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1.  Structure of CbpA J-Domain Bound to the Regulatory Protein CbpM Explains Its Specificity and Suggests Evolutionary Link between CbpM and Transcriptional Regulators 
PLoS ONE  2014;9(6):e100441.
CbpA is one of the six E. coli DnaJ/Hsp40 homologues of DnaK co-chaperones and the only one that is additionally regulated by a small protein CbpM, conserved in γ-proteobacteria. CbpM inhibits the co-chaperone and DNA binding activities of CbpA. This regulatory function of CbpM is accomplished through reversible interaction with the N-terminal J-domain of CbpA, which is essential for the interaction with DnaK. CbpM is highly specific for CbpA and does not bind DnaJ despite the high degree of structural and functional similarity between the J-domains of CbpA and DnaJ. Here we report the crystal structure of the complex of CbpM with the J-domain of CbpA. CbpM forms dimers and the J-domain of CbpA interacts with both CbpM subunits. The CbpM-binding surface of CbpA is highly overlapping with the CbpA interface for DnaK, providing a competitive model for regulation through forming mutually exclusive complexes. The structure also provides the explanation for the strict specificity of CbpM for CbpA, which we confirmed by making mutants of DnaJ that became regulated by CbpM. Interestingly, the structure of CbpM reveals a striking similarity to members of the MerR family of transcriptional regulators, suggesting an evolutionary connection between the functionally distinct bacterial co-chaperone regulator CbpM and the transcription regulator HspR.
doi:10.1371/journal.pone.0100441
PMCID: PMC4063869  PMID: 24945826
2.  Divergent Aging Characteristics in CBA/J and CBA/CaJ Mouse Cochleae 
Two inbred mouse strains, CBA/J and CBA/CaJ, have been used nearly interchangeably as ‘good hearing’ standards for research in hearing and deafness. We recently reported, however, that these two strains diverge after 1 year of age, such that CBA/CaJ mice show more rapid elevation of compound action potential (CAP) thresholds at high frequencies (Ohlemiller, Brain Res. 1277: 70–83, 2009). One contributor is progressive decline in endocochlear potential (EP) that appears only in CBA/CaJ. Here, we explore the cellular bases of threshold and EP disparities in old CBA/J and CBA/CaJ mice. Among the major findings, both strains exhibit a characteristic age (∼18 months in CBA/J and 24 months in CBA/CaJ) when females overtake males in sensitivity decline. Strain differences in progression of hearing loss are not due to greater hair cell loss in CBA/CaJ, but instead appear to reflect greater neuronal loss, plus more pronounced changes in the lateral wall, leading to EP decline. While both male and female CBA/CaJ show these pathologies, they are more pronounced in females. A novel feature that differed sharply by strain was moderate loss of outer sulcus cells (or ‘root’ cells) in spiral ligament of the upper basal turn in old CBA/CaJ mice, giving rise to deep indentations and void spaces in the ligament. We conclude that CBA/CaJ mice differ both quantitatively and qualitatively from CBA/J in age-related cochlear pathology, and model different types of presbycusis.
doi:10.1007/s10162-010-0228-1
PMCID: PMC2975886  PMID: 20706857
presbycusis; stria vascularis; spiral ligament; endocochlear potential; hair cells; outer sulcus cells; marginal cells; gender effects; spiral ganglion
3.  Cloning, recombinant production, crystallization and preliminary X-ray diffraction studies of a family 84 glycoside hydrolase from Clostridium perfringens  
Crystallization of a family 84 glycoside hydrolase, a putative virulence factor, secreted by C. perfringens is reported.
Clostridium perfringens is a ubiquitous environmental organism that is capable of causing a variety of diseases in mammals, including gas gangrene and necrotic enteritis in humans. The activity of a secreted hyaluronidase, attributed to the NagH protein, contributes to the pathogenicity of this organism. The family 84 catalytic module of one of the three homologues of NagH found in C. perfringens (ATCC 13124) has been cloned. The 69 kDa catalytic module of NagJ, here called GH84C, was overproduced in Escherichia coli and purified by immobilized metal-affinity chromatography (IMAC). Crystals belonging to space group I222 or I212121 with unit-cell parameters a = 130.39, b = 150.05, c = 155.43 Å were obtained that diffracted to 2.1 Å. Selenomethionyl crystals have also been produced, leading to the possibility of solving the phase problem by MAD using synchrotron radiation.
doi:10.1107/S1744309105024012
PMCID: PMC1978112  PMID: 16511172
Clostridium perfringens; hyaluronidases; family 84 glycoside hydrolases; carbohydrates; hexosaminidases
4.  Beyond Surface Characteristics: A New Health Text-Specific Readability Measurement 
Accurate readability assessment of health related materials is a critical first step in producing easily understandable consumer health information resources and personal health records. Existing general readability formulas may not always be appropriate for the medical/consumer health domain. We developed a new health-specific readability pilot measure, based on the differences in semantic and syntactic features as well as text unit length. The tool was tested with 4 types of materials: consumer health texts, electronic health records, health news articles, and scientific biomedical journals. The results were compared with those produced by three commonly used general readability formulas. While the general formulas underestimated the difficulty of health records by placing them at the same grade levels as consumer health texts, our method rated health records as the most difficult type of documents. Our ratings, however, were highly correlated with general formulas ratings of consumer health, news, and journal articles (r=0.81~0.85, p<.0001).
PMCID: PMC2655856  PMID: 18693870
readability; consumer health informatics
5.  Calculation and Visualization of Atomistic Mechanical Stresses in Nanomaterials and Biomolecules 
PLoS ONE  2014;9(12):e113119.
Many biomolecules have machine-like functions, and accordingly are discussed in terms of mechanical properties like force and motion. However, the concept of stress, a mechanical property that is of fundamental importance in the study of macroscopic mechanics, is not commonly applied in the biomolecular context. We anticipate that microscopical stress analyses of biomolecules and nanomaterials will provide useful mechanistic insights and help guide molecular design. To enable such applications, we have developed Calculator of Atomistic Mechanical Stress (CAMS), an open-source software package for computing atomic resolution stresses from molecular dynamics (MD) simulations. The software also enables decomposition of stress into contributions from bonded, nonbonded and Generalized Born potential terms. CAMS reads GROMACS topology and trajectory files, which are easily generated from AMBER files as well; and time-varying stresses may be animated and visualized in the VMD viewer. Here, we review relevant theory and present illustrative applications.
doi:10.1371/journal.pone.0113119
PMCID: PMC4263534  PMID: 25503996
6.  Localised JAK/STAT Pathway Activation Is Required for Drosophila Wing Hinge Development 
PLoS ONE  2013;8(5):e65076.
Extensive morphogenetic remodelling takes place during metamorphosis from a larval to an adult insect body plan. These changes are particularly intricate in the generation of the dipteran wing hinge, a complex structure that is derived from an apparently simple region of the wing imaginal disc. Using the characterisation of original outstretched alleles of the unpaired locus as a starting point, we demonstrate the role of JAK/STAT pathway signalling in the process of wing hinge development. We show that differences in JAK/STAT signalling within the proximal most of three lateral folds present in the wing imaginal disc is required for fold morphology and the subsequent differentiation of the first and second auxiliary sclerites as well as the posterior notal wing process. Changes in these domains are consistent with the established fate map of the wing disc. We show that outstretched wing posture phenotypes arise from the loss of a region of Unpaired expression in the proximal wing fold and demonstrate that this results in a decrease in JAK/STAT pathway activity. Finally we show that reduction of JAK/STAT pathway activity within the proximal wing fold is sufficient to phenocopy the outstretched phenotype. Taken together, we suggest that localised Unpaired expression and hence JAK/STAT pathway activity, is required for the morphogenesis of the adult wing hinge, providing new insights into the link between signal transduction pathways, patterning and development.
doi:10.1371/journal.pone.0065076
PMCID: PMC3669132  PMID: 23741461
7.  Correlated Evolution of Positions within Mammalian cis Elements 
PLoS ONE  2013;8(2):e55521.
Transcriptional regulation critically depends on proper interactions between transcription factors (TF) and their cognate DNA binding sites. The widely used model of TF-DNA binding – the Positional Weight Matrix (PWM) – presumes independence between positions within the binding site. However, there is evidence to show that the independence assumption may not always hold, and the extent of interposition dependence is not completely known. We hypothesize that the interposition dependence should partly be manifested as correlated evolution at the positions. We report a Maximum-Likelihood (ML) approach to infer correlated evolution at any two positions within a PWM, based on a multiple alignment of 5 mammalian genomes. Application to a genome-wide set of putative cis elements in human promoters reveals a prevalence of correlated evolution within cis elements. We found that the interdependence between two positions decreases with increasing distance between the positions. The interdependent positions tend to be evolutionarily more constrained and moreover, the dependence patterns are relatively similar across structurally related transcription factors. Although some of the detected mutational dependencies may be due to context-dependent genomic hyper-mutation, notably CG to TG, the majority is likely due to context-dependent preferences for specific nucleotide combinations within the cis elements. Patterns of evolution at individual nucleotide positions within mammalian TF binding sites are often significantly correlated, suggesting interposition dependence. The proposed methodology is also applicable to other classes of non-coding functional elements. A detailed investigation of mutational dependencies within specific motifs could reveal preferred nucleotide combinations that may help refine the DNA binding models.
doi:10.1371/journal.pone.0055521
PMCID: PMC3568137  PMID: 23408994
8.  Expression of Mutant Huntingtin in Leptin Receptor-Expressing Neurons Does Not Control the Metabolic and Psychiatric Phenotype of the BACHD Mouse 
PLoS ONE  2012;7(12):e51168.
Metabolic and psychiatric disturbances occur early on in the clinical manifestation of Huntington’s disease (HD), a neurodegenerative disorder caused by an expanded CAG repeat in the huntingtin (HTT) gene. Hypothalamus has emerged as an important site of pathology and alterations in this area and its neuroendocrine circuits may play a role in causing early non-motor symptoms and signs in HD. Leptin is a hormone that controls energy homeostasis by signaling through leptin receptors in the hypothalamus. Disturbed leptin action is implicated in both obesity and depression and altered circulating levels of leptin have been reported in both clinical HD and rodent models of the disease. Pathological leptin signaling may therefore be involved in causing the metabolic and psychiatric disturbances of HD. Here we tested the hypothesis that expression of mutant HTT in leptin receptor carrying neurons plays a role in the development of the non-motor phenotype in the BACHD mouse model. Our results show that inactivation of mutant HTT in leptin receptor-expressing neurons in the BACHD mouse using cross-breeding based on a cre-loxP system did not have an effect on the metabolic phenotype or anxiety-like behavior. The data suggest that mutant HTT disrupts critical hypothalamic pathways by other mechanisms than interfering with intracellular leptin signaling.
doi:10.1371/journal.pone.0051168
PMCID: PMC3519539  PMID: 23251447
9.  Hermansky-Pudlak Protein Complexes, AP-3 and BLOC-1, Differentially Regulate Presynaptic Composition in the Striatum and Hippocampus 
Endosomal sorting mechanisms mediated by AP-3 and BLOC-1 are perturbed in Hermansky-Pudlak Syndrome, a human genetic condition characterized by albinism and prolonged bleeding (OMIM #203300). Additionally, mouse models defective in either one of these complexes possess defective synaptic vesicle biogenesis (Newell-Litwa et al., 2009). These synaptic vesicle phenotypes were presumed uniform throughout the brain. However, here we report that AP-3 and BLOC-1 differentially regulate the composition of pre-synaptic terminals in the striatum and dentate gyrus of the hippocampus. Quantitative immunoelectron microscopy demonstrated that the majority of AP-3 immunoreactivity in both wild type striatum and hippocampus localizes to pre-synaptic axonal compartments, where it regulates synaptic vesicle size. In the striatum, loss of AP-3 (Ap3dmh/mh) resulted in decreased synaptic vesicle size. In contrast, loss of AP-3 in the dentate gyrus increased synaptic vesicle size, thus suggesting anatomically specific AP-3-regulatory mechanisms. Loss-of-function alleles of BLOC-1, Pldnpa/pa and Mutedmu/mu, revealed that this complex acts as a brain-region specific regulator of AP-3. In fact, BLOC-1 deficiencies selectively reduced AP-3 and AP-3 cargo immunoreactivity in pre-synaptic compartments within the dentate gyrus both at the light and/or electron microscopy level. However, the striatum did not exhibit these BLOC-1-null phenotypes. Our results demonstrate that distinct brain regions differentially regulate AP-3-dependent synaptic vesicle biogenesis. We propose that anatomically restricted mechanisms within the brain diversify the biogenesis and composition of synaptic vesicles.
doi:10.1523/JNEUROSCI.3400-09.2010
PMCID: PMC2824551  PMID: 20089890
Synapse; Synaptic; dentate gyrus; striatum; presynaptic regulation; Membrane
10.  Erratum 
Journal of Heredity  2013;104(5):735.
doi:10.1093/jhered/est048
PMCID: PMC3889212
11.  Congenital hypotrichosis in an Ayrshire calf 
The Canadian Veterinary Journal  1989;30(3):249-250.
Images
PMCID: PMC1681004  PMID: 17423263
12.  Mapping of the Domestic Cat “SILVER” Coat Color Locus Identifies a Unique Genomic Location for Silver in Mammals 
Journal of Heredity  2009;100(Suppl 1):S8-S13.
The SILVER locus has been mapped in the domestic cat, identifying a unique genomic location distinct from that of any known reported gene associated with silver or hypopigmentation in mammals. A demonstrated lack of linkage to SILV, the strong candidate gene for silver, led to the initiation of a genome scan utilizing 2 pedigrees segregating for silver coat color. Linkage mapping defined a genomic region for SILVER as a 3.3-Mb region, (95.87–99.21 Mb) on chromosome D2, (peak logarithm of the odds = 10.5, θ = 0), which displays conserved synteny to a genomic interval between 118.58 and 121.85 Mb on chromosome 10 in the human genome. In the domestic cat, mutations at the SILVER locus suppress the development of pigment in the hair, but in contrast to other mammalian silver variants, there is an apparently greater influence on the production of pheomelanin than eumelanin pigment. The mapping of a novel locus for SILVER offers much promise in identifying a gene that may help elucidate aspects of pheomelanogenesis, a pathway that has been very elusive, and illustrates the promise of the cat genome project in increasing our understanding of basic biological processes of general relevance for mammals.
doi:10.1093/jhered/esp018
PMCID: PMC3307065  PMID: 19398491
coat color; domestic cat; genetic linkage mapping; pheomelanogenic; SILVER
13.  Development of MHC-Linked Microsatellite Markers in the Domestic Cat and Their Use to Evaluate MHC Diversity in Domestic Cats, Cheetahs, and Gir Lions 
Journal of Heredity  2014;105(4):493-505.
Diversity within the major histocompatibility complex (MHC) reflects the immunological fitness of a population. MHC-linked microsatellite markers provide a simple and an inexpensive method for studying MHC diversity in large-scale studies. We have developed 6 MHC-linked microsatellite markers in the domestic cat and used these, in conjunction with 5 neutral microsatellites, to assess MHC diversity in domestic mixed breed (n = 129) and purebred Burmese (n = 61) cat populations in Australia. The MHC of outbred Australian cats is polymorphic (average allelic richness = 8.52), whereas the Burmese population has significantly lower MHC diversity (average allelic richness = 6.81; P < 0.01). The MHC-linked microsatellites along with MHC cloning and sequencing demonstrated moderate MHC diversity in cheetahs (n = 13) and extremely low diversity in Gir lions (n = 13). Our MHC-linked microsatellite markers have potential future use in diversity and disease studies in other populations and breeds of cats as well as in wild felid species.
doi:10.1093/jhered/esu017
PMCID: PMC4048552  PMID: 24620003
Acinonyx jubatus; Felis catus; major histocompatibility complex; Panthera leo
14.  Genetic Status and Timing of a Weevil Introduction to Santa Cruz Island, Galápagos 
Journal of Heredity  2014;105(3):365-380.
Successful invasive species can overcome or circumvent the potential genetic loss caused by an introduction bottleneck through a rapid population expansion and admixture from multiple introductions. We explore the genetic makeup and the timing of a species introduction to Santa Cruz Island in the Galápagos archipelago. We investigate the presence of processes that can maintain genetic diversity in populations of the broad-nosed weevil Galapaganus howdenae howdenae. Analyses of combined genotypes for 8 microsatellite loci showed evidence of past population size reductions through moment and likelihood-based estimators. No evidence of admixture through multiple introductions was found, but substantial current population sizes (N0 298, 95% credible limits 50–2300), genetic diversity comparable with long-established endemics (Mean number of alleles = 3.875), and lack of genetic structure across the introduced range (F ST = 0.01359) could suggest that foundations are in place for populations to rapidly recover any loss of genetic variability. The time estimates for the introduction into Santa Cruz support an accidental transfer during the colonization period (1832–1959) predating the spurt in human population growth. Our evaluation of the genetic status of G. h. howdenae suggests potential for population growth in addition to our field observations of a concurrent expansion in range and feeding preferences towards protected areas and endemic host plants.
doi:10.1093/jhered/est096
PMCID: PMC3984438  PMID: 24399746
bottlenecks; Galapaganus h. howdenae; microsatellite loci; Msvar; older introduction; range expansion
15.  Clock Gene Evolution: Seasonal Timing, Phylogenetic Signal, or Functional Constraint? 
Journal of Heredity  2014;105(3):407-415.
Genetic determinants of seasonal reproduction are not fully understood but may be important predictors of organism responses to climate change. We used a comparative approach to study the evolution of seasonal timing within a fish community in a natural common garden setting. We tested the hypothesis that allelic length variation in the PolyQ domain of a circadian rhythm gene, Clock1a, corresponded to interspecific differences in seasonal reproductive timing across 5 native and 1 introduced cyprinid fishes (n = 425 individuals) that co-occur in the Rio Grande, NM, USA. Most common allele lengths were longer in native species that initiated reproduction earlier (Spearman’s r = −0.70, P = 0.23). Clock1a allele length exhibited strong phylogenetic signal and earlier spawners were evolutionarily derived. Aside from length variation in Clock1a, all other amino acids were identical across native species, suggesting functional constraint over evolutionary time. Interestingly, the endangered Rio Grande silvery minnow (Hybognathus amarus) exhibited less allelic variation in Clock1a and observed heterozygosity was 2- to 6-fold lower than the 5 other (nonimperiled) species. Reduced genetic variation in this functionally important gene may impede this species’ capacity to respond to ongoing environmental change.
doi:10.1093/jhered/esu008
PMCID: PMC3984439  PMID: 24558102
circadian rhythms; climate change; Clock; comparative biology; molecular ecology; phenology
16.  Evidence of Positive Selection for a Glycogen Synthase (GYS1) Mutation in Domestic Horse Populations 
Journal of Heredity  2013;105(2):163-172.
A dominantly inherited gain-of-function mutation in the glycogen synthase (GYS1) gene, resulting in excess skeletal muscle glycogen, has been identified in more than 30 horse breeds. This mutation is associated with the disease Equine Polysaccharide Storage Myopathy Type 1, yet persists at high frequency in some breeds. Under historical conditions of daily work and limited feed, excess muscle glycogen may have been advantageous, driving the increase in frequency of this allele. Fine-scale DNA sequencing in 80 horses and genotype assays in 279 horses revealed a paucity of haplotypes carrying the mutant allele when compared with the wild-type allele. Additionally, we found increased linkage disequilibrium, measured by relative extended haplotype homozygosity, in haplotypes carrying the mutation compared with haplotypes carrying the wild-type allele. Coalescent simulations of Belgian horse populations demonstrated that the high frequency and extended haplotype associated with the GYS1 mutation were unlikely to have arisen under neutrality or due to population demography. In contrast, in Quarter Horses, elevated relative extended haplotype homozygosity was associated with multiple haplotypes and may be the result of recent population expansion or a popular sire effect. These data suggest that the GYS1 mutation underwent historical selection in the Belgian, but not in the Quarter Horse.
doi:10.1093/jhered/est075
PMCID: PMC3920812  PMID: 24215078
equine; gain of function; glycogen synthase; Polysaccharide Storage Myopathy; selection
17.  The American Quarter Horse: Population Structure and Relationship to the Thoroughbred 
Journal of Heredity  2013;105(2):148-162.
A breed known for its versatility, the American Quarter Horse (QH), is increasingly bred for performance in specific disciplines. The impact of selective breeding on the diversity and structure of the QH breed was evaluated using pedigree analysis and genome-wide SNP data from horses representing 6 performance groups (halter, western pleasure, reining, working cow, cutting, and racing). Genotype data (36 037 single nucleotide polymorphisms [SNPs]) from 36 Thoroughbreds were also evaluated with those from the 132 performing QHs to evaluate the Thoroughbred’s influence on QH diversity. Results showed significant population structure among all QH performance groups excepting the comparison between the cutting and working cow horses; divergence was greatest between the cutting and racing QHs, the latter of which had a large contribution of Thoroughbred ancestry. Significant coancestry and the potential for inbreeding exist within performance groups, especially when considering the elite performers. Relatedness within performance groups is increasing with popular sires contributing disproportionate levels of variation to each discipline. Expected heterozygosity, inbreeding, F ST, cluster, and haplotype analyses suggest these QHs can be broadly classified into 3 categories: stock, racing, and pleasure/halter. Although the QH breed as a whole contains substantial genetic diversity, current breeding practices have resulted in this variation being sequestered into subpopulations.
doi:10.1093/jhered/est079
PMCID: PMC3920813  PMID: 24293614
breeds; coancestry; equine; performance; relatedness; selection
18.  Genetic Architecture of a Hormonal Response to Gene Knockdown in Honey Bees 
Journal of Heredity  2015;106(2):155-165.
Variation in endocrine signaling is proposed to underlie the evolution and regulation of social life histories, but the genetic architecture of endocrine signaling is still poorly understood. An excellent example of a hormonally influenced set of social traits is found in the honey bee (Apis mellifera): a dynamic and mutually suppressive relationship between juvenile hormone (JH) and the yolk precursor protein vitellogenin (Vg) regulates behavioral maturation and foraging of workers. Several other traits cosegregate with these behavioral phenotypes, comprising the pollen hoarding syndrome (PHS) one of the best-described animal behavioral syndromes. Genotype differences in responsiveness of JH to Vg are a potential mechanistic basis for the PHS. Here, we reduced Vg expression via RNA interference in progeny from a backcross between 2 selected lines of honey bees that differ in JH responsiveness to Vg reduction and measured JH response and ovary size, which represents another key aspect of the PHS. Genetic mapping based on restriction site-associated DNA tag sequencing identified suggestive quantitative trait loci (QTL) for ovary size and JH responsiveness. We confirmed genetic effects on both traits near many QTL that had been identified previously for their effect on various PHS traits. Thus, our results support a role for endocrine control of complex traits at a genetic level. Furthermore, this first example of a genetic map of a hormonal response to gene knockdown in a social insect helps to refine the genetic understanding of complex behaviors and the physiology that may underlie behavioral control in general.
doi:10.1093/jhered/esu086
PMCID: PMC4323067  PMID: 25596612
Apis mellifera; complex trait genetics; genetic architecture juvenile hormone; social evolution; vitellogenin
19.  The Global Invertebrate Genomics Alliance (GIGA): Developing Community Resources to Study Diverse Invertebrate Genomes 
Journal of Heredity  2013;105(1):1-18.
Over 95% of all metazoan (animal) species comprise the “invertebrates,” but very few genomes from these organisms have been sequenced. We have, therefore, formed a “Global Invertebrate Genomics Alliance” (GIGA). Our intent is to build a collaborative network of diverse scientists to tackle major challenges (e.g., species selection, sample collection and storage, sequence assembly, annotation, analytical tools) associated with genome/transcriptome sequencing across a large taxonomic spectrum. We aim to promote standards that will facilitate comparative approaches to invertebrate genomics and collaborations across the international scientific community. Candidate study taxa include species from Porifera, Ctenophora, Cnidaria, Placozoa, Mollusca, Arthropoda, Echinodermata, Annelida, Bryozoa, and Platyhelminthes, among others. GIGA will target 7000 noninsect/nonnematode species, with an emphasis on marine taxa because of the unrivaled phyletic diversity in the oceans. Priorities for selecting invertebrates for sequencing will include, but are not restricted to, their phylogenetic placement; relevance to organismal, ecological, and conservation research; and their importance to fisheries and human health. We highlight benefits of sequencing both whole genomes (DNA) and transcriptomes and also suggest policies for genomic-level data access and sharing based on transparency and inclusiveness. The GIGA Web site (http://giga.nova.edu) has been launched to facilitate this collaborative venture.
doi:10.1093/jhered/est084
PMCID: PMC4072906  PMID: 24336862
biodiversity; comparative genomics; consortium; evolution; GIGA; invertebrates; metazoa
20.  No Boundaries: Genomes, Organisms, and Ecological Interactions Responsible for Divergence and Reproductive Isolation 
Journal of Heredity  2014;105(Suppl 1):756-770.
Revealing the genetic basis of traits that cause reproductive isolation, particularly premating or sexual isolation, usually involves the same challenges as most attempts at genotype–phenotype mapping and so requires knowledge of how these traits are expressed in different individuals, populations, and environments, particularly under natural conditions. Genetic dissection of speciation phenotypes thus requires understanding of the internal and external contexts in which underlying genetic elements are expressed. Gene expression is a product of complex interacting factors internal and external to the organism including developmental programs, the genetic background including nuclear–cytotype interactions, epistatic relationships, interactions among individuals or social effects, stochasticity, and prevailing variation in ecological conditions. Understanding of genomic divergence associated with reproductive isolation will be facilitated by functional expression analysis of annotated genomes in organisms with well-studied evolutionary histories, phylogenetic affinities, and known patterns of ecological variation throughout their life cycles. I review progress and prospects for understanding the pervasive role of host plant use on genetic and phenotypic expression of reproductive isolating mechanisms in cactophilic Drosophila mojavensis and suggest how this system can be used as a model for revealing the genetic basis for species formation in organisms where speciation phenotypes are under the joint influences of genetic and environmental factors.
doi:10.1093/jhered/esu039
PMCID: PMC4170711  PMID: 25149252
cactus; courtship song; cuticular hydrocarbon; Drosophila; gene ontology; microarray; Sonoran Desert; speciation; transcriptome
21.  Patterns of Population Structure for Inshore Bottlenose Dolphins along the Eastern United States 
Journal of Heredity  2013;104(6):765-778.
Globally distributed, the bottlenose dolphin (Tursiops truncatus) is found in a range of offshore and coastal habitats. Using 15 microsatellite loci and mtDNA control region sequences, we investigated patterns of genetic differentiation among putative populations along the eastern US shoreline (the Indian River Lagoon, Florida, and Charleston Harbor, South Carolina) (microsatellite analyses: n = 125, mtDNA analyses: n = 132). We further utilized the mtDNA to compare these populations with those from the Northwest Atlantic, Gulf of Mexico, and Caribbean. Results showed strong differentiation among inshore, alongshore, and offshore habitats (ФST = 0.744). In addition, Bayesian clustering analyses revealed the presence of 2 genetic clusters (populations) within the 250 km Indian River Lagoon. Habitat heterogeneity is likely an important force diversifying bottlenose dolphin populations through its influence on social behavior and foraging strategy. We propose that the spatial pattern of genetic variation within the lagoon reflects both its steep longitudinal transition of climate and also its historical discontinuity and recent connection as part of Intracoastal Waterway development. These findings have important management implications as they emphasize the role of habitat and the consequence of its modification in shaping bottlenose dolphin population structure and highlight the possibility of multiple management units existing in discrete inshore habitats along the entire eastern US shoreline.
doi:10.1093/jhered/est070
PMCID: PMC3796761  PMID: 24129993
Indian River Lagoon; microsatellite; mtDNA; Tursiops truncatus
22.  Composite Linkage Map and Enhanced Genome Map for Culex pipiens Complex Mosquitoes 
Journal of Heredity  2013;104(5):649-655.
We report here the development of 65 novel microsatellite loci and construction of a composite genetic linkage map for Culex pipiens complex mosquitoes. Microsatellites were identified by in silico screening of the Culex quinquefasciatus genome assembly. Cross-species utility of 73 microsatellites for population studies in C. pipiens sensu stricto and C. quinquefasciatus was evaluated by genotyping a subset of samples collected in Indiana, United States, and Point Fortin, Trinidad. Allele frequencies of 67 microsatellites were within Hardy–Weinberg expectations in both population subsets. A composite linkage map was constructed based on restriction fragment length polymorphism and microsatellite polymorphisms in 12 independent F1 intercross mapping populations. The composite map consists of 61 marker loci totaling 183.9 cM distributed across the 3 linkage groups. These loci cover 29.5, 88.8, and 65.6 cM on chromosomes I–III, respectively, and allow for assignment of 10.4% of the genome assembly and 13.5% of the protein coding genes to chromosome position. Our results suggest that these microsatellites will be useful for mapping and population studies of 2 pervasive species in the C. pipiens complex. Moreover, the composite map presented here will serve as a basis for the construction of high-resolution genetic and physical maps, as well as detection of quantitative trait loci to aid in the investigation of complex genetic traits influencing phenotypes of interest.
doi:10.1093/jhered/est040
PMCID: PMC3741631  PMID: 23846985
composite linkage map; Culex quinquefasciatus; genome assembly; house mosquito; SSR; supercontigs
23.  OptiMAS: A Decision Support Tool for Marker-Assisted Assembly of Diverse Alleles 
Journal of Heredity  2013;104(4):586-590.
Current advances in plant genotyping lead to major progress in the knowledge of genetic architecture of traits of interest. It is increasingly important to develop decision support tools to help breeders and geneticists to conduct marker-assisted selection methods to assemble favorable alleles that are discovered. Algorithms have been implemented, within an interactive graphical interface, to 1) trace parental alleles throughout generations, 2) propose strategies to select the best plants based on estimated molecular scores, and 3) efficiently intermate them depending on the expected value of their progenies. With the possibility to consider a multi-allelic context, OptiMAS opens new prospects to assemble favorable alleles issued from diverse parents and further accelerate genetic gain.
doi:10.1093/jhered/est020
PMCID: PMC3678297  PMID: 23576670
marker-assisted selection; plant breeding; QTL; multiparental designs; gene pyramiding
24.  Several Classical Mouse Inbred Strains, Including DBA/2, NOD/Lt, FVB/N, and SJL/J, Carry a Putative Loss-of-Function Allele of Gpr84  
Journal of Heredity  2013;104(4):565-571.
G protein–coupled receptor 84 (GPR84) is a 7-transmembrane protein expressed on myeloid cells that can bind to medium-chain free fatty acids in vitro. Here, we report the discovery of a 2-bp frameshift deletion in the second exon of the Gpr84 gene in several classical mouse inbred strains. This deletion generates a premature stop codon predicted to result in a truncated protein lacking the transmembrane domains 4-7. We sequenced Gpr84 exon 2 from 58 strains representing different groups in the mouse family tree and found that 14 strains are homozygous for the deletion. Some of these strains are DBA/1J, DBA/2J, FVB/NJ, LG/J, MRL/MpJ, NOD/LtJ, and SJL/J. However, the deletion was not found in any of the wild-derived inbred strains analyzed. Haplotype analysis suggested that the deletion originates from a unique mutation event that occurred more than 100 years ago, preceding the development of the first inbred strain (DBA), from a Mus musculus domesticus source. As GPR84 ostensibly plays a role in the biology of myeloid cells, it could be relevant 1) to consider the existence of this Gpr84 nonsense mutation in several mouse strains when choosing a mouse model to study immune processes and 2) to consider reevaluating data obtained using such strains.
doi:10.1093/jhered/est023
PMCID: PMC3954108  PMID: 23616478
spontaneous mutations; G protein–coupled receptors; inbred mice; mouse models
25.  Inventory and Phylogenetic Analysis of Meiotic Genes in Monogonont Rotifers 
Journal of Heredity  2013;104(3):357-370.
A long-standing question in evolutionary biology is how sexual reproduction has persisted in eukaryotic lineages. As cyclical parthenogens, monogonont rotifers are a powerful model for examining this question, yet the molecular nature of sexual reproduction in this lineage is currently understudied. To examine genes involved in meiosis, we generated partial genome assemblies for 2 distantly related monogonont species, Brachionus calyciflorus and B. manjavacas. Here we present an inventory of 89 meiotic genes, of which 80 homologs were identified and annotated from these assemblies. Using phylogenetic analysis, we show that several meiotic genes have undergone relatively recent duplication events that appear to be specific to the monogonont lineage. Further, we compare the expression of “meiosis-specific” genes involved in recombination and all annotated copies of the cell cycle regulatory gene CDC20 between obligate parthenogenetic (OP) and cyclical parthenogenetic (CP) strains of B. calyciflorus. We show that “meiosis-specific” genes are expressed in both CP and OP strains, whereas the expression of one of the CDC20 genes is specific to cyclical parthenogenesis. The data presented here provide insights into mechanisms of cyclical parthenogenesis and establish expectations for studies of obligate asexual relatives of monogononts, the bdelloid rotifer lineage.
doi:10.1093/jhered/est011
PMCID: PMC3622358  PMID: 23487324
asexual reproduction; cyclical parthenogenesis; evolution of sex

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