Browsing by Subject "Gene sequence"

Now showing 1 - 9 of 9

Open Access
Demographically-based evaluation of genomic regions under selection in domestic dogs
(Public Library of Science, 2016) Freedman, A. H.; Schweizer, R. M.; Vecchyo, D. Ortega-Del; Han, E.; Davis, B. W.; Gronau, I.; Silva, P. M.; Galaverni, M.; Fan, Z.; Marx, P.; Lorente-Galdos, B.; Ramirez, O.; Hormozdiari, F.; Alkan C.; Vilà, C.; Squire K.; Geffen, E.; Kusak, J.; Boyko, A. R.; Parker, H. G.; Lee C.; Tadigotla, V.; Siepel, A.; Bustamante, C. D.; Harkins, T. T.; Nelson, S. F.; Marques Bonet, T.; Ostrander, E. A.; Wayne, R. K.; Novembre, J.
Controlling for background demographic effects is important for accurately identifying loci that have recently undergone positive selection. To date, the effects of demography have not yet been explicitly considered when identifying loci under selection during dog domestication. To investigate positive selection on the dog lineage early in the domestication, we examined patterns of polymorphism in six canid genomes that were previously used to infer a demographic model of dog domestication. Using an inferred demographic model, we computed false discovery rates (FDR) and identified 349 outlier regions consistent with positive selection at a low FDR. The signals in the top 100 regions were frequently centered on candidate genes related to brain function and behavior, including LHFPL3, CADM2, GRIK3, SH3GL2, MBP, PDE7B, NTAN1, and GLRA1. These regions contained significant enrichments in behavioral ontology categories. The 3rdtop hit, CCRN4L, plays a major role in lipid metabolism, that is supported by additional metabolism related candidates revealed in our scan, including SCP2D1 and PDXC1. Comparing our method to an empirical outlier approach that does not directly account for demography, we found only modest overlaps between the two methods, with 60% of empirical outliers having no overlap with our demography-based outlier detection approach. Demography-aware approaches have lower-rates of false discovery. Our top candidates for selection, in addition to expanding the set of neurobehavioral candidate genes, include genes related to lipid metabolism, suggesting a dietary target of selection that was important during the period when proto-dogs hunted and fed alongside hunter-gatherers. © 2016, Public Library of Science. All Rights Reserved.
Open Access
Determining the origin of synchronous multifocal bladder cancer by exome sequencing
(BioMed Central Ltd., 2015) Acar, Ö.; Özkurt, E.; Demir, G.; Saraç, H.; Alkan C.; Esen, T.; Somel, M.; Lack, N. A.
Background: Synchronous multifocal tumours are commonly observed in urothelial carcinomas of the bladder. The origin of these physically independent tumours has been proposed to occur by either intraluminal migration (clonal) or spontaneous transformation of multiple cells by carcinogens (field effect). It is unclear which model is correct, with several studies supporting both hypotheses. A potential cause of this uncertainty may be the small number of genetic mutations previously used to quantify the relationship between these tumours. Methods: To better understand the genetic lineage of these tumours we conducted exome sequencing of synchronous multifocal pTa urothelial bladder cancers at a high depth, using multiple samples from three patients. Results: Phylogenetic analysis of high confidence single nucleotide variants (SNV) demonstrated that the sequenced multifocal bladder cancers arose from a clonal origin in all three patients (bootstrap value 100 %). Interestingly, in two patients the most common type of tumour-associated SNVs were cytosine mutations of TpC*dinucleotides (Fisher's exact test p < 10-41), likely caused by APOBEC-mediated deamination. Incorporating these results into our clonal model, we found that TpC*type mutations occurred 2-5× more often among SNVs on the ancestral branches than in the more recent private branches (p < 10-4) suggesting that TpC*mutations largely occurred early in the development of the tumour. Conclusions: These results demonstrate that synchronous multifocal bladder cancers frequently arise from a clonal origin. Our data also suggests that APOBEC-mediated mutations occur early in the development of the tumour and may be a driver of tumourigenesis in non-muscle invasive urothelial bladder cancer.
Open Access
Early postzygotic mutations contribute to de novo variation in a healthy monozygotic twin pair
(B M J Group, 2014) Dal, G. M.; Ergüner, B.; Saǧıroǧlu, M. S.; Yüksel, B.; Onat, O. E.; Alkan C.; Özçelik, T.
Background: Human de novo single-nucleotide variation (SNV) rate is estimated to range between 0.82-1.70×10-8 mutations per base per generation. However, contribution of early postzygotic mutations to the overall human de novo SNV rate is unknown. Methods: We performed deep whole-genome sequencing (more than 30-fold coverage per individual) of the whole-blood-derived DNA samples of a healthy monozygotic twin pair and their parents. We examined the genotypes of each individual simultaneously for each of the SNVs and discovered de novo SNVs regarding the timing of mutagenesis. Putative de novo SNVs were validated using Sanger-based capillary sequencing. Results: We conservatively characterised 23 de novo SNVs shared by the twin pair, 8 de novo SNVs specific to twin I and 1 de novo SNV specific to twin II. Based on the number of de novo SNVs validated by Sanger sequencing and the number of callable bases of each twin, we calculated the overall de novo SNV rate of 1.31×10-8 and 1.01×10-8 for twin I and twin II, respectively. Of these, rates of the early postzygotic de novo SNVs were estimated to be 0.34×10-8 for twin I and 0.04×10-8 for twin II. Conclusions: Early postzygotic mutations constitute a substantial proportion of de novo mutations in humans. Therefore, genome mosaicism resulting from early mitotic events during embryogenesis is common and could substantially contribute to the development of diseases.
Open Access
A high-coverage genome sequence from an archaic Denisovan individual
(American Association for the Advancement of Science (A A A S), 2012-10-12) Meyer, M.; Kircher, M.; Gansauge, Marie-Theres; Li, H.; Racimo, F.; Mallick, S.; Schraiber, J. G.; Jay, F.; Prüfer, K.; Filippo, Cesare de; Sudmant, P. H.; Alkan C.; Fu, Q.; Do, R.; Rohland, N.; Tandon, A.; Siebauer, M.; Green, R. E.; Bryc, K.; Briggs, A. W.; Stenzel, U.; Dabney, J.; Shendure, J.; Kitzman, J.; Hammer, M. F.; Shunkov, M. V.; Derevianko, A. P.; Patterson, N.; Andrés, A. M.; Eichler, E. E.; Slatkin, M.; Reich, D.; Kelso, J.; Pääbo, S.
We present a DNA library preparation method that has allowed us to reconstruct a high-coverage (30x) genome sequence of a Denisovan, an extinct relative of Neandertals. The quality of this genome allows a direct estimation of Denisovan heterozygosity indicating that genetic diversity in these archaic hominins was extremely low. It also allows tentative dating of the specimen on the basis of "missing evolution" in its genome, detailed measurements of Denisovan and Neandertal admixture into present-day human populations, and the generation of a near-complete catalog of genetic changes that swept to high frequency in modern humans since their divergence from Denisovans.
Open Access
Insights into autism spectrum disorder genomic architecture and biology from 71 risk loci
(Cell Press, 2015) Sanders, S. J.; He, X.; Willsey, A. J.; Ercan-Sencicek, A. G.; Samocha, K. E.; Cicek, A. E.; Murtha, M. T.; Bal, V. H.; Bishop, S. L.; Dong, S.; Goldberg, A. P.; Jinlu, C.; Keaney, J. F.; Keaney III, J. F.; Mandell, J. D.; Moreno-De-Luca, D.; Poultney, C. S.; Robinson, E. B.; Smith L.; Solli-Nowlan, T.; Su, M. Y.; Teran, N. A.; Walker, M. F.; Werling, D. M.; Beaudet, A. L.; Cantor, R. M.; Fombonne, E.; Geschwind, D. H.; Grice, D. E.; Lord, C.; Lowe, J. K.; Mane, S. M.; Martin, D.M.; Morrow, E. M.; Talkowski, M. E.; Sutcliffe, J. S.; Walsh, C. A.; Yu, T. W.; Ledbetter, D. H.; Martin, C. L.; Cook, E. H.; Buxbaum, J. D.; Daly, M. J.; Devlin, B.; Roeder, K.; State, M. W.
Analysis of de novo CNVs (dnCNVs) from the full Simons Simplex Collection (SSC) (N = 2,591 families) replicates prior findings of strong association with autism spectrum disorders (ASDs) and confirms six risk loci (1q21.1, 3q29, 7q11.23, 16p11.2, 15q11.2-13, and 22q11.2). The addition of published CNV data from the Autism Genome Project (AGP) and exome sequencing data from the SSC and the Autism Sequencing Consortium (ASC) shows that genes within small de novo deletions, but not within large dnCNVs, significantly overlap the high-effect risk genes identified by sequencing. Alternatively, large dnCNVs are found likely to contain multiple modest-effect risk genes. Overall, we find strong evidence that de novo mutations are associated with ASD apart from the risk for intellectual disability. Extending the transmission and de novo association test (TADA) to include small de novo deletions reveals 71 ASD risk loci, including 6 CNV regions (noted above) and 65 risk genes (FDR ≤ 0.1). Through analysis of de novo mutations in autism spectrum disorder (ASD), Sanders et al. find that small deletions, but not large deletions/duplications, contain one critical gene. Combining CNV and sequencing data, they identify 6 loci and 65 genes associated with ASD.
Open Access
PATIKA: an integrated visual environment for collaborative construction and analysis of cellular pathways
(Oxford University Press, 2002-06) Demir, Emek; Babur, Özgün; Doğrusöz, Uğur; Gürsoy, Atilla; Nişancı, Gürkan; Çetin Atalay, Rengül; Öztürk, Mehmet
Motivation: Availability of the sequences of entire genomes shifts the scientific curiosity towards the identification of function of the genomes in large scale as in genome studies. In the near future, data produced about cellular processes at molecular level will accumulate with an accelerating rate as a result of proteomics studies. In this regard, it is essential to develop tools for storing, integrating, accessing, and analyzing this data effectively. Results: We define an ontology for a comprehensive representation of cellular events. The ontology presented here enables integration of fragmented or incomplete pathway information and supports manipulation and incorporation of the stored data, as well as multiple levels of abstraction. Based on this ontology, we present the architecture of an integrated environment named PATIKA (Pathway Analysis Tool for Integration and Knowledge Acquisition). PATIKA is composed of a server-side, scalable, object-oriented database and client-side editors to provide an integrated, multi-user environment for visualizing and manipulating network of cellular events. This tool features automated pathway layout, functional computation support, advanced querying and a user-friendly graphical interface. We expect that PATIKA will be a valuable tool for rapid knowledge acquisition, microarray generated large-scale data interpretation, disease gene identification, and drug development.
Open Access
PATIKA: an integrated visual environment for collaborative construction and analysis of cellular pathways
(American Society for Biochemistry and Molecular Biology(ASBMB), 2002-09) Demir, Emek; Babur, Özgün; Doğrusöz, Uğur; Gürsoy, Atilla; Nişancı, Gürkan; Çetin Atalay, Rengül; Öztürk, Mehmet
Open Access
A privacy-preserving solution for compressed storage and selective retrieval of genomic data
(Cold Spring Harbor Laboratory Press, 2016) Huang Z.; Ayday, E.; Lin, H.; Aiyar, R. S.; Molyneaux, A.; Xu, Z.; Fellay, J.; Steinmetz, L. M.; Hubaux, Jean-Pierre
In clinical genomics, the continuous evolution of bioinformatic algorithms and sequencing platforms makes it beneficial to store patients' complete aligned genomic data in addition to variant calls relative to a reference sequence. Due to the large size of human genome sequence data files (varying from 30 GB to 200 GB depending on coverage), two major challenges facing genomics laboratories are the costs of storage and the efficiency of the initial data processing. In addition, privacy of genomic data is becoming an increasingly serious concern, yet no standard data storage solutions exist that enable compression, encryption, and selective retrieval. Here we present a privacy-preserving solution named SECRAM (Selective retrieval on Encrypted and Compressed Reference-oriented Alignment Map) for the secure storage of compressed aligned genomic data. Our solution enables selective retrieval of encrypted data and improves the efficiency of downstream analysis (e.g., variant calling). Compared withBAM, thede factostandard for storing aligned genomic data, SECRAM uses 18%less storage. Compared with CRAM, one of the most compressed nonencrypted formats (using 34% less storage than BAM), SECRAM maintains efficient compression and downstream data processing, while allowing for unprecedented levels of security in genomic data storage. Compared with previous work, the distinguishing features of SECRAM are that (1) it is position-based insteadofread-based,and(2)itallowsrandomqueryingofasubregionfromaBAM-likefileinanencryptedform.Ourmethod thus offers a space-saving, privacy-preserving, and effective solution for the storage of clinical genomic data.
Open Access
Skewed X inactivation in an X linked nystagmus family resulted from a novel, p.R229G, missense mutation in the FRMD7 gene
(BMJ Group, 2008) Kaplan, Y.; Vargel, I.; Kansu, T.; Akin, B.; Rohmann, E.; Kamaci, S.; Uz, E.; Ozcelik, T.; Wollnik, B.; Akarsu, N. A.
Aims: This study aimed to identify the underlying genetic defect of a large Turkish X linked nystagmus (NYS) family. Methods: Both Xp11 and Xq26 loci were tested by linkage analysis. The 12 exons and intron-exon junctions of the FRMD7 gene were screened by direct sequencing. X chromosome inactivation analysis was performed by enzymatic predigestion of DNA with a methylation-sensitive enzyme, followed by PCR of the polymorphic CAG repeat of the androgen receptor gene. Results: The family contained 162 individuals, among whom 28 had NYS. Linkage analysis confirmed the Xq26 locus. A novel missense c.686C>G mutation, which causes the substitution of a conserved arginine at amino acid position 229 by glycine (p.R229G) in exon 8 of the FRMD7 gene, was observed. This change was not documented in 120 control individuals. The clinical findings in a female who was homozygous for the mutation were not different from those of affected heterozygous females. Skewed X inactivation was remarkable in the affected females of the family. Conclusions: A novel p.R229G mutation in the FRMD7 gene causes the NYS phenotype, and skewed X inactivation influences the manifestation of the disease in X linked NYS females.