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bioRxiv2021

Dissecting the genetic architecture of quantitative traits using genome-wide identity-by-descent sharing among full-sibs

Additive and dominance genetic variances underlying the expression of quantitative traits are important quantities for predicting short-term responses to selection, but they are notoriously challenging to estimate in most non-model wild populations. Specifically, large-sized or panmictic populations may be characterized by low variance in genetic relatedness among individuals which in turn, can prevent accurate estimation of quantitative genetic parameters. We used estimates of genome-wide identity-by-descent (IBD) sharing from autosomal SNP loci to estimate quantitative genetic parameters for ecologically important traits in nine-spined sticklebacks (Pungitius pungitius) from a large, outbred population. Using empirical and simulated datasets, with varying sample sizes and pedigree complexity, we assessed the performance of different crossing schemes in estimating additive genetic variance and heritability for all traits. We found that low variance in relatedness characteristic of wild outbred populations with high migration rate can impair the estimation of quantitative genetic parameters and bias heritability estimates downwards. On the other hand, the use of a half-sib/full-sib design allowed precise estimation of genetic variance components, and revealed significant additive variance and heritability for all measured traits, with negligible dominance contributions. Genome-partitioning and QTL mapping analyses revealed that most traits had a polygenic basis and were controlled by genes at multiple chromosomes. Furthermore, different QTL contributed to variation in the same traits in different populations suggesting heterogenous underpinnings of parallel evolution at the phenotypic level. Our results provide important guidelines for future studies aimed at estimating adaptive potential in the wild, particularly for those conducted in outbred large-sized populations.

evolutionary biology↗

bioRxiv2021

SNP- Based Assessment of Genetic Purity and Diversity in Maize Hybrid Breeding

Assessment of genetic purity of inbred lines and their resultant F1 hybrids is an essential quality control check in maize hybrid breeding, variety release and seed production. In this study, genetic purity, parent-offspring relationship and diversity among the inbred lines were assessed using 92 single-nucleotide polymorphism (SNP) markers. A total of 188 maize genotypes, comprising of 26 inbred lines, four doubled haploid (DH) lines and 158 single-cross maize hybrids were investigated in this study using Kompetitive Allele Specific Polymerase Chain Reaction (KASP) genotyping assays. The bi-allelic data was analyzed for genetic purity and diversity parameters using GenAlex software. The SNP markers were highly polymorphic and 90% had polymorphic information content (PIC) values of > 0.3. Pairwise genetic distances among the lines ranged from 0.05 to 0.56, indicating a high level of dissimilarity among the inbred lines. Maximum genetic distance of (0.56) was observed for CKDHL0089, CML443 and CB323, while the lowest (0.05) was between I-42 and I-40. The majority (67%) of the inbred lines studied were genetically pure with residual heterozygosity of <5%, while only 33% were had heterozygosity levels of >5%. Inbred lines, which were not pure, require purification through further inbreeding. Cluster analysis partitioned the lines into three distinct genetic clusters with the potential to contribute new beneficial alleles to the maize breeding program. Out of the 68 hybrids (43%) that passed the parent-offspring test, seven hybrids namely; SCHP29, SCHP95, SCHP94, SCHP134, SCHP44, SCHP114 and SCHP126, were selected as potential candidates for further evaluation and release due to their outstanding yield performance.

molecular biology↗

bioRxiv2021

Increasing temperature weakens the positive effect of genetic diversity on population growth

Genetic diversity and temperature increases associated with global climate change, are known to independently influence population growth and extinction risk. Whether increasing temperature may influence the effect of genetic diversity on population growth, however, is not known. We address this issue in the model protist system Tetrahymena thermophila. We test the hypothesis that at temperatures closer to the species thermal optimum (i.e., the temperature at which population growth is maximal), genetic diversity should have a weaker effect on population growth compared to temperatures away from the thermal optimum. To do so, we grew populations of T. thermophila with varying levels of genetic diversity at increasingly warmer temperatures and quantified their intrinsic population growth rate, r. We found that genetic diversity increases population growth at cooler temperatures, but that as temperature increases, this effect almost completely disappears. We also show that a combination of changes in the amount of expressed genetic diversity (G), plastic changes in population growth across temperatures (E), and strong GxE interactions, underlie this temperature effect. Our results uncover important but largely overlooked temperature effects that have implications for the management of small populations with depauperate genetic stocks in an increasingly warming world.

ecology↗

bioRxiv2021

Error minimization and specificity could emerge in a genetic code as by-products ofprebiotic evolution

The emergence of the genetic code was a major transition in the evolution from a prebiotic RNA world to the earliest modern cells1. A prominent feature of the standard genetic code is error minimization, or the tendency of mutations to be unusually conservative in preserving biophysical features of the amino acid2-6. While error minimization is often assumed to result from natural selection, it has also been speculated that error minimization may be a by-product of emergence of the genetic code3. During establishment of the genetic code in an RNA world, self-aminoacylating ribozymes would enforce the mapping of amino acids to anticodons. Here we show that expansion of the genetic code, through co-option of ribozymes for new substrates, could result in error minimization as an emergent property. Using self-aminoacylating ribozymes previously identified during an exhaustive search of sequence space7, we measured the activity of thousands of candidate ribozymes on alternative substrates (activated analogs for tryptophan, phenylalanine, leucine, isoleucine, valine, and methionine). Related ribozymes exhibited preferences for biophysically similar substrates, indicating that co-option of existing ribozymes to adopt additional amino acids into the genetic code would itself lead to error minimization. Furthermore, ribozyme activity was positively correlated with specificity, indicating that selection for increased activity would also lead to increased specificity. These results demonstrate that by-products of the evolution and functional expansion of a ribozyme system could lead to adaptive properties of a genetic code. Such spandrels could thus underlie significant prebiotic developments.

biochemistry↗

bioRxiv2021

Genetic structure correlates with ethnolinguistic diversity in eastern and southern Africa

African populations are the most diverse in the world yet are sorely underrepresented in medical genetics research. Here, we examine the structure of African populations using genetic and comprehensive multigenerational ethnolinguistic data from the Neuropsychiatric Genetics of African Populations-Psychosis study (NeuroGAP-Psychosis) consisting of 900 individuals from Ethiopia, Kenya, South Africa, and Uganda. We find that self-reported language classifications meaningfully tag underlying genetic variation that would be missed with consideration of geography alone, highlighting the importance of culture in shaping genetic diversity. Leveraging our uniquely rich multi-generational ethnolinguistic metadata, we track language transmission through the pedigree, observing the disappearance of several languages in our cohort as well as notable shifts in frequency over three generations. We find suggestive evidence for the rate of language transmission in matrilineal groups having been higher than that for patrilineal ones. We highlight both the diversity of variation within the African continent, as well as how within-Africa variation can be informative for broader variant interpretation; many variants appearing rare elsewhere are common in parts of Africa. The work presented here improves the understanding of the spectrum of genetic variation in African populations and highlights the enormous and complex genetic and ethnolinguistic diversity within Africa.

genomics↗

bioRxiv2021

Genetic isolation by distance underlies color pattern divergence in red-eyed treefrogs (Agalychnis callidryas)

Investigating the spatial distribution of genetic and phenotypic variation can provide insights into the evolutionary processes that shape diversity in natural systems. We characterized patterns of genetic and phenotypic diversity to learn about drivers of color-pattern diversification in red-eyed treefrogs (Agalychnis callidryas) in Costa Rica. Along the Pacific coast, red-eyed treefrogs have conspicuous leg color patterning that transitions from orange in the north to purple in the south. We measured phenotypic variation of frogs, with increased sampling at sites where the orange-to-purple transition occurs. At the transition zone, we discovered the co-occurrence of multiple color-pattern morphs. To explore possible causes of this variation, we generated a SNP dataset to analyze population genetic structure, measure genetic diversity, and infer the processes that mediate genotype-phenotype dynamics. We investigated how patterns of genetic relatedness correspond with individual measures of color pattern along the coast, including testing for the role of hybridization in geographic regions where orange and purple phenotypic groups co-occur. We found no evidence that color-pattern polymorphism in the transition zone arose through recent hybridization. Instead, a strong pattern of genetic isolation by distance (IBD) indicates that color-pattern variation was either retained through other processes such as ancestral color polymorphisms or ancient secondary contact, or else it was generated by novel mutations. We found that phenotype changes along the Pacific coast more than would be expected based on genetic divergence and geographic distance alone. Combined, our results suggest the possibility of selective pressures acting on color pattern at a small geographic scale.

evolutionary biology↗

bioRxiv2021

System genetics in the rat HXB/BXH family identifies Tti2 as a pleiotropic quantitative trait gene for adult hippocampal neurogenesis and serum glucose

Neurogenesis in the adult hippocampus contributes to learning and memory in the healthy brain but is dysregulated in metabolic and neurodegenerative diseases. The molecular relationships between neural stem cell activity, adult neurogenesis, and global metabolism are largely unknown. Here we applied unbiased systems genetic methods to quantify genetic covariation among adult neurogenesis and metabolic phenotypes in peripheral tissues of a genetically diverse family of rat strains, derived from a cross between the spontaneously hypertensive (SHR/OlaIpcv) strain and Brown Norway (BN-Lx/Cub). The HXB/BXH family is a very well established model to dissect genetic variants that modulate metabolic and cardiovascular disease and we have accumulated deep phenome and transcriptome data in a FAIR-compliant resource for systematic and integrative analyses. Here we measured rates of precursor cell proliferation, survival of new neurons, and gene expression in the hippocampus of the entire HXB/BXH family, including both parents. These data were combined with published metabolic phenotypes to detect a neurometabolic quantitative trait locus (QTL) for serum glucose and neuronal survival. We subsequently fine-mapped a key phenotype to a locus that includes the telo2-interacting protein 2 gene (Tti2)--a chaperone that modulates the activity and stability of PIKK kinases. To validate variants in or near Tti2 as a cause for differences in neurogenesis and glucose levels, we generated a targeted frameshift mutation on the SHR/OlaIpcv background. Heterozygous SHR-Tti2+/- mutants had lower rates of hippocampal neurogenesis and hallmarks of dysglycemia compared to wild-type littermates. Our findings highlight Tti2 as a causal genetic and molecular link between glucose metabolism and structural brain plasticity. In humans, more than 800 genomic variants are linked to TTI2 expression, seven of which have associations to protein and blood stem cell factor concentrations, blood pressure and frontotemporal dementia. Author summaryMetabolic and neurological disorders are often comorbid, suggesting that biological pathways which orchestrate peripheral homeostasis and the integrity of the nervous system intersect. The genetic architecture behind these relationships is still poorly described, in part because molecular processes in the human brain are very difficult to study. We thus used a rodent genetic reference population to investigate links between adult hippocampal neurogenesis-- a cellular plasticity mechanism important for learning flexibility--and metabolism. We measured adult neurogenesis in the family of 30 HXB/BXH rat recombinant inbred strains, who are characterised by stable differences in metabolism, behaviour, and gene expression levels. Because gene variants affecting distinct traits segregated into different members of the family, we discovered that previously published phenotypes correlated to adult neurogenesis due to shared genomic sequence. We found that expression levels of Tti2--a part of a specialised protein chaperone complex regulating stability of PIKK kinases--were concomitantly influencing adult neurogenesis and serum glucose levels. In human populations hundreds of genomic variants regulate TTI2 expression, potentially affecting brain function and glucose homeostasis.

neuroscience↗

bioRxiv2021

The crucial role of genome-wide genetic variation in conservation

The unprecedented rate of extinction calls for efficient use of genetics to help conserve biodiversity. Several recent genomic and simulation-based studies have argued that the field of conservation biology has placed too much focus on the conservation of genome-wide genetic variation, and that this approach should be replaced with another that focuses instead on managing the subset of functional genetic variation that is thought to affect fitness. Here, we critically evaluate the feasibility and likely benefits of this approach in conservation. We find that population genetics theory and empirical results show that the conserving genome-wide genetic variation is generally the best approach to prevent inbreeding depression and loss of adaptive potential from driving populations towards extinction. Focusing conservation efforts on presumably functional genetic variation will only be feasible occasionally, often misleading, and counterproductive when prioritized over genome-wide genetic variation. Given the increasing rate of habitat loss and other environmental changes, failure to recognize the detrimental effects of lost genome-wide variation on long-term population viability will only worsen the biodiversity crisis.

evolutionary biology↗

bioRxiv2021

Genetic diversity assessment of neem (Azadirachta indica A. Juss) in northern Nigeria

Neem is a tropical tree that can adapt to a wide range of places and particularly to semi-arid conditions. As at present, it is grown in many Asian countries and also in the tropical regions of the western hemisphere. Genetic variability and diversity are a major requirement needed for both immediate results and the one ones thereafter adaptation of plant types in their original domain. The evaluation of genetic diversity of any species is extremely crucial for their sustainability, continuity, survival and gene manipulation. Major breakthroughs in the field of molecular biology was able to develop several tools for the investigation of genetic diversity at the genome level to determine phylogenetic relationships among inter or intra-species. The advent of molecular markers for the detection and exploitation of DNA polymorphism is one of the major breakthroughs in the world of molecular genetics. The importance of genetic diversity in plant germplasm conservation, especially in economically important species such as Azadirachtaindica, is enormous, particularly in Nigeria. The question is whether A. indica from different Agro-ecological zones have genetic variations or similarities. This was the bane of the current study, which used RAPD to look atgenetic diversity of 27 randomly selected neem trees within the agro-ecological zones in Northern Nigeria. A total of 9 primers were employed out of which only 5 were responsive (OPA-02, OPA-03, OPA-15 and OPA-19). These primers showed dissimilarities in the visible DNA bands among the various tree samples. There was evidence of genetic dissimilarities among the trees sampled. Differences in percentage polymorphism was reported, where it was reportedly highest among the Borno State tree samples (97.44%), compared to those in Yobe State with no polymorphism.

plant biology↗

bioRxiv2021

Testing for genetic assimilation with phylogenetic comparative analysis: Conceptual, methodological, and statistical considerations

Genetic assimilation is a process that leads to reduced phenotypic plasticity during adaptation to novel conditions, a potentially important phenomenon under global environmental change. Null expectations when testing for genetic assimilation, however, are not always clear. For instance, the statistical artifact of regression to the mean could bias us towards detecting genetic assimilation when it has not occurred. Likewise, the specific mechanism underlying plasticity expression may affect null expectations under neutral evolution. We used macroevolutionary numerical simulations to examine both of these important issues and their interaction, varying whether or not plasticity evolves, the evolutionary mechanism, trait measurement error, and experimental design. We also modified an existing reaction norm correction method to account for phylogenetic non-independence. We found: 1) regression to the mean is pervasive and can generate spurious support for genetic assimilation; 2) experimental design and post-hoc correction can minimize this spurious effect; and 3) neutral evolution can produce patterns consistent with genetic assimilation without constraint or selection, depending on the mechanism of plasticity expression. Additionally, we re-analyzed published macroevolutionary data supporting genetic assimilation, and found that support was lost after proper correction. Considerable caution is thus required whenever investigating genetic assimilation and reaction norm evolution at macroevolutionary scales.

evolutionary biology↗

bioRxiv2022

Development of the First Tractable Genetic System for Parvimonas micra, a Ubiquitous Pathobiont in Human Dysbiotic Disease

Parvimonas micra is a Gram-positive obligate anaerobe and a typical member of the human microbiome. P. micra is among the most highly enriched species at numerous sites of mucosal dysbiotic disease and is closely associated with the development of multiple types of malignant tumors. Despite its strong association with disease, surprisingly little is known about P. micra pathobiology, which is directly attributable to its longstanding genetic intractability. To address this problem, we directly isolated a collection of P. micra strains from odontogenic abscess clinical specimens and then screened these isolates for natural competence. Amazingly, all of the P. micra clinical isolates exhibited various levels of natural competence, including the reference strain ATCC 33270. By exploiting this ability, we were able to employ cloning-independent methodologies to engineer and complement a variety of targeted chromosomal genetic mutations directly within low passage clinical isolates. To create the first P. micra genetic system, we employed renilla-based bioluminescence for highly sensitive reporter studies. This reporter system was then applied for the development of the novel Theo+ theophylline-inducible riboswitch for tunable gene expression studies over a broad dynamic range. Finally, we demonstrate the feasibility of generating Mariner-based Tn-seq libraries for forward genetic screening in P. micra. With the availability of a highly efficient transformation protocol and the current suite of genetic tools, P. micra should now be considered as a fully genetically tractable organism suitable for molecular genetic research. The methods presented here provide a clear path to investigate the understudied role of P. micra in polymicrobial infections and tumorigenesis.

microbiology↗

bioRxiv2022

Genetic load in incomplete lupus erythematosus

Incomplete lupus erythematosus (ILE) patients have lupus features but insufficient criteria for systemic lupus erythematosus (SLE) classification. Some ILE patients transition to SLE, but most avoid major organ involvement. This study tested whether the milder disease course in ILE is influenced by reduced SLE-risk allele genetic load. We calculated the genetic load based on 99 SLE-associated risk alleles in European American SLE patients (>4 ACR-1997 criteria, n=171), ILE patients (3 ACR-1997 criteria; n=174), a subset of ILE patients not meeting SLICC classification (ILESLICC, n=119), and healthy controls (n=133). ILE and SLE patients had significantly greater SLE-risk allele genetic load compared to healthy controls, while ILESLICC patients had a trend toward an increased genetic load, although not statistically significant. However, the genetic load did not differ between ILE and SLE. In conclusion, ILE and SLE patients have comparable genetic loads of SLE risk loci, suggesting similar genetic predisposition between these conditions. Phenotypic differences between SLE and ILE may instead be influenced by ILE-specific variants and gene-environment interactions.

immunology↗

bioRxiv2022

Structure-informed microbial population genetics elucidate selective pressures that shape protein evolution

Comprehensive sampling of natural genetic diversity with metagenomics enables highly resolved insights into the interplay between ecology and evolution. However, intra-population genomic variation represents the outcome of both stochastic and selective forces, making it difficult to identify whether variants are maintained by adaptive, neutral, or purifying processes. This is partly due to the reliance on gene sequences to interpret variants, which disregards the physical properties of three-dimensional gene products that define the functional landscape on which selection acts. Here we describe an approach to analyze genetic variation in the context of predicted protein structures, and apply it to study a marine microbial population within the SAR11 subclade 1a.3.V, which dominates low-latitude surface oceans. Our analyses reveal a tight association between the patterns of nonsynonymous polymorphism, selective pressures, and structural properties of proteins such as per-site relative solvent accessibility and distance to ligands, which explain up to 59% of genetic variance in some genes. In glutamine synthetase, a central gene in nitrogen metabolism, we observe decreased occurrence of nonsynonymous variants from ligand binding sites as a function of nitrate concentrations in the environment, revealing genetic targets of distinct evolutionary pressures maintained by nutrient availability. Our data also reveals that rare codons are purified from ligand binding sites when genes are under high selection, demonstrating the utility of structure-aware analyses to study the variants that likely impact translational processes. Overall, our work yields insights into the governing principles of evolution that shape the genetic diversity landscape within a globally abundant population, and makes available a software framework for structure-aware investigations of microbial population genetics. SignificanceIncreasing availability of metagenomes offers new opportunities to study evolution, but the equal treatment of all variants limits insights into drivers of sequence diversity. By capitalizing on recent advances in protein structure prediction capabilities, our study examines subtle evolutionary dynamics of a microbial population that dominates surface oceans through the lens of structural biology. We demonstrate the utility of structure-informed metrics to understand the distribution of nonsynonymous polymorphism, establish insights into the impact of changing nutrient availability on protein evolution, and show that even synonymous variants are scrutinized strictly to maximize translational efficiency when selection is high. Overall, our work illustrates new opportunities for discovery at the intersection between metagenomics and structural bioinformatics, and offers an interactive and scalable software platform to visualize and analyze genetic variants in the context of predicted protein structures and ligand-binding sites.

microbiology↗

bioRxiv2022

Genetic diversity and characterization of circular replication(Rep)-encoding single-stranded (CRESS) DNA viruses

The CRESS-DNA viruses are the ubiquitous virus detected in almost all eukaryotic life trees and play an essential role in the maintaining ecosystem of the globe. Still, their genetic diversity is not fully understood. Here we bring to light the genetic diversity of Replication (Rep) and Capsid (Cap) proteins of CRESS-DNA viruses. We divided the Rep protein of the CRESS-DNA virus into ten clusters using CLANS and phylogenetic analyzes. Also, most of the Rep protein in Rep cluster 1 (R1) and R2 (Circoviridae, Smacoviridae, Nanoviridae, and CRESSV1-5) contain the Viral_Rep superfamily and P-loop_NTPase superfamily domains, while the Rep protein of viruses in other clusters has no such characterized functional domain. The Circoviridae, Nanoviridae, and CRESSV1-3 viruses contain two domains, such as Viral_Rep and P-loop_NTPase; the CRESSV4 and CRESSV5 viruses have only the Viral_Rep domain, and most of the sequences in the pCRESS-related group have only P-loop_NTPase, and Smacoviridae do not have these two domains. Further, we divided the Cap protein of the CRESS-DNA virus into 20 clusters using CLANS and phylogenetic analyzes. The Rep and Cap proteins of Circoviridae and Smacoviridae are grouped into a specific cluster. Cap protein of CRESS-DNA viruses grouped with one cluster and Rep protein with another cluster. Further, our study reveals that selection pressure plays a significant role in the evolution of CRESS-DNA viruses Rep and Cap genes rather than mutational pressure. We hope this study will help determine the genetic diversity of CRESS-DNA viruses as more sequences are discovered in the future. ImportanceThe genetic diversity of CRESS-DNA viruses is not fully understood. CRESS-DNA viruses are classified as CRESSV1 to CRESSV6 using only Rep protein. This study revealed that the Rep protein of the CRESS-DNA viruses is classified as CRESSV1 to CRESSV6 groups and the new Smacoviridae-related, CRESSV2-related pCRESS-related, Circoviridae-related, and 1 to 4 outgroups, according to the Viral_Rep and P-loop_NTPase domain organization, CLANS, and phylogenetic analysis. Furthermore, for the first time in this study, the Cap protein of CRESS-DNA viruses was classified into 20 distinct clusters by CLANS and phylogenetic analysis. Through this classification, the genetic diversity of CRESS-DNA viruses clarifies the possibility of recombinations in Cap and Rep proteins. Finally, it has been shown that selection pressure plays a significant role in the evolution and genetic diversity of Cap and Rep proteins. This study explains the genetic diversity of CRESS-DNA viruses and hopes that it will help classify future detected viruses.

microbiology↗

bioRxiv2022

Genetic and environmental drivers of large-scale epigenetic variation in Thlaspi arvense

Natural plant populations often harbour substantial heritable variation in DNA methylation. However, a thorough understanding of the genetic and environmental drivers of this epigenetic variation requires large-scale and high-resolution data, which currently exist only for a few model species. Here, we studied 207 lines of the annual weed Thlaspi arvense (field pennycress), collected across a large latitudinal gradient in Europe and propagated in a common environment. By screening for variation in DNA sequence and DNA methylation using whole-genome (bisulfite) sequencing, we found significant epigenetic population structure across Europe. Average levels of DNA methylation were strongly context-dependent, with highest DNA methylation in CG context, particularly in transposable elements and in intergenic regions. Residual DNA methylation variation within all contexts was associated with genetic variants, which often co-localized with annotated methylation machinery genes but also with new candidates. Variation in DNA methylation was also significantly associated with climate of origin, with methylation levels being higher in warmer regions and lower in more variable climates. Finally, we used variance decomposition to assess genetic versus environmental associations with differentially methylation regions (DMRs). We found that while genetic variation was generally the strongest predictor of DMRs, the strength of environmental associations increased from CG to CHG and CHH, with climate-of-origin as the strongest predictor in about one third of the CHH DMRs. In summary, our data show that natural epigenetic variation in Thlaspi arvense is significantly associated with both DNA sequence and environment of origin, and that the relative importance of the two factors strongly depends on the sequence context of DNA methylation. T. arvense is an emerging biofuel and winter cover crop; our results may hence be relevant for breeding efforts and agricultural practices in the context of rapidly changing environmental conditions. Author SummaryVariation within species is an important level of biodiversity, and it is key for future adaptation. Besides variation in DNA sequence, plants also harbour heritable variation in DNA methylation, and we want to understand the evolutionary significance of this epigenetic variation, in particular how much of it is under genetic control, and how much is associated with the environment. We addressed these questions in a high-resolution molecular analysis of 207 lines of the common plant field pennycress (Thlaspi arvense), which we collected across Europe, propagated under standardized conditions, and sequenced for their genetic and epigenetic variation. We found large geographic variation in DNA methylation, associated with both DNA sequence and climate of origin. Genetic variation was generally the stronger predictor of DNA methylation variation, but the strength of environmental association varied between different sequence contexts. Climate-of-origin was the strongest predictor in about one third of the differentially methylated regions in the CHH context, which suggests that epigenetic variation may play a role in the short-term climate adaptation of pennycress. As pennycress is currently being domesticated as a new biofuel and winter cover crop, our results may be relevant also for agriculture, particularly in changing environments.

evolutionary biology↗

bioRxiv2022

Transcriptome-wide Analyses of Adipose Tissue in Outbred Rats Reveal Genetic Regulatory Mechanisms Relevant for Human Obesity

Transcriptomic analysis in metabolically active tissues allows a systems genetics approach to identify causal genes and networks involved in metabolic disease. Outbred heterogeneous stock (HS) rats are used for genetic mapping of complex traits, but to-date, a systems genetics analysis of metabolic tissues has not been done. We investigated whether adiposity-associated genes and gene co-expression networks in outbred heterogeneous stock (HS) rats overlap those found in humans. We analyzed RNAseq data from adipose tissue of 415 male HS rats, correlated these transcripts with body weight (BW) and compared transcriptome signatures to two human cohorts: the African American Genetics of Metabolism and Expression and Metabolic Syndrome in Men. We used weighted gene co-expression network analysis to identify adiposity-associated gene networks and mediation analysis to identify genes under genetic control whose expression drives adiposity. We identified 554 orthologous "consensus genes" whose expression correlates with BW in the rat and with body mass index (BMI) in both human cohorts. Consensus genes fell within eight co-expressed networks and were enriched for genes involved in immune system function, cell growth, extracellular matrix organization and lipid metabolic processes. We identified 19 consensus genes for which genetic variation may influence BW via their expression, including those involved in lipolysis (e.g., Hcar1), inflammation (e.g., Rgs1), adipogenesis (e.g., Tmem120b) or no previously known role in obesity (e.g., St14, Msa4a6). Strong concordance between HS rat and human BW/BMI associated transcripts demonstrates translational utility of the rat model, while identification of novel genes expands our knowledge of the genetics underlying obesity.

genomics↗

bioRxiv2022

An atlas of genetic scores to predict multi-omic traits

Genetically predicted levels of multi-omic traits can uncover the molecular underpinnings of common phenotypes in a highly efficient manner. Here, we utilised a large cohort (INTERVAL; N=50,000 participants) with extensive multi-omic data for plasma proteomics (SomaScan, N=3,175; Olink, N=4,822), plasma metabolomics (Metabolon HD4, N=8,153), serum metabolomics (Nightingale, N=37,359), and whole blood Illumina RNA sequencing (N=4,136). We used machine learning to train genetic scores for 17,227 molecular traits, including 10,521 which reached Bonferroni-adjusted significance. We evaluated genetic score performances in external validation across European, Asian and African American ancestries, and assessed their longitudinal stability within diverse individuals. We demonstrated the utility of these multi-omic genetic scores by quantifying the genetic control of biological pathways and by generating a synthetic multi-omic dataset of UK Biobank to identify disease associations using a phenome-wide scan. Finally, we developed a portal (OmicsPred.org) to facilitate public access to all genetic scores and validation results as well as to serve as a platform for future extensions and enhancements of multi-omic genetic scores.

genomics↗

bioRxiv2022

Which life history strategy can maintain high genetic diversity in plants?

Classifying a variety of plant life histories is an important step to understand ecological and evolutionary background of life history diversification in plants. Principal component analysis (PCA) of life history traits, as well as elasticity analysis using a ternary diagram, successfully categorized the diverse life histories and clarified their link to various ecological characteristics, such as population dynamics, functional traits, and conservation status. However, the relationships with population genetic properties, including genetic diversity, have not been explored very much. In this study, we overlaid annual change rate of expected heterozygosity{eta} on life history spectrum obtained by PCA and elasticity analysis to examine which life history strategy can maintain high genetic diversity over time. We found that{eta} gradually changed along the fast-slow continuum and that slow-paced life histories maintained high genetic diversity, probably due to generation overlap. Elasticity analysis showed that life histories that highly depend on stasis also maintained genetic diversity. As genetic diversity reflects adaptive potential to environmental changes, our study provides a new genetic perspective on adaptative evolution and population viability to life history study.

ecology↗