SEARCH · bioRxiv Science

Results for “Genetics”

Search indexed bioRxiv preprints in genomics, neuroscience, cell biology and bioinformatics. Read source abstracts and check manuscript versions; preprints are not peer reviewed.

Quote a phrase for an exact phrase match. Source license links do not imply unrestricted reuse.

At least 1,333 records · Page 74Linked to original sources

bioRxiv2015

MicroRNAs provide the first evidence of genetic link between diapause and aging in vertebrates

Diapause and aging are controlled by overlapping genetic mechanisms in C.elegans and these include microRNAs (miRNAs). Here, we investigated miRNA regulation in embryos of annual killifish that naturally undergo diapause to overcome desiccation of their habitats. We compared miRNA expression in diapausing and non-diapausing embryos in three independent lineages of killifish. We identified 13 miRNAs with similar regulation in all three lineages. One of these is miR-430, which is known as key regulator of early embryonic development in fish. We further tested whether this regulation overlaps with the aging-dependent regulation of miRNAs in one annual species: Nothobranchius furzeri. We found that miR-101a and miR-18a are regulated in the same direction during diapause and aging. These results provide the first evidence that overlapping genetic networks control diapause and aging in vertebrates and suggest that diapause mimics aging to some extent.

Genomics↗

bioRxiv2015

Concurrent origins of the genetic code and the homochirality of life, and the origin and evolution of biodiversity. Part I: Observations and explanations

The post-genomic era has brought opportunities to bridge traditionally separate fields on early history of life. New methods promote a deeper understanding of the origin of biodiversity. Relative stabilities of base triplexes are able to regulate base substitutions in triplex DNAs. We constructed a roadmap based on such a regulation to explain concurrent origins of the genetic code and the homochirality of life. Based on the recruitment order of codons in the roadmap and the complete genome sequences, we reconstructed the three-domain tree of life. The Phanerozoic biodiversity curve has been reconstructed based on genomic, climatic and eustatic data; this result supports tectonic cause of mass extinctions. Our results indicate that chirality played a crucial role in the origin and evolution of life. Here is Part I of my two-part series paper; technical details are in Part II of this paper (see \"Concurrent origins of the genetic code and the homochirality of life, and the origin and evolution of biodiversity. Part II: Technical appendix\" on bioRxiv).

Evolutionary Biology↗

bioRxiv2015

Efficient genotype compression and analysis of large genetic variation datasets

The economy of human genome sequencing has catalyzed ambitious efforts to interrogate the genomes of large cohorts in search of new insight into the genetic basis of disease. This manuscript introduces Genotype Query Tools (GQT) as a new indexing strategy and toolset that addresses an analytical bottleneck by enabling interactive analyses based on genotypes, phenotypes and sample relationships. Speed improvements are achieved by operating directly on a compressed genotype index without decompression. GQTs data compression ratios increase favorably with cohort size and relative analysis performance improves in kind. We demonstrate substantial performance improvements over state-of-the-art tools using datasets from the 1000 Genomes Project (46 fold), the Exome Aggregation Consortium (443 fold), and simulated datasets of up to 100,000 genomes (218 fold). Furthermore, we show that this indexing strategy facilitates population and statistical genetics measures such as principal component analysis and burden tests. Based on its computational efficiency and by complementing existing toolsets, GQT provides a flexible framework for current and future analyses of massive genome datasets.

Genomics↗

bioRxiv2015

Characterizing and Prototyping Genetic Networks with Cell-Free Transcription-Translation Reactions

A central goal of synthetic biology is to engineer cellular behavior by engineering synthetic gene networks for a variety of biotechnology and medical applications. The process of engineering gene networks often involves an iterative design-build-test cycle, whereby the parts and connections that make up the network are built, characterized and varied until the desired network function is reached. Many advances have been made in the design and build portions of this cycle. However, the slow process of in vivo characterization of network function often limits the timescale of the testing step. Cell-free transcription-translation (TX-TL) systems offer a simple and fast alternative to performing these characterizations in cells. Here we provide an overview of a cell-free TX-TL system that utilizes the native Escherichia coli TX-TL machinery, thereby allowing a large repertoire of parts and networks to be characterized. As a way to demonstrate the utility of cell-free TX-TL, we illustrate the characterization of two genetic networks: an RNA transcriptional cascade and a protein regulated incoherent feed-forward loop. We also provide guidelines for designing TX-TL experiments to characterize new genetic networks. We end with a discussion of current and emerging applications of cell free systems.\n\nAbbreviations

Synthetic Biology↗

bioRxiv2015

Are Genetic Interactions Influencing Gene Expression Evidence for Biological Epistasis or Statistical Artifacts?

The importance of epistasis - or statistical interactions between genetic variants - to the development of complex disease in humans has long been controversial. Genome-wide association studies of statistical interactions influencing human traits have recently become computationally feasible and have identified many putative interactions. However, several factors that are difficult to address confound the statistical models used to detect interactions and make it unclear whether statistical interactions are evidence for true molecular epistasis. In this study, we investigate whether there is evidence for epistasis regulating gene expression after accounting for technical, statistical, and biological confounding factors that affect interaction studies. We identified 1,119 (FDR=5%) interactions within cis-regulatory regions that regulate gene expression in human lymphoblastoid cell lines, a tightly controlled, largely genetically determined phenotype. Approximately half of these interactions replicated in an independent dataset (363 of 803 tested). We then performed an exhaustive analysis of both known and novel confounders, including ceiling/floor effects, missing genotype combinations, haplotype effects, single variants tagged through linkage disequilibrium, and population stratification. Every replicated interaction could be explained by at least one of these confounders, and replication in independent datasets did not protect against this issue. Assuming the confounding factors provide a more parsimonious explanation for each interaction, we find it unlikely that cis-regulatory interactions contribute strongly to human gene expression. As this calls into question the relevance of interactions for other human phenotypes, the analytic framework used here will be useful for protecting future studies of epistasis against confounding.

Genomics↗

bioRxiv2015

Evolution of color phenotypes in two distantly related species of stick insect: different ecological regimes acting on similar genetic architectures

Recurrent (e.g. parallel or convergent) evolution is widely cited as evidence for natural selections central role in evolution but can also highlight constraints affecting evolution. Here we describe the evolution of green and melanistic color phenotypes in two species of stick insect: Timema podura and T. cristinae. We show that similar color phenotypes of these species (1) cluster in phenotypic space and (2) confer crypsis on different plant microhabitats. We then use genome-wide association mapping to determine the genetic architecture of color in T. podura, and compare this to previous results in T. cristinae. In both species, color is under simple genetic control, dominance relationships of melanistic and green alleles are the same, and SNPs associated with color phenotypes colocalize to the same genomic region. These results differ from those of typical parallel phenotypes because the form of selection acting on color differs between species: a balance of multiple sources of selection acting within host species maintains the color polymorphism in T. cristinae whereas T. podura color phenotypes are under divergent selection between hosts. Our results highlight how different adaptive landscapes can result in the evolution of similar phenotypic variation, and suggest the same genomic region is involved.

Evolutionary Biology↗

bioRxiv2015

Combining niche modelling, land use-change, and genetic information to assess the conservation status of Pouteria splendens populations in Central Chile

BackgroundPouteria splendens (lucumo chileno) is an endemic shrub to the coastal areas of Central Chile classified as Endangered and Rare by the Chilean threatened species list, but as Lower Risk (LR) by IUCN. Based in historical records some authors have hypothesized that P. splendens originally formed a large metapopulation, but due to habitat loss and fragmentation these populations have been reduced to two main areas separated by 100 km, neither of both currently protected by the Chilean system of protected areas. Knowledge about this species is scarce and no studies have provided evidence to support the large metapopulation hypothesis. This gap of knowledge limits our availability to gauge the real urgency to conserve remaining P. splendens populations, which can generate tragic consequences in light of the increasing land-use change and climatic change that are facing these populations. In this study we combined niche modelling, land-use information, future climatic scenarios, and conservation genetics techniques, to test the hypothesis of a potential original large metapopulation, evaluate the role of land-use change in population decline, assess the threats this species may face in the future, and combine the generated information to re-assess its conservation status using the IUCN criteria.\n\nResultsOur results show that locations with P. splendens are fewer than described in the literature. Results from the niche modelling and genetic analyses support the hypothesis of an originally large metapopulation that was recently reduced and fragmented by anthropogenic land-use change. Future climate change could increase the range of suitable habitats for P. splendens towards inland areas; however the high level of fragmentation of these new areas is expected to preclude colonization processes.\n\nConclusionsBased on our results we recommend urgent actions towards the conservation of this species, including (1) re-evaluating its current IUCN conservation status and reclassifying it as Endangered (EN), and (2) take immediate actions to develop strategies that effectively protect the remaining populations.

Ecology↗

bioRxiv2015

Diverse phenotypic and genetic responses to short-term selection in evolving Escherichia coli populations

Beneficial mutations fuel adaptation by altering phenotypes that enhance the fit of organisms to their environment. However, the phenotypic effects of mutations often depend on ecological context, making the distribution of effects across multiple environments essential to understanding the true nature of beneficial mutations. Studies that address both the genetic basis and ecological consequences of adaptive mutations remain rare. Here, we characterize the direct and pleiotropic fitness effects of a collection of 21 first-step beneficial mutants derived from naive and adapted genotypes used in a long-term experimental evolution of Escherichia coli. Whole-genome sequencing was used to identify most beneficial mutations. In contrast to previous studies, we find diverse fitness effects of mutations selected in a simple environment and few cases of genetic parallelism. The pleiotropic effects of these mutations were predominantly positive but some mutants were highly antagonistic in alternative environments. Further, the fitness effects of mutations derived from the adapted genotypes were dramatically reduced in nearly all environments. These findings suggest that many beneficial variants are accessible from a single point on the fitness landscape, and the fixation of alternative beneficial mutations may have dramatic consequences for niche breadth reduction via metabolic erosion.

Evolutionary Biology↗

bioRxiv2015

Analysis of protein-coding genetic variation in 60,706 humans

Large-scale reference data sets of human genetic variation are critical for the medical and functional interpretation of DNA sequence changes. Here we describe the aggregation and analysis of high-quality exome (protein-coding region) sequence data for 60,706 individuals of diverse ethnicities generated as part of the Exome Aggregation Consortium (ExAC). The resulting catalogue of human genetic diversity contains an average of one variant every eight bases of the exome, and provides direct evidence for the presence of widespread mutational recurrence. We show that this catalogue can be used to calculate objective metrics of pathogenicity for sequence variants, and to identify genes subject to strong selection against various classes of mutation; we identify 3,230 genes with near-complete depletion of truncating variants, 72% of which have no currently established human disease phenotype. Finally, we demonstrate that these data can be used for the efficient filtering of candidate disease-causing variants, and for the discovery of human \"knockout\" variants in protein-coding genes.

Genomics↗

bioRxiv2015

XMRF: An R package to Fit Markov Networks to High-Throughput Genetics Data

MotivationTechnological advances in medicine have led to a rapid proliferation of high-throughput \"omics\" data. Tools to mine this data and discover disrupted disease networks are needed as they hold the key to understanding complicated interactions between genes, mutations and aberrations, and epi-genetic markers.\n\nResultsWe developed an R software package, XMRF, that can be used to fit Markov Networks to various types of high-throughput genomics data. Encoding the models and estimation techniques of the recently proposed exponential family Markov Random Fields (Yang et al., 2012), our software can be used to learn genetic networks from RNA-sequencing data (counts via Poisson graphical models), mutation and copy number variation data (categorical via Ising models), and methylation data (continuous via Gaussian graphical models).\n\nAvailabilityXMRF is available from the CRAN Project and Github at: https://github.com/zhandong/XMRF

Bioinformatics↗

bioRxiv2015

Expression weighted cell type enrichments reveal genetic and cellular nature of major brain disorders

The cell types that trigger the primary pathology in many brain diseases remain largely unknown. One route to understanding the primary pathological cell type for a particular disease is to identify the cells expressing susceptibility genes. Although this is straightforward for monogenic conditions where the causative mutation may alter expression of a cell type specific marker, methods are required for the common polygenic disorders. We developed the Expression Weighted Cell Type Enrichment (EWCE) method that uses single cell transcriptomes to generate the probability distribution associated with a gene list having an average level of expression within a cell type. Following validation, we applied EWCE to human genetic data from cases of epilepsy, Schizophrenia, Autism, Intellectual Disability, Alzheimers disease, Multiple Sclerosis and anxiety disorders. Genetic susceptibility primarily affected microglia in Alzheimers and Multiple Sclerosis; was shared between interneurons and pyramidal neurons in Autism and Schizophrenia; while intellectual disabilities and epilepsy were attributable to a range of cell-types, with the strongest enrichment in interneurons. We hypothesized that the primary cell type pathology could trigger secondary changes in other cell types and these could be detected by applying EWCE to transcriptome data from diseased tissue. In Autism, Schizophrenia and Alzheimers disease we find evidence of pathological changes in all of the major brain cell types. These findings give novel insight into the cellular origins and progression in common brain disorders. The methods can be applied to any tissue and disorder and have applications in validating mouse models.

Neuroscience↗

bioRxiv2015

Evidence of adoption, monozygotic twinning, and low inbreeding rates in a large genetic pedigree of polar bears

Multigenerational pedigrees have been developed for free-ranging populations of many species, are frequently used to describe mating systems, and are used in studies of quantitative genetics. Here, we document the development of a 4449-individual pedigree for the Western Hudson Bay subpopulation of polar bears (Ursus maritimus), created from relationships inferred from field and genetic data collected over six generations of bears sampled between 1966 and 2011. Microsatellite genotypes for 22-25 loci were obtained for 2945 individuals, and parentage analysis was performed using the program FRANO_SCPLOWZC_SCPLOW, including additional offspring-dam associations known only from capture data. Parentage assignments for a subset of 859 individuals were confirmed using an independent high-density set of single nucleotide polymorphisms. To account for unsampled males in our population, we performed half-sib-full-sib analysis to reconstruct males using the program COLONY, resulting in a final pedigree containing 2957 assigned maternities and 1861 assigned paternities with only one observed case of inbreeding between close relatives. During genotyping, we identified two independently captured two-year-old males with identical genotypes at all 25 loci, showing--for the first time--a case of monozygotic twinning among polar bears. In addition, we documented six new cases of cub adoption, which we attribute to cub misidentification or misdirected maternal care by a female bereaved of her young. Importantly, none of these adoptions could be attributed to reduced female vigilance caused by immobilization to facilitate scientific handling, as has previously been suggested.

Zoology↗

bioRxiv2015

Genetic recombination as DNA repair

Maintenance of sexual reproduction and genetic recombination imposes physiological costs when compared to parthenogenic reproduction, most prominently: for maintaining the corresponding (molecular) machinery, for finding a mating partner, and through the decreased fraction of females in a population, which decreases the reproductive capacity. Based on principles from information theory, we have previously developed a new population genetic model, and applying it in simulations, we have recently hypothesized that all species maintain the maximum genomic complexity that is required by their niche and allowed by their mutation rate and selection intensity. Applying this idea to the complexity overhead of recombination maintenance, its costs must be more than compensated by an additional capacity for complexity in recombining populations. Here, we show a simple mechanism, where recombination helps to maintain larger biases of alleles frequencies in a population, so the advantageous alleles can have increased frequency. This allows recombining populations to maintain higher fitness and phenotypic efficiency in comparison with asexual populations with the same parameters. Random mating alone already significantly increases the ability to maintain genomic and phenotypic complexity. Sexual selection provides additional capacity for this complexity. The model can be considered as a unifying synthesis of previous hypotheses about the roles of recombination in Muller's ratchet, mutation purging and Red Queen dynamics, because the introduction of recombination both increases population frequencies of beneficial alleles and decreases detrimental ones. In addition, we suggest simple explanations for niche-dependent prevalence of transient asexuality and the exceptional asexual lineage of Bdelloid rotifers.

Evolutionary Biology↗

bioRxiv2016

A Genetically Encoded Reporter for Diffusion Weighted Magnetic Resonance Imaging

The ability to monitor gene expression in intact, optically opaque animals is important for a multitude of applications including longitudinal imaging of transgene expression and long term tracking of cell based therapeutics. Magnetic resonance imaging (MRI) could enable such monitoring with high spatial and temporal resolution. However, existing MRI reporter genes, based primarily on metal-binding proteins or chemical exchange saturation transfer probes, are limited by their reliance on metal ions or relatively low sensitivity. In this work, we introduce a new class of genetically encoded reporters for MRI that work by altering water diffusivity. We show that overexpression of the human water channel aquaporin 1 (AQP1) produces robust contrast in diffusion weighted MRI by increasing effective water diffusivity in tissues by over 100% without affecting cell viability or morphology. Low levels of AQP1 expression ({small tilde}1 M), or mixed populations comprising as few as 10% AQP1-expressing cells, produce sufficient contrast to be observed by MRI. We demonstrate the utility of AQP1 in vivo by imaging gene expression in intracranial tumor xenografts. Overall, our results establish AQP1 as a new, metal-free, nontoxic and sensitive genetically encoded reporter for diffusion weighted MRI.

Bioengineering↗

bioRxiv2016

Genetic evidence for natural selection in humans in the contemporary United States

Recent findings from molecular genetics now make it possible to test directly for natural selection by analyzing whether genetic variants associated with various phenotypes have been under selection. I leverage these findings to construct polygenic scores that use individuals' genotypes to predict their body mass index, educational attainment (EA), glucose concentration, height, schizophrenia, total cholesterol, and (in females) age at menarche. I then examine associations between these scores and fitness to test whether natural selection has been occurring. My study sample includes individuals of European ancestry born between 1931 and 1953 in the Health and Retirement Study, a representative study of the US population. My results imply that natural selection has been slowly favoring lower EA in both females and males, and are suggestive that natural selection may have favored a higher age at menarche in females. For EA, my estimates imply a rate of selection of about -1.5 months of education per generation (which pales in comparison with the increases in EA observed in contemporary times). Though they cannot be projected over more than one generation, my results provide additional evidence that humans are still evolving--albeit slowly, especially when compared to the rapid secular changes that have occurred over the past few generations due to cultural and environmental factors.

Evolutionary Biology↗

bioRxiv2016

Does linked selection explain the narrow range of genetic diversity across species?

The relatively narrow range of genetic polymorphism levels across species has been a major source of debate since the inception of molecular population genetics. Recently Corbett-Detig et al found evidence that linked selection strongly constrains levels of polymorphism in species with large census sizes. Here I reexamine this claim and find weak support for this conclusion. While linked selection is an important determinant of polymorphism levels along the genome in many species, we currently lack compelling evidence that it is a major determinant of polymorphism levels among obligately sexual species.

Evolutionary Biology↗

bioRxiv2016

Natural selection and genetic diversity in the butterfly Heliconius melpomene

A combination of selective and neutral evolutionary forces shape patterns of genetic diversity in nature. Among the insects, most previous analyses of the roles of drift and selection in shaping variation across the genome have focused on the genus Drosophila. A more complete understanding of these forces will come from analysing other taxa that differ in population demography and other aspects of biology. We have analysed diversity and signatures of selection in the neotropical Heliconius butterflies using resequenced genomes from 58 wild-caught individuals of H. melpomene, and another 21 resequenced genomes representing 11 related species. By comparing intra-specific diversity and inter-specific divergence, we estimate that 31% of amino acid substitutions between Heliconius species are adaptive. Diversity at putatively neutral sites is negatively correlated with the local density of coding sites as well as non-synonymous substitutions, and positively correlated with recombination rate, indicating widespread linked selection. This process also manifests in significantly reduced diversity on longer chromosomes, consistent with lower recombination rates. Although hitchhiking around beneficial non-synonymous mutations has significantly shaped genetic variation in H. melpomene, evidence for strong selective sweeps is limited overall. We did however identify two regions where distinct haplotypes have swept in different populations, leading to increased population differentiation. On the whole, our study suggests that positive selection is less pervasive in these butterflies as compared to fruit flies; a fact that curiously results in very similar levels of neutral diversity in these very different insects.

Evolutionary Biology↗

bioRxiv2016

Antimicrobial functions of lactoferrin promote genetic conflicts in ancient primates and modern humans

Lactoferrin is a multifunctional mammalian immunity protein that limits microbial growth through sequestration of nutrient iron. Additionally, lactoferrin possesses cationic protein domains that directly bind and inhibit diverse microbes. The implications for these dual functions on lactoferrin evolution and genetic conflicts with pathogens remain unclear. Here we show that lactoferrin has been subject to recurrent episodes of positive selection during primate divergence predominately at antimicrobial peptide surfaces consistent with long-term antagonism by pathogens. An abundant lactoferrin polymorphism in human populations and Neanderthals also exhibits signatures of positive selection across primates, linking ancient host-microbe conflicts to modern human genetic variation. Rapidly evolving sites in lactoferrin further correspond to molecular interfaces with pathogenic bacteria causing meningitis, pneumonia, and sepsis. Because microbes actively target lactoferrin to acquire iron, we propose that the emergence of antimicrobial activity provided a pivotal mechanism of adaptation sparking evolutionary conflicts via acquisition of new protein functions.

Evolutionary Biology↗