Analysis of concordance of different haplotype block partitioning algorithms

BACKGROUND: Different classes of haplotype block algorithms exist and the ideal dataset to assess their performance would be to comprehensively re-sequence a large genomic region in a large population. Such data sets are expensive to collect. Alternatively, we performed coalescent simulations to generate haplotypes with a high marker density and compared block partitioning results from diversity based, LD based, and information theoretic algorithms under different values of SNP density and allele frequency. RESULTS: We simulated 1000 haplotypes using the standard coalescent for three world populations – European, African American, and East Asian – and applied three classes of block partitioning algorithms – diversity based, LD based, and information theoretic. We assessed algorithm differences in number, size, and coverage of blocks inferred under different conditions of SNP density, allele frequency, and sample size. Each algorithm inferred blocks differing in number, size, and coverage under different density and allele frequency conditions. Different partitions had few if any matching block boundaries. However they still overlapped and a high percentage of total chromosomal region was common to all methods. This percentage was generally higher with a higher density of SNPs and when rarer markers were included. CONCLUSION: A gold standard definition of a haplotype block is difficult to achieve, but collecting haplotypes covered with a high density of SNPs, partitioning them with a variety of block algorithms, and identifying regions common to all methods may be the best way to identify genomic regions that harbor SNP variants that cause disease

Association of TMTC2 with human nonsyndromic sensorineural hearing loss

IMPORTANCE: Sensorineural hearing loss (SNHL) is commonly caused by conditions that affect cochlear structures or the auditory nerve, and the genes identified as causing SNHL to date only explain a fraction of the overall genetic risk for this debilitating disorder. It is likely that other genes and mutations also cause SNHL. OBJECTIVE: To identify a candidate gene that causes bilateral, symmetric, progressive SNHL in a large multigeneration family of Northern European descent. DESIGN, SETTING, AND PARTICIPANTS: In this prospective genotype and phenotype study performed from January 1, 2006, through April 1, 2016, a 6-generation family of Northern European descent with 19 individuals having reported early-onset hearing loss suggestive of an autosomal dominant inheritance were studied at a tertiary academic medical center. In addition, 179 unrelated adult individuals with SNHL and 186 adult individuals reporting nondeafness were examined. MAIN OUTCOMES AND MEASURES: Sensorineural hearing loss. RESULTS: Nine family members (5 women [55.6%]) provided clinical audiometric and medical records that documented hearing loss. The hearing loss is characterized as bilateral, symmetric, progressive SNHL that reached severe to profound loss in childhood. Audiometric configurations demonstrated a characteristic dip at 1000 to 2000 Hz. All affected family members wear hearing aids or have undergone cochlear implantation. Exome sequencing and linkage and association analyses identified a fully penetrant sequence variant (rs35725509) on chromosome 12q21 (logarithm of odds, 3.3) in the TMTC2 gene region that segregates with SNHL in this family. This gene explains the SNHL occurrence in this family. The variant is also associated with SNHL in a cohort of 363 unrelated individuals (179 patients with confirmed SNHL and 184 controls, P = 7 x 10-4). CONCLUSIONS AND RELEVANCE: A previously uncharacterized gene, TMTC2, has been identified as a candidate for causing progressive SNHL in humans. This finding identifies a novel locus that causes autosomal dominant SNHL and therefore a more detailed understanding of the genetic basis of SNHL. Because TMTC2 has not been previously reported to regulate auditory function, the discovery reveals a potentially new, uncharacterized mechanism of hearing loss

Global haplotype partitioning for maximal associated SNP pairs

<p>Abstract</p> <p>Background</p> <p>Global partitioning based on pairwise associations of SNPs has not previously been used to define haplotype blocks within genomes. Here, we define an association index based on LD between SNP pairs. We use the Fisher's exact test to assess the statistical significance of the LD estimator. By this test, each SNP pair is characterized as associated, independent, or not-statistically-significant. We set limits on the maximum acceptable proportion of independent pairs within all blocks and search for the partitioning with maximal proportion of associated SNP pairs. Essentially, this model is reduced to a constrained optimization problem, the solution of which is obtained by iterating a dynamic programming algorithm.</p> <p>Results</p> <p>In comparison with other methods, our algorithm reports blocks of larger average size. Nevertheless, the haplotype diversity within the blocks is captured by a small number of tagSNPs. Resampling HapMap haplotypes under a block-based model of recombination showed that our algorithm is robust in reproducing the same partitioning for recombinant samples. Our algorithm performed better than previously reported models in a case-control association study aimed at mapping a single locus trait, based on simulation results that were evaluated by a block-based statistical test. Compared to methods of haplotype block partitioning, we performed best on detection of recombination hotspots.</p> <p>Conclusion</p> <p>Our proposed method divides chromosomes into the regions within which allelic associations of SNP pairs are maximized. This approach presents a native design for dimension reduction in genome-wide association studies. Our results show that the pairwise allelic association of SNPs can describe various features of genomic variation, in particular recombination hotspots.</p

A Comprehensive Map of Mobile Element Insertion Polymorphisms in Humans

As a consequence of the accumulation of insertion events over evolutionary time, mobile elements now comprise nearly half of the human genome. The Alu, L1, and SVA mobile element families are still duplicating, generating variation between individual genomes. Mobile element insertions (MEI) have been identified as causes for genetic diseases, including hemophilia, neurofibromatosis, and various cancers. Here we present a comprehensive map of 7,380 MEI polymorphisms from the 1000 Genomes Project whole-genome sequencing data of 185 samples in three major populations detected with two detection methods. This catalog enables us to systematically study mutation rates, population segregation, genomic distribution, and functional properties of MEI polymorphisms and to compare MEI to SNP variation from the same individuals. Population allele frequencies of MEI and SNPs are described, broadly, by the same neutral ancestral processes despite vastly different mutation mechanisms and rates, except in coding regions where MEI are virtually absent, presumably due to strong negative selection. A direct comparison of MEI and SNP diversity levels suggests a differential mobile element insertion rate among populations

<i><span style="font-size:21.5pt;mso-bidi-font-size:13.5pt;font-family:"Times New Roman","serif"">In vivo </span></i><span style="font-size:22.5pt;mso-bidi-font-size:14.5pt; font-family:"Times New Roman","serif"">and <i><span style="font-size: 21.5pt;mso-bidi-font-size:13.5pt;font-family:"Times New Roman","serif"">in vitro </span></i><span style="font-size:22.5pt;mso-bidi-font-size:14.5pt; font-family:"Times New Roman","serif"">evaluation for immunomodulatory activity of three marine animal extracts with reference to phagocytosis </span></span>

1399-1402<span style="font-size: 16.5pt;mso-bidi-font-size:8.5pt;font-family:" times="" new="" roman","serif""="">The whole body ether extracts of a marine prawn <span style="font-size: 15.5pt;mso-bidi-font-size:7.5pt;font-family:" arial","sans-serif""="">Nematopaleamon tenuipes <span style="font-size:16.5pt;mso-bidi-font-size:8.5pt; font-family:" times="" new="" roman","serif""="">and two gastropods viz. Euchelus asper <span style="font-size:16.5pt;mso-bidi-font-size:8.5pt; font-family:" times="" new="" roman","serif""="">and <span style="font-size: 15.5pt;mso-bidi-font-size:7.5pt;font-family:" arial","sans-serif""="">Hemifusus pugilinus, <span style="font-size:16.5pt;mso-bidi-font-size:8.5pt;font-family: " times="" new="" roman","serif""="">obtained by Soxhlet extraction and cold percolation were tested for their effects on phagocytosis by <i style="mso-bidi-font-style: normal"><span style="font-size:16.0pt;mso-bidi-font-size:8.0pt;font-family: " times="" new="" roman","serif""="">in<span style="font-size:16.0pt; mso-bidi-font-size:8.0pt;font-family:" times="" new="" roman","serif""=""> vitro <span style="font-size:16.5pt;mso-bidi-font-size:8.5pt;font-family: " times="" new="" roman","serif""="">(slide method) and by <i style="mso-bidi-font-style: normal"><span style="font-size:16.0pt;mso-bidi-font-size:8.0pt;font-family: " times="" new="" roman","serif""="">in<span style="font-size:16.0pt; mso-bidi-font-size:8.0pt;font-family:" times="" new="" roman","serif""=""> vivo <span style="font-size:16.5pt;mso-bidi-font-size:8.5pt;font-family: " times="" new="" roman","serif""="">(carbon clearance) methods. Extract of E. asper <span style="font-size:16.5pt;mso-bidi-font-size:8.5pt; font-family:" times="" new="" roman","serif""="">exhibits immunostimulatory activity <span style="font-size:16.0pt;mso-bidi-font-size: 8.0pt;font-family:" times="" new="" roman","serif""="">in vivo<span style="font-size:15.5pt;mso-bidi-font-size:7.5pt; font-family:" arial","sans-serif""=""> <span style="font-size:16.5pt; mso-bidi-font-size:8.5pt;font-family:" times="" new="" roman","serif""="">and immunosuppressant activity in viv<span style="font-size:15.5pt;mso-bidi-font-size:7.5pt;font-family: " arial","sans-serif""="">o. <span style="font-size:16.5pt;mso-bidi-font-size: 8.5pt;font-family:" times="" new="" roman","serif""="">The <i style="mso-bidi-font-style: normal"><span style="font-size:16.0pt;mso-bidi-font-size:8.0pt;font-family: " times="" new="" roman","serif""="">in<span style="font-size:16.0pt; mso-bidi-font-size:8.0pt;font-family:" times="" new="" roman","serif""=""> vitro <span style="font-size:16.5pt;mso-bidi-font-size:8.5pt;font-family: " times="" new="" roman","serif""="">test for <span style="font-size:15.5pt; mso-bidi-font-size:7.5pt;font-family:" arial","sans-serif""="">N. tenuipes and <span style="font-size:16.0pt;mso-bidi-font-size:8.0pt;font-family: " arial","sans-serif""="">H. <span style="font-size:15.5pt; mso-bidi-font-size:7.5pt;font-family:" arial","sans-serif""="">pugilinus shows biphasic activity, but the former shows immunostimulatory while the later shows immunosuppressant activity <span style="font-size:15.5pt;mso-bidi-font-size: 7.5pt;font-family:" arial","sans-serif""="">in vivo test. </span

Efficacies of plant phenolic compounds on sodium butyrate induced anti-tumour activity

861-864The ability of the differentiation inducing agent sodium butyrate (NaB) alone or combined with plant -derived phenolic compounds to produce growth inhibition in human erythroleukemic cells was investigated. As a single agent,curcumin produced a marked inhibition of proliferation indicated by its low concentration used. The effect of phenolics on the cell cycle could probably contribute to the augmented antiproliferative activity of NaB. The present data show that quercetin produced synergistic effect in terms of cell killing in association with NaB. Both curcumin and ferulic acid potentiated NaB induced reduction of cell number. When NaB was added before exposure to graded doses of quercetin it did induce a greater inhibitory effect. The combination of NaB and quercetin seems less effective on S180 ascites tumour cells. As a single agent quercetin was found to be the most efficacious on S180 tumour model

<span style="font-size:12.0pt;line-height: 115%;font-family:"Times New Roman";mso-fareast-font-family:"Times New Roman"; mso-ansi-language:EN-IN;mso-fareast-language:EN-IN;mso-bidi-language:HI" lang="EN-IN">Influence of antiangiogenic fraction from <i>Diogenes</i> <i>avarus</i> (Heller) on fertility and implantation in mice</span>

581-588<span style="font-size:12.0pt;line-height: 115%;font-family:" times="" new="" roman";mso-fareast-font-family:"times="" roman";="" mso-ansi-language:en-in;mso-fareast-language:en-in;mso-bidi-language:hi"="" lang="EN-IN">The methanol extract isolated from hermit crab, D. avarus degenerated ovarion and uterine ti ssues in cyclic and pregnant mice, treated before and after the implantation. Immunohi stochemical staining using CD31 and Factor VIII specific to endothelial cells showed reduction in microvessel density. The hormonal assay showed decrease in the progesterone secretion in all experimental mice. </span

Evaluation of immunomodulatory activity of extracts from marine animals

22-27The whole body ether extracts of a marine prawn Nematopaleamon tenuipes (PEP), two gastropods viz. Euchelus asper (EAE) and Hemifusus pugilinus (HPE), and acetone extract of a fish Rastrelliger kanagurta (MA), were tested for their effects on Delayed type Hypersensitivity (DTH) reaction and Plaque Forming Cell (PFC) assay. The Delayed type Hypersensitive reaction assay for HPE and PEP as well as MA showed stimulation but EAE was found to be less effective. In the PFC assay HPE and MA showed immunostimulation whereas PEP and EAE showed immunosuppression. PEP was further resolved into two fractions, which were tested for in vitro lymphocyte proliferation assay as well as antiproliferative assay. It is concluded that the test extracts possess immunomodulatory property

Inhibitory effect of cinnamoyl compounds against human malignant cell line

216-220In the present study, anti-proliferative effects of dietary polyphenolic compounds have been observed and demonstrated the strong anticancer efficacy of curcumin (CMN), an active constituent of dietary spice (turmeric) using human leukemia cancer cell line. CMN inhibited the proliferation of K562 leukemic cells by induction of apoptosis. The current study demonstrated synergy with combination of drug therapy, and suggested that combination of ferulic acid and cisplatin synergistically inhibited cellular proliferation. Cytotoxic synergy was observed independent of the sequence of addition of two drugs to cultured cells. The synergized growth inhibitory effect with cisplatin was probably associated with G2-M arrest in cell cycle progression. These findings suggested that among the cinnamoyl compounds, CMN was most potent and FER appeared to be a better modulating agent on human malignant cell line

Effect of Bombay high crude oil and its water-soluble fraction on growth and metabolism of diatom Thalassiosira sp.

251-255Effect of Bombay high crude oil (BHC) and its water-soluble fraction (WSF) on growth and metabolism of the phytoplankton, Thalassiosira sp. was assessed. The study revealed the signs of acute toxicity at higher concentrations of crude oil (0.5%) and WSF (40%), while stimulatory effect was observed at lower concentrations (0.01 and 0.1% of BHC and 5, 10% of WSF). WSF at higher concentrations (20 and 40%) caused reduction in DNA and RNA of the diatom. At lower concentrations it caused increase in protein and RNA content indicating increased metabolism. High concentrations of oil and its fraction had inhibitory effect on growth, protein content and nucleic acid content. This indicates that biosynthesis of these molecules may be probable targets for toxicity of oil