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1.  Selection on Horizontally Transferred and Duplicated Genes in Sinorhizobium (Ensifer), the Root-Nodule Symbionts of Medicago 
Genome Biology and Evolution  2014;6(5):1199-1209.
Structural variation, including variation in gene copy number and presence or absence of genes, is a widespread and important source of genomic variation. We used whole-genome DNA sequences from 48 strains of Sinorhizobium (recently renamed Ensifer), including 20 strains of Sinorhizobium meliloti and 12 strains of S. medicae that were the focus of the analyses, to study the fitness effects of new structural variants created by duplication and horizontal gene transfer. We find that derived duplicated and horizontally transferred (HT) genes segregate at lower frequency than synonymous and nonsynonymous nucleotide variants in S. meliloti and S. medicae. Furthermore, the relative frequencies of different types of variants are more similar in S. medicae than in S. meliloti, the species with the larger effective population size. These results are consistent with the hypothesis that most duplications and HT genes have deleterious effects. Diversity of duplications, as measured by segregating duplicated genes per gene, is greater than nucleotide diversity, consistent with a high rate of duplication. Our results suggest that the vast majority of structural variants found among closely related bacterial strains are short-lived and unlikely to be involved in species-wide adaptation.
doi:10.1093/gbe/evu090
PMCID: PMC4040998  PMID: 24803571
pangenome; mutation; purifying selection; fitness effects; structural variation
2.  Candidate Genes and Genetic Architecture of Symbiotic and Agronomic Traits Revealed by Whole-Genome, Sequence-Based Association Genetics in Medicago truncatula 
PLoS ONE  2013;8(5):e65688.
Genome-wide association study (GWAS) has revolutionized the search for the genetic basis of complex traits. To date, GWAS have generally relied on relatively sparse sampling of nucleotide diversity, which is likely to bias results by preferentially sampling high-frequency SNPs not in complete linkage disequilibrium (LD) with causative SNPs. To avoid these limitations we conducted GWAS with >6 million SNPs identified by sequencing the genomes of 226 accessions of the model legume Medicago truncatula. We used these data to identify candidate genes and the genetic architecture underlying phenotypic variation in plant height, trichome density, flowering time, and nodulation. The characteristics of candidate SNPs differed among traits, with candidates for flowering time and trichome density in distinct clusters of high linkage disequilibrium (LD) and the minor allele frequencies (MAF) of candidates underlying variation in flowering time and height significantly greater than MAF of candidates underlying variation in other traits. Candidate SNPs tagged several characterized genes including nodulation related genes SERK2, MtnodGRP3, MtMMPL1, NFP, CaML3, MtnodGRP3A and flowering time gene MtFD as well as uncharacterized genes that become candidates for further molecular characterization. By comparing sequence-based candidates to candidates identified by in silico 250K SNP arrays, we provide an empirical example of how reliance on even high-density reduced representation genomic makers can bias GWAS results. Depending on the trait, only 30–70% of the top 20 in silico array candidates were within 1 kb of sequence-based candidates. Moreover, the sequence-based candidates tagged by array candidates were heavily biased towards common variants; these comparisons underscore the need for caution when interpreting results from GWAS conducted with sparsely covered genomes.
doi:10.1371/journal.pone.0065688
PMCID: PMC3669257  PMID: 23741505
3.  Pleistocene Speciation in the Genus Populus (Salicaceae) 
Systematic Biology  2012;61(3):401-412.
The macroevolutionary consequences of recent climate change remain controversial, and there is little paleobotanical or morphological evidence that Pleistocene (1.8–0.12 Ma) glacial cycles acted as drivers of speciation, especially among lineages with long generation times, such as trees. We combined genetic and ecogeographic data from 2 closely related North American tree species, Populus balsamifera and P. trichocarpa (Salicacaeae), to determine if their divergence coincided with and was possibly caused by Pleistocene climatic events. We analyzed 32 nuclear loci from individuals of P. balsamifera and P. trichocarpa to produce coalescent-based estimates of the divergence time between the 2 species. We coupled the coalescent analyses with paleodistribution models to assess the influence of climate change on species' range. Furthermore, measures of niche overlap were used to investigate patterns of ecological differentiation between species. We estimated the divergence date of P. balsamifera and P. trichocarpa at approximately 75 Ka, which corresponds closely with the onset of Marine Isotope Stage 4 (∼76 Ka) and a rapid increase in global ice volume. Significance tests of niche overlap, in conjunction with genetic estimates of migration, suggested that speciation occurred in allopatry, possibly resulting from the environmental effects of Pleistocene glacial cycles. Our results indicate that the divergence of keystone tree species, which have shaped community diversity in northern North American ecosystems, was recent and may have been a consequence of Pleistocene-era glaciation and climate change.
doi:10.1093/sysbio/syr120
PMCID: PMC3529545  PMID: 22213709
Glaciation; isolation-with-migration; MIMAR; North America; species distribution model
4.  Comparative genomics of the core and accessory genomes of 48 Sinorhizobium strains comprising five genospecies 
Genome Biology  2013;14(2):R17.
Background
The sinorhizobia are amongst the most well studied members of nitrogen-fixing root nodule bacteria and contribute substantial amounts of fixed nitrogen to the biosphere. While the alfalfa symbiont Sinorhizobium meliloti RM 1021 was one of the first rhizobial strains to be completely sequenced, little information is available about the genomes of this large and diverse species group.
Results
Here we report the draft assembly and annotation of 48 strains of Sinorhizobium comprising five genospecies. While S. meliloti and S. medicae are taxonomically related, they displayed different nodulation patterns on diverse Medicago host plants, and have differences in gene content, including those involved in conjugation and organic sulfur utilization. Genes involved in Nod factor and polysaccharide biosynthesis, denitrification and type III, IV, and VI secretion systems also vary within and between species. Symbiotic phenotyping and mutational analyses indicated that some type IV secretion genes are symbiosis-related and involved in nitrogen fixation efficiency. Moreover, there is a correlation between the presence of type IV secretion systems, heme biosynthesis and microaerobic denitrification genes, and symbiotic efficiency.
Conclusions
Our results suggest that each Sinorhizobium strain uses a slightly different strategy to obtain maximum compatibility with a host plant. This large genome data set provides useful information to better understand the functional features of five Sinorhizobium species, especially compatibility in legume-Sinorhizobium interactions. The diversity of genes present in the accessory genomes of members of this genus indicates that each bacterium has adopted slightly different strategies to interact with diverse plant genera and soil environments.
doi:10.1186/gb-2013-14-2-r17
PMCID: PMC4053727  PMID: 23425606
5.  Host Genotype Shapes the Foliar Fungal Microbiome of Balsam Poplar (Populus balsamifera) 
PLoS ONE  2013;8(1):e53987.
Foliar fungal communities of plants are diverse and ubiquitous. In grasses endophytes may increase host fitness; in trees, their ecological roles are poorly understood. We investigated whether the genotype of the host tree influences community structure of foliar fungi. We sampled leaves from genotyped balsam poplars from across the species' range, and applied 454 amplicon sequencing to characterize foliar fungal communities. At the time of the sampling the poplars had been growing in a common garden for two years. We found diverse fungal communities associated with the poplar leaves. Linear discriminant analysis and generalized linear models showed that host genotypes had a structuring effect on the composition of foliar fungal communities. The observed patterns may be explained by a filtering mechanism which allows the trees to selectively recruit fungal strains from the environment. Alternatively, host genotype-specific fungal communities may be present in the tree systemically, and persist in the host even after two clonal reproductions. Both scenarios are consistent with host tree adaptation to specific foliar fungal communities and suggest that there is a functional basis for the strong biotic interaction.
doi:10.1371/journal.pone.0053987
PMCID: PMC3543377  PMID: 23326555
6.  Surgery versus Active Monitoring in Intermittent Exotropia (SamExo): study protocol for a pilot randomised controlled trial 
Trials  2012;13:192.
Background
Childhood intermittent exotropia [X(T)] is a type of strabismus (squint) in which one eye deviates outward at times, usually when the child is tired. It may progress to a permanent squint, loss of stereovision and/or amblyopia (reduced vision). Treatment options for X(T) include eye patches, glasses, surgery and active monitoring. There is no consensus regarding how this condition should be managed, and even when surgery is the preferred option clinicians disagree as to the optimal timing. Reports on the natural history of X(T) are limited, and there is no randomised controlled trial (RCT) evidence on the effectiveness or efficiency of surgery compared with active monitoring. The SamExo (Surgery versus Active Monitoring in Intermittent Exotropia) pilot study has been designed to test the feasibility of such a trial in the UK.
Methods
Design: an external pilot patient randomised controlled trial.
Setting: four UK secondary ophthalmology care facilities at Newcastle NHS Hospitals Foundation Trust, Sunderland Eye Infirmary, Moorfields Eye Hospital and York NHS Trust.
Participants: children aged between 6 months and 16 years referred with suspected and subsequently diagnosed X(T). Recruitment target is a total of 144 children over a 9-month period, with 120 retained by 9-month outcome visit.
Randomisation: permuted blocks stratified by collaborating centre, age and severity of X(T).
Interventions: initial clinical assessment; randomisation (eye muscle surgery or active monitoring); 3-, 6- and 9-month (primary outcome) clinical assessments; participant/proxy completed questionnaire covering time and travel costs, health services use and quality of life (Intermittent Exotropia Questionnaire); qualitative interviews with parents to establish reasons for agreeing or declining participation in the pilot trial.
Outcomes: recruitment and retention rates; nature and extent of participation bias; nature and extent of biases arising from crossover or loss to follow-up; reasons for agreeing/declining participation; variability of cure rates (to inform power calculations for a definitive RCT); completion rates of outcome measures.
Discussion
The SamExo pilot trial will provide important pointers regarding the feasibility of a full RCT of immediate surgery versus deferred surgery/active monitoring. The results of this pilot, including differences in cure rates, will inform the design of a definitive RCT.
Trial registration
ISRCTN44114892
doi:10.1186/1745-6215-13-192
PMCID: PMC3521171  PMID: 23072556
Intermittent exotropia; Divergent strabismus; Surgery; Feasibility studies; Pilot study; Randomised controlled trial; Children; Parents; Qualitative research
7.  Population Genomics of the Facultatively Mutualistic Bacteria Sinorhizobium meliloti and S. medicae 
PLoS Genetics  2012;8(8):e1002868.
The symbiosis between rhizobial bacteria and legume plants has served as a model for investigating the genetics of nitrogen fixation and the evolution of facultative mutualism. We used deep sequence coverage (>100×) to characterize genomic diversity at the nucleotide level among 12 Sinorhizobium medicae and 32 S. meliloti strains. Although these species are closely related and share host plants, based on the ratio of shared polymorphisms to fixed differences we found that horizontal gene transfer (HGT) between these species was confined almost exclusively to plasmid genes. Three multi-genic regions that show the strongest evidence of HGT harbor genes directly involved in establishing or maintaining the mutualism with host plants. In both species, nucleotide diversity is 1.5–2.5 times greater on the plasmids than chromosomes. Interestingly, nucleotide diversity in S. meliloti but not S. medicae is highly structured along the chromosome – with mean diversity (θπ) on one half of the chromosome five times greater than mean diversity on the other half. Based on the ratio of plasmid to chromosome diversity, this appears to be due to severely reduced diversity on the chromosome half with less diversity, which is consistent with extensive hitchhiking along with a selective sweep. Frequency-spectrum based tests identified 82 genes with a signature of adaptive evolution in one species or another but none of the genes were identified in both species. Based upon available functional information, several genes identified as targets of selection are likely to alter the symbiosis with the host plant, making them attractive targets for further functional characterization.
Author Summary
Facultative mutualisms are relationships between two species that can live independently, but derive benefits when living together with their mutualistic partners. The facultative mutualism between rhizobial bacteria and legume plants contributes approximately half of all biologically fixed nitrogen, an essential plant nutrient, and is an important source of nitrogen to both natural and agricultural ecosystems. We resequenced the genomes of 44 strains of two closely related species of the genus Sinorhizobium that form facultative mutualisms with the model legme Medicago truncatula. These data provide one of the most complete examinations of genomic diversity segregating within microbial species that are not causative agents of human illness. Our analyses reveal that horizontal gene transfer, a common source of new genes in microbial species, disproportionately affects genes with direct roles in the rhizobia-plant symbiosis. Analyses of nucleotide diversity segregating within each species suggests that strong selection, along with genetic hitchhiking has sharply reduced diversity along an entire chromosome half in S. meliloti. Despite the two species' ecological similarity, we did not find evidence for selection acting on the same genetic targets. In addition to providing insight into the evolutionary history of rhizobial, this study shows the feasibility and potential power of applying population genomic analyses to microbial species.
doi:10.1371/journal.pgen.1002868
PMCID: PMC3410850  PMID: 22876202
8.  Interactions between Soil Habitat and Geographic Range Location Affect Plant Fitness 
PLoS ONE  2012;7(5):e36015.
Populations are often found on different habitats at different geographic locations. This habitat shift may be due to biased dispersal, physiological tolerances or biotic interactions. To explore how fitness of the native plant Chamaecrista fasciculata depends on habitat within, at and beyond its range edge, we planted seeds from five populations in two soil substrates at these geographic locations. We found that with reduced competition, lifetime fitness was always greater or equivalent in one habitat type, loam soils, though early-season survival was greater on sand soils. At the range edge, natural populations are typically found on sand soil habitats, which are also less competitive environments. Early-season survival and fitness differed among source populations, and when transplanted beyond the range edge, range edge populations had greater fitness than interior populations. Our results indicate that even when the optimal soil substrate for a species does not change with geographic range location, the realized niche of a species may be restricted to sub-optimal habitats at the range edge because of the combined effects of differences in abiotic and biotic effects (e.g. competitors) between substrates.
doi:10.1371/journal.pone.0036015
PMCID: PMC3355151  PMID: 22615745
9.  Fine-Scale Population Recombination Rates, Hotspots, and Correlates of Recombination in the Medicago truncatula Genome 
Genome Biology and Evolution  2012;4(5):726-737.
Recombination rates vary across the genome and in many species show significant relationships with several genomic features, including distance to the centromere, gene density, and GC content. Studies of fine-scale recombination rates have also revealed that in several species, there are recombination hotspots, that is, short regions with recombination rates 10–100 greater than those in surrounding regions. In this study, we analyzed whole-genome resequence data from 26 accessions of the model legume Medicago truncatula to gain insight into the genomic features that are related to high- and low-recombination rates and recombination hotspots at 1 kb scales. We found that high-recombination regions (1-kb windows among those in the highest 5% of the distribution) on all three chromosomes were significantly closer to the centromere, had higher gene density, and lower GC content than low-recombination windows. High-recombination windows are also significantly overrepresented among some gene functional categories—most strongly NB–ARC and LRR genes, both of which are important in plant defense against pathogens. Similar to high-recombination windows, recombination hotspots (1-kb windows with significantly higher recombination than the surrounding region) are significantly nearer to the centromere than nonhotspot windows. By contrast, we detected no difference in gene density or GC content between hotspot and nonhotspot windows. Using linear model wavelet analysis to examine the relationship between recombination and genomic features across multiple spatial scales, we find a significant negative correlation with distance to the centromere across scales up to 512 kb, whereas gene density and GC content show significantly positive and negative correlations, respectively, only up to 64 kb. Correlations between recombination and genomic features, particularly gene density and polymorphism, suggest that they are scale dependent and need to be assessed at scales relevant to the evolution of those features.
doi:10.1093/gbe/evs046
PMCID: PMC3381680  PMID: 22554552
recombination; centromere; gene density; GC content; autocorrelation; wavelet analysis
10.  The improving outcomes in intermittent exotropia study: outcomes at 2 years after diagnosis in an observational cohort 
BMC Ophthalmology  2012;12:1.
Background
The purpose of this study was to investigate current patterns of management and outcomes of intermittent distance exotropia [X(T)] in the UK.
Methods
This was an observational cohort study which recruited 460 children aged < 12 years with previously untreated X(T). Eligible subjects were enrolled from 26 UK hospital ophthalmology clinics between May 2005 and December 2006. Over a 2-year period of follow-up, clinical data were prospectively recorded at standard intervals from enrolment. Data collected included angle, near stereoacuity, visual acuity, control of X(T) measured with the Newcastle Control Score (NCS), and treatment. The main outcome measures were change in clinical outcomes (angle, stereoacuity, visual acuity and NCS) in treated and untreated X(T), 2 years from enrolment (or, where applicable, 6 months after surgery). Change over time was tested using the chi-square test for categorical, Wilcoxon test for non-parametric and paired-samples t-test for parametric data.
Results
At follow-up, data were available for 371 children (81% of the original cohort). Of these: 53% (195) had no treatment; 17% (63) had treatment for reduced visual acuity only (pure refractive error and amblyopia); 13% (50) had non surgical treatment for control (spectacle lenses, occlusion, prisms, exercises) and 17% (63) had surgery. Only 0.5% (2/371) children developed constant exotropia. The surgically treated group was the only group with clinically significant improvements in angle or NCS. However, 8% (5) of those treated surgically required second procedures for overcorrection within 6 months of the initial procedure and at 6-month follow-up 21% (13) were overcorrected.
Conclusions
Many children in the UK with X(T) receive active monitoring only. Deterioration to constant exotropia, with or without treatment, is rare. Surgery appears effective in improving angle of X(T) and NCS, but rates of overcorrection are high.
doi:10.1186/1471-2415-12-1
PMCID: PMC3293086  PMID: 22257496
11.  Heterosis Is Prevalent for Multiple Traits in Diverse Maize Germplasm 
PLoS ONE  2009;4(10):e7433.
Background
Heterosis describes the superior phenotypes observed in hybrids relative to their inbred parents. Maize is a model system for studying heterosis due to the high levels of yield heterosis and commercial use of hybrids.
Methods
The inbred lines from an association mapping panel were crossed to a common inbred line, B73, to generate nearly 300 hybrid genotypes. Heterosis was evaluated for seventeen phenotypic traits in multiple environments. The majority of hybrids exhibit better-parent heterosis in most of the hybrids measured. Correlations between the levels of heterosis for different traits were generally weak, suggesting that the genetic basis of heterosis is trait-dependent.
Conclusions
The ability to predict heterosis levels using inbred phenotype or genetic distance between the parents varied for the different traits. For some traits it is possible to explain a significant proportion of the heterosis variation using linear modeling while other traits are more difficult to predict.
doi:10.1371/journal.pone.0007433
PMCID: PMC2757727  PMID: 19823591
12.  Context dependence in the coevolution of plant and rhizobial mutualists 
Several mechanisms are expected to rapidly rid mutualisms of genetic variation in partner quality. Variation for mutualist quality, however, appears to be widespread. We used a model legume–rhizobium mutualism to test for evidence that context-dependent selection may maintain variation in partner quality. In a greenhouse experiment using 10 natural populations of Medicago truncatula and two strains of Sinorhizobium medicae, we detected significant genotype×genotype (G×G) interactions for plant fitness, indicating that the most beneficial rhizobium strain depends on the host genotype. In a second experiment using a subset of the plant populations used in the first experiment, we detected significant G×G interactions for both plant and rhizobium fitness. Moreover, the plant population with which rhizobium strains gained the greatest benefit depended on the nitrogen environment. Finally, we found that in a high nitrogen environment, all plant populations had lower fitness when inoculated with a 1 : 1 mixture of strains than with the worse single strain alone, suggesting that nitrogen shifts the exchange of benefits in favour of rhizobia. Our data suggest that genotype, nitrogen and biotic dependency might contribute to the maintenance of genetic variation in mutualist quality when coupled with spatial or temporal heterogeneity in the environment.
doi:10.1098/rspb.2007.0495
PMCID: PMC2270936  PMID: 17535796
genotype by environment; coevolution; cheating; symbiosis; cooperation; partner choice

Results 1-12 (12)