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bioRxiv2020

The Genetic Architecture of Leaf Stable Carbon Isotope Composition in Zea mays and the Effect of Transpiration Efficiency on Elemental Accumulation

With increased demand on freshwater resources for agriculture, it is imperative that more water-use efficient crops are developed. Leaf stable carbon isotope composition, {delta}13C, is a proxy for transpiration efficiency and a possible tool for breeders, but the underlying mechanisms effecting {delta}13C in C4 plants are not known. It has been suggested that differences in specific leaf area, which potentially reflects variation in internal CO2 diffusion, can impact leaf {delta}13C. However, at this point the relationship has not been tested in maize. Furthermore, although it is known that water movement is important for elemental uptake, it is not clear how manipulation of transpiration for increased water-use efficiency may impact nutrient accumulation. Here we characterize the underlying genetic architecture of leaf {delta}13C and test its relationship to specific leaf area and the ionome in four biparental populations of maize. Five significant QTL for leaf {delta}13C were identified, including both novel QTL as well as some that were identified previously in maize kernels. One of the QTL regions contains an Erecta-like gene, the ortholog of which has been shown to regulate transpiration efficiency and leaf {delta}13C in Arabidopsis. Our data does not support a relationship between {delta}13C and specific leaf area, and of the 19 elements analyzed, only a weak correlation between molybdenum and {delta}13C was detected. Together these data begin to build a genetic understanding of leaf {delta}13C in maize and suggest the potential to improve plant water use without significantly influencing elemental homeostasis. Article SummaryQuantitative genetics approaches were used to investigate the genetic architecture of leaf stable carbon isotope discrimination ({delta}13C) in maize. Developing a better understanding of leaf {delta}13C could facilitate its use in breeding for reduced transpirational water loss. Several genomic regions were identified that contribute to the variation observed in leaf {delta}13C. Furthermore, contrary to what has been observed in other species, leaf {delta}13C was not correlated with specific leaf area. Finally, a leaf ionomic analysis indicates that a reduction in transpiration, and thus mass flow, would not result in a decrease in nutrient accumulation.

plant biology↗

bioRxiv2020

Lipid metabolic stress in development defines which genetically-susceptible DYT-TOR1A mice develop disease

There has been enormous progress defining the genetic landscape of disease. However, genotypes rarely fully predict neurological phenotypes, and we rarely understand why. TOR1A +/{Delta}gag that causes dystonia with ~30% penetrance is a classic case. Here we show, in inbred mice, that +/{Delta}gag affects embryonic brain lipid metabolism with sex-skewed reduced penetrance. Penetrance is affected by environmental context, including maternal diet. The lipid metabolic defect resolves during post-natal development. Nevertheless, we discover dystonia-like symptoms in ~30% of juvenile female Tor1a+/{Delta}gag mice, and prevent these symptoms by genetically suppressing abnormal lipid metabolism. We conclude that Tor1a+/{Delta}gag embryos poorly buffer metabolic stress in utero, resulting in a period of abnormal metabolism that hardwires the brain for dystonia in later life. The data show unexpected and profound impacts of sex, and thus highlight the importance of examining male and female animal models of disease. Significance StatementThe genetic landscape of neurological disease is relatively well mapped. However, we typically cannot explain why some mutations only cause disease in a subset of individuals. A classic case is DYT-TOR1A dystonia that only develops in 30% of TOR1A+/{Delta}gag carriers. We now find that ~30% of inbred female Tor1a+/{Delta}gag mice develop abnormal brain lipid metabolism as embryos, while males are spared. The percentage is affected by maternal diet. Further, this period of abnormal lipid metabolism causes dystonia-like symptoms in juvenile mice. These data show how an environmentally-sensitive event of development defines which genetically-susceptible individuals develop disease in later life. They also highlight the importance of examining male and female animal models of disease.

neuroscience↗

bioRxiv2020

Delineating the Genetic Component of Gene Expression in Major Depression

BackgroundMajor Depression (MD) is determined by a multitude of factors including genetic risk variants which regulate gene expression (GE). Here, we examined the genetic component of GE in MD by performing a Transcriptome-Wide Association Study (TWAS), inferring GE-trait relationships from genetic, transcriptomic and phenotypic information. MethodGenes differentially expressed in depression were identified with the TWAS FUSION method, based on summary statistics from the largest genome-wide association analysis of MD (Ncases = 135,458) and GE levels from 20 tissue datasets. Follow-up analyses were performed to extensively characterize the identified associations: colocalization, conditional, and fine-mapping analyses together with functionally-enriched pathway investigations. ResultsTranscriptome-wide significant GE differences between cases and controls were found at 91 genes, 50 of which were not found in previous MD TWASs. Of the 91 significant genes, eight represented strong, colocalized, and potentially causal associations with depression, which were independent from the effect of nearby genes. Such "high-confidence associations" include NEGR1, CTC-467M3.3, TMEM106B, CTD-2298J14.2, CCDC175, ESR2, PROX2, ZC3H7B. Lastly, TWAS-based enrichment analysis highlighted dysregulation of gene sets for long term potentiation, dendritic shaft, and memory processes in MD. ConclusionThis study has shed light on the genetic component of GE in depression by characterizing the identified associations, unravelling novel risk genes, and determining which associations are congruent with a causal model. These findings can be used as a resource for prioritizing and designing subsequent functional studies of MD.

genomics↗

bioRxiv2020

Genomic evidence for recurrent genetic admixture during domestication mediterranean olive trees (Olea europaea).

BackgroundThe olive tree (Olea europaea L. subsp. europaea, Oleaceae) has been the most economic perennial crop for Mediterranean countries since its domestication around 6,000 years ago. Two taxonomic varieties are currently recognized: cultivated (var. europaea) and wild (var. sylvestris) trees. To shed light into the recent evolution and domestication of the olive tree, we sequenced the genomes of twelve individuals: ten var. europaea, one var. sylvestris, and one outgroup taxon (subsp. cuspidata). All of them were analysed together with an improved assembly of var. europaea reference genome and the available assembly of var. sylvestris. ResultsOur analyses show that cultivated olives exhibit slightly lower levels of overall genetic diversity than wild forms, and that this can be partially explained by the occurrence of a mild population bottleneck 5000-7000 years ago during the primary domestication period. We also provide the first phylogenetic analysis of genome-wide sequences, which supports a continuous process of domestication of the olive tree. This, together with population structure and introgression analyses highlights genetic admixture with wild populations across the Mediterranean Basin in the course of domestication. ConclusionsAltogether, our results suggest that a primary domestication area in the eastern Mediterranean basin was followed by numerous secondary events across most countries of southern Europe and northern Africa, often involving genetic admixture with genetically rich wild populations, particularly from the western Mediterranean Basin. Based on selection tests and a search for selective sweeps, we found that genes associated with stress response and developmental processes were positively selected in cultivars. However, we did not find evidence that genes involved in fruit size or oil content were under positive selection.

evolutionary biology↗

bioRxiv2020

CiBER-seq dissects genetic networks by quantitative CRISPRi profiling of expression phenotypes

To realize the promise of CRISPR/Cas9-based genetics, approaches are needed to quantify a specific, molecular phenotype across genome-wide libraries of genetic perturbations. We address this challenge by profiling transcriptional, translational, and post-translational reporters using CRISPR interference with barcoded expression reporter sequencing (CiBER-seq). Our barcoding approach connects an entire library of guides to their individual phenotypic consequences using pooled sequencing. We show that CiBER-seq profiling fully recapitulates the integrated stress response (ISR) pathway in yeast. Genetic perturbations causing uncharged tRNA accumulation activated ISR reporter transcription. Surprisingly, tRNA insufficiency also activated the reporter, independent of the Gcn2 kinase that senses uncharged tRNAs. By uncovering alternate triggers for ISR activation, we illustrate how precise, comprehensive CiBER-seq profiling provides a powerful and broadly applicable tool for dissecting genetic networks.

genomics↗

bioRxiv2020

Thermal adaptation rather than demographic history drives genetic structure inferred by copy number variants in a marine fish

Increasing evidence shows that structural variants represent an overlooked aspect of genetic variation with consequential evolutionary roles. Among those, copy number variants (CNVs), including duplicated genomic region and transposable elements (TEs) may contribute to local adaptation and/or reproductive isolation among divergent populations. Those mechanisms suppose that CNVs could be important drivers of population genetic structure, whose study is generally restricted to the use of SNPs. Taking advantage of recent developments allowing CNV analysis from RAD-seq data, we investigated how variation in fitness-related traits, local thermal conditions and demographic history are associated with CNVs, and how subsequent copy number variation drives population genetic structure in a marine fish, the capelin (Mallotus villosus). We collected 1536 DNA samples from 35 sampling sites in the north Atlantic Ocean and identified 6620 CNVs. We found associations between CNVs and the gonadosomatic index, suggesting that duplicated regions could affect female fitness by modulating oocyte production. We also detected 105 CNV candidates associated with water temperature, among which 20% corresponded to genomic regions located within the sequence of protein-coding genes, suggesting local adaptation to cold water by means of gene amplification. We also identified 175 CNVs associated with the divergence of three parapatric glacial lineages, of which 24% were located within protein-coding genes, which might contribute to genetic incompatibilities and ultimately, reproductive isolation. Lastly, our analyses unveiled a hierarchical, complex CNV population structure determined by temperature and local geography, that was very different from that inferred based on SNPs in a previous study. Our findings underscore the complementarity of those two types of markers in population genomics studies.

genomics↗

bioRxiv2020

Genetic Distance Calculation Based on Locality Sensitive Hashing

Measuring the genetic relatedness between different species is one of the major challenges in the field of phylogenetics. Genetic distance calculation based on DNA data is highly using a mechanism to determine inter species relationships. Genetic distance computation can be further bifurcated as alignment-free sequencing and alignment based sequencing. With this research we are presenting alignment free genetic distance calculation technique which is based on locality sensitive hashing(LSH). By this approach we are hashing large DNA sequences into numeric arrays and make comparison more efficient and simplified.

bioinformatics↗

bioRxiv2020

Mathematical modeling of genetic pest management through female lethality with independently segregating alleles

Many novel genetic approaches are under development to combat insect pests. One genetic strategy aims to suppress or locally eliminate a species through large, repeated releases of genetically engineered strains that render female offspring unviable under field conditions. Strains with this female-killing (FK) characteristic have been developed either with all of the molecular components in a single construct or with the components in two constructs inserted at independently assorting loci. Strains with two constructs are typically considered to be only of value as research tools and for producing solely male offspring in rearing factories which are subsequently sterilized by radiation before release. A concern with the two-construct strains is that once released, the two constructs would become separated and therefore non-functional. The only FK strains that have been released in the field without sterilization are single-construct strains. Here, we use a population genetics model with density dependence to evaluate the relative effectiveness of female killing approaches based on single- and two-construct arrangements. We find that, in general, the single-construct arrangement results in slightly faster population suppression, but the two-construct arrangement can eventually cause stronger suppression and cause local elimination with a smaller release size. Based on our results, there is no a priori reason that males carrying two independently segregating constructs need to be sterilized prior to release. In some cases, a fertile release would be more efficient for population suppression.Competing Interest StatementThe authors have declared no competing interest.View Full Text

evolutionary biology↗

bioRxiv2020

Class I Aminoacyl-tRNA Synthetase Urzyme and CP1 Modules have Distinct Genetic Origins

The provenance of the aminoacyl-tRNA synthetases (aaRS) poses unusually challenging questions because of their role in the emergence and evolution of genetic coding. We investigate evidence about their ancestry from highly curated structure-based multiple sequence alignments of a small "scaffold" that is structurally invariant in all 10 canonical Class I aaRS. Statistically different values of two uncorrelated phylogenetic metrics--residue by residue conservation derived from Clustal and row-by-row cladistic congruence derived from BEAST2--suggest that the Class I scaffold is a mosaic assembled from distinct, successive genetic sources. These data are especially significant in light of: (i) experimental fragmentations of the Class I scaffold into three partitions that retain catalytic activities in proportion to their length; and (ii) multiple sources of evidence that two of these partitions arose from an ancestral Class I aaRS gene encoding a Class II ancestor in frame on the opposite strand. Two additional metrics output by BEAST2 vary in accordance with the presumed functionality endowed by the various modules. The new evidence supplements previous aaRS phylogenies. It identifies a previously characterized 46-residue Class I "protozyme" as preceding the adaptive radiation of the superfamily containing variations of the Rossmann dinucleotide binding fold related to amino acid discrimination, and thus as root of that molecular tree. Such a rooting is consistent with near simultaneous emergence of genetic coding and the origin of the proteome, resolving a conundrum posed by previous inferences that Class I aaRS evolved long after the genetic code had been implemented in an RNA world. Further, it establishes a timeline for the growth of coding from a binary amino acid alphabet by pinpointing discontinuous enhancements of aaRS fidelity. Author SummaryPhylogenetic analysis uncovers evolutionary connections between different protein superfamily members. We describe complementary, uncorrelated, phylogenetic metrics that support multiple evolutionary histories for different segments within members of the Class I aminoacyl-tRNA synthetase superfamily. Using a carefully curated 3D crystal structure superposition as the primary source of the multiple sequence alignment substantially reduced dependence of these metrics on empirical amino acid substitution matrices. Two metrics are derived from the amino acid distribution observed in each successive position. A third depends on how individual sequences distribute into phylogenetic tree branches for each of the ten amino acids activated by the superfamily. All metrics confirm that a segment previously identified as an inserted element is, indeed, a more recent acquisition, despite its structural conservation. The residue-by-residue conservation metrics reveal significant co-variation of mutational frequencies between a core segment that forms the amino acid binding site and a neighboring segment derived from the more recent insertion element. We attribute that covariation to the differentiation of superfamily members as evolutionary divergence enhanced amino acid specificity. Finally, evidence that the insertion element is a recent acquisition implies a new branching order for much of the proteome.

evolutionary biology↗

bioRxiv2020

Evolutionary Genetic Species Detected in Prokaryotes by Applying the K/θ Ratio to DNA Sequences

Previous papers in this series described the "evolutionary genetic species concept" which is based on population genetic theory and should be applicable to any organism. Also described was a species criterion, the K/{theta} ratio, that delimits independently evolving evolutionary species based on single-gene sequences, and its application to sexual and asexual eukaryotes was illustrated. Here, we show how the evolutionary genetic species concept and the K/{theta} ratio can be applied to bacteria, using the sequences from some genes of the core genome that are rarely, if ever, transferred horizontally between different species. This completes the demonstration that K/{theta} is a general method for species delimitation, applicable to all organisms. Also, it adds to the evidence that bacteria have species in the most general sense, even though they have the ability to exchange genes across species boundaries. Finally, we show that a published critique of the use of K/{theta} [≥] 4 as a criterion for independently evolving species rests on two errors in the application of population/evolutionary genetic theory.

evolutionary biology↗

bioRxiv2020

Synthetic Maturation of Multilineage Human Liver Organoids via Genetically Guided Engineering

Pluripotent stem cell (PSC)-derived organoids are emerging as novel human-based microphysiological models but display immature phenotypes with limited subsets of endothelial or stromal cells. Here we demonstrate that in vitro manipulation of gene regulatory networks (GRNs) in PSC-derived liver organoids selected either through computational analysis or targeted tissue design can advance tissue maturation in vitro. Through an unbiased comparison with the genetic signature of mature livers, we identify downregulated GRNs in fetal liver organoids compared to adult livers. We demonstrate that overexpression of PROX1 and ATF5, together with targeted CRISPR-based transcriptional activation of endogenous CYP3A4, drives maturation in vitro. Single cell analyses reveal hepatobiliary-, endothelial-, and stellate-like cell populations. The engineered organoids demonstrate enhanced vasculogenesis, capture native liver characteristics (e.g. FXR signaling, CYP3A4 activity), and exhibit therapeutic potential in mice. Collectively, our approach provides a genetically guided framework for engineering developmentally advanced multilineage tissues from hiPSCs. HIGHLIGHTSO_LIIn vitro tissue maturation via genetically encoded molecular programs C_LIO_LIComputational analysis to identify maturation transcription factors in liver organoids C_LIO_LIPromoting vascularization of organoids via genetically encoded molecular programs C_LIO_LISingle cell analysis of parenchymal and non-parenchymal cells C_LIO_LIModeling of native liver functions and in vivo therapeutic potential C_LI Graphical Abstract O_FIG O_LINKSMALLFIG WIDTH=168 HEIGHT=200 SRC="FIGDIR/small/087445v1_ufig1.gif" ALT="Figure 1"> View larger version (49K): org.highwire.dtl.DTLVardef@6ec32aorg.highwire.dtl.DTLVardef@1cf2eeforg.highwire.dtl.DTLVardef@1128748org.highwire.dtl.DTLVardef@16fb5a7_HPS_FORMAT_FIGEXP M_FIG C_FIG

bioengineering↗

bioRxiv2020

Host genetic and environmental factors shape the human gut resistome

BackgroundUnderstanding and controlling the spread of antimicrobial resistance is one of the greatest challenges of modern medicine. To this end many efforts focus on characterising the human resistome or the set of antibiotic resistance determinants within the microbiome of an individual. Aside from antibiotic use, other host environmental and genetic factors that may shape the resistome remain relatively underexplored. MethodsUsing gut metagenome data from 250 TwinsUK female twins, we quantified known antibiotic resistance genes to estimate gut microbiome antibiotic resistance potential for 41 types of antibiotics and resistance mechanisms. Using heritability modelling, we assessed the influence of host genetic and environmental factors on the gut resistome. We then explored links between gut resistome, host health and specific environmental exposures using linear mixed effect models adjusted for age, BMI, alpha diversity and family structure. ResultsWe considered gut microbiome antibiotic resistance to 21 classes of antibiotics, for which resistance genes were detected in over 90% of our population sample. Using twin modelling, we estimated that on average about 25% of resistome variability could be attributed to host genetic influences. Greatest heritability estimates were observed for resistance potential to acriflavine (70%), dalfopristin (51%), clindamycin (48%), aminocoumarin (48%) and the total score summing across all antibiotic resistance genes (38%). As expected, the majority of resistome variability was attributed to host environmental factors specific to an individual. We compared antibiotic resistance profiles to multiple environmental exposures, lifestyle and health factors. The strongest associations were observed with alcohol and vegetable consumption, followed by high cholesterol medication and antibiotic usage. Overall, inter-individual variation in host environment showed modest associations with antibiotic resistance profiles, and host health status had relatively minor signals. ConclusionOur results identify host genetic and environmental influences on the human gut resistome. The findings improve our knowledge of human factors that influence the spread of antibiotic resistance genes and may contribute towards helping to attenuate it.

microbiology↗

bioRxiv2020

The genetic architecture of post-zygotic reproductive isolation between Anopheles coluzzii and An. quadriannulatus

AbstractThe Anopheles gambiae complex is comprised of eight morphologically indistinguishable species and has emerged as a model system for the study of speciation genetics due to the rapid radiation of its member species over the past two million years. Male hybrids between most An. gambiae complex species pairs are sterile, and some genotype combinations in hybrid males cause inviability. We investigated the genetic basis of hybrid male inviability and sterility between An. coluzzii and An. quadriannulatus by measuring segregation distortion and performing a QTL analysis of sterility in a backcross population. Hybrid males were inviable if they inherited the An. coluzzii X chromosome and were homozygous at one or more loci in 18.9 Mb region of chromosome 3. The An. coluzzii X chromosome has a disproportionately large effect on hybrid sterility when introgressed into an An. quadriannulatus genetic background. Additionally, an epistatic interaction between the An. coluzzii X and a 1.12 Mb, pericentric region of the An. quadriannulatus 3L chromosome arm has a statistically significant contribution to the hybrid sterility phenotype. This same epistatic interaction occurs when the An. coluzzii X is introgressed into the genetic background of An. arabiensis, the sister species of An. quadriannulatus, suggesting that this may represent one of the first Dobzhansky-Muller incompatibilities to evolve early in the radiation of the Anopheles gambiae species complex. We describe the additive effects of each sterility QTL, epistatic interactions between them, and genes within QTL with protein functions related to mating behavior, reproduction, spermatogenesis, and microtubule morphogenesis, whose divergence may contribute to post-zygotic reproductive isolation between An. coluzzii and An. quadriannulatus.

evolutionary biology↗

bioRxiv2020

Development of a genetic evaluation for hair shedding in American Angus cattle to improve thermotolerance

BackgroundHeat stress and fescue toxicosis caused by ingesting tall fescue infected with the endophytic fungus Epichloe coenophiala represent two of the most prevalent stressors to beef cattle in the United States, costing the beef industry millions of dollars each year. The rate at which a beef cow sheds her winter coat early in the summer is an indicator of adaptation to heat and an economically relevant trait in many parts of the U.S. Further, research suggests that early-summer hair shedding may be reflective of tolerance to fescue toxicosis, as vasoconstriction induced by fescue toxicosis limits the ability of an animal to shed its winter coat. Here, we developed parameters for routine genetic evaluation of hair shedding score in American Angus cattle and identified genomic loci associated with variation in hair shedding score via genome-wide association analysis (GWAA). ResultsHair shedding score was found to be moderately heritable (h2 = 0.34 to 0.40), with differing repeatability estimates between cattle grazing versus not grazing endophyte-infected tall fescue. Our results suggest modestly negative genetic and phenotypic correlations between a dams hair shedding score (lower score is earlier shedding) and the weaning weight of her calf, one metric of performance. Together, these results indicate that economic gains can be made via the use of hair shedding score breeding values to select for heat tolerant cattle. GWAA identified 176 variants significant at FDR < 0.05. Functional enrichment analyses using genes within 50 Kb of these variants identified pathways involved in keratin formation, prolactin signaling, host-virus interaction, and other biological processes. ConclusionsThis work contributes to a continuing trend in the development of genetic evaluations for environmental adaptation. The results of this work will aid beef cattle producers in selecting more sustainable and climate-adapted cattle, as well as enable the development of similar routine genetic evaluations in other breeds.

genomics↗

bioRxiv2020

The effect of dispersal and preferential mating on the genetic control of mosquitoes

Mosquito-borne diseases cause significant social and economic damage across much of the globe. New biotechnologies that utilise manipulations of the mosquito genome have been developed to combat disease. The successful implementation of genetic mosquito control technologies may depend upon ecological, evolutionary and environmental factors, as well as the specifications of the chosen technology. Understanding the influence of these external factors will help inform how best to deploy a chosen technology to control vectors of infectious diseases. We use a continuous-time stochastic spatial network model of a mosquito life-cycle coupled to population genetics models to investigate the impact of releasing seven types of genetic control technology: a self-limiting lethal gene, two underdominance threshold gene drives, two homing gene drives and two Wolbachia systems. We apply the mathematical framework to understand control interventions of two archetypes of mosquito species: a short-range dispersing Aedes aegypti and comparatively longer-range dispersing Anopheles gambiae. We show that mosquito dispersal behaviour is an extremely important factor in determining the outcome of a release programme. Assortative mating - where the mating success of genetically modified males is lower than their wild counterparts - can facilitate the spatial containment of gene drives. The rapid evolution of strong mating preference can damage the efficacy of control efforts for all control technologies. We suggest that there cannot be a one-size-fits-all approach to regulation and implementation of vector control; there must be application-specific control plans that take account of understudied ecological, evolutionary and environmental factors.

ecology↗

bioRxiv2020

The impact of genetic diversity on gene essentiality within the E. coli species

Bacteria from the same species can differ widely in their gene content. In E. coli, the set of genes shared by all strains, known as the core genome, represents about half the number of genes present in any strain. While recent advances in bacterial genomics have enabled to unravel genes required for fitness in various experimental conditions at the genome scale, most studies have focused on model strains. As a result, the impact of this genetic diversity on core processes of the bacterial cell largely remains to be investigated. Here, we developed a new CRISPR interference platform for high-throughput gene repression that is compatible with most E. coli isolates and closely-related species. We applied it to assess the importance of [~]3,400 nearly ubiquitous genes in 3 growth media in 18 representative E. coli strains spanning most common phylogroups and lifestyles of the species. Our screens highlighted extensive variations in gene essentiality between strains and conditions. Unlike variations in gene expression level, variations in gene essentiality do not recapitulate the strains phylogeny. Investigation of the genetic determinants for these variations highlighted the importance of epistatic interactions with mobile genetic elements. In particular, we showed how mobile genetic elements can trigger the essentiality of core genes that are usually nonessential. This study provides new insights into the evolvability of gene essentiality and argues for the importance of studying various isolates from the same species in bacterial genomics.

genomics↗

bioRxiv2020

The genetic organization of subcortical volumetric change is stable throughout the lifespan

While development and aging of the cerebral cortex show a similar topographic organization and are mainly governed by the same genes, it is unclear whether the same is true for subcortical structures, which follow fundamentally different ontogenetic and phylogenetic principles than the cerebral cortex. To test the hypothesis that genetically governed neurodevelopmental processes can be traced in subcortical structures throughout life, we analyzed a longitudinal magnetic resonance imaging dataset (n = 974, age 4-89 years), identifying five clusters of longitudinal change in development. With some exceptions, these clusters followed placement along the cranial axis in embryonic brain development, suggesting continuity in the pattern of change from prenatal stages. Developmental change patterns were conserved through the lifespan and predicted general cognitive function in an age-invariant manner. The results were replicated in longitudinal data from the Lifebrain consortium (n = 756, age 19-83 years). Genetic contributions to longitudinal brain changes were calculated from the Vietnam Era Twin Study of Aging (n = 331 male twins, age 51-60 years), revealing that distinct sets of genes tended to govern change for each developmental cluster. This finding was confirmed with single nucleotide polymorphisms and cross-sectional MRI data from the UK Biobank (n = 20,588, age 40-69), demonstrating significantly higher co-heritability among structures belonging to the same developmental clusters. Together, these results suggest that coordination of subcortical change adheres to fundamental principles of lifespan continuity, genetic organization and age-invariant relationships to cognitive function. Significance statementHere we show that subcortical change during childhood development is organized in clusters. These clusters tend to follow the main gradient of embryonic brain development, and are stable across life. This means that subcortical regions changing together in childhood also change together throughout the rest of life, in accordance with a lifespan perspective on brain development and aging. Twin and single nucleotide polymorphism-based heritability analyses in middle-aged and older adults showed that volume and volume change of regions within each developmental cluster tended to be governed by the same sets of genes. Thus, volumetric changes across subcortical regions are tightly organized, and the coordinated change can be described in a lifespan perspective according to ontogenetic and genetic influences.

neuroscience↗

bioRxiv2020

Ten Genetic Loci Identified for Milk Yield, Fat, and Protein in Holstein Cattle

High-yield and high-quality of milk are the primary goals of dairy production. Understanding the genetic architecture underlying these milk production traits is beneficial so that genetic variants can be targeted toward the genetic improvement. In this study, we measured five milk production traits in Holstein cattle population from China. These traits included milk yield, protein yield, fat yields; fat percentage and protein percentages. We used the estimated breeding values as dependent variables to conduct the genome-wide association studies (GWAS). Breeding values were estimated through pedigree relationships by using a mixed linear model for individuals with and without phenotypic data. Genotyping was carried out on the individuals with phenotypes by using the Illumina BovineSNP150 BeadChip. The association analyses were conducted by using the Fixed and random model Circulating Probability Unification (FarmCPU) method. A total of ten SNPs was detected above the genome-wide significant threshold, including six located in previously reported QTL regions. We found eight candidate genes within distances of 120 kb upstream or downstream to the associated SNPs. The most significant SNP is on DGAT1 gene affecting milk fat and protein percentage. These genetic variants and candidate genes would be valuable resources to enhance dairy cattle breeding.

genomics↗