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  • 1
    Publication Date: 2015-08-07
    Description: Primary ciliary dyskinesia (PCD) is an autosomal-recessive disorder resulting from loss of normal ciliary function. Symptoms include neonatal respiratory distress, chronic sinusitis, bronchiectasis, situs inversus , and infertility. Clinical features may be subtle and highly variable, making the diagnosis of PCD challenging. The diagnosis can be confirmed with ciliary ultrastructure analysis and/or molecular genetic testing of 32 PCD-associated genes. However, because of this genetic heterogeneity, comprehensive molecular genetic testing is not considered the standard of care, and the most efficient molecular approach has yet to be elucidated. Here, we propose a cost-effective and time-efficient molecular genetic algorithm to solve cases of PCD. We conducted targeted copy number variation (CNV) analysis and/or whole-exome sequencing on 20 families (22 patients) from a subset of 45 families (52 patients) with a clinical diagnosis of PCD who did not have a molecular genetic diagnosis after Sanger sequencing of 12 PCD-associated genes. This combined molecular genetic approach led to the identification of 4 of 20 (20%) families with clinically significant CNVs and 7 of 20 (35%) families with biallelic pathogenic mutations in recently identified PCD genes, resulting in an increased molecular genetic diagnostic rate of 55% (11/20). In patients with a clinical diagnosis of PCD, whole-exome sequencing followed by targeted CNV analysis results in an overall molecular genetic yield of 76% (34/45).
    Electronic ISSN: 2160-1836
    Topics: Biology
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  • 2
    Publication Date: 2016-01-07
    Description: We accumulated mutations for 1952 generations in 79 initially identical, haploid lines of the fission yeast Schizosaccharomyces pombe , and then performed whole-genome sequencing to determine the mutation rates and spectrum. We captured 696 spontaneous mutations across the 79 mutation accumulation (MA) lines. We compared the mutation spectrum and rate to a recently published equivalent experiment on the same species, and to another model ascomycetous yeast, the budding yeast Saccharomyces cerevisiae . While the two species are approximately 600 million years diverged from each other, they share similar life histories, genome size and genomic G/C content. We found that Sc. pombe and S. cerevisiae have similar mutation rates, but Sc. pombe exhibits a stronger insertion bias. Intriguingly, we observed an increased mutation rate at cytosine nucleotides, specifically CpG nucleotides, which is also seen in S. cerevisiae . However, the absence of methylation in Sc. pombe and the pattern of mutation at these sites, primarily C -〉 A as opposed to C -〉 T, strongly suggest that the increased mutation rate is not caused by deamination of methylated cytosines. This result implies that the high mutability of CpG dinucleotides in other species may be caused in part by a methylation-independent mechanism. Many of our findings mirror those seen in the recent study, despite the use of different passaging conditions, indicating that MA is a reliable method for estimating mutation rates and spectra.
    Electronic ISSN: 2160-1836
    Topics: Biology
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  • 3
    Publication Date: 2016-02-05
    Description: We describe a suite of predictive models, coined FAST m C , for nonreference, cost-effective exploration and comparative analysis of context-specific DNA methylation levels. Accurate estimations of true DNA methylation levels can be obtained from as few as several thousand short-reads generated from whole-genome bisulfite sequencing. These models make high-resolution time course or developmental and large diversity studies practical regardless of species, genome size, and availability of a reference genome.
    Electronic ISSN: 2160-1836
    Topics: Biology
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  • 4
    Publication Date: 2013-07-13
    Description: We performed a mutation accumulation (MA) experiment in the social amoeba Dictyostelium discoideum to estimate the rate and distribution of effects of spontaneous mutations affecting eight putative fitness traits. We found that the per-generation mutation rate for most fitness components is 0.0019 mutations per haploid genome per generation or larger. This rate is an order of magnitude higher than estimates for fitness components in the unicellular eukaryote Saccharomyces cerevisiae , even though the base-pair substitution rate is two orders of magnitude lower. The high rate of fitness-altering mutations observed in this species may be partially explained by a large mutational target relative to S. cerevisiae . Fitness-altering mutations also may occur primarily at simple sequence repeats, which are common throughout the genome, including in coding regions, and may represent a target that is particularly likely to give fitness effects upon mutation. The majority of mutations had deleterious effects on fitness, but there was evidence for a substantial fraction, up to 40%, being beneficial for some of the putative fitness traits. Competitive ability within the multicellular slug appears to be under weak directional selection, perhaps reflecting the fact that slugs are sometimes, but not often, comprised of multiple clones in nature. Evidence for pleiotropy among fitness components across MA lines was absent, suggesting that mutations tend to act on single fitness components.
    Electronic ISSN: 2160-1836
    Topics: Biology
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  • 5
    Publication Date: 2018-01-05
    Description: Metabolic homeostasis is coordinately controlled by diverse inputs. Understanding these regulatory networks is vital to combating metabolic disorders. The nematode Caenorhabditis elegans has emerged as a powerful, genetically tractable model system for the discovery of lipid regulatory mechanisms. Here we introduce DBL-1 , the C. elegans homolog of bone morphogenetic protein 2/4 (BMP2/4), as a significant regulator of lipid homeostasis. We used neutral lipid staining and a lipid droplet marker to demonstrate that both increases and decreases in DBL-1 /BMP signaling result in reduced lipid stores and lipid droplet count. We find that lipid droplet size, however, correlates positively with the level of DBL-1 /BMP signaling. Regulation of lipid accumulation in the intestine occurs through non-cell-autonomous signaling, since expression of SMA-3 , a Smad signal transducer, in the epidermis (hypodermis) is sufficient to rescue the loss of lipid accumulation. Finally, genetic evidence indicates that DBL-1 /BMP functions upstream of Insulin/IGF-1 Signaling in lipid metabolism. We conclude that BMP signaling regulates lipid metabolism in C. elegans through interorgan signaling to the Insulin pathway, shedding light on a less well-studied regulatory mechanism for metabolic homeostasis.
    Electronic ISSN: 2160-1836
    Topics: Biology
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  • 6
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    Genetics Society of America (GSA)
    Publication Date: 2018-01-05
    Description: Autosomal drivers violate Mendel’s law of segregation in that they are overrepresented in gametes of heterozygous parents. For drivers to be polymorphic within populations rather than fixing, their transmission advantage must be offset by deleterious effects on other fitness components. In this paper, we develop an analytical model for the evolution of autosomal drivers that is motivated by the neocentromere drive system found in maize. In particular, we model both the transmission advantage and deleterious fitness effects on seed viability, pollen viability, seed to adult survival mediated by maternal genotype, and seed to adult survival mediated by offspring genotype. We derive general, biologically intuitive conditions for the four most likely evolutionary outcomes and discuss the expected evolution of autosomal drivers given these conditions. Finally, we determine the expected equilibrium allele frequencies predicted by the model given recent estimates of fitness components for all relevant genotypes and show that the predicted equilibrium is within the range observed in maize land races for levels of drive at the low end of what has been observed.
    Electronic ISSN: 2160-1836
    Topics: Biology
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  • 7
    Publication Date: 2007-01-01
    Description: The radiocarbon results (and Bayesian modeling) of 15 samples of carbonized food residues removed from the external surface of rim sherds of cooking pots indicate that shellyware pottery first appeared in Perth, Scotland, around cal AD 910–1020 (95% probability) and that it had disappeared by cal AD 1020–1140 (95% probability). Previously, it had been suggested that this pottery could not date to before AD 1150. These data, together with 14C analyses carried out on leather artifacts and a sample of wattle from a ditch lining, also demonstrate that there was occupation in Perth about 100 yr or more prior to the granting of royal burgh status to Perth in the 1120s.
    Print ISSN: 0033-8222
    Electronic ISSN: 1945-5755
    Topics: Archaeology , Energy, Environment Protection, Nuclear Power Engineering , Geosciences
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  • 8
    Publication Date: 2010-01-01
    Description: This study follows on from previous research at Perth, Scotland, in which we dated carbonized food residues removed from the external surface of rim sherds of cooking pots of London Sandy Shellyware pottery (Museum of London Pottery Fabric Code SSW). The 15 residues that were dated produced 14C ages between 910 ± 35 and 1085 ± 40 BP. We have now carried out radiocarbon measurements on similar residues from the same fabric obtained from the Billingsgate excavations in London and the Bryggen excavations in Bergen, Norway. The London and Bergen measurements gave age ranges of 905 ± 35 to 1115 ± 35 BP and 920 ± 35 to 1055 ± 35 BP, respectively, both very similar to the Perth age range. The measurements at each site are in agreement with our Bayesian model assumption that they belong to a single phase of activity. The model estimates the introduction of London Sandy Shellyware in London to cal AD 820–1020, in Perth to cal AD 930–1020, and in Bergen to cal AD 980–1030 (95% probability). Further modeling predicts that it fell out of use in the reverse order.
    Print ISSN: 0033-8222
    Electronic ISSN: 1945-5755
    Topics: Archaeology , Energy, Environment Protection, Nuclear Power Engineering , Geosciences
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  • 9
    Publication Date: 1977-03-01
    Print ISSN: 0022-4634
    Electronic ISSN: 1474-0680
    Topics: Geosciences , Political Science
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  • 10
    Publication Date: 1973-09-01
    Description: At the end of a Cornell seminar a few weeks ago, a student remarked that the great difficulty in studying Southeast Asian history lay in the immense size of the area, and in the fact that it contained so many different countries. I agreed, but commented that they all belonged to Southeast Asia, and I went on, “If you were. to take indigenes from the different countries and dress them all exactly alike, it would be extremely difficult, if not impossible, to identify the country of origin of each and all.”
    Print ISSN: 0022-4634
    Electronic ISSN: 1474-0680
    Topics: Geosciences , Political Science
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