes approach to estimating ordinary differential equation (ODE) models of gene expression, from which we derive a similarity metric between genes called the Bayesian lead-lag R2 (LLR2). Importantly, the calculation of the LLR2 leverages biological databases that document known interactions amongst genes; this information is automatically used to define informative prior distributions on the ODE models parameters. As a result, the LLR2 is a biologically-informed metric that can be used to identify clusters or networks of functionally-related genes with co-moving or time-delayed expression patterns. We then derive data-driven shrinkage parameters from Steins unbiased risk estimate that optimally balance the ODE models fit to both data and external biological information. Using real gene expression data, we demonstrate that our methodology allows us to recover interpretable gene clusters and sparse networks. These results reveal new insights about the dynamics of biological systems.

genomics↗

bioRxiv2021

Multiple recent sex chromosome fusions in Drosophila virilis associated with elevated satellite DNA abundance

The karyotype, or number and arrangement of chromosomes, has varying levels of stability across both evolution and disease. Karyotype changes often originate from DNA breaks near the centromeres of chromosomes, which generally contain long arrays of tandem repeats or satellite DNA. Drosophila virilis possesses among the highest relative satellite abundances of studied species, with almost half its genome composed of three related 7bp satellites. We discovered a strain of D. virilis that we infer recently underwent three independent chromosome fusion events involving the X and Y chromosomes, in addition to one subsequent fission event. Here we isolate, characterize and propose a timeline for the chromosome fusions in this strain which we believe demonstrates a remarkable karyotype instability. We discovered that one of the substrains with an X-autosome fusion has a X-to-Y chromosome nondisjunction rate 20x higher than the D. virilis reference strain (21% vs. 1%). Finally, we found an overall higher rate of DNA breakage in the substrain with higher satellite DNA compared to a genetically similar substrain with less satellite DNA. This suggests satellite DNA abundance may play a role in the risk of genome instability. Overall, we introduce a novel system consisting of a single strain with four different karyotypes, which we believe will be useful for future studies of genome instability, centromere function, and sex chromosome evolution.

evolutionary biology↗

bioRxiv2021

Experimental demonstration of tethered gene drive systems for confined population modification or suppression

Homing gene drives hold great promise for the genetic control of natural populations. However, current homing systems are capable of spreading uncontrollably between populations connected by even marginal levels of migration. This could represent a substantial sociopolitical barrier to the testing or deployment of such drives and may generally be undesirable when the objective is only local population control, such as suppression of an invasive species outside of its native range. Tethered drive systems, in which a locally confined gene drive provides the CRISPR nuclease needed for a homing drive, could provide a solution to this problem, offering the power of a homing drive and confinement of the supporting drive. Here, we demonstrate the engineering of a tethered drive system in Drosophila, using a regionally confined CRISPR Toxin-Antidote Recessive Embryo (TARE) drive to support modification and suppression homing drives. Each drive was able to bias inheritance in its favor, and the TARE drive was shown to spread only when released above a threshold frequency in experimental cage populations. After the TARE drive had established in the population, it facilitated the spread of a subsequently released split homing modification drive (to all individuals in the cage) and of a homing suppression drive (to its equilibrium frequency). Our results show that the tethered drive strategy is a viable and easily engineered option for providing confinement of homing drives to target populations.

genetics↗

bioRxiv2021

A homing suppression gene drive with multiplexed gRNAs maintains high drive conversion efficiency and avoids functional resistance alleles

Gene drives are engineered alleles that can bias inheritance in their favor, allowing them to spread throughout a population. They could potentially be used to modify or suppress pest populations, such as mosquitoes that spread diseases. CRISPR/Cas9 homing drives, which copy themselves by homology-directed repair in drive/wild-type heterozygotes, are a powerful form of gene drive, but they are vulnerable to resistance alleles that preserve the function of their target gene. Such resistance alleles can prevent successful population suppression. Here, we constructed a homing suppression drive in Drosophila melanogaster that utilized multiplexed gRNAs to inhibit the formation of functional resistance alleles in its female fertility target gene. The selected gRNA target sites were close together, preventing reduction in drive conversion efficiency. The construct reached a moderate equilibrium frequency in cage populations without apparent formation of resistance alleles. However, a moderate fitness cost prevented elimination of the cage population, showing the importance of using highly efficient drives in a suppression strategy, even if resistance can be addressed. Nevertheless, our results experimentally demonstrate the viability of the multiplexed gRNAs strategy in homing suppression gene drives.

genetics↗

bioRxiv2021

Fitness effects of CRISPR endonucleases in Drosophila melanogaster populations

CRISPR/Cas9 systems provide a highly efficient and flexible genome editing technology with numerous potential applications in areas ranging from gene therapy to population control. Some proposed applications involve CRISPR/Cas9 endonucleases integrated into an organisms genome, which raises questions about potentially harmful effects to the transgenic individuals. One application where this is particularly relevant are CRISPR-based gene drives, which promise a mechanism for rapid genetic alteration of entire populations. The performance of such drives can strongly depend on fitness costs experienced by drive carriers, yet relatively little is known about the magnitude and causes of these costs. Here, we assess the fitness effects of genomic CRISPR/Cas9 expression in Drosophila melanogaster cage populations by tracking allele frequencies of four different transgenic constructs, designed to disentangle direct fitness costs due to the integration, expression, and target-site activity of Cas9 from costs due to potential off-target cleavage. Using a maximum likelihood framework, we find a moderate level of fitness costs due to off-target effects but do not detect significant direct costs. Costs of off-target effects are minimized for a construct with Cas9HF1, a high-fidelity version of Cas9. We further demonstrate that using Cas9HF1 instead of standard Cas9 in a homing drive achieves similar drive conversion efficiency. Our results suggest that gene drives should be designed with high-fidelity endonucleases and may have implications for other applications that involve genomic integration of CRISPR endonucleases.

evolutionary biology↗

bioRxiv2021

Inferred Clades of Transposable Elements in Drosophila Suggest Co-evolution with piRNAs

Transposable elements (TEs) are self-replicating "genetic parasites" ubiquitous to eukaryotic genomes. In addition to conflict between TEs and their host genomes, TEs of the same family are in competition with each other. They compete for the same genomic niches while experiencing the same regime of copy-number selection. This suggests that competition among TEs may favor the emergence of new variants that can outcompete their ancestral forms. To investigate the sequence evolution of TEs, we developed a method to infer clades: collections of TEs that share SNP variants and represent distinct TE family lineages. We applied this method to a panel of 85 Drosophila melanogaster genomes and found that the genetic variation of several TE families shows significant population structure that arises from the population- specific expansions of single clades. We used population genetic theory to classify these clades into younger versus older clades and found that younger clades are associated with a greater abundance of sense and antisense piRNAs per copy than older ones. Further, we find that the abundance of younger, but not older clades, is positively correlated with antisense piRNA production, suggesting a general pattern where hosts preferentially produce antisense piRNAs from recently active TE variants. Together these findings suggest a pattern whereby new TE variants arise by mutation and then increase in copy number, followed by the host producing antisense piRNAs that may be used to silence these emerging variants.

genetics↗

bioRxiv2021

The genetic basis of Drosophila melanogaster defense against Beauveria bassiana explored through evolve and resequence and quantitative trait locus mapping

Many of the molecular mechanisms for antifungal immunity in Drosophila melanogaster have been defined, but relatively little is known about the genetic basis for variation in antifungal immunity in natural populations. Using two population genetic approaches, Quantitative Trait Locus (QTL) Mapping and Evolve and Resequence (E&R), we explored the genetics underlying D. melanogaster immune defense against infection with the fungus Beauveria bassiana. Immune defense was highly variable both in the recombinant inbred lines from the Drosophila Synthetic Population Resource used for our QTL Mapping and in the synthetic outbred populations used in our E&R study. Survivorship of infection improved dramatically over just 10 generations in the E&R study, and continued to increase for an additional 9 generations, revealing a trade-off with uninfected longevity. Populations selected for increased defense against B. bassiana evolved cross resistance to a second, distinct B. bassiana strain but not to bacterial pathogens. The QTL mapping study revealed that sexual dimorphism in defense depends on host genotype, and the E&R study indicated that dimorphism also depends on the specific pathogen to which the host is exposed. Both the QTL Mapping and E&R experiments generated lists of potentially causal candidate genes, although these lists were non-overlapping.

genomics↗

bioRxiv2021

Copy number evolution in simple and complex tandem repeats across the C57BL/6 and C57BL/10 inbred mouse lines

Simple sequence tandem repeats are among the most rapidly evolving compartments of the genome. Some repeat expansions are associated with mammalian disease or meiotic segregation distortion, yet the rates of copy number change across generations are not well known. Here, we use 14 distinct sub-lineages of the C57BL/6 and C57BL/10 inbred mouse strains, which have been evolving independently over about 300 generations, to estimate the rates of copy number changes in genome-wide tandem repeats. Rates of change varied across simple repeats and across lines. Notably, CAG, whose expansions in coding regions are associated with many neurological and other genetic disorders, was highly stable in copy number, likely indicating purifying selection. Rates of change were generally positively correlated with copy number, but the direction and magnitude of changes varied across lines. Some mouse lines experienced consistent losses or gains across most genome-wide simple repeats, but this did not correlate with copy number changes in complex repeats. Rates of copy number change were similar between simple repeats and the much more abundant complex repeats once they were normalized by copy number. Finally, the Y-specific centromeric repeat had a 4-fold higher rate of change than the homologous centromeric repeat on other chromosomes. Structural differences in satellite complexity, or restriction to the Y chromosome and the elevated mutation rate of the male germline, may explain the higher rate of change. Overall, our work underscores the mutational fluidity of long tandem arrays of repeats, and the correlations and constraints between genome-wide tandem repeats which suggest that turnover is not a completely neutral process.

evolutionary biology↗

bioRxiv2021

Migration Restores Hybrid Incompatibility Driven By Nuclear-Mitochondrial Sexual Conflict

In the mitochondrial genome, sexual asymmetry in transmission allows the accumulation of male-harming mutations since selection acts only on the effect of the mutation in females. Called the "Mothers Curse", this phenomenon induces a selective pressure for nuclear variants that compensate for this reduction in male fitness. Previous work has demonstrated the existence of these interactions and their potential to act as Dobzhansky-Muller incompatibilities, contributing to reproductive isolation between populations. However, it is not clear how readily they would give rise to and sustain hybrid incompatibilities. Here, we use computer simulations in SLiM 3 to investigate the consequences of sexually antagonistic mitochondrial-nuclear interactions in a subdivided population. We consider distinct migration schemes and vary the chromosomal location, and consequently the transmission pattern, of nuclear restorers. Disrupting these co-evolved interactions results in less-fit males, skewing the sex ratio toward females. Restoration of male fitness depends on both the chromosomal location of nuclear restorer loci and the migration scheme. Our results show that these interactions may act as Dobzhansky-Muller incompatibilities, but their strength is not enough to drive population isolation. Overall, this model shows the varied ways in which populations can respond to migrations disruption of co-evolved mitochondrial-nuclear interactions.

evolutionary biology↗

bioRxiv2020

Leveraging phenotypic variability to identify genetic interactions in human phenotypes

While thousands of loci have been associated with human phenotypes, the role of gene-environment (GxE) interactions in determining individual risk of human diseases remains unclear. This is partly due to the severe erosion of statistical power resulting from the massive number of statistical tests required to detect such interactions. Here, we focus on improving the power of GxE tests by developing a statistical framework for assessing quantitative trait loci (QTLs) associated with the trait means and/or trait variances. When applying this framework to body mass index (BMI), we find that GxE discovery and replication rates are significantly higher when prioritizing genetic variants associated with the variance of the phenotype (vQTLs) compared to assessing all genetic variants. Moreover, we find that vQTLs are enriched for associations with other non-BMI phenotypes having strong environmental influences, such as diabetes or ulcerative colitis. We show that GxE effects first identified in quantitative traits such as BMI can be used for GxE discovery in disease phenotypes such as diabetes. A clear conclusion is that strong GxE interactions mediate the genetic contribution to body weight and diabetes risk.

genetics↗