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bioRxiv2021

Transmission distortion and genetic incompatibilities between alleles in a multigenerational mouse advanced intercross line

Background/ObjectivesWhile direct additive and dominance effects on complex traits have been mapped repeatedly, additional genetic factors contributing to the heterogeneity of complex traits have been scarcely investigated. To assess genetic background effects, we investigated transmission ratio distortions (TRDs) of alleles from parent to offspring using an advanced intercross line (AIL) of an initial cross between the mouse inbred strains C57BL/6NCrl (B6N) and BFMI860-12 (BFMI). Subjects/Methods341 males of generation 28 and their respective 61 parents and 66 grandparents were genotyped using Mega Mouse Universal Genotyping Arrays (MegaMUGA). TRDs were investigated using allele transmission asymmetry tests, and pathway overrepresentation analysis was performed. Sequencing data was used to test for overrepresentation of non-synonymous SNPs in TRD regions. Genetic incompatibilities were tested using the Bateson-Dobzhansky-Muller two-locus model. Results62 TRD regions were detected, many in close proximity to the telocentric centromere. TRD regions contained 44.5% more non-synonymous SNPs than randomly selected regions (182 vs. 125.9 {+/-} 17.0, P < 1x10-4). Testing for genetic incompatibilities between TRD regions identified 29 genome-wide significant incompatibilities between TRD regions (P(BF) < 0.05). Pathway overrepresentation analysis of genes in TRD regions showed that DNA methylation, epigenetic regulation of RNA, and meiotic/meiosis regulation pathways were affected independent of the parental origin of the TRD. Paternal BFMI TRD regions showed overrepresentation in the small interfering RNA (siRNA) biogenesis and in the metabolism of lipids and lipoproteins. Maternal B6N TRD regions harbored genes involved in meiotic recombination, cell death, and apoptosis pathways. The analysis of genes in TRD regions suggests the potential distortion of protein-protein interactions influencing obesity and diabetic retinopathy as a result of disadvantageous combinations of allelic variants in Aass, Pgx6 and Nme8. ConclusionsUsing an AIL significantly improves the resolution at which we can investigate TRD. Our analysis implicates distortion of protein-protein interactions as well as meiotic drive as the underlying mechanisms leading to the observed TRD in our AIL. Furthermore, genes with large amounts of non-synonymous SNPs located in TRD regions are more likely to be involved in pathways that are related to the phenotypic differences between the parental strains. Genes in these TRD regions provide new targets for investigating genetic adaptation, protein-protein interactions, and determinants of complex traits such as obesity.

genetics↗

bioRxiv2021

CRISPRa screen on a genetic risk locus shared by multiple autoimmune diseases identifies a dysfunctional enhancer that affects IRF8 expression through cooperative lncRNA and DNA methylation machinery

Dysregulated transcription factors represent a major class of drug targets that mediate the abnormal expression of many critical genes involved in SLE and other autoimmune diseases. Although strong evidence suggests that natural human genetic variation affects basal and inducible gene expression, it is still a considerable challenge to establish a biological link between GWAS-identified non-coding genetic risk variants and their regulated gene targets. Here, we combine genetic data, epigenomic data, and CRISPR activation (CRISPRa) assays to screen for functional variants regulating IRF8 expression. Using CRISPR-mediated deletion and 3D chromatin structure analysis, we demonstrate that the locus containing rs2280381 is a cell-type-specific distal enhancer for IRF8 that spatially interacts with the IRF8 promoter. Further, rs2280381 mediates IRF8 expression through enhancer RNA AC092723.1, which recruits TET1 to the IRF8 promoter to modulate IRF8 expression by affecting methylation levels. The alleles of rs2280381 modulate PU.1 binding and chromatin state to differentially regulate AC092723.1 and IRF8 expression. Our work illustrates a strategy to define the functional genetic variants modulating transcription factor gene expression levels and identifies the biologic mechanism by which autoimmune diseases risk genetic variants contribute to the pathogenesis of disease.

genetics↗

bioRxiv2021

On the Etiology of Aesthetic Chills: a Behavioral Genetic Study

Aesthetic chills, broadly defined as a somatic marker of peak emotional-hedonic responses, are experienced by individuals across a variety of human cultures. Yet individuals vary widely in the propensity of feeling them. These individual differences have been studied in relation to demographics, personality, and neurobiological and physiological factors, but no study to date has explored the genetic etiological sources of variation. To partition genetic and environmental sources of variation in the propensity of feeling aesthetic chills, we fitted a biometrical genetic model to data from 14127 twins (from 8995 pairs), collected by the Netherlands Twin Register. Both genetic and unique environmental factors accounted for variance in aesthetic chills, with heritability estimated at .36 ([.33, .39] 95% CI). We found females more prone than males to report feeling aesthetic chills. However, a test for genotype x sex interaction did not show evidence that heritability differs between sexes. We thus show that the propensity of feeling aesthetic chills is not shaped by nurture alone, but it also reflects underlying genetic propensities.

genetics↗

bioRxiv2021

High genome plasticity and frequent genetic exchange in Leishmania tropica isolates from Afghanistan, Iran and Syria

BackgroundThe kinetoplastid protozoan Leishmania tropica mainly causes cutaneous leishmaniasis in humans in the Middle East, and relapse or treatment failure after treatment are common in this area. L. tropicas digenic life cycle includes distinct stages in the vector sandfly and the mammalian host. Sexual reproduction and genetic exchange appear to occur more frequently than in other Leishmania species. Understanding these processes is complicated by chromosome instability during cell division that yields aneuploidy, recombination and heterozygosity. This combination of rare recombination and aneuploid permits may reveal signs of hypothetical parasexual mating, where diploid cells fuse to form a transient tetraploid that undergoes chromosomal recombination and gradual chromosomal loss. Methodology/Principal FindingsThe genome-wide SNP diversity from 22 L. tropica isolates showed chromosome-specific runs of patchy heterozygosity and extensive chromosome copy number variation. All these isolates were collected during 2007-2017 in Sweden from patients infected in the Middle East and included isolates from a patient possessing two genetically distinct leishmaniasis infections three years apart with no evidence of re-infection. We found differing ancestries on the same chromosome (chr36) across multiple samples: matching the reference genome with few derived alleles, followed by blocks of heterozygous SNPs, and then by clusters of homozygous SNPs with specific recombination breakpoints at an inferred origin of replication. Other chromosomes had similar marked changes in heterozygosity at strand-switch regions separating polycistronic transcriptional units. Conclusion/SignificanceThese large-scale intra- and inter-chromosomal changes in diversity driven by recombination and aneuploidy suggest multiple mechanisms of cell reproduction and diversification in L. tropica, including mitotic, meiotic and parasexual processes. It underpins the need for more genomic surveillance of Leishmania, to detect emerging hybrids that could spread more widely and to better understand the association between genetic variation and treatment outcome. Furthering our understanding of Leishmania genome evolution and ancestry will aid better diagnostics and treatment for cutaneous leishmaniasis caused by L.tropica in the Middle East. Author SummaryCutaneous leishmaniasis is mainly caused by Leishmania tropica in the Middle East, where it is known for treatment failure and a need for prolonged and/or multiple treatments. Several factors affect the clinical presentation and treatment outcome, such as host genetic variability and specific immune response, as well as environmental factors and the vector species. Little is known about the parasite genome and its influence on treatment response. By analysing the genome of 22 isolates of L. tropica, we have revealed extensive genomic variation and a complex population structure with evidence of genetic exchange within and among the isolates, indicating a possible presence of sexual or parasexual mechanisms. Understanding the Leishmania genome better may improve future treatment and better understanding of treatment failure and relapse.

genetics↗

bioRxiv2021

The entomopathogenic nematode Steinernema hermaphroditum is a self-fertilizing hermaphrodite and a genetically tractable system for the study of parasitic and mutualistic symbiosis

Entomopathogenic nematodes, including Heterorhabditis and Steinernema, are parasitic to insects and contain mutualistically symbiotic bacteria in their intestines (Photorhabdus and Xenorhabdus, respectively) and therefore offer opportunities to study both mutualistic and parasitic symbiosis. The establishment of genetic tools in entomopathogenic nematodes has been impeded by limited genetic tractability, inconsistent growth in vitro, variable cryopreservation, and low mating efficiency. We obtained the recently described Steinernema hermaphroditum strain CS34 and optimized its in vitro growth, with a rapid generation time on a lawn of its native symbiotic bacteria Xenorhabdus griffiniae. We developed a simple and efficient cryopreservation method. Previously, S. hermaphroditum isolated from insect hosts was described as first-generation hermaphroditic and second-generation gonochoristic. We discovered that CS34, when grown in vitro, produced consecutive generations of autonomously reproducing hermaphrodites accompanied by rare males. We performed mutagenesis screens in S. hermaphroditum that produced mutant lines with visible and heritable phenotypes. Genetic analysis of the mutants demonstrated that this species reproduces by self-fertilization rather than parthenogenesis and that its sex is determined chromosomally. Genetic mapping has thus far identified markers on the X chromosome and three of four autosomes. We report that S. hermaphroditum CS34 is the first consistently hermaphroditic entomopathogenic nematode and is suitable for genetic model development to study naturally occurring mutualistic symbiosis and insect parasitism.

genetics↗

bioRxiv2021

Genetic effect modification of cis-acting C-reactive protein variants in cardiometabolic disease status

Mendelian randomization (MR) studies carried out among patients with a particular health condition should establish the genetic instrument influences the exposure in that subgroup, however this is normally investigated in the general population. Here, we investigated whether the genetic associations of four cis-acting C-reactive protein (CRP) variants differed between participants with and without three cardiometabolic conditions: obesity, type 2 diabetes, and cardiovascular disease. Associations of cis-genetic variants with CRP differed between obese and non-obese individuals. A multivariable analysis suggested strong independent associations of the gene-by-body mass index (BMI) interaction on CRP (P<1.18x10-8 for the CRP variants). Applying MR, we observed strong causal effect of BMI on CRP (P=2.14x10-65). In summary, our study indicates that genetic associations with CRP differ across disease sub-groups, with evidence to suggest that BMI is an effect modifier. MR studies of disease progression should report on the genetic instrument-exposure association in the disease subgroup under investigation.

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bioRxiv2021

Can DNA help trace the local trade of pangolins? A genetic assessment of white-bellied pangolins from the Dahomey Gap (West Africa)

We conducted in the Dahomey Gap (DG) a pioneer study on the genetic tracing of the African pangolin trade. We sequenced and genotyped 189 white-bellied pangolins from 18 forests and 12 wildlife markets using one mitochondrial fragment and 20 microsatellites loci. Tree-based assignment procedure showed the endemicity of the pangolin trade, as strictly fed by the lineage endemic to the DG (DGL). DGL populations were characterized by low levels of genetic diversity, an overall absence of equilibrium, inbreeding depression and lack of geographic structure. We identified a 92-98% decline in DGL effective population size 200-500 ya -concomitant with major political transformations along the Slave Coast- leading to contemporaneous estimates inferior to minimum viable population size. Genetic tracing suggested that wildlife markets from the DG sourced through the entire DGL range. Our loci provided the necessary power to distinguish among all the genotyped pangolins, tracing the dispatch of same individuals on the markets and within local communities. We developed an approach combining rarefaction analysis of private allele frequencies and cross-validation with observed data that could trace five traded pangolins to their forest origin, c. 200-300 km away from the markets. Although the genetic toolkit that we designed from traditional markers can prove helpful to trace the pangolin trade, our tracing ability was limited by the lack of population structure within DGL. Given the deleterious combination of genetic, demographic and trade-related factors affecting DGL populations, the conservation status of white-bellied pangolins in the DG should be urgently re-evaluated.

genetics↗

bioRxiv2021

North and East African mitochondrial genetic variation needs further characterization towards precision medicine

IntroductionMitochondria are maternally inherited cell organelles with their own genome, and perform various functions in eukaryotic cells such as energy production and cellular homeostasis. Due to their inheritance and manifold biological roles in health and disease, mitochondrial genetics serves a dual purpose of tracing the history as well as disease susceptibility of human populations across the globe. This work requires a comprehensive catalogue of commonly observed genetic variations in the mitochondrial DNAs for all regions throughout the world. So far, however, certain regions, such as North and East Africa have been understudied. ObjectivesTo address this shortcoming, we have created the most comprehensive quality-controlled North and East African mitochondrial dataset to date and use it for characterizing mitochondrial genetic variation in this region. MethodsWe compiled 11 published cohorts with novel data for mitochondrial genomes from 159 Sudanese individuals. We combined these 641 mitochondrial sequences with sequences from the 1000 Genomes (n=2,504) and the Human Genome Diversity Project (n=828) and used the tool haplocheck for extensive quality control and detection of in-sample contamination, as well as Nanopore long read sequencing for haplogroup validation of 18 samples. ResultsUsing a subset of high-coverage mitochondrial sequences, we predict 15 potentially novel haplogroups in North and East African subjects and observe likely phylogenetic deviations from the established PhyloTree reference for haplogroups L0a1 and L2a1. ConclusionOur findings demonstrate common hitherto unexplored variants in mitochondrial genomes of North and East Africa that lead to novel phylogenetic relationships between haplogroups present in these regions. These observations call for further in-depth population genetic studies in that region to enable the prospective use of mitochondrial genetic variation for precision medicine.

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bioRxiv2022

Complex genetic architecture underlying the plasticity of maize agronomic traits

Phenotypic plasticity is the property of a given genotype to produce multiple phenotypes in response to changing environmental conditions. Understanding the genetic basis of phenotypic plasticity and establishing a predictive model is highly relevant for future agriculture under changing climate. Here, we report findings on the genetic basis of phenotypic plasticity for 23 complex traits using a maize diverse population, planted at five sites with distinct environmental conditions and genotyped with ~ 6.60 million SNPs. We found that altitude-related environmental factors were main drivers for across site variation in flowering time traits but not plant architecture and yield traits. For 23 traits, we detected 109 QTLs, of which 29 was for mean, 66 was for plasticity, and 14 for both parameters, besides, 80% of the QTLs were interreacted with the environment. The effects of several QTLs changed in magnitude or sign, driving variation in phenotype plasticity, and we further experimentally validated one plastic gene ZmTPS14.1 whose effect was likely mediated by the compensation effect of ZmSPL6 which was from the downstream pathway probably. By integrating genetic diversity, environmental variation, and their interaction in a joint model, we could provide site-specific predictions with increased accuracy by as much as 15.5%, 3.8%, and 4.4% for DTT, PH, and EW, respectively. Overall, we revealed a complex genetic architecture involving multiallelic, pleiotropy, and genotype by environment interaction underlying maize complex trait mean and plasticity variation. Our study thus provided novel insights into the dynamic genetic architectures of agronomic traits in response to changing environments, paving a practical route to precision agriculture.

genetics↗

bioRxiv2022

Genetic Regulation of Circular RNA Expression in Human Aortic Smooth Muscle Cells and Vascular Traits

BackgroundCircular RNAs (circRNAs) are a class of non-coding RNAs that have cell-type specific expression and are relevant in cardiovascular disease. Aortic smooth muscle cells (SMCs) play a crucial role in cardiovascular disease by differentiating from a quiescent to proliferative phenotype. The role of circRNAs in SMCs and their relevance to cardiovascular disease is largely unexplored. ResultsIn this study, we employ a systems genetics approach to identify circRNA transcripts at a genome wide level and their relevance in cardiovascular traits. We quantified circRNA expression across 151 quiescent and proliferative human aortic SMCs from multiethnic donors. We identified 1,589 expressed circRNAs. Between quiescent and proliferative SMCs, we identified 173 circRNAs which were differentially expressed. To characterize the genetic regulation of circRNA expression, we associated the genotypes of 6.3 million single nucleotide polymorphisms (SNPs) with circRNA abundance and found 96 circRNAs which were associated with genetic loci. Three SNPs were associated with circRNA expression in proliferative SMCs but not in quiescent SMCs. We identified 6 SNPs which had distinct association directions with circRNA isoforms from the same gene. Lastly, to identify the relevance of circRNAs in cardiovascular disease, we overlapped genetic loci associated with circRNA expression with vascular disease related GWAS loci. We identified 7 blood pressure, 1 myocardial infarction, and 3 coronary artery disease loci which were associated with a circRNA transcript (circZKSCAN1, circFOXK2, circANKRD36, circLARP4, circCEP85L, circGTF3C2, circPDS5A, circSLC4A7, and chr17:42610108|42659552) but not mRNA transcript. ConclusionsOverall, our results provide mechanistic insight into the regulation of circRNA expression and the genetic basis of cardiovascular disease.

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bioRxiv2022

Genetic background influences survival of infections with Salmonella enterica serovar Typhimurium in the Collaborative Cross

Salmonella infections typically cause self-limiting gastroenteritis, but in some individuals these bacteria can spread systemically and cause disseminated disease. Salmonella Typhimurium (STm), which causes severe systemic disease in most inbred mice, has been used as a model for disseminated disease. To screen for new infection phenotypes across a range of host genetics, we orally infected 32 Collaborative Cross (CC) mouse strains with STm and monitored their disease progression for seven days by telemetry. Our data revealed a broad range of phenotypes across CC strains in many parameters including survival, bacterial colonization, tissue damage, complete blood counts (CBC), and serum cytokines. Eighteen CC strains survived to day 7, while fourteen susceptible strains succumbed to infection before day 7. Several CC strains had sex differences in survival and colonization. Surviving strains had lower pre-infection baseline temperatures and were less active during their daily active period. Core body temperature disruptions were detected earlier after STm infection than activity disruptions, making temperature a better detector of illness. All CC strains had STm in spleen and liver, but susceptible strains were more highly colonized. Tissue damage was weakly negatively correlated to survival. We identified loci associated with survival on Chromosomes (Chr) 1, 2, 4, 7. Polymorphisms in Ncf2 and Slc11a1, known to reduce survival in mice after STm infections, are located in the Chr 1 interval, and the Chr 7 association overlaps with a previously identified QTL peak called Ses2. We identified two new genetic regions on Chr 2 and 4 associated with susceptibility to STm infection. Our data reveal the diversity of responses to STm infection across a range of host genetics and identified new candidate regions for survival of STm infection. Author SummarySalmonella Typhimurium (STm) infections typically cause self-limiting diarrheal symptoms, but in some individuals, the bacteria can spread throughout the body and cause life-threatening infection. We used a population of genetically different mice (Collaborative Cross) to identify their range of responses to STm infection. We identified a broad range of outcomes across these different mice, including a group of mice susceptible to lethal infection and a group that survived our 7 day study. We found that mice that survived STm infection had a cooler core body temperature before infection than susceptible mice, while remaining active. Thus, body temperature, rather than activity, appears to be a better predictor of poor outcomes after STm infection. We identified several regions of the mouse genome that are associated with outcome after STm infection. One of these regions, mouse Chromosome (Chr) 1 has genes that are already known to influence susceptibility to STm infection. Two other regions that we identified to influence survival after STm infection, located on mouse Chr 2 and 4, are novel and contain numerous genes of interest that may be linked to susceptibility. Our work defines the utility of exploring how host genetic diversity influences infection outcomes with bacterial pathogens.

genetics↗

bioRxiv2022

Genetic structure analysis on leopard cat reveals the effects of habitat fragmentation on subpopulation differentiation in Beijing

In the face of habitat shrinkage and segregation, the survival of wild cats looks bleak. Interpreting the population genetic structure during habitat fragmentation is critical to planning effective management strategies. To reveal the segregation effects of road construction and human settlement on population genetic structure, we noninvasively analyzed fecal DNA samples from leopard cats (Prionailurus bengalensis) from five nature reserves in mountainous areas around Beijing. We focused on molecular microsatellite markers and the mitochondrial control region. A total of 112 individual leopard cats were identified among 601 samples of scat, and generally moderate population genetic diversity was detected. Microsatellite marker-based gene flow (Nm) and STRUCTURE analyses showed no obvious discrepancies among the subpopulations; however, the calculation of genetic distance and construction of a phylogenetic tree of the mitochondrial control region revealed a trend toward differentiation from the other subpopulations in the Songshan subpopulation, which indicates habitat fragmentation effects. Because the isolated Songshan subpopulation may evolve independently, we suggest that its genetic structure be monitored every 5 years to detect any changes and that individuals be introduced as needed to maintain the viability of this subpopulation.

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bioRxiv2022

Specificity and overlap in the genetic architectures of functional and structural connectivity within cerebral resting-state networks

The functional connectivity and dynamics of resting-state networks (RSN-FC) are vital for cognitive functioning. RSN-FC is heritable and partially translates to the anatomical architecture of white matter, but the genetic component of structural connections of RSNs (RSN-SC) and their potential genetic overlap with RSN-FC remains unknown. Here we perform genome-wide association studies (Ndiscovery=24,336; Nreplication=3,412) and in silico annotation on RSN-SC and RSN-FC. We identify the first genes for visual network-SC, that are involved in axon guidance and synaptic functioning and show that genetic variation in RSN-FC impacts biological processes related to brain disorders that have previously been associated with FC alterations in those same RSNs. Correlations of the genetic components of RSNs are mostly observed within the functional domain, whereas less overlap is observed within the structural domain and between the functional and structural domains. This study advances the understanding of the complex functional organization of the brain and its structural underpinnings from a genetics viewpoint.

genetics↗

bioRxiv2022

A genetic strategy to measure insulin signaling regulation and physiology in Drosophila

Insulin regulation is a hallmark of health, and impaired insulin signaling promotes metabolic diseases like diabetes mellitus. However, current assays for measuring insulin signaling in all animals remain semi-quantitative and lack the sensitivity, tissue-specificity or temporal resolution needed to quantify in vivo physiological signaling dynamics. Insulin signal transduction is remarkably conserved across metazoans, including insulin-dependent phosphorylation and regulation of Akt/Protein kinase B. Here, we generated transgenic fruit flies permitting tissue-specific expression of an immunoepitope-labelled Akt (AktHF). We developed enzyme-linked immunosorption assays (ELISA) to quantify picomolar levels of phosphorylated (pAktHF) and total AktHF in single flies, revealing dynamic tissue-specific physiological regulation of pAktHF in response to fasting and re-feeding, exogenous insulin, or targeted genetic suppression of established insulin signaling regulators. Genetic screening revealed Pp1-87B as an unrecognized regulator of Akt and insulin signaling. Tools and concepts here provide opportunities to discover tissue-specific regulators of in vivo insulin signaling responses. Author SummaryInsulin is an essential hormone that controls metabolism in all animals, by regulating energy use and growth of target tissues. Impaired insulin signaling ("resistance") in humans underlies development of type 2 diabetes, a pandemic disease causing significant morbidity and mortality. The genetic risk for insulin resistance is complex, and studies of diabetes are limited by a lack of tools to measure insulin resistance in a sensitive, quantitative, and tissue-specific way. Here, we describe a new technique to measure the strength of insulin signaling in fruit flies. By combining fruit fly genetics with antibody-based assays, we can quantify phosphorylated Akt, an evolutionarily conserved target of insulin signaling, in specific tissues of the adult fly. We show this technique can detect changes in insulin signaling after fasting and refeeding, addition of exogenous insulin, or genetic disruption of the insulin signaling pathway. We used this method to discover a new regulator of insulin signaling, a phosphatase enzyme encoded by Pp1-87B. This exciting new tool should advance our ability to study and discover additional regulators of insulin signaling and resistance.

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bioRxiv2022

An empirical study of sex-stratified vs. sex-combined analysis in the presence of genetic effect heterogeneity

The effect of a genetic variant on a complex trait may differ between female and male, and in the presence of such genetic effect heterogeneity, sex-stratified analysis is often used. For example, genetic effects are sex-specific for testosterone levels, and sex-stratified analysis of testosterone in literature provided easy-to-interpret, sex-specific effect size estimates. However, from the perspective of association testing power, sex-stratified analysis may not be the best approach. As sex-specific genetic effect implies SNPxSex interaction effect, jointly testing SNP main and SNPxSex interaction effects may be more powerful than sex-stratified analysis or the standard main-effect testing approach. Moreover, since individual data may be unavailable, it is then of interest to study if the interaction analysis can be derived from sex-stratified summary statistics. We considered several different sex-combined methods and evaluated them through extensive simulation studies. We observed that a) the joint SNP main and SNPxSex interaction analysis is most robust to a wide range of genetic models, and b) this joint interaction testing result can be obtained by quadratically combining sex-stratified summary statistics (i.e. squared sum of the sex-stratified summary statistics). We then reanalysed the testosterone levels of the UK Biobank data using sex-combined interaction analysis, which identified 27 new loci that were missed by the sex-stratified approach and the standard sex-combined analysis. Finally, we provide supporting association evidence for nine new loci, uniquely identified by the sex-combined interaction analysis, from earlier association studies of either testosterone level or steroid biosynthesis pathway where testosterone is synthesized. We thus recommend sex-combined interaction analysis, particularly for traits with known sex differences, for most powerful association testing, then followed by sex-stratified analysis for effect size estimation and interpretation.

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bioRxiv2022

Complex Traits and Candidate Genes: Estimation of Genetic Variance Components Across Modes of Inheritance

Large-effect loci--those discovered by genome-wide association studies or linkage mapping--associated with key traits segregate amidst a background of minor, often undetectable genetic effects in both wild and domesticated plants and animals. Accurately attributing mean differences and variance explained to the correct components in the linear mixed model (LMM) analysis is important for both selecting superior progeny and parents in plant and animal breeding, but also for gene therapy and medical genetics in humans. Marker-assisted prediction (MAP) and its successor, genomic prediction (GP), have many advantages for selecting superior individuals and understanding disease risk. However, these two approaches are less often integrated to simultaneously study the modes of inheritance of complex traits. This simulation study demonstrates that the average semivariance can be applied to models incorporating Mendelian, oligogenic, and polygenic terms, simultaneously, and yields accurate estimates of the variance explained for all relevant terms. Our previous research focused on large-effect loci and polygenic variance exclusively, and in this work we want to synthesize and expand the average semivariance framework to a multitude of different genetic architectures and the corresponding mixed models. This framework independently accounts for the effects of large-effect loci and the polygenic genetic background and is universally applicable to genetics studies in humans, plants, animals, and microbes.

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bioRxiv2022

Reciprocal recurrent selection based on genetic complementation: An efficient way to build heterosis in diploids due to directional dominance

Depending on the trait architecture and reproduction system, selection strategies in plant breeding focus on the accumulation of additive, dominance effects, or both. Innovation in the accumulation of dominance-effect-based heterosis has been limited since the proposal of GCA-based approaches and very few strategies to exploit it better have been proposed. We propose the use of a new surrogate of genetic complementation between genetic pools to increase accumulation of dominance effects and heterosis. We simulated breeding programs to show how reciprocal recurrent selection by genetic complementation would build the dominance-based heterosis but cheaper than GCA-based approaches and used real phenotypic data from hybrid maize to demonstrate the underlying concepts. We found reciprocal recurrent selection by genetic complementation to be an attractive and viable strategy to exploit dominance, build de novo heterotic pools and boost the current GCA-based approaches. If demonstrated in practice, we hypothesized that this approach would lower the cost of breeding drastically and contribute to food security. Key messageHeterotic patterns can be developed quickly through genetic complementation surrogates to produce high-performance hybrids at a low cost in diploid species displaying dominance and boost GCA-based approaches in hybrid breeding.

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bioRxiv2022

Genetic diversity in global populations of the Critically Endangered addax (Addax nasomaculatus) and its implications for conservation

Threatened species are frequently patchily distributed across small wild populations, ex situ populations managed with varying levels of intensity, and reintroduced populations. Best practice advocates for integrated management across in situ and ex situ populations. Wild addax (Addax nasomaculatus) now number fewer than 100 individuals, yet thousands of addax remain in ex situ populations, which can provide addax for reintroductions, as has been the case in Tunisia in the mid-1980s. However, integrated management requires genetic data to ascertain the relationships between wild and ex situ populations that have incomplete knowledge of founder origins, management histories and pedigrees. We undertook a global assessment of genetic diversity across wild, ex situ, and reintroduced populations in Tunisia to assist conservation planning for this Critically Endangered species. We show that the remnant wild populations retain more mitochondrial haplotypes which are more evolutionarily diverse than the entirety of the ex situ populations across Europe, North America and the United Arab Emirates, and the reintroduced Tunisian population. Additionally, 1704 SNPs revealed that whilst population structure within the ex situ population is minimal, each population carries unique diversity. Finally, we show that careful selection of founders and subsequent genetic management is vital to ensure genetic diversity is provided to, and minimise drift and inbreeding within, reintroductions. Our results highlight a vital need to conserve the last remaining wild addax population, and we provide a genetic foundation for determining integrated conservation strategies to prevent extinction and optimise future reintroductions.

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