Publications by authors named "Elizabeth Spriggs"

33 Publications

Evolution of Castanea in North America: restriction-site-associated DNA sequencing and ecological modeling reveal a history of radiation, range shifts, and disease.

Am J Bot 2021 Sep 14. Epub 2021 Sep 14.

The College of New Jersey, 2000 Pennington Road, Ewing, NJ, 08628, USA.

Premise: Although chestnuts and chinquapins are some of the best known and most widely loved of any plants in North America, relatively little genomic sequencing has been done, and much is still unknown about their evolution.

Methods: We used double-digest restriction-site-associated DNA (ddRAD) sequencing data to infer the species-level phylogeny for Castanea and assess the phylogeography of the North American species using samples collected from populations that span the full extent of the species' ranges. We also constructed species distribution models using digitized herbarium specimens and observational data from field surveys.

Results: We identified strong population structure within Castanea dentata (American chestnut) that reflects a stepwise northern migration since the last glacial maximum. Our species distribution models further confirmed this scenario and matched closely with the Castanea fossil pollen record. We also found significant structure within the Castanea pumila lineage, most notably a genetic cluster that corresponds to the frequently recognized Castanea pumila var. ozarkensis.

Conclusions: The two North American Castanea species have contrasting patterns of population structure, but each is typical of plant phylogeography in North America. Within the C. pumila complex, we found novel genetic structure that provides new insights about C. pumila taxonomy. Our results also identified a series of distinctive populations that will be valuable in ongoing efforts to conserve and restore chestnuts and chinquapins in North America.
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http://dx.doi.org/10.1002/ajb2.1726DOI Listing
September 2021

Data sharing to improve concordance in variant interpretation across laboratories: results from the Canadian Open Genetics Repository.

J Med Genet 2021 Apr 19. Epub 2021 Apr 19.

Trillium Health Partners, Mississauga, Ontario, Canada.

Background: This study aimed to identify and resolve discordant variant interpretations across clinical molecular genetic laboratories through the Canadian Open Genetics Repository (COGR), an online collaborative effort for variant sharing and interpretation.

Methods: Laboratories uploaded variant data to the Franklin Genoox platform. Reports were issued to each laboratory, summarising variants where conflicting classifications with another laboratory were noted. Laboratories could then reassess variants to resolve discordances. Discordance was calculated using a five-tier model (pathogenic (P), likely pathogenic (LP), variant of uncertain significance (VUS), likely benign (LB), benign (B)), a three-tier model (LP/P are positive, VUS are inconclusive, LB/B are negative) and a two-tier model (LP/P are clinically actionable, VUS/LB/B are not). We compared the COGR classifications to automated classifications generated by Franklin.

Results: Twelve laboratories submitted classifications for 44 510 unique variants. 2419 variants (5.4%) were classified by two or more laboratories. From baseline to after reassessment, the number of discordant variants decreased from 833 (34.4% of variants reported by two or more laboratories) to 723 (29.9%) based on the five-tier model, 403 (16.7%) to 279 (11.5%) based on the three-tier model and 77 (3.2%) to 37 (1.5%) based on the two-tier model. Compared with the COGR classification, the automated Franklin classifications had 94.5% sensitivity and 96.6% specificity for identifying actionable (P or LP) variants.

Conclusions: The COGR provides a standardised mechanism for laboratories to identify discordant variant interpretations and reduce discordance in genetic test result delivery. Such quality assurance programmes are important as genetic testing is implemented more widely in clinical care.
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http://dx.doi.org/10.1136/jmedgenet-2021-107738DOI Listing
April 2021

Targeting galectin-3 with a high-affinity antibody for inhibition of high-grade serous ovarian cancer and other MUC16/CA-125-expressing malignancies.

Sci Rep 2021 Feb 12;11(1):3718. Epub 2021 Feb 12.

Division of Hematology-Oncology, Massachusetts General Hospital, 55 Fruit St, Boston, MA, 02114, USA.

The lectin, galectin-3 (Gal3), has been implicated in a variety of inflammatory and oncogenic processes, including tumor growth, invasion, and metastasis. The interactions of Gal3 and MUC16 represent a potential targetable pathway for the treatment of MUC16-expressing malignancies. We found that the silencing of Gal3 in MUC16-expressing breast and ovarian cancer cells in vitro inhibited tumor cell invasion and led to attenuated tumor growth in murine models. We therefore developed an inhibitory murine monoclonal anti-Gal3 carbohydrate-binding domain antibody, 14D11, which bound human and mouse Gal3 but did not bind human Galectins-1, -7, -8 or -9. Competition studies and a docking model suggest that the 14D11 antibody competes with lactose for the carbohydrate binding pocket of Gal3. In MUC16-expressing cancer cells, 14D11 treatment blocked AKT and ERK1/2 phosphorylation, and led to inhibition of cancer cell Matrigel invasion. Finally, in experimental animal tumor models, 14D11 treatment led to prolongation of overall survival in animals bearing flank tumors, and retarded lung specific metastatic growth by MUC16 expressing breast cancer cells. Our results provide evidence that antibody based Gal3 blockade may be a viable therapeutic strategy in patients with MUC16-expressing tumors, supporting further development of human blocking antibodies against Gal3 as potential cancer therapeutics.
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http://dx.doi.org/10.1038/s41598-021-82686-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7881041PMC
February 2021

Isolated sulfite oxidase deficiency: a founder mutation.

Cold Spring Harb Mol Case Stud 2020 12 17;6(6). Epub 2020 Dec 17.

London Health Sciences Centre, Western University, London, Ontario N6A 5A5, Canada.

Isolated sulfite oxidase deficiency is a rare autosomal recessive inborn error of sulfur metabolism. Clinical features generally include devastating neurologic dysfunction, ectopia lentis, and increased urinary excretion of sulfite, thiosulfate, and -sulfocysteine. Missed diagnosis is not unusual because of variability in the sensitivity of the urinary sulfite and thiosulfate screening test. We present clinical, biochemical, and molecular data on two unrelated patients with isolated sulfite oxidase deficiency. The two patients belong to an Indigenous genetic isolate in Manitoba, Canada. Both patients (one male and one female, both now deceased) developed neonatal seizures and demonstrated progressive neurodevelopmental delay. Based on increased urinary excretion of sulfite, thiosulfate, and -sulfocysteine and normal serum uric acid levels, sulfite oxidase deficiency was suspected. Both patients have a homozygous 4-bp deletion, 1347-1350delTTGT in the sulfite oxidase gene (), predicting a premature termination of the sulfite oxidase protein leading to absence of the carboxy-terminal third portion of the protein. This domain contains most of the contact sites essential for enzyme dimerization. This deletion mutation resulted in sulfite oxidase deficiency with early-onset severe clinical phenotype.
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http://dx.doi.org/10.1101/mcs.a005900DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7784486PMC
December 2020

Joint Phylogenetic Estimation of Geographic Movements and Biome Shifts during the Global Diversification of Viburnum.

Syst Biol 2021 Jan;70(1):67-85

Department of Ecology & Evolutionary Biology, Yale University, PO Box 208106, New Haven, CT 06520, USA.

Phylogeny, molecular sequences, fossils, biogeography, and biome occupancy are all lines of evidence that reflect the singular evolutionary history of a clade, but they are most often studied separately, by first inferring a fossil-dated molecular phylogeny, then mapping on ancestral ranges and biomes inferred from extant species. Here we jointly model the evolution of biogeographic ranges, biome affinities, and molecular sequences, while incorporating fossils to estimate a dated phylogeny for all of the 163 extant species of the woody plant clade Viburnum (Adoxaceae) that we currently recognize in our ongoing worldwide monographic treatment of the group. Our analyses indicate that while the major Viburnum lineages evolved in the Eocene, the majority of extant species originated since the Miocene. Viburnum radiated first in Asia, in warm, broad-leaved evergreen (lucidophyllous) forests. Within Asia, we infer several early shifts into more tropical forests, and multiple shifts into forests that experience prolonged freezing. From Asia, we infer two early movements into the New World. These two lineages probably first occupied warm temperate forests and adapted later to spreading cold climates. One of these lineages (Porphyrotinus) occupied cloud forests and moved south through the mountains of the Neotropics. Several other movements into North America took place more recently, facilitated by prior adaptations to freezing in the Old World. We also infer four disjunctions between Asia and Europe: the Tinus lineage is the oldest and probably occupied warm forests when it spread, whereas the other three were more recent and in cold-adapted lineages. These results variously contradict published accounts, especially the view that Viburnum radiated initially in cold forests and, accordingly, maintained vessel elements with scalariform perforations. We explored how the location and biome assignments of fossils affected our inference of ancestral areas and biome states. Our results are sensitive to, but not entirely dependent upon, the inclusion of fossil biome data. It will be critical to take advantage of all available lines of evidence to decipher events in the distant past. The joint estimation approach developed here provides cautious hope even when fossil evidence is limited. [Biogeography; biome; combined evidence; fossil pollen; phylogeny; Viburnum.].
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http://dx.doi.org/10.1093/sysbio/syaa027DOI Listing
January 2021

Genome-wide analysis identifies rare copy number variations associated with inflammatory bowel disease.

PLoS One 2019 11;14(6):e0217846. Epub 2019 Jun 11.

Department of Biochemistry and Medical Genetics and The George and Fay Yee Centre for Healthcare Innovation, University of Manitoba, Winnipeg, Manitoba, Canada.

Background: Inflammatory bowel disease (IBD) is an idiopathic, chronic disorder of unclear etiology with an underlying genetic predisposition. Recent genome-wide association studies have identified more than 200 IBD susceptibility loci, but the causes of IBD remain poorly defined. We hypothesized that rare (<0.1% population frequency) gene copy number variations (CNVs) could play an important mechanism for risk of IBD. We aimed to examine changes in DNA copy number in a population-based cohort of patients with IBD and search for novel genetic risk factors for IBD.

Methods: DNA samples from 243 individuals with IBD from the Manitoba IBD Cohort Study and 2988 healthy controls were analyzed using genome-wide SNP microarray technology. Three CNV calling algorithms were applied to maximize sensitivity and specificity of CNV detection. We identified IBD-associated genes affected by rare CNV from comparing the number of overlapping CNVs in IBD samples with the number of overlapping CNVs in controls for each gene.

Results: 4,402 CNVs detected by two or three algorithms intersected 7,061 genes, in at least one analyzed sample. Four genes (e.g. DUSP22 and IP6K3) intersected by rare deletions and fourteen genes (e.g. SLC25A10, PSPN, GTF2F1) intersected by rare duplications demonstrated significant association with IBD (FDR-adjusted p-value < 0.01). Of these, ten genes were functionally related to immune response and intracellular signalling pathways. Some of these genes were also identified in other IBD related genome-wide association studies. These suggested that the identified genes may play a role in the risk of IBD.

Conclusion: Our results revealed new genomic loci associated with IBD, which suggested the role of rare CNVs in IBD risk.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0217846PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6559655PMC
February 2020

Differences in flowering time maintain species boundaries in a continental radiation of Viburnum.

Am J Bot 2019 06 23;106(6):833-849. Epub 2019 May 23.

Department of Ecology and Evolutionary Biology, Yale University, P.O. Box 208106, New Haven, Connecticut, 06520, USA.

Premise: We take an integrative approach in assessing how introgression and Pleistocene climate fluctuations have shaped the diversification of the core Lentago clade of Viburnum, a group of five interfertile species with broad areas of sympatry. We specifically tested whether flowering time plays a role in maintaining species isolation.

Methods: RAD-seq data for 103 individuals were used to infer the species relationships and the genetic structure within each species. Flowering times were compared among species on the basis of historical flowering dates documented by herbarium specimens.

Results: Within each species, we found a strong relationship between flowering date and latitude, such that southern populations flower earlier than northern ones. In areas of sympatry, the species flower in sequence rather than simultaneously, with flowering dates offset by ≥9 d for all species pairs. In two cases it appears that the offset in flowering times is an incidental consequence of adaptation to differing climates, but in the recently diverged sister species V. prunifolium and V. rufidulum, we find evidence that reinforcement led to reproductive character displacement. Long-term trends suggest that the two northern-most species are flowering earlier in response to recent climate change.

Conclusions: We argue that speciation in the Lentago clade has primarily occurred through ecological divergence of allopatric populations, but differences in flowering time were essential to maintain separation of incipient species when they came into secondary contact. This combination of factors may underlie diversification in many other plant clades.
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http://dx.doi.org/10.1002/ajb2.1292DOI Listing
June 2019

Restriction-Site-Associated DNA Sequencing Reveals a Cryptic Viburnum Species on the North American Coastal Plain.

Syst Biol 2019 03;68(2):187-203

Department of Ecology and Evolutionary Biology, Yale University, PO Box 208106, New Haven, CT 06520-8106, USA.

Species are the starting point for most studies of ecology and evolution, but the proper circumscription of species can be extremely difficult in morphologically variable lineages, and there are still few convincing examples of molecularly informed species delimitation in plants. Here, we focus on the Viburnum nudum complex, a highly variable clade that is widely distributed in eastern North America. Taxonomic treatments have mostly divided this complex into northern (V. nudum var. cassinoides) and southern (V. nudum var. nudum) entities, but additional names have been proposed. We used multiple lines of evidence, including RADseq, morphological, and geographic data, to test how many independently evolving lineages exist within the V. nudum complex. Genetic clustering and phylogenetic methods revealed three distinct groups-one lineage that is highly divergent, and two others that are recently diverged and morphologically similar. A combination of evidence that includes reciprocal monophyly, lack of introgression, and discrete rather than continuous patterns of variation supports the recognition of all three lineages as separate species. These results identify a surprising case of cryptic diversity in which two broadly sympatric species have consistently been lumped in taxonomic treatments. The clarity of our findings is directly related to the dense sampling and high-quality genetic data in this study. We argue that there is a critical need for carefully sampled and integrative species delimitation studies to clarify species boundaries even in well-known plant lineages. Studies following the model that we have developed here are likely to identify many more cryptic lineages and will fundamentally improve our understanding of plant speciation and patterns of species richness.
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http://dx.doi.org/10.1093/sysbio/syy084DOI Listing
March 2019

Sterile marginal flowers increase visitation and fruit set in the hobblebush (Viburnum lantanoides, Adoxaceae) at multiple spatial scales.

Ann Bot 2019 01;123(2):381-390

Department of Ecology and Evolutionary Biology, Yale University, New Haven, CT, USA.

Background And Aims: Enlarged sterile flowers on the periphery of inflorescences increase the attractiveness of floral displays, and previous studies have generally demonstrated that these have positive effects on insect visitation and/or reproductive success. However, experiments have not specifically been designed to examine the benefits of sterile flowers under conditions that reflect the early stages in their evolution, i.e. when plants that produce sterile flowers are at low frequency.

Methods: Over three years, three experiments were performed in natural populations of Viburnum lantanoides, which produces sterile marginal flowers (SMFs). The first experiment established that fruit production in V. lantanoides increases with the receipt of outcross pollen. The second tested the role of SMFs under extant conditions, comparing fruit production in two populations composed entirely of intact plants or entirely of plants with the SMFs removed. The third was designed to mimic the presumed context in which SMFs first evolved; here, SMFs were removed from all but a few plants in a population, and rates of insect visitation and fruit set were compared between plants with intact and denuded SMFs.

Key Results: In comparing whole populations, the presence of SMFs nearly doubled fruit set. Under simulated 'ancestral' conditions within a population, plants with intact SMFs received double the insect visits and produced significantly more fruits than denuded plants. There was no significant effect of the number of inflorescences or fertile flowers on insect visitation or fruit set, indicating that the presence of SMFs accounted for these differences.

Conclusions: The presence of SMFs significantly increased pollinator attraction and female reproductive success both in contemporary and simulated ancestral contexts, indicating that stabilizing selection is responsible for their maintenance, and directional selection likely drove their evolution when they first appeared. This study demonstrates a novel approach to incorporating historically relevant scenarios into experimental studies of floral evolution.
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http://dx.doi.org/10.1093/aob/mcy117DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6344212PMC
January 2019

Topological Data Analysis as a Morphometric Method: Using Persistent Homology to Demarcate a Leaf Morphospace.

Front Plant Sci 2018 25;9:553. Epub 2018 Apr 25.

Department of Ecology and Evolutionary Biology, Yale University, New Haven, CT, United States.

Current morphometric methods that comprehensively measure shape cannot compare the disparate leaf shapes found in seed plants and are sensitive to processing artifacts. We explore the use of persistent homology, a topological method applied as a filtration across simplicial complexes (or more simply, a method to measure topological features of spaces across different spatial resolutions), to overcome these limitations. The described method isolates subsets of shape features and measures the spatial relationship of neighboring pixel densities in a shape. We apply the method to the analysis of 182,707 leaves, both published and unpublished, representing 141 plant families collected from 75 sites throughout the world. By measuring leaves from throughout the seed plants using persistent homology, a defined morphospace comparing all leaves is demarcated. Clear differences in shape between major phylogenetic groups are detected and estimates of leaf shape diversity within plant families are made. The approach predicts plant family above chance. The application of a persistent homology method, using topological features, to measure leaf shape allows for a unified morphometric framework to measure plant form, including shapes, textures, patterns, and branching architectures.
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http://dx.doi.org/10.3389/fpls.2018.00553DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5996898PMC
April 2018

Leaf Form Evolution in Viburnum Parallels Variation within Individual Plants.

Am Nat 2018 02 8;191(2):235-249. Epub 2017 Dec 8.

Few studies have critically evaluated how morphological variation within individual organisms corresponds to variation within and among species. Subindividual variation in plants facilitates such studies because their indeterminate modular growth generates multiple serially homologous structures along growing axes. Focusing on leaf form, we evaluate how subindividual trait variation relates to leaf evolution across Viburnum, a clade of woody angiosperms. In Viburnum we infer multiple independent origins of wide/lobed leaves with toothed margins from ancestors with elliptical, smooth-margined leaves. We document leaf variation along the branches of individual plants of 28 species and among populations across the wide range of Viburnum dentatum. We conclude that when novel leaf forms evolved in Viburnum, they were intercalated at the beginning of the seasonal leaf sequence, which then generated a repeated spectrum of leaf forms along each branch (seasonal heteroblasty). We hypothesize that the existence of such a spectrum then facilitated additional evolutionary shifts, including reversions to more ancestral forms. We argue that the recurrent production of alternative phenotypes provides opportunities to canalize the production of particular forms and that this phenomenon has played an important role in generating macroscale patterns.
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http://dx.doi.org/10.1086/695337DOI Listing
February 2018

Data sharing as a national quality improvement program: reporting on BRCA1 and BRCA2 variant-interpretation comparisons through the Canadian Open Genetics Repository (COGR).

Genet Med 2018 03 20;20(3):294-302. Epub 2017 Jul 20.

Pathology and Laboratory Medicine, Mount Sinai Hospital, Toronto, Ontario, Canada.

PurposeThe purpose of this study was to develop a national program for Canadian diagnostic laboratories to compare DNA-variant interpretations and resolve discordant-variant classifications using the BRCA1 and BRCA2 genes as a case study.MethodsBRCA1 and BRCA2 variant data were uploaded and shared through the Canadian Open Genetics Repository (COGR; http://www.opengenetics.ca). A total of 5,554 variant observations were submitted; classification differences were identified and comparison reports were sent to participating laboratories. Each site had the opportunity to reclassify variants. The data were analyzed before and after the comparison report process to track concordant- or discordant-variant classifications by three different models.ResultsVariant-discordance rates varied by classification model: 38.9% of variants were discordant when using a five-tier model, 26.7% with a three-tier model, and 5.0% with a two-tier model. After the comparison report process, the proportion of discordant variants dropped to 30.7% with the five-tier model, to 14.2% with the three-tier model, and to 0.9% using the two-tier model.ConclusionWe present a Canadian interinstitutional quality improvement program for DNA-variant interpretations. Sharing of variant knowledge by clinical diagnostic laboratories will allow clinicians and patients to make more informed decisions and lead to better patient outcomes.
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http://dx.doi.org/10.1038/gim.2017.80DOI Listing
March 2018

Correlation, causation, and the evolution of leaf teeth: A reply to Givnish and Kriebel.

Am J Bot 2017 04 20;104(4):509-515. Epub 2017 Apr 20.

Department of Ecology and Evolutionary Biology, Yale University, P.O. Box 208106, New Haven, Connecticut 06520-8106 USA.

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http://dx.doi.org/10.3732/ajb.1700075DOI Listing
April 2017

New insights on the sister lineage of percomorph fishes with an anchored hybrid enrichment dataset.

Mol Phylogenet Evol 2017 05 27;110:27-38. Epub 2017 Feb 27.

Department of Ecology & Evolutionary Biology and Peabody Museum of Natural History, Yale University, New Haven, CT 06520, USA; Peabody Museum of Natural History, Yale University, New Haven, CT 06520, USA.

Percomorph fishes represent over 17,100 species, including several model organisms and species of economic importance. Despite continuous advances in the resolution of the percomorph Tree of Life, resolution of the sister lineage to Percomorpha remains inconsistent but restricted to a small number of candidate lineages. Here we use an anchored hybrid enrichment (AHE) dataset of 132 loci with over 99,000 base pairs to identify the sister lineage of percomorph fishes. Initial analyses of this dataset failed to recover a strongly supported sister clade to Percomorpha, however, scrutiny of the AHE dataset revealed a bias towards high GC content at fast-evolving codon partitions (GC bias). By combining several existing approaches aimed at mitigating the impacts of convergence in GC bias, including RY coding and analyses of amino acids, we consistently recovered a strongly supported clade comprised of Holocentridae (squirrelfishes), Berycidae (Alfonsinos), Melamphaidae (bigscale fishes), Cetomimidae (flabby whalefishes), and Rondeletiidae (redmouth whalefishes) as the sister lineage to Percomorpha. Additionally, implementing phylogenetic informativeness (PI) based metrics as a filtration method yielded this same topology, suggesting PI based approaches will preferentially filter these fast-evolving regions and act in a manner consistent with other phylogenetic approaches aimed at mitigating GC bias. Our results provide a new perspective on a key issue for studies investigating the evolutionary history of more than one quarter of all living species of vertebrates.
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http://dx.doi.org/10.1016/j.ympev.2017.02.017DOI Listing
May 2017

Misconceptions on Missing Data in RAD-seq Phylogenetics with a Deep-scale Example from Flowering Plants.

Syst Biol 2017 05;66(3):399-412

Department of Ecology and Evolutionary Biology, Yale University, PO Box 208106, New Haven, CT, 06520, USA.

Restriction-site associated DNA (RAD) sequencing and related methods rely on the conservation of enzyme recognition sites to isolate homologous DNA fragments for sequencing, with the consequence that mutations disrupting these sites lead to missing information. There is thus a clear expectation for how missing data should be distributed, with fewer loci recovered between more distantly related samples. This observation has led to a related expectation: that RAD-seq data are insufficiently informative for resolving deeper scale phylogenetic relationships. Here we investigate the relationship between missing information among samples at the tips of a tree and information at edges within it. We re-analyze and review the distribution of missing data across ten RAD-seq data sets and carry out simulations to determine expected patterns of missing information. We also present new empirical results for the angiosperm clade Viburnum (Adoxaceae, with a crown age >50 Ma) for which we examine phylogenetic information at different depths in the tree and with varied sequencing effort. The total number of loci, the proportion that are shared, and phylogenetic informativeness varied dramatically across the examined RAD-seq data sets. Insufficient or uneven sequencing coverage accounted for similar proportions of missing data as dropout from mutation-disruption. Simulations reveal that mutation-disruption, which results in phylogenetically distributed missing data, can be distinguished from the more stochastic patterns of missing data caused by low sequencing coverage. In Viburnum, doubling sequencing coverage nearly doubled the number of parsimony informative sites, and increased by >10X the number of loci with data shared across >40 taxa. Our analysis leads to a set of practical recommendations for maximizing phylogenetic information in RAD-seq studies. [hierarchical redundancy; phylogenetic informativeness; quartet informativeness; Restriction-site associated DNA (RAD) sequencing; sequencing coverage; Viburnum.].
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http://dx.doi.org/10.1093/sysbio/syw092DOI Listing
May 2017

Development of a diagnostic DNA chip to screen for 30 autosomal recessive disorders in the Hutterite population.

Mol Genet Genomic Med 2016 May 19;4(3):312-21. Epub 2016 Jan 19.

Departments of Biochemistry & Medical GeneticsUniversity of ManitobaWinnipegCanada; Pediatrics & Child HealthUniversity of Manitoba745 Bannatyne Ave.WinnipegMB R3E 0J9Canada; Clinical Biochemistry and GeneticsDiagnostic Services Manitoba at Health Sciences CentreWinnipegMB R3A 1R9Canada.

Background: The Hutterites are a religious isolate living in colonies across the North American prairies. This population originated from approximately 90 founders, resulting in a number of genetic diseases that are overrepresented, underrepresented, or unique. The founder effect in this population increases the likelihood that Hutterite couples carry the same recessive mutations. We have designed a diagnostic chip on a fee-for-service basis with Asper Biotech to provide Hutterites with the option of comprehensive carrier screening.

Methods: A total of 32 disease-causing mutations in 30 genes were selected and primers were designed for array primer extension-based testing. Selected mutations were limited to those leading to autosomal recessive disorders, maintaining its primary use as a test for determining carrier status.

Results: The DNA chip was developed and validated using 59 DNA controls for all but one of the mutations, for which a synthetic control was used. All mutations were readily detected except for a duplication causing restrictive dermopathy where heterozygotes and homozygotes could only be distinguished by sequencing. Blinded testing of 12 additional samples from healthy Hutterites was performed by Asper Biotech using chip testing. All known mutations from previous molecular testing were detected on the chip. As well, additional mutations identified by the chip in these 12 samples were subsequently verified by a second method.

Conclusions: Our analysis indicates that the chip is a sensitive and specific means of carrier testing in the Hutterite population and can serve as a model for other founder populations.
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http://dx.doi.org/10.1002/mgg3.206DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4867565PMC
May 2016

C4 photosynthesis boosts growth by altering physiology, allocation and size.

Nat Plants 2016 04 18;2(5):16038. Epub 2016 Apr 18.

Department of Animal and Plant Sciences, University of Sheffield, Sheffield S10 2TN, UK.

C4 photosynthesis is a complex set of leaf anatomical and biochemical adaptations that have evolved more than 60 times to boost carbon uptake compared with the ancestral C3 photosynthetic type(1-3). Although C4 photosynthesis has the potential to drive faster growth rates(4,5), experiments directly comparing C3 and C4 plants have not shown consistent effects(1,6,7). This is problematic because differential growth is a crucial element of ecological theory(8,9) explaining C4 savannah responses to global change(10,11), and research to increase C3 crop productivity by introducing C4 photosynthesis(12). Here, we resolve this long-standing issue by comparing growth across 382 grass species, accounting for ecological diversity and evolutionary history. C4 photosynthesis causes a 19-88% daily growth enhancement. Unexpectedly, during the critical seedling establishment stage, this enhancement is driven largely by a high ratio of leaf area to mass, rather than fast growth per unit leaf area. C4 leaves have less dense tissues, allowing more leaves to be produced for the same carbon cost. Consequently, C4 plants invest more in roots than C3 species. Our data demonstrate a general suite of functional trait divergences between C3 and C4 species, which simultaneously drive faster growth and greater investment in water and nutrient acquisition, with important ecological and agronomic implications.
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http://dx.doi.org/10.1038/nplants.2016.38DOI Listing
April 2016

Unpacking a century-old mystery: Winter buds and the latitudinal gradient in leaf form.

Am J Bot 2016 06 24;103(6):975-8. Epub 2016 May 24.

Department of Ecology and Evolutionary Biology, Yale University, PO Box 208106, New Haven, Connecticut 06520-8106.

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http://dx.doi.org/10.3732/ajb.1600129DOI Listing
June 2016

PWS/AS MS-MLPA Confirms Maternal Origin of 15q11.2 Microduplication.

Case Rep Genet 2015 7;2015:474097. Epub 2015 May 7.

Departments of Biochemistry & Medical Genetics and Pediatrics & Child Health, University of Manitoba, Winnipeg, MB, Canada R3E 0J9 ; Genetics & Metabolism Program, WRHA, Winnipeg, MB, Canada R3A 1R9 ; Molecular Diagnostic Laboratory, HSC, Diagnostic Services of Manitoba, 820 Sherbrook Street, Winnipeg, MB, Canada R3A 1K9.

The proximal region of the long arm of chromosome 15q11.2-q13 is associated with various neurodevelopmental disorders, including Prader-Willi (PWS) and Angelman (AS) syndromes, autism, and other developmental abnormalities resulting from deletions and duplications. In addition, this region encompasses imprinted genes that cause PWS or AS, depending on the parent-of-origin. This imprinting allows for diagnosis of PWS or AS based on methylation status using methylation sensitive (MS) multiplex ligation dependent probe amplification (MLPA). Maternally derived microduplications at 15q11.2-q13 have been associated with autism and other neuropsychiatric disorders. Multiple methods have been used to determine the parent-of-origin for 15q11.2-q13 microdeletions and microduplications. In the present study, a four-year-old nondysmorphic female patient with developmental delay was found to have a de novo ~5 Mb duplication within 15q11.2 by oligonucleotide genomic array. In order to determine the significance of this microduplication to the clinical phenotype, the parent-of-origin needed to be identified. The PWS/AS MS-MLPA assay is generally used to distinguish between deletion and uniparental disomy (UPD) of 15q11.2-q13, resulting in either PWS or AS. However, our study shows that PWS/AS MS-MLPA can also efficiently distinguish the parental origin of duplications of 15q11.2-q13.
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http://dx.doi.org/10.1155/2015/474097DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4439467PMC
June 2015

Temperate radiations and dying embers of a tropical past: the diversification of Viburnum.

New Phytol 2015 Jul 3;207(2):340-354. Epub 2015 Feb 3.

Department of Ecology and Evolutionary Biology, Yale University, PO Box 208106, New Haven, CT, 06520, USA.

We used a near-complete phylogeny for the angiosperm clade Viburnum to assess lineage diversification rates, and to examine possible morphological and ecological factors driving radiations. Maximum-likelihood and Bayesian approaches identified shifts in diversification rate and possible links to character evolution. We inferred the ancestral environment for Viburnum and changes in diversification dynamics associated with subsequent biome shifts. Viburnum probably diversified in tropical forests of Southeast Asia in the Eocene, with three subsequent radiations in temperate clades during the Miocene. Four traits (purple fruits, extrafloral nectaries, bud scales and toothed leaves) were statistically associated with higher rates of diversification. However, we argue that these traits are unlikely to be driving diversification directly. Instead, two radiations were associated with the occupation of mountainous regions and a third with repeated shifts between colder and warmer temperate forests. Early-branching depauperate lineages imply that the rare lowland tropical species are 'dying embers' of once more diverse lineages; net diversification rates in Viburnum likely decreased in these tropical environments after the Oligocene. We suggest that 'taxon pulse' dynamics might characterize other temperate plant lineages.
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http://dx.doi.org/10.1111/nph.13305DOI Listing
July 2015

A case of an infant with compound heterozygous mutations for hypertrophic cardiomyopathy producing a phenotype of left ventricular noncompaction.

Can J Cardiol 2014 Oct 12;30(10):1249.e1-3. Epub 2014 Jun 12.

Department of Laboratory Medicine and Pathology, University of Alberta, and Stollery Children's Hospital, Edmonton, Alberta, Canada.

A male infant was born to a 38-year-old G1P0 mother with hypertrophic cardiomyopathy (HCM). Fetal echocardiography was suspicious for HCM; however, postnatal echocardiography demonstrated features consistent with left ventricular noncompaction (LVNC). The infant was initially stable but presented at 2 months of age in cardiogenic shock. On genetic analysis, both parents were heterozygous for mutations associated with HCM. The proband was a compound heterozygote. This case, in which 2 mutations for HCM produced a phenotype of LVNC, has not been demonstrated in humans and raises the question of whether HCM and LVNC represent a continuum of pathologic processes.
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http://dx.doi.org/10.1016/j.cjca.2014.05.021DOI Listing
October 2014

Germline mosaicism in X-linked periventricular nodular heterotopia.

BMC Neurol 2014 Jun 7;14:125. Epub 2014 Jun 7.

Department of Biochemistry and Medical Genetics Faculty of Medicine, University of Manitoba, Winnipeg, MB, Canada.

Background: X-linked periventricular nodular heterotopia is a disorder of neuronal migration resulting from mutations in the filamin A gene. This is an X-linked dominant condition where most affected patients are female and present with seizures. Extra-cerebral features such as cardiac abnormalities and thrombocytopenia have also been documented. Loss of function mutations in filamin A are predicted to result in prenatal lethality in males. Somatic mosaicism and mutations that lead to partial loss of function of the protein are hypothesized to explain viability of males reported in the literature. We report the first case of germline mosaicism involving a loss of function mutation in filamin A in a family where brain MRI, clinical exam, and mutation analysis is normal in both biological parents.

Case Presentation: The index patient, a 39 year old female with normal development, had her first seizure at 24 years with no evidence of any precipitating factors. Brain MRI shows bilateral periventricular nodular heterotopia. She has thrombocytopenia and an echocardiogram at age 32 years revealed a mildly dilated aortic root and ascending aorta with mild aortic regurgitation. The second patient, the 36 year old younger sister of the index case, is currently healthy with no evidence of seizures or cardiac abnormalities. Her brain MRI is consistent with bilateral periventricular nodular heterotopia. The mother is healthy at 57 years of age with a normal brain MRI. The father is healthy at 59 years of age with a normal brain MRI. DNA sequencing of lymphocyte extracted DNA from the two sisters shows a c.2002C > T transition in exon 13 of filamin A resulting in a p.Gln668Ter mutation. This nonsense mutation was not detected in peripheral blood lymphocytes from the unaffected parents.

Conclusion: This report provides evidence for germline mosaicism in filamin A-associated periventricular nodular heterotopia. This case must now be considered when providing genetic counseling to families where a proband presents as an isolated case and parental investigations are unremarkable.
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http://dx.doi.org/10.1186/1471-2377-14-125DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4057563PMC
June 2014

C4 photosynthesis promoted species diversification during the Miocene grassland expansion.

PLoS One 2014 16;9(5):e97722. Epub 2014 May 16.

Department of Ecology and Evolutionary Biology, Brown University, Providence, Rhode Island, United States of America.

Identifying how organismal attributes and environmental change affect lineage diversification is essential to our understanding of biodiversity. With the largest phylogeny yet compiled for grasses, we present an example of a key physiological innovation that promoted high diversification rates. C4 photosynthesis, a complex suite of traits that improves photosynthetic efficiency under conditions of drought, high temperatures, and low atmospheric CO2, has evolved repeatedly in one lineage of grasses and was consistently associated with elevated diversification rates. In most cases there was a significant lag time between the origin of the pathway and subsequent radiations, suggesting that the 'C4 effect' is complex and derives from the interplay of the C4 syndrome with other factors. We also identified comparable radiations occurring during the same time period in C3 Pooid grasses, a diverse, cold-adapted grassland lineage that has never evolved C4 photosynthesis. The mid to late Miocene was an especially important period of both C3 and C4 grass diversification, coincident with the global development of extensive, open biomes in both warm and cool climates. As is likely true for most "key innovations", the C4 effect is context dependent and only relevant within a particular organismal background and when particular ecological opportunities became available.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0097722PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4023962PMC
August 2015

Molecular dating, evolutionary rates, and the age of the grasses.

Syst Biol 2014 Mar 28;63(2):153-65. Epub 2013 Nov 28.

Department of Animal and Plant Sciences, University of Sheffield, Western Bank, Sheffield S10 2TN, UK; Department of Ecology and Evolutionary Biology, Brown University, 80 Waterman St., Providence, RI 02912, USA; Department of Biology & Burke Museum of Natural History and Culture, University of Washington, 24 Kincaid Hall, Seattle, WA 98195, USA; Department of Ecology and Evolution, Biophore, Quartier Sorge, University of Lausanne, 1015 Lausanne, Switzerland; Swiss Institute of Bioinformatics, Quartier Sorge, University of Lausanne, 1015 Lausanne, Switzerland.

Many questions in evolutionary biology require an estimate of divergence times but, for groups with a sparse fossil record, such estimates rely heavily on molecular dating methods. The accuracy of these methods depends on both an adequate underlying model and the appropriate implementation of fossil evidence as calibration points. We explore the effect of these in Poaceae (grasses), a diverse plant lineage with a very limited fossil record, focusing particularly on dating the early divergences in the group. We show that molecular dating based on a data set of plastid markers is strongly dependent on the model assumptions. In particular, an acceleration of evolutionary rates at the base of Poaceae followed by a deceleration in the descendants strongly biases methods that assume an autocorrelation of rates. This problem can be circumvented by using markers that have lower rate variation, and we show that phylogenetic markers extracted from complete nuclear genomes can be a useful complement to the more commonly used plastid markers. However, estimates of divergence times remain strongly affected by different implementations of fossil calibration points. Analyses calibrated with only macrofossils lead to estimates for the age of core Poaceae ∼51-55 Ma, but the inclusion of microfossil evidence pushes this age to 74-82 Ma and leads to lower estimated evolutionary rates in grasses. These results emphasize the importance of considering markers from multiple genomes and alternative fossil placements when addressing evolutionary issues that depend on ages estimated for important groups.
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http://dx.doi.org/10.1093/sysbio/syt072DOI Listing
March 2014

Sexual dysfunction in female cancer survivors.

Am J Clin Oncol 2014 Feb;37(1):101-6

*Warren Alpert Medical School of Brown University †Department of Ecology and Evolutionary Biology, Brown University ‡Center for Sexuality, Intimacy, and Fertility, Women & Infants' Hospital, Providence, RI §Southern California Center for Sexual Health and Survivorship Medicine, Newport Beach, CA.

Cancer survivors face a myriad of long-term effects of their disease, diagnosis, and treatment, and chief among many are problems associated with sexual dysfunction. Yet despite their frequency and the degree of distress they cause patients, sexual dysfunction is not effectively screened for or treated, and this is particularly true in female survivors. Inconsistently performed general sexual health screening at all facets of cancer care and survivorship ultimately translates into missed attempts to identify and treat dysfunction when it does arise. In this paper, we will review the current research and clinical practices addressing sexual dysfunction in female cancer survivors and propose questions in need of future research attention. This article will review the phases of sexual response and how each may be affected by the physical and emotional stress of cancer diagnosis and treatment. We will then discuss existing tools for assessment of sexual function and approaches to their treatment. Finally, we will conclude with advice to health care professionals based on current research and suggest questions for future study.
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http://dx.doi.org/10.1097/COC.0b013e318248d89dDOI Listing
February 2014

Large Genomic Deletions in CACNA1A Cause Episodic Ataxia Type 2.

Front Neurol 2011 9;2:51. Epub 2011 Sep 9.

Department of Neurology, University of California, Los Angeles Los Angeles, CA, USA.

Episodic ataxia (EA) syndromes are heritable diseases characterized by dramatic episodes of imbalance and incoordination. EA type 2 (EA2), the most common and the best characterized subtype, is caused by mostly nonsense, splice site, small indel, and sometimes missense mutations in CACNA1A. Direct sequencing of CACNA1A fails to identify mutations in some patients with EA2-like features, possibly due to incomplete interrogation of CACNA1A or defects in other EA genes not yet defined. Previous reports described genomic deletions between 4 and 40 kb in EA2. In 47 subjects with EA (26 with EA2-like features) who tested negative for mutations in the known EA genes, we used multiplex ligation-dependent probe amplification to analyze CACNA1A for exonic copy number variations. Breakpoints were further defined by long-range PCR. We identified distinct multi-exonic deletions in three probands with classic EA2-like features: episodes of prolonged vertigo and ataxia triggered by stress and fatigue, interictal nystagmus, with onset during infancy or early childhood. The breakpoints in all three probands are located in Alu sequences, indicating errors in homologous recombination of Alu sequences as the underlying mechanism. The smallest deletion spanned exons 39 and 40, while the largest deletion spanned 200 kb, missing all but the first three exons. One deletion involving exons 39 through 47 arose spontaneously. The search for mutations in CACNA1A appears most fruitful in EA patients with interictal nystagmus and onset early in life. The finding of large heterozygous deletions suggests haploinsufficiency as a possible pathomechanism of EA2.
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http://dx.doi.org/10.3389/fneur.2011.00051DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3169784PMC
November 2011

Contemporaneous and recent radiations of the world's major succulent plant lineages.

Proc Natl Acad Sci U S A 2011 May 2;108(20):8379-84. Epub 2011 May 2.

Department of Ecology and Evolutionary Biology, Brown University, Providence, RI 02912, USA.

The cacti are one of the most celebrated radiations of succulent plants. There has been much speculation about their age, but progress in dating cactus origins has been hindered by the lack of fossil data for cacti or their close relatives. Using a hybrid phylogenomic approach, we estimated that the cactus lineage diverged from its closest relatives ≈35 million years ago (Ma). However, major diversification events in cacti were more recent, with most species-rich clades originating in the late Miocene, ≈10-5 Ma. Diversification rates of several cactus lineages rival other estimates of extremely rapid speciation in plants. Major cactus radiations were contemporaneous with those of South African ice plants and North American agaves, revealing a simultaneous diversification of several of the world's major succulent plant lineages across multiple continents. This short geological time period also harbored the majority of origins of C(4) photosynthesis and the global rise of C(4) grasslands. A global expansion of arid environments during this time could have provided new ecological opportunity for both succulent and C(4) plant syndromes. Alternatively, recent work has identified a substantial decline in atmospheric CO(2) ≈15-8 Ma, which would have strongly favored C(4) evolution and expansion of C(4)-dominated grasslands. Lowered atmospheric CO(2) would also substantially exacerbate plant water stress in marginally arid environments, providing preadapted succulent plants with a sharp advantage in a broader set of ecological conditions and promoting their rapid diversification across the landscape.
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http://dx.doi.org/10.1073/pnas.1100628108DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3100969PMC
May 2011

A large novel deletion in the APC promoter region causes gene silencing and leads to classical familial adenomatous polyposis in a Manitoba Mennonite kindred.

Hum Genet 2008 Dec 4;124(5):535-41. Epub 2008 Nov 4.

Samuel Lunenfeld Research Institute, Mount Sinai Hospital, 60 Murray St., Toronto, Box 30, ON, M5T 3L9, Canada.

Familial adenomatous polyposis (FAP) is an autosomal dominant syndrome caused by the inheritance of germline mutations in the APC tumour suppressor gene. The vast majority of these are nonsense and frameshift mutations resulting in a truncated protein product and abnormal function. While APC promoter hypermethylation has been previously documented, promoter-specific deletion mutations have not been reported. In a large Canadian Mennonite polyposis kindred, we identified a large novel germline deletion in the APC promoter region by linkage analysis and MLPA. By RT-PCR and sequence analysis, this mutation was found to result in transcriptional silencing of the APC allele. A few genetic disorders have been characterized as over-represented in the Manitoba Mennonite population, however, the incidence of cancer has not been recognized as increased in this population as compared to other Manitoba ethnic groups. This study strengthens the likelihood that this novel APC promoter mutation is linked to this unique population as a founder mutation.
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http://dx.doi.org/10.1007/s00439-008-0579-4DOI Listing
December 2008

The use of ancestral haplotypes in the molecular diagnosis of familial breast cancer.

Genet Test 2007 ;11(3):208-15

Molecular Diagnostic Laboratory, Diagnostic Services of Manitoba, Winnipeg, Manitoba, Canada.

Mutations in BRCA1 and BRCA2 account for about 40% of families with an inherited susceptibility to breast and/or ovarian cancer. Mutational analysis of these two genes has become the standard of care for families with a strong suggestion of inherited susceptibility. Methodologies for screening vary, but one of the more popular techniques is dHPLC, due to its combination of high sensitivity and low cost. The presence of a large number of polymorphisms in the two BRCA genes complicates dHPLC analysis, often leading to complex elution profiles. There are concerns that a pattern produced by a sample heterozygous for a polymorphism may be very similar to that produced by a sample heterozygous for a unique mutation within the same amplicon. Further molecular analysis is often required to resolve whether any given shift is due to a polymorphism or a disease-causing mutation. The use of ancestral haplotypes was explored as a means to minimize the need for further analysis. Groups of 86 patients were genotyped for 12 BRCA1 polymorphisms or 20 BRCA2 polymorphisms. For BRCA1, eight distinct haplotypes were identified, which are largely derivatives of two main lineages. For BRCA2, 17 distinct haplotypes were identified, leading to a much more complex polymorphic pattern. With this knowledge, we have defined a system to determine which patients, if any, require further investigations. This method could be used to supplement any comprehensive screening methodology for other large genes that lie within strong regions of linkage disequilibrium such as NF1, CFTR, MLH1, or MSH2.
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http://dx.doi.org/10.1089/gte.2006.0518DOI Listing
January 2008
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