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Abstract Background Linkage analysis is a useful tool for detecting genetic variants that regulate a trait of interest, especially genes associated with a given disease. Although penetrance parameters play an important role in determining gene location, they are assigned arbitrary values according to the researcher’s intuition or as estimated by the maximum likelihood principle. Several methods exist by which to evaluate the maximum likelihood estimates of penetrance, although not all of these are supported by software packages and some are biased by marker genotype information, even when disease development is due solely to the genotype of a single allele. Findings Programs for exploring the maximum likelihood estimates of penetrance parameters were developed using the R statistical programming language supplemented by external C functions. The software returns a vector of polynomial coefficients of penetrance parameters, representing the likelihood of pedigree data. From the likelihood polynomial supplied by the proposed method, the likelihood value and its gradient can be precisely computed. To reduce the effect of the supplied dataset on the likelihood function, feasible parameter constraints can be introduced into maximum likelihood estimates, thus enabling flexible exploration of the penetrance estimates. An auxiliary program generates a perspective plot allowing visual validation of the model’s convergence. The functions are collectively available as the MLEP R package. Conclusions Linkage analysis using penetrance parameters estimated by the MLEP package enables feasible localization of a disease locus. This is shown through a simulation study and by demonstrating how the package is used to explore maximum likelihood estimates. Although the input dataset tends to bias the likelihood estimates, the method yields accurate results superior to the analysis using intuitive penetrance values for disease with low allele frequencies. MLEP is part of the Comprehensive R Archive Network and is freely available at http://cran.r-project.org/web/packages/MLEP/index.html.

An algorithm for functional evaluation of the likelihood of paternal and maternal recombination fractions for pedigree data is proposed. The idea behind the algorithm is that the probability of affected status and certain marker genotypes of ancestors is inherited by their descendants along with the inheritance of certain haplotypes. In this algorithm, the likelihood is evaluated by a single recursive call for each terminal sibling set along with the inheritance flow. The advantage of the algorithm is not only the simplicity of its implementation, but also its functional form of evaluation. The likelihood is obtained as a polynomial of the recombination fractions, making it easier to validate the likelihood more carefully, resulting in a more accurate localization of the disease locus. We report an experimental implementation of this algorithm in R, together with several practical applications. [ABSTRACT FROM PUBLISHER]

Japan Pharmacogenomics Data Science Consortium (JPDSC) has assembled a database for conducting pharmacogenomics (PGx) studies in Japanese subjects. The database contains the genotypes of 2.5 million single-nucleotide polymorphisms (SNPs) and 5 human leukocyte antigen loci from 2994 Japanese healthy volunteers, as well as 121 kinds of clinical information, including self-reports, physiological data, hematological data and biochemical data. In this article, the reliability of our data was evaluated by principal component analysis (PCA) and association analysis for hematological and biochemical traits by using genome-wide SNP data. PCA of the SNPs showed that all the samples were collected from the Japanese population and that the samples were separated into two major clusters by birthplace, Okinawa and other than Okinawa, as had been previously reported. Among 87 SNPs that have been reported to be associated with 18 hematological and biochemical traits in genome-wide association studies (GWAS), the associations of 56 SNPs were replicated using our data base. Statistical power simulations showed that the sample size of the JPDSC control database is large enough to detect genetic markers having a relatively strong association even when the case sample size is small. The JPDSC database will be useful as control data for conducting PGx studies to explore genetic markers to improve the safety and efficacy of drugs either during clinical development or in post-marketing. [ABSTRACT FROM AUTHOR]

Endocannabinoids are known to mediate retrograde suppression of synaptic transmission, modulate synaptic plasticity, and influence learning and memory. The 2-arachidonoylglycerol (2-AG) produced by diacylglycerol lipase α (DGLα) is regarded as the major endo-cannabinoid that causes retrograde synaptic suppression. To determine how 2-AG signaling influences learning and memory, we subjected DGLα knock-out mice to two learning tasks. We tested the mice using habituation and odor-guided transverse patterning tasks that are known to involve the dentate gyrus and the CA1, respectively, of the hippocampus. We found that DGLα knock-out mice showed significantly faster habituation to an odor and a new environment than wild-type littermates with normal performance in the transverse patterning task. In freely moving animals, long-term potentiation (LTP) induced by theta burst stimulation was significantly larger at perforant path- granule cell synapses in the dentate gyrus of DGLα knock-out mice. Importantly, prior induction of synaptic potentiation at this synapse caused a significant retardation of habituation in DGLα knock-out but not in wild-type littermates. The excitability of granule cells became higher in DGLα knock-out mice after they generated action potentials. Since no differences were found in intrinsic membrane properties and responses to odor stimuli in granule cells, the elevated excitability is considered to result from enhanced activity of an excitatory recurrent network composed of granule cells and mossy cells. These results suggest that retrograde 2-AG signaling negatively regulates habituation by suppressing excitatory recurrent network activity and reducing LTP in the dentate gyrus. [ABSTRACT FROM AUTHOR]

In the middle of the 20 th century, adult neurogenesis and rapid eye movement sleep were discovered independently in mammals. The former prompted the idea to apply this rare cellular regenerative capacity in the adult central nervous system to restore damaged brain circuitry, and the latter led to the finding of dynamic brain state changes during sleep and their functional ramifications, including those for memory consolidation. Recently, calcium imaging analysis and optogenetic manipulation have enabled the examination of the activity of specific neuronal populations with precise timing. These technological advances, which allow for the investigation of adult-born neuron activity during sleep in mice, led us to discover its essential function for memory consolidation.

Background/aim: Overall survival for the high-risk group of neuroblastoma (NB) patients still remains at 40-50%, necessitating the establishment of a curable treatment. LIM domain only 1 (LMO1) gene encoding a transcriptional regulator is an NB-susceptibility gene with a tumor-promoting activity. Previously we conducted chromatin immunoprecipitation and DNA sequencing analyses on NB cell lines and identified 3 protein-coding genes regulated by LMO1. In this study, we extended our analyses to capture microRNA genes directly or indirectly regulated by LMO1., Materials and Methods: Using microarrays, we conducted a comparative gene expression analysis on an NB cell line SK-N-SH; between the cells with and without LMO1 suppression., Results: Overall, 18 microRNAs were identified to be indirectly down-regulated by LMO1 including 7 microRNAs of the let-7 family, whose cell proliferation inhibitory activity was observed., Conclusion: Target genes of the LMO1-regulated microRNAs and their relevant pathways may be a potential therapeutic target., (Copyright© 2018, International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.)

Background/aim: Overall survival for the high-risk group of neuroblastoma (NB) remains at 40-50%. An integrative genomics study revealed that LIM domain only 1 (LMO1) encoding a transcriptional regulator to be an NB-susceptibility gene with a tumor-promoting activity, that needs to be revealed., Materials and Methods: We conducted chromatin immunoprecipitation and DNA sequencing analyses and cell proliferation assays on two NB cell lines., Results: We identified three genes regulated by LMO1 in the cells, LIM and senescent cell antigen-like domains 1 (LIMS1), Ras suppressor protein 1 (RSU1) and relaxin 2 (RLN2). LIMS1 and RSU1 encode proteins functioning with integrin-linked kinase (ILK), and inhibition of LIMS1, ILK or RLN2 by shRNA reduced cell proliferation of the NB cells, which was also suppressed with an ILK inhibiting compound Cpd 22., Conclusion: The downstream of LMO1-regulatory cascade includes a tumor-promoting LIMS1/ILK pathway, which has a potential to be a novel therapeutic target., (Copyright© 2018, International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.)