Natural Genetic Variation Research Articles

Analytic and Translational Genetics

Understanding the influence of genetics on human disease is among the primary goals for biology and medicine. To this end, the direct study of natural human genetic variation has provided valuable insights into human physiology and disease as well as into the origins and migrations of humans. In this review, we discuss the foundations of population genetics, which provide a crucial context to the study of human genes and traits. In particular, genome-wide association studies and similar methods have revealed thousands of genetic loci associated with diseases and traits, providing invaluable information into the biology of these traits. Simultaneously, as the study of rare genetic variation has expanded, so-called human knockouts have elucidated the function of human genes and the therapeutic potential of targeting them.

The maize shoot ionome: Its interaction partners, predictive power, and genetic determinants.

An improved understanding of how to manipulate the accumulation and enrichment of mineral elements in aboveground plant tissues holds promise for future resource efficient and sustainable crop production. The objectives of this study were to (a) evaluate the influence of Fe regimes on mineral element concentrations and contents in the maize shoot as well as their correlations, (b) examine the predictive ability of physiological and morphological traits of individual genotypes of the IBM population from the concentration of mineral elements, and (c) identify genetic factors influencing the mineral element composition within and across Fe regimes. We evaluated the concentration and content of 12 mineral elements in shoots of the IBM population grown in sufficient and deficient Fe regimes and found for almost all mineral elements a significant (α = 0.05) genotypic variance. Across all mineral elements, the variance of genotype*Fe regime interactions was on average even more pronounced. High prediction abilities indicated that mineral elements are powerful predictors of morphological and physiological traits. Furthermore, our results suggest that ZmHMA2/3 and ZmMOT1 are major players in the natural genetic variation of Cd and Mo concentrations and contents of maize shoots, respectively.

Can We Use Gene-Editing to Induce Apomixis in Sexual Plants?

Apomixis, the asexual formation of seeds, is a potentially valuable agricultural trait. Inducing apomixis in sexual crop plants would, for example, allow breeders to fix heterosis in hybrid seeds and rapidly generate doubled haploid crop lines. Molecular models explain the emergence of functional apomixis, i.e., apomeiosis + parthenogenesis + endosperm development, as resulting from a combination of genetic or epigenetic changes that coordinate altered molecular and developmental steps to form clonal seeds. Apomixis-like features and synthetic clonal seeds have been induced with limited success in the sexual plants rice and maize by using gene editing to mutate genes related to meiosis and fertility or via egg-cell specific expression of embryogenesis genes. Inducing functional apomixis and increasing the penetrance of apomictic seed production will be important for commercial deployment of the trait. Optimizing the induction of apomixis with gene editing strategies that use known targets as well as identifying alternative targets will be possible by better understanding natural genetic variation in apomictic species. With the growing availability of genomic data and precise gene editing tools, we are making substantial progress towards engineering apomictic crops.

The Ancestral Caenorhabditis elegans Cuticle Suppresses rol-1.

Genetic background commonly modifies the effects of mutations. We discovered that worms mutant for the canonical rol-1 gene, identified by Brenner in 1974, do not roll in the genetic background of the wild strain CB4856. Using linkage mapping, association analysis and gene editing, we determined that N2 carries an insertion in the collagen gene col-182 that acts as a recessive enhancer of rol-1 rolling. From population and comparative genomics, we infer the insertion is derived in N2 and related laboratory lines, likely arising during the domestication of Caenorhabditis elegans, and breaking a conserved protein. The ancestral version of col-182 also modifies the phenotypes of four other classical cuticle mutant alleles, and the effects of natural genetic variation on worm shape and locomotion. These results underscore the importance of genetic background and the serendipity of Brenner’s choice of strain.

Unraveling waterlogging tolerance-related traits with QTL analysis in reciprocal intervarietal introgression lines using genotyping by sequencing in rapeseed (Brassica napus L.)

Soil waterlogging is a major environmental stress that suppresses the growth and productivity of rapeseed (Brassica napus L.). Natural genetic variations in waterlogging tolerance (WT) were observed but no QTL mapping has been done for WT related traits in rapeseed. In this study, QTL associated with three WT related traits including relative root length (RRL), relative hypocotyl length (RHL) and relative fresh weight (RFW) were dissected using a set of reciprocal introgression lines (ILs) derived from the cross GH01×ZS9, which showed significant difference in WT. Genotyping-by-sequencing (GBS) of the populations were performed, totally 1 468 and 1 450 binned SNPs were identified for GIL (GH01 as the recurrent parent) and ZIL (ZS9 as the recurrent parent) population, respectively. A total of 66 distinct QTLs for WT at the seedling establishment stage including 31 for RRL, 17 for RHL and 18 for RFW were detected. Among the 66 QTLs, 20 (29.4%) QTLs were detected in both genetic backgrounds and then they were integrated into six QTL clusters, which can be targeted in rapeseed breeding for improvement of WT through marker-assisted selection (MAS). Based on the physical positions of SNPs and the functional annotation of the Arabidopsis thaliana genome, 56 genes within the six QTL cluster regions were selected as preliminary candidate genes, then the resequencing and transcriptome information about parents were applied to narrow the extent of candidate genes. Twelve genes were determined as candidates for the six QTL clusters, some of them involved in RNA/protein degradation, most of them involved in oxidation-reduction process. These findings provided genetic resources, candidate genes to address the urgent demand of improving WT in rapeseed breeding.

The ATGL lipase cooperates with ABHD5 to mobilize lipids for hepatitis C virus assembly.

Lipid droplets are essential cellular organelles for storage of fatty acids and triglycerides. The hepatitis C virus (HCV) translocates several of its proteins onto their surface and uses them for production of infectious progeny. We recently reported that the lipid droplet-associated α/β hydrolase domain-containing protein 5 (ABHD5/CGI-58) participates in HCV assembly by mobilizing lipid droplet-associated lipids. However, ABHD5 itself has no lipase activity and it remained unclear how ABHD5 mediates lipolysis critical for HCV assembly. Here, we identify adipose triglyceride lipase (ATGL) as ABHD5 effector and new host factor involved in the hepatic lipid droplet degradation as well as in HCV and lipoprotein morphogenesis. Modulation of ATGL protein expression and lipase activity controlled lipid droplet lipolysis and virus production. ABHD4 is a paralog of ABHD5 unable to activate ATGL or support HCV assembly and lipid droplet lipolysis. Grafting ABHD5 residues critical for activation of ATGL onto ABHD4 restored the interaction between lipase and co-lipase and bestowed the pro-viral and lipolytic functions onto the engineered protein. Congruently, mutation of the predicted ABHD5 protein interface to ATGL ablated ABHD5 functions in lipid droplet lipolysis and HCV assembly. Interestingly, minor alleles of ABHD5 and ATGL associated with neutral lipid storage diseases in human, are also impaired in lipid droplet lipolysis and their pro-viral functions. Collectively, these results show that ABHD5 cooperates with ATGL to mobilize triglycerides for HCV infectious virus production. Moreover, viral manipulation of lipid droplet homeostasis via the ABHD5-ATGL axis, akin to natural genetic variation in these proteins, emerges as a possible mechanism by which chronic HCV infection causes liver steatosis.

Assessing genetic diversity and population structure of sugarcane cultivars, progenitor species and genera using microsatellite (SSR) markers.

Sugarcane is one among the most important commercial crops used to produce sugar, ethanol, and other byproducts, which significantly contributes in the GDP of India and many other countries around the world. Genetic diversity is a platform for any breeding program of a plant species. Estimation of the genetic variability and population structure play a vital role for conservation planning and management of plant genetic resources. Genetic variability serves as a source of noble alleles responsible for key agronomic and quality traits, which ultimately form basis for identification and selection of promising parents for breeding programs. In the present study genetic diversity and population structure of 139 accessions of the genus Saccharum, allied genera of family Poaceae and cultivars were assessed using informative microsatellite (SSR) markers. A sum of 427 alleles was produced using 61 polymorphic primers and number of alleles generated was ranged from 2 to 13 with an average of 7 alleles per locus. PIC values were ranged from 0.35 to 0.90, with a mean value of 0.66 for all the markers evaluated. Cluster analysis based on UPGMA method revealed three major clusters which were further subdivided into nine subclusters. Population structure analysis also established three subpopulations of used accession set, however there were no correlation of sub-groupings with that of place of origin. AMOVA analysis also confirmed that 83% and 17% of total variations were attributed to the within- and between-populations, correspondingly, demonstrating greater exchange of gene pool across places of origin. The principal component analysis (PCA) demonstrated the distribution of accessions in the scatter-plot was substantially dispersed, revealing rich genetic diversity among accessions of different species. The findings from this study will be useful in breeding programs for introgression of noble alleles into modern cultivars by exploiting natural genetic variation existing in sugarcane genetic resources.

Neurodiversity and deficit perspectives in The Washington Post’s coverage of autism

Media representations can perpetuate stereotypes about marginalized groups. Autism is often portrayed as a series of deficits needing correction. Many autistic self-advocates argue, however, that their neurological characteristics represent natural genetic variation—neurodiversity—and that they are not in need of a “cure.” The current study examined articles about autism on The Washington Post website from January 2007 through December 2016. It was hypothesized that articles would contain more elements of the neurodiversity perspective over time. Each article was coded for its overall valence, four measures of neurodiversity, and four deficit measures. Mean valence and mean composite neurodiversity scores significantly increased over time, while the mean composite deficit score significantly decreased over time. While the data suggest positive trends towards the neurodiversity perspective, they also reveal that some aspects of the deficit view of autism did not change over this time period in this news outlet. Points of interest Autism is often portrayed as entirely negative, but it has been argued that autism represents a form of diversity (neurodiversity) that should be recognized and respected. The current study examined how autism was portrayed in an influential US newspaper (The Washington Post) from 2007 to 2016. Later articles about autism were more likely to use words like neurodiversity, more likely to highlight strengths of autistic people, and more frequently described accommodations for autistic people. They also focused less on identifying causes of autism but continued to use negative terms and very few articles contained the perspectives of autistic individuals themselves. Although some progress seems to have been made in the portrayal of autism, there is still room for improvement.

Natural genetic variation in Stim1 creates stroke in the spontaneously hypertensive rat

Similar to humans, the risk of cerebrovascular disease in stroke-prone spontaneously hypertensive rats (SHR-A3/SHRSP) arises from naturally occurring genetic variation. In the present study, we show the involvement of genetic variation affecting the store-operated calcium signaling gene, Stim1, in the pathogenesis of stroke in SHR. Stim1 is a key lymphocyte activation signaling molecule and contains functional variation in SHR-A3 that diverges from stroke-resistant SHR-B2. We created a SHR-A3 congenic line in which Stim1 was substituted with the corresponding genomic segment from SHR-B2. Compared with SHR-A3 rats, Stim1 congenic SHR-A3 (SHR-A3(Stim1-B2)) have reduced cerebrovascular disease in response to salt loading including lower neurological deficit scores and cerebral edema. Microbleeds and major hemorrhages occurred in over half of SHR-A3 rats. These lesions were absent in SHR-A3(Stim1-B2) rats. Loss of Stim1 function in mice and humans is associated with antibody-mediated autoimmunity due to defects in T lymphocyte helper function to B cells. We investigated autoantibody formation using a high-density protein array to detect the presence of IgG and IgM autoantibodies in SHR-A3. Autoantibodies to key cerebrovascular stress proteins were detected that were reduced in the congenic line.

How Natural Genetic Variation Shapes Behavior.

Nervous systems allow animals to acutely respond and behaviorally adapt to changes and recurring patterns in their environment at multiple timescales-from milliseconds to years. Behavior is further shaped at intergenerational timescales by genetic variation, drift, and selection. This sophistication and flexibility of behavior makes it challenging to measure behavior consistently in individual subjects and to compare it across individuals. In spite of these challenges, careful behavioral observations in nature and controlled measurements in the laboratory, combined with modern technologies and powerful genetic approaches, have led to important discoveries about the way genetic variation shapes behavior. A critical mass of genes whose variation is known to modulate behavior in nature is finally accumulating, allowing us to recognize emerging patterns. In this review, we first discuss genetic mapping approaches useful for studying behavior. We then survey how variation acts at different levels-in environmental sensation, in internal neuronal circuits, and outside the nervous system altogether-and then discuss the sources and types of molecular variation linked to behavior and the mechanisms that shape such variation. We end by discussing remaining questions in the field.

Natural Genetic Variation Underlying Tiller Development in Barley (Hordeum vulgare L).

In barley (Hordeum vulgare L.), lateral branches called tillers contribute to grain yield and define shoot architecture, but genetic control of tiller number and developmental rate are not well characterized. The primary objectives of this work were to examine relationships between tiller number and other agronomic and morphological traits and identify natural genetic variation associated with tiller number and rate, and related traits. We grew 768 lines from the USDA National Small Grain Collection in the field and collected data over two years for tiller number and rate, and agronomic and morphological traits. Our results confirmed that spike row-type and days to heading are correlated with tiller number, and as much as 28% of tiller number variance was associated with these traits. In addition, negative correlations between tiller number and leaf width and stem diameter were observed, indicating trade-offs between tiller development and other vegetative growth. Thirty-three quantitative trait loci (QTL) were associated with tiller number or rate. Of these, 40% overlapped QTL associated with days to heading and 22% overlapped QTL associated with spike row-type, further supporting that tiller development is associated with these traits. Some QTL associated with tiller number or rate, including the major QTL on chromosome 3H, were not associated with other traits, suggesting that some QTL may be directly related to rate of tiller development or axillary bud number. These results enhance our knowledge of the genetic control of tiller development in barley, which is important for optimizing tiller number and rate for yield improvement.

Genome–Phenome Wide Association in Maize and Arabidopsis Identifies a Common Molecular and Evolutionary Signature

Linking natural genetic variation to trait variation can help determine the functional roles ofdifferent genes. Variations of one or several traits are often assessed separately. High-throughput phenotyping and data mining can capture dozens or hundreds of traits from the same individuals. Here, we test the association between markers within a gene and many traits simultaneously. This genome–phenome wide association study (GPWAS) is both a multi-marker and multi-trait test. Genes identified using GPWAS with 260 phenotypic traits in maize were enriched for genes independently linked to phenotypic variation. Traits associated with classical mutants were consistent with reported phenotypes for mutant alleles. Genes linked to phenomic variation in maize using GPWAS shared molecular, population genetic, and evolutionary features with classical mutants in maize. Genes linked to phenomic variation in Arabidopsis using GPWAS are significantly enriched in genes with known loss-of-function phenotypes. GPWAS may be an effective strategy to identify genes in which loss-of-function alleles produce mutant phenotypes. The shared signatures present in classical mutants and genes identified using GPWAS may be markers for genes with a role in specifying plant phenotypes generally or pleiotropy specifically.

Rapid evolution in plant-microbe interactions - an evolutionary genomics perspective.

Access to greater genomic resolution through new sequencing technologies is transforming the field of plant pathology. As scientists embrace these new methods, some overarching patterns and observations come into focus. Evolutionary genomic studies are used to determine not only the origins of pathogen lineages and geographic patterns of genetic diversity, but also to discern how natural selection structures genetic variation across the genome. With greater and greater resolution, we can now pinpoint the targets of selection on a large scale. At multiple levels, crypsis and convergent evolution are evident. Host jumps and shifts may be more pervasive than once believed, and hybridization and horizontal gene transfer (HGT) likely play important roles in the emergence of genetic novelty.

Pulling the Hood off Genetic Susceptibility to Hypertensive Renal Disease

Pulling the Hood off Genetic Susceptibility to Hypertensive Renal Disease

Gene expression networks in the Drosophila Genetic Reference Panel.

A major challenge in modern biology is to understand how naturally occurring variation in DNA sequences affects complex organismal traits through networks of intermediate molecular phenotypes. This question is best addressed in a genetic mapping population in which all molecular polymorphisms are known and for which molecular endophenotypes and complex traits are assessed on the same genotypes. Here, we performed deep RNA sequencing of 200 Drosophila Genetic Reference Panel inbred lines with complete genome sequences and for which phenotypes of many quantitative traits have been evaluated. We mapped expression quantitative trait loci for annotated genes, novel transcribed regions, transposable elements, and microbial species. We identified host variants that affect expression of transposable elements, independent of their copy number, as well as microbiome composition. We constructed sex-specific expression quantitative trait locus regulatory networks. These networks are enriched for novel transcribed regions and target genes in heterochromatin and euchromatic regions of reduced recombination, as well as genes regulating transposable element expression. This study provides new insights regarding the role of natural genetic variation in regulating gene expression and generates testable hypotheses for future functional analyses.

Functional effects of variation in transcription factor binding highlight long-range gene regulation by epromoters.

Identifying DNA cis-regulatory modules (CRMs) that control the expression of specific genes is crucial for deciphering the logic of transcriptional control. Natural genetic variation can point to the possible gene regulatory function of specific sequences through their allelic associations with gene expression. However, comprehensive identification of causal regulatory sequences in brute-force association testing without incorporating prior knowledge is challenging due to limited statistical power and effects of linkage disequilibrium. Sequence variants affecting transcription factor (TF) binding at CRMs have a strong potential to influence gene regulatory function, which provides a motivation for prioritizing such variants in association testing. Here, we generate an atlas of CRMs showing predicted allelic variation in TF binding affinity in human lymphoblastoid cell lines and test their association with the expression of their putative target genes inferred from Promoter Capture Hi-C and immediate linear proximity. We reveal >1300 CRM TF-binding variants associated with target gene expression, the majority of them undetected with standard association testing. A large proportion of CRMs showing associations with the expression of genes they contact in 3D localize to the promoter regions of other genes, supporting the notion of ‘epromoters’: dual-action CRMs with promoter and distal enhancer activity.

Molecular profiling of beer wort fermentation diversity across natural Saccharomyces eubayanus isolates.

SummaryThe utilization of S. eubayanus has recently become a topic of interest due to the novel organoleptic properties imparted to beer. However, the utilization of S. eubayanus in brewing requires the comprehension of the mechanisms that underlie fermentative differences generated from its natural genetic variability. Here, we evaluated fermentation performance and volatile compound production in ten genetically distinct S. eubayanus strains in a brewing fermentative context. The evaluated strains showed a broad phenotypic spectrum, some of them exhibiting a high fermentation capacity and high levels of volatile esters and/or higher alcohols. Subsequently, we obtained molecular profiles by generating ‘end‐to‐end’ genome assemblies, as well as metabolome and transcriptome profiling of two Patagonian isolates exhibiting significant differences in beer aroma profiles. These strains showed clear differences in concentrations of intracellular metabolites, including amino acids, such as valine, leucine and isoleucine, likely impacting the production of 2‐methylpropanol and 3‐methylbutanol. These differences in the production of volatile compounds are attributed to gene expression variation, where the most profound differentiation is attributed to genes involved in assimilatory sulfate reduction, which in turn validates phenotypic differences in H2S production. This study lays a solid foundation for future research to improve fermentation performance and select strains for new lager styles based on aroma and metabolic profiles.

Unexpected cell type-dependent effects of autophagy on polyglutamine aggregation revealed by natural genetic variation in C. elegans

BackgroundMonogenic protein aggregation diseases, in addition to cell selectivity, exhibit clinical variation in the age of onset and progression, driven in part by inter-individual genetic variation. While natural genetic variants may pinpoint plastic networks amenable to intervention, the mechanisms by which they impact individual susceptibility to proteotoxicity are still largely unknown.ResultsWe have previously shown that natural variation modifies polyglutamine (polyQ) aggregation phenotypes in C. elegans muscle cells. Here, we find that a genomic locus from C. elegans wild isolate DR1350 causes two genetically separable aggregation phenotypes, without changing the basal activity of muscle proteostasis pathways known to affect polyQ aggregation. We find that the increased aggregation phenotype was due to regulatory variants in the gene encoding a conserved autophagy protein ATG-5. The atg-5 gene itself conferred dosage-dependent enhancement of aggregation, with the DR1350-derived allele behaving as hypermorph. Surprisingly, increased aggregation in animals carrying the modifier locus was accompanied by enhanced autophagy activation in response to activating treatment. Because autophagy is expected to clear, not increase, protein aggregates, we activated autophagy in three different polyQ models and found a striking tissue-dependent effect: activation of autophagy decreased polyQ aggregation in neurons and intestine, but increased it in the muscle cells.ConclusionsOur data show that cryptic natural variants in genes encoding proteostasis components, although not causing detectable phenotypes in wild-type individuals, can have profound effects on aggregation-prone proteins. Clinical applications of autophagy activators for aggregation diseases may need to consider the unexpected divergent effects of autophagy in different cell types.

Diverse biological processes coordinate the transcriptional response to nutritional changes in a Drosophila melanogaster multiparent population

BackgroundEnvironmental variation in the amount of resources available to populations challenge individuals to optimize the allocation of those resources to key fitness functions. This coordination of resource allocation relative to resource availability is commonly attributed to key nutrient sensing gene pathways in laboratory model organisms, chiefly the insulin/TOR signaling pathway. However, the genetic basis of diet-induced variation in gene expression is less clear.ResultsTo describe the natural genetic variation underlying nutrient-dependent differences, we used an outbred panel derived from a multiparental population, the Drosophila Synthetic Population Resource. We analyzed RNA sequence data from multiple female tissue samples dissected from flies reared in three nutritional conditions: high sugar (HS), dietary restriction (DR), and control (C) diets. A large proportion of genes in the experiment (19.6% or 2471 genes) were significantly differentially expressed for the effect of diet, and 7.8% (978 genes) for the effect of the interaction between diet and tissue type (LRT, Padj. < 0.05). Interestingly, we observed similar patterns of gene expression relative to the C diet, in the DR and HS treated flies, a response likely reflecting diet component ratios. Hierarchical clustering identified 21 robust gene modules showing intra-modularly similar patterns of expression across diets, all of which were highly significant for diet or diet-tissue interaction effects (FDR Padj. < 0.05). Gene set enrichment analysis for different diet-tissue combinations revealed a diverse set of pathways and gene ontology (GO) terms (two-sample t-test, FDR < 0.05). GO analysis on individual co-expressed modules likewise showed a large number of terms encompassing many cellular and nuclear processes (Fisher exact test, Padj. < 0.01). Although a handful of genes in the IIS/TOR pathway including Ilp5, Rheb, and Sirt2 showed significant elevation in expression, many key genes such as InR, chico, most insulin peptide genes, and the nutrient-sensing pathways were not observed.ConclusionsOur results suggest that a more diverse network of pathways and gene networks mediate the diet response in our population. These results have important implications for future studies focusing on diet responses in natural populations.

Molecular and genetic bases of heat stress responses in crop plants and breeding for increased resilience and productivity.

To ensure the food security of future generations and to address the challenge of the 'no hunger zone' proposed by the FAO (Food and Agriculture Organization), crop production must be doubled by 2050, but environmental stresses are counteracting this goal. Heat stress in particular is affecting agricultural crops more frequently and more severely. Since the discovery of the physiological, molecular, and genetic bases of heat stress responses, cultivated plants have become the subject of intense research on how they may avoid or tolerate heat stress by either using natural genetic variation or creating new variation with DNA technologies, mutational breeding, or genome editing. This review reports current understanding of the genetic and molecular bases of heat stress in crops together with recent approaches to creating heat-tolerant varieties. Research is close to a breakthrough of global relevance, breeding plants fitter to face the biggest challenge of our time.