Multiple genetic and environmental factors interact to determine an individual’s predisposition to non-alcoholic fatty liver disease and its phenotypic characteristics. Association studies have found a number of alleles associated with the development of non-alcoholic steatohepatitis. Our aim was to investigate whether multiple risk-associated alleles may be present in affected monozygotic twins, indicating underlying genetic predisposition to non-alcoholic steatohepatitis. We determined the genotype of 14 candidate gene poly- morphisms (at 11 unlinked loci) in a set of monozygotic twins who presented with cirrhosis within 18 months of each other. Genotyp- ing revealed multiple singlenucleotide polymorphisms at 9 independent loci in genes PNPLA3, APOC3, GCKR, TRIB1, LYPLAL1, PPP1R3B, COL13A1, and EFCAB4B, previously implicated in contributing to non-alcoholic steatohepatitis pathogenesis. In conclu- sion, this case series illustrates the potential cumulative effect of multiple polymorphisms in the development and potential progres- sion of a complex trait such as NASH cirrhosis.
has been observed in the development and progression of nu- merous human cancers [19–21]. Singlenucleotide poly- morphisms (SNPs) are the most common type of variation in the human genome. SNPs present in the miRNA gene regions can alter expression, lead to maturation to aberrant miRNA, and affect target binding affinity and specificity . Many epidemiological studies have examined the asso- ciation of miRNA SNPs with cancer susceptibility . In BC, several case–control studies and meta-analyses have evaluated associations between miRNA gene polymor- phisms and BC risk in European [23–28], Asian [29, 30], Arab , and Jewish  populations. With the exception of one study in a Brazilian population , the contribution of variant miRNA genes to BC in South American women had been unexplored. In this study, we selected specific SNPs in five miR and evaluated the effects of these SNPs on miR expression and biological function. Recent studies have demonstrated that miR-27a exhibits oncogenic activity
Bioscope version 1.3 was used to map and pair the reads to the NCBI human genome refer- ence (hg19, GRCh37). Singlenucleotide variants (SNVs) and indels were selected for subse- quent analysis by the following four criteria. First, all SNPs selected were new variants that had not previously been associated with AS. Also all the selected variants resulted in a non-synony- mous aminoacid change in the protein that was able to modify the functionality based on a pre- dictive model. The SNPs on the promoter should be present in regions for transcription factor binding also based on a predictive model. Second, the MAF differences of each SNP should be greater than 20% between selected patients and the general population. Third, the depth of cov- erage of the exome sequencing should be greater than 30. Finally, these SNPs should be included in genes of immunological relevance or that encode proteins associated with osteo- genesis and/or cellular adhesion. We also searched for previously unreported protein-altering variants that occurred in more than one subject and in the promoter.
Quantitative Structure - Activity Relationships (QSARs) are widely used for predicting protein properties  and Quantitative Protein (or Proteome)-Disease Relationships (QPDRs) [27-33] for disease prediction. Recent works using complex networks of proteins or mass spectra of the human serum proteome have contributed to create theoretical models for cancer diagnosis and screening for cancer-related molecules in the case of colorectal [34,35], breast [34,36] and prostate [37-39] cancers. In a similar way, a Quantitative Genotype - Disease Relationship (QGDR) can be established in order to automatically evaluate schizophrenia DNA sequences using SNP data. Methods such as artificial neural networks , support vector machines , evolutionary computation [42,43] and other Machine Learning techniques  have been used in order to find the best classification models. This work presents a study of schizophrenia QGDR classification using only singlenucleotide polymorphisms from Galician patients . Thus, this information of the DNA molecule will be used as the input for several machine learning techniques that search for the best classification model capable of evaluating new schizophrenia DNA sequences (see Figure 1).
Background: The incidence of Alzheimer ’ s disease, particularly in developing countries, is expected to increase exponentially as the population ages. Continuing research in this area is essential in order to better understand this disease and develop strategies for treatment and prevention. Genome-wide association studies have identified several loci as genetic risk factors of AD aside from apolipoprotein E such as bridging integrator (BIN1), clusterin (CLU), ATP-binding cassette sub-family A member 7 (ABCA7), complement receptor 1 (CR1) and phosphatidylinositol binding clathrin assembly protein (PICALM). However genetic research in developing countries is often limited by lack of funding and expertise. This study therefore developed and validated a simple, cost effective polymerase chain reaction based technique to determine these singlenucleotide polymorphisms.
Comparative studies carried out in metazoans have found that miRNAs differ from other genetic entities in three characteristics. First, they present remarkable sequence conservation. When Drosophila melanogaster miRNAs were assessed they showed sequence conservation levels even higher than elongation factor 1a and histone H3 genes, which are often used to elucidate the deepest branches on the tree of life. Similar results where found when comparing human miRNAs with those of other eutherians sharing a common ancestor approximately 100 Mya. Again, the level of nucleotide diversity of miRNAs was extremely low and even comparable to the rate of change of DNA sequences coding for 18S rRNA (Sempere et al., 2006). Although these results are based on the limited amount of miRNAs known at the time, the remarkable sequence conservation of established miRNAs has been confirmed by subsequent studies. Secondly, miRNA genes are continuously added to metazoan genomes which results in lineage-specific sets that when reconstructed correlate with established phylogenetic relationships. And lastly, once miRNA genes are established on a genome they are rarely lost. All together these evolutionary trends have allowed to reconstruct the origin of various miRNA gene families in great detail.
The recognition of pathogen-derived structures by C-type lectins and the chemotactic activity mediated by the CCL2/CCR2 axis are critical steps in determining the host immune response to fungi. The present study was designed to investigate whether the presence of singlenucleotide polymorphisms (SNPs) within DC-SIGN, Dectin-1, Dectin-2, CCL2 and CCR2 genes influence the risk of developing Invasive Pulmonary Aspergillosis (IPA). Twenty-seven SNPs were selected using a hybrid functional/tagging approach and genotyped in 182 haematological patients, fifty-seven of them diagnosed with proven or probable IPA according to the 2008 EORTC/MSG criteria. Association analysis revealed that carriers of the Dectin-1 rs3901533 T/T
It is well established that in addition to viral genotype, viral load and environmental factors, variations in host ge- netics strongly influence the disease outcome associated with HCV infection. Singlenucleotide polymorphisms (SNPs) in host genes, e. g. genes involved in humoral and cellular immune responses and genes associated with acti- vation of antiviral mechanism, could determine the conse- quence of infection either towards viral clearance or progression to chronicity. 11,12
sociated with rs6265 (Raznahan et al, 2009). Other studies that have evaluated the association of this polymorphism and ASD have been studied in different populations. Yoo et al. (2014) conducted a family-based study evaluating four variants of BDNF gene in the Korean population. In a sim- ilar study in Japan, Nishumura et al. (2007) evaluated 25 variants. In China, Cheng et al. (2009) evaluated this asso- ciation in a case and control study with four BDNF variants. These studies found no significant association with Val- 66Met and ASD. In Mexico, there are no previous studies evaluating this association. However, Márquez et al. (2013) conducted a singlenucleotide polymorphism case and con- trol study and found a significant association of OCD and Val66Met in the Mexican population. Recently, our group found an association with rs6265 and body mass index on bipolar patients (Morales-Marín et al., 2016). All these ev- idences show the involvement of this gene in psychiatric diseases.
ABSTRACT The human Y chromosome contains highly informative markers for making historical infer- ences about the pre-Columbian peopling of Americas. However, the scarcity of these markers has limited its use in the inference of shared ancestry and past migra- tions relevant to the origin of the culturally and biologi- cally diverse Native Americans. To identify new singlenucleotide polymorphisms (SNPs) and increase the phy- logenetic resolution of the major haplogroup Q found in the Americas, we have performed a search for new poly- morphisms based on sequencing divergent Y chromo- somes identiﬁed by microsatellite haplotype analysis.
The diversity of the five singlenucleotide polymorphisms located in genes of the TP53 path- way ( TP53 , rs1042522; MDM2 , rs2279744; MDM4 , rs1563828; USP7 , rs1529916; and LIF , rs929271) were studied in a total of 282 individuals belonging to Quechua, Aymara, Chivay, Cabanaconde, Yanke, Taquile, Amantani, Anapia, Uros, Guarani Ñandeva, and Guarani Kaiowá populations, characterized as Native American or as having a high level ( > 90%) of Native American ancestry. In addition, published data pertaining to 100 persons from five other Native American populations (Surui, Karitiana, Maya, Pima, and Piapoco) were analyzed. The populations were classified as living in high altitude ( 2,500 m) or in lowlands ( < 2,500 m). Our analyses revealed that alleles USP7- G, LIF- T, and MDM2- T showed significant evidence that they were selected for in relation to harsh environmental variables related to high altitudes. Our results show for the first time that alleles of classical TP53 network genes have been evolutionary co-opted for the successful human coloniza- tion of the Andes.
the multifactorial origin of gastric cancer . Environmental factors, such as smoking and alcohol consumption , also play an important role in gastric carcinogenesis. In spite of these long-term recognized associations, the molecular bases of gastric cancer and precancerous lesions are just beginning to be unraveled . These emerging data show that mutations in coding genes are not the only relevant fac- tors in carcinogenesis, but also alterations in the noncoding regions of the genome [10, 19]. Noncoding genomics, which ultimately controls the transcriptional machinery, includes singlenucleotide polymorphisms (SNPs), DNA methylation, miRNAs in regulatory regions, and other noncoding RNAs, among other topics. Histone modification is one of these other fields within noncoding genomics during malignant transformation, which is beyond the scope of this review and we refer the reader to other excellent and extensive recent reviews in this area [20, 21]. Based on an emerging body of evidence, noncoding genomics may be used for the discovery of novel and specific biomarkers, urgently needed to improve screening results and reduce gastric cancer mortality. This review focuses on the role of the noncoding genome in the pathogenesis of gastric cancer and the gastric precancerous cascade.
There have been attempts to explain the mechanisms by which patients show different response to the same drug used to treat ALL. The difficulty of explaining the response to drugs is due to the influence of genetic factors such as singlenucleotide polymorphisms (SNPs) in genes encoding proteins and enzymes involved in the transport and metabolism of drugs, which have been associated with differences in the response to chemotherapy in several cancers . However, there are few studies addressing the association of SNPs with response to methotrexate in patients with acute lymphoblastic leukemia. There are no studies in Mexico regarding the -401C/T and +452C/T polymorphisms of GGH, therefore, it was important to determine their distribution in the Mexican population and its association with the lack of response to MTX, due to the variation in response to MTX treatment in patients with ALL.
Human mitochondrial DNA (mtDNA) encodes 37 genes, but only 13 of these genes are transcripted into 13 polypeptides. They constitute essential subunits of the mitochondrial oxidative phosphorylation enzyme complexes, which provide the principal source of ATP (DiMauro and Schon, 2003 ; Wallace, 2005). The function of mitochondrion-encoded proteins is affected by amino acid substitutions, but they can also be indirectly affected by mutations in mtDNA control regions. mtDNA mutations have accumulated throughout human history and they are present in groups of human populations: the mitochondrial haplogroups. Each mitochondrial haplogroup is defined as a collection of haplotypes characterized by specific singlenucleotide polymorphisms (SNPs). SNPs are present in indigenous populations and this has been attributed to genetic drift and/or possible climate selection (Mishmar et al., 2003 ; Ruiz-Pesini et al., 2004).
2.2.2. Single-molecule reaction: Single-molecule studies are crucial to understand the trajectories of molecules as they un- dergo reactions. For this reason, considerable effort has been made in this area, and the application of the origami tech- nique has given the opportunity to solve many spatial and iso- lation problems because of its nanometric resolution and ad- dressability. In addition, any functionality that can be conjugat- ed with DNA can be placed on the origami surface, thereby serving as a molecular recognition probe. Some of the applica- tions described in the above could be also considered single- molecule reactions, for example RNA hybridization assays or Figure 5. Examples of precise material organization on DNA origami surfaces. A) Orthogonal decoration of DNA origami, raising the controversy of face-up or face-down disposition of the nanostructures over mica surfaces for visualization. Reprinted with permission from ref. . Copyright 2010, Wiley. B) Distance- dependence study of multivalent interactions of a-thrombin with two binding aptamers (TBA) on an origami platform. Adapted with permission from ref. . Copyright 2008 Nature Publishing Group. C) Construction of a streptavidin nanoarray on a DNA origami, by size-selective capture of one streptavi- din tetramer in each well. Adapted with permission from ref. . Copyright 2009, Wiley. D) Assembly of zinc-finger proteins (ZFP) on DNA origami struc- tures, to enable placement of multiple engineered proteins at different locations. Reprinted with permission from ref. [121a] . Copyright 2012, Wiley.
The TNF-related apoptosis inducing ligand (TRAIL)/TRAIL receptor system participates in crucial steps in immune cell activation or differentiation. It is able to inhibit proliferation and activation of T cells and to induce apoptosis of neurons and oligodendrocytes, and seems to be implicated in autoimmune diseases. Thus, TRAIL and TRAIL receptor genes are potential candidates for involvement in susceptibility to multiple sclerosis (MS). To test whether single-nucleotide polymorphisms (SNPs) in the human genes encoding TRAIL, TRAILR-1, TRAILR-2, TRAILR-3 and TRAILR-4 are associated with MS susceptibility, we performed a candidate gene case-control study in the Spanish population. 59 SNPs in the TRAIL and TRAIL receptor genes were analysed in 628 MS patients and 660 controls, and validated in an additional cohort of 295 MS patients and 233 controls. Despite none of the SNPs withstood the highly conservative Bonferroni correction, three SNPs showing uncorrected p values,0.05 were successfully replicated: rs4894559 in TRAIL gene, p = 9.86 10 24 , OR = 1.34; rs4872077, in TRAILR-1 gene, p = 0.005, OR = 1.72; and rs1001793 in TRAILR-2 gene, p = 0.012, OR = 0.84. The combination of the alleles G/T/ A in these SNPs appears to be associated with a reduced risk of developing MS (p = 2.126 10 25 , OR = 0.59). These results
from 69 individuals and 1,710 nucleotides). RAxML-7.2.8 (Stamatakis 2006, 2008) was run from the CIPRES Science Gateway (Miller et al. 2010). This software is capable to assign and estimate separate model parameters for individual genes of multi-gene alignments (Stamatakis 2006) and implements the general time reversible (GTR) substitution model for all partitions. Therefore, we partitioned our data by genes. A GTRCATI model of nucleotide substitution was implemented, and 1000 automatic bootstraps were performed, followed by a search for the best-scoring ML tree. Gaps were considered as missing data. An additional ML analysis was performed in PhyML (Guindon et al. 2010) that was run through the ATGC Bioinformatics Platform (http://www.atgc-montpellier.fr/), implementing a GTR model of nucleotide substitution, 1,000 non-parametric bootstraps, and considering gaps as missing data. All other parameters were set to their default values, and in this case, data were not partitioned by genes. BA was carried out using the software MrBayes v. 3.0B4 (Huelsenbeck and Ronquist 2001) through the CIPRES Science Gateway. Models of evolution for each partition were obtained from MrModelTest v2.3 (Johan Nylander, http://www.abc.se/~nylander/). This software selected the HKY + I + G model for the COI partition, the K80 model for ANT, and the GTR + I + G model for either ITS. Gaps were treated as missing data. The analysis was performed with 15,000,000 generations initiated with a random starting tree, sampling every 1,000 generations and allowing the program to estimate the likelihood parameters required. Stationarity was assessed using the web-based software AWTY (Nylander et al. 2008). Results collected prior to stationarity were discarded as burn-in. A MP bootstrap consensus tree was retrieved from Paup4.0b10 (Swofford 2002) using the heuristic search method. Parameters were set as follows: gaps were treated as a ‘fifth state’ (this applies to the ITS1 and ITS2 sequences), multistate taxa were interpreted as uncertainty (this applies to the ANT sequences), starting trees were obtained via stepwise addition, the number of trees held at each step during stepwise addition was one, and the branch-swapping algorithm selected was TBR. The robustness of the obtained topology was assessed after running 1,000 non-parametric bootstraps. All phylogenetic trees were edited in FigTree 1.2.2. (Andrew Rambaut, http://tree.bio.ed.ac.uk/software/figtree/).
An important finding of this study was that whilst no single SNP was found to be reliably predictive, there was significant predictive value of the genomic data through using the genomic evaluation as proposed by Meuwissen et al. . The best predictor included information on lifestyle as well as the genomic predictor, but it was clearly established that the genomics made a substantial contribution to the accuracy. The model including the covariates and the genomic data reached an accuracy of 0.29 for a dog that was outside the current dataset (e.g. a newborn dog), and thus is only weakly predictive of the phenotype. However three points should be remembered. Firstly this accuracy was achieved using 80% of the data (the other 20% were used for cross-validation), and that the total data consisted of only 219 infected animals, of which only 104 had developed the disease. Secondly, this accuracy is the prediction of a phenotype and not the underlying genetic liability, and the accuracy of predicting the genetic liability is likely to be greater. In random sample with continuous traits the accuracy would be scaled by 1/h (.1) where h is the square root of the heritability. The structure of the data prevents us from proposing any correction. Thirdly the value of using genomics is that the genomic data can be accumulated over time with increasing accuracy of prediction. One might anticipate that further collection of cases and controls would increase accuracy to levels that have the potential for making a clinical impact on breeding for resistance away from the development of pathology, i.e. toleration of the parasite.
Systemic sclerosis (SSc) is a fibrotic autoimmune disease in which the genetic component plays an important role. One of the strongest SSc association signals outside the human leukocyte antigen (HLA) region corresponds to interferon (IFN) regulatory factor 5 (IRF5), a major regulator of the type I IFN pathway. In this study we aimed to evaluate whether three different haplotypic blocks within this locus, which have been shown to alter the protein function influencing systemic lupus erythematosus (SLE) susceptibility, are involved in SSc susceptibility and clinical phenotypes. For that purpose, we genotyped one representative single-nucleotide polymorphism (SNP) of each block (rs10488631, rs2004640, and rs4728142) in a total of 3,361 SSc patients and 4,012 unaffected controls of Caucasian origin from Spain, Germany, The Netherlands, Italy and United Kingdom. A meta-analysis of the allele frequencies was performed to analyse the overall effect of these IRF5 genetic variants on SSc. Allelic combination and dependency tests were also carried out. The three SNPs showed strong associations with the global disease (rs4728142: P = 1.34 6 10 28 , OR = 1.22, CI 95% = 1.14–1.30; rs2004640: P = 4.60 610 27 ,
It has been suggested that interleukin-4 (IL-4) and its receptor, encoded by IL4R, could play a role in the patho- genesis of RA [8,10] because diminished production of IL- 4 may contribute to the T H 1-mediated autoimmune inflam- matory response characteristic of this disease [11,12]. Fur- thermore, an imbalance in the T H 1-to-T H 2 ratio in the adaptive immune response occurs in a variety of immune disorders, including RA. Seven single-nucleotide polymor- phisms (SNPs) have been identified in the coding region of IL4R [13-15]. Two of these SNPs, rs1805010 (I50V) and rs1801275 (Q551R), are nonsynonymous  and are thought to be important in asthma and atopic diseases, as IL-4 plays a major role in IgE production [15,17].