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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↗

bioRxiv2016

The mutational landscape of EGFR-, MYC-, and Kras- driven genetically-engineered mouse models of lung adenocarcinoma

Genetically-engineered mouse models (GEMMs) of cancer are increasingly being utilized to assess putative driver mutations identified by large scale sequencing of human cancer genomes. In order to accurately interpret experiments that introduce additional mutations, an understanding of the somatic genetic profile and evolution of GEMM tumors is necessary. Here, we performed whole exome sequencing of tumors from three GEMMs of lung adenocarcinoma driven by mutant EGFR, mutant Kras or by overexpression of MYC. Tumors from EGFR- and Kras- driven models exhibited respectively 0.02 and 0.07 non-synonymous mutations/megabase, a dramatically lower average mutational frequency than observed in human lung adenocarcinomas. Tumors from models driven by strong cancer drivers (mutant EGFR and Kras) harbored few mutations in known cancer genes, whereas tumors driven by MYC, a weaker initiating oncogene in the murine lung, acquired recurrent clonal oncogenic Kras mutations. In addition, although EGFR- and Kras- driven models both exhibited recurrent whole chromosome DNA copy number alterations, the specific chromosomes altered by gain or loss were different in each model. These data demonstrate that GEMM tumors exhibit relatively simple somatic genotypes compared to human cancers of a similar type, making these autochthonous model systems useful for additive engineering approaches to assess the potential of novel mutations on tumorigenesis, cancer progression, and drug sensitivity.

Cancer Biology↗

bioRxiv2016

The evolution of coercive policing in genetically mixed groups: the case of plasmid copy number control

Policing is a widespread mechanism regulating cooperation in both human and animal social groups. Policing can promote the evolution and maintenance of cooperation among non-relatives by tying the reproductive success of individuals to the efficiency and success of the group. In this paper, we investigate the evolution of reproductive policing using a multi-scale computational model inspired by the copy number control system of conjugative bacterial plasmids. Our results show that the repression of competition through policing can evolve across a very broad range of migration (plasmid conjugation) rates, improving system-level performance and bringing efficiency gains to the group beyond those achievable by pure self-restraint. Reproductive policing acts to increase genetic relatedness by reducing variation in group size which, in turn, reduces the heterogeneity of the plasmid population. When among-group migration is high, coercive policing strategies are favoured, characterized by high levels of policing coupled with relatively lower obedience. Coercive policing strategies preferentially limit the reproduction of rival lineages while, at the same time, maintaining effective collective reproductive control.\n\nAuthor SummaryThe emergence and maintenance of cooperation is a topic of great importance in evolutionary biology. The evolution of cooperation has been explained in the context of kin selection when there is sufficient genetic relatedness among interacting individuals. When there is insufficient relatedness, the presence of alternative mechanisms, such as mutual policing, can promote the evolution and maintenance of cooperation by tying the reproductive success of individual to the efficiency and success of the group. In this paper, we investigate the evolution of reproductive policing using an agent-based computational model inspired by a simple and elegant biological example: replication control among conjugative plasmids, a class of molecular symbionts of bacterial hosts. Our results show that the repression of competition through policing evolves and improves plasmid group performance beyond levels achievable by self-restraint, across a very broad range of migration rates. Under conditions of high migration (frequent conjugation), we observe the evolution of coercive policing strategies that limit the reproduction of rival lineages by investing disproportionately in policing relative to their obedience to the policing trait.

Evolutionary Biology↗

bioRxiv2016

Global and local connectivity differences converge with gene expression in a neurodevelopmental disorder of known genetic origin

Knowledge of genetic cause in neurodevelopmental disorders can highlight molecular and cellular processes critical for typical development. Furthermore, the relative homogeneity of neurodevelopmental disorders of known genetic origin allows the researcher to establish the subsequent neurobiological processes that mediate cognitive and behavioural outcomes. The current study investigated white matter structural connectivity in a group of individuals with intellectual disability due to mutations in ZDHHC9. In addition to shared cause of cognitive impairment, these individuals have a shared cognitive profile, involving oro-motor control difficulties and expressive language impairment. Analysis of structural network properties using graph theory measures showed global reductions in mean clustering coefficient and efficiency in the ZDHHC9 group, with maximal differences in frontal and parietal areas. Regional variation in clustering coefficient and local efficiency across cortical regions in cases and controls were significantly associated with known pattern of expression of ZDHHC9 in the normal adult human brain. The results demonstrate that a mutation in a single gene impacts upon white matter organisation across the whole-brain, but also shows regionally specific effects, according to variation in gene expression. Furthermore, these regionally specific patterns may link to specific developmental mechanisms, and correspond to specific cognitive deficits.

Neuroscience↗

bioRxiv2016

A natural encoding of genetic variation in a Burrows-Wheeler Transform to enable mapping and genome inference

We show how positional markers can be used to encode genetic variation within aBurrows-Wheeler Transform (BWT), and use this to construct a generalisation ofthe traditional \"reference genome\", incorporating known variation within aspecies. Our goal is to support the inference of the closest mosaic of previouslyknown sequences to the genome(s) under analysis.\n\nOur scheme results in an increased alphabet size, and by using a wavelet tree encoding of the BWT we reduce the performance impact on rank operations. We give a specialised form of the backward search that allows variation-aware exact matching. We implement this, and demonstrate the cost of constructing an index of the whole human genome with 8 million genetic variants is 25GB of RAM. We also show that inferring a closer reference can close large kilobase-scale coverage gaps in P. falciparum.

Bioinformatics↗

bioRxiv2016

Factors affecting intra-island genetic connectivity and diversity of an abundant and widespread island endemic, the San Clemente Island night lizard.

Habitat loss and fragmentation is one of the most severe threats to global biodiversity. Because human development often fragments natural areas into habitat \"islands\", studies which characterize the genetic structure of species isolated on oceanic islands may provide insight into the management of anthropogenic habitat islands. The San Clemente Island night lizard, Xantusia riversiana reticulata, is endemic to two California Channel Islands, each with a history of anthropogenic disturbance. We genotyped 917 individuals from San Clemente Island and Santa Barbara Island at 23 microsatellite loci to quantify population structure and identify natural and anthropogenic landscape features affecting intra-island connectivity. We found significant, but shallow, population structure on each island with sites < 400 m apart identified as distinct genepools. Landscape genetic analyses identified conductive habitat as California boxthorn and prickly pear cactus on both islands. Landscape features which decreased connectivity were unique to each island and included natural and human-mediated features. These results can inform management plans on each island by identifying habitat targets for mitigation and restoration efforts designed to improve connectivity. Our results highlight the need for considering fine-scale features correlated with contemporary and historical patterns of fragmentation, especially in small and isolated habitats on the mainland that may be analogous to oceanic islands.

Ecology↗

bioRxiv2016

A genetically encoded inhibitor of 53BP1 to stimulate homology-based gene editing

The expanding repertoire of programmable nucleases such as Cas9 brings new opportunities in genetic medicine1-3. In many cases, these nucleases are engineered to induce a DNA double-strand break (DSB) to stimulate precise genome editing by homologous recombination (HR). However, HR efficiency is nearly always hindered by competing DSB repair pathways such as non-homologous end-joining (NHEJ). HR is also profoundly suppressed in non-replicating cells, thus precluding the use of homology-based genome engineering in a wide variety4 of cell types. Here, we report the development of a genetically encoded inhibitor of 53BP1 (known as TP53BP1), a regulator of DSB repair pathway choice5. 53BP1 promotes NHEJ over HR by suppressing end resection, the formation of 3-prime single-stranded DNA tails, which is the rate-limiting step in HR initiation. 53BP1 also blocks the recruitment of the HR factor BRCA1 to DSB sites in G1 cells4,6. The inhibitor of 53BP1 (or i53) was identified through the screening of a massive combinatorial library of engineered ubiquitin variants by phage display7. i53 binds and occludes the ligand binding site of the 53BP1 Tudor domain with high affinity and selectivity, blocking its ability to accumulate at sites of DNA damage. i53 is a potent selective inhibitor of 53BP1 and enhances gene targeting and chromosomal gene conversion, two HR-dependent reactions. Finally, i53 can also activate HR in G1 cells when combined with the activation of end-resection and KEAP1 inhibition. We conclude that 53BP1 inhibition is a robust tool to enhance precise genome editing by canonical HR pathways.

Molecular Biology↗

bioRxiv2016

Transition from environmental to partial genetic sex determination in Daphnia through the evolution of a female-determining incipient W-chromosome

Sex chromosomes can evolve during the evolution of genetic sex determination (GSD) from environmental sex determination (ESD). Despite theoretical attention, early mechanisms involved in the transition from ESD to GSD have yet to be studied in nature. No mixed ESD-GSD animal species have been reported, except for some species of Daphnia, small freshwater crustaceans in which sex is usually determined solely by the environment, but in which a dominant female sex-determining locus is present in some populations. This locus follows Mendelian single-locus inheritance, but has otherwise not been characterized genetically. We now show that the sex-determining genomic region maps to the same low-recombining peri-centromeric region of linkage group 3 (LG3) in three highly divergent populations of D. magna, and spans 3.6 Mb. Despite low levels of recombination, the associated region contains signs of historical recombination, suggesting a role for selection acting on several genes thereby maintaining linkage disequilibrium among the 36 associated SNPs. The region carries numerous genes involved in sex differentiation in other taxa, including transformer2 and sox9. Taken together, the region determining the NMP phenotype shows characteristics of a sex-related supergene, suggesting that LG3 is potentially an incipient W chromosome despite the lack of significant additional restriction of recombination between Z and W. The occurrence of the female-determining locus in a pre-existing low recombining region illustrates one possible form of recombination suppression in sex chromosomes. D. magna is a promising model for studying the evolutionary transitions from ESD to GSD and early sex chromosome evolution.

Preprint↗

bioRxiv2016

Population and individual effects of non-coding variants inform genetic risk factors

Identifying functional non-coding variants can enhance genome interpretation and inform novel genetic risk factors. We used whole genomes and peripheral white blood cell transcriptomes from 624 Sardinian individuals to identify non-coding variants that contribute to population, family, and individual differences in transcript abundance. We identified 21,183 independent expression quantitative trait loci (eQTLs) and 6,768 independent splicing quantitative trait loci (sQTLs) influencing 73 and 41% of all tested genes. When we compared Sardinian eQTLs to those previously identified in Europe, we identified differentiated eQTLs at genes involved in malarial resistance and multiple sclerosis, reflecting the long-term epidemiological history of the islands population. Taking advantage of pedigree data for the population sample, we identify segregating patterns of outlier gene expression and allelic imbalance in 61 Sardinian trios. We identified 809 expression outliers (median z-score of 2.97) averaging 13.3 genes with outlier expression per individual. We then connected these outlier expression events to rare non-coding variants. Our results provide new insight into the effects of non-coding variants and their relationship to population history, traits and individual genetic risk.

Genomics↗

bioRxiv2016

OncoSimulR: genetic simulation of cancer progression with arbitrary epistasis and mutator genes

OncoSimulR implements forward-in-time genetic simulations of diallelic loci in asexual populations with special focus on cancer progression. Fitness can be defined as an arbitrary function of genetic interactions between multiple genes or modules of genes, including epistasis, restrictions in the order of accumulation of mutations, and order effects. Mutation rates can be made to differ between genes, and can be affected by (anti)mutator genes. Also available are sampling from single or multiple simulations, including single-cell sampling, plotting the parent-child relationships of the clones and generating and plotting random fitness landscapes.\n\nAvailability and implementationImplemented in R and C++, freely available from BioConductor for Linux, Mac, and Windows under the GNU GPL license. Version 2.3.12 or higher available from: http://www.bioconductor.org/packages/devel/bioc/html/OncoSimulR.html. GitHub repository at: https://github.com/rdiaz02/OncoSimul.

Bioinformatics↗

bioRxiv2016

Statistical Association Mapping of Population-Structured Genetic Data

Association mapping of genetic diseases has attracted extensive research interest during the recent years. However, most of the methodologies introduced so far suffer from spurious inference of the disease-causing sites due to population inhomogeneities. In this paper, we introduce a statistical framework to compensate for this shortcoming by equipping the current methodologies with a state-of-the-art clustering algorithm being widely used in population genetics applications. The proposed framework jointly infers the disease causal factors and the hidden population structures. In this regard, a Markov Chain-Monte Carlo (MCMC) procedure has been employed to assess the posterior probability distribution of the model parameters. We have implemented our proposed framework on a software package whose performance is extensively evaluated on a number of synthetic datasets, and compared to some of the well-known existing methods such as STRUCTURE. It has been shown that in extreme scenarios, up to 10 - 15% of improvement in the inference accuracy is achieved with a moderate increase in computational complexity.

Bioinformatics↗

bioRxiv2016

Genetically targeted 3D visualisation of Drosophila neurons under Electron Microscopy and X-Ray Microscopy using miniSOG

Large dimension, high-resolution imaging is important for neural circuit visualisation as neurons have both long- and short-range patterns: from axons and dendrites to the numerous synapses at their endings. Electron Microscopy (EM) is the favoured approach for synaptic resolution imaging but how such structures can be segmented from high-density images within large volume datasets remains challenging.\n\nFluorescent probes are widely used to localise synapses, identify cell-types and in tracing studies. The equivalent EM approach would benefit visualising such labelled structures from within sub-cellular, cellular, tissue and neuroanatomical contexts.\n\nHere we developed genetically-encoded, electron-dense markers using miniSOG. We demonstrate their ability in 1) labelling cellular sub-compartments of genetically-targeted neurons, 2) generating contrast under different EM modalities, and 3) segmenting labelled structures from EM volumes using computer-assisted strategies. We also tested non-destructive X-ray imaging on whole Drosophila brains to evaluate contrast staining. This enables us to target specific regions for EM volume acquisition.

Neuroscience↗