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Data-Mining Approach for Screening of Rare Genetic Elements Associated

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Turk J Biochem 2019; 44(6): 848–854 Research Article Muhammad Zubair Mahboob, Arslan Hamid, Nada Mushtaq, Sana Batool, Hina Batool, Nadia Zeeshan, Muhammad Ali, Kalsoom Sughra* and Naeem Mahmood Ashraf* Data-mining approach for screening of rare genetic elements associated with predisposition of prostate cancer in South-Asian populations Güney Asya Popülasyonlarında Prostat Kanseri Predispozisyonuyla İlişkili Nadir Genetik Elementlerin Taranmasında Veri Madenciliği Yaklaşımı https://doi.org/10.1515/tjb-2018-0454 Materials and methods: Genome-wide association studies Received November 9, 2018; accepted May 23, 2019; previously (GWAS) catalog and Gene Expression Omnibus (GEO) fur- published online August 30, 2019 nished PCa-related genetic studies. Database for Anno- Abstract tation, Visualization and Integrated Discovery (DAVID) functionally annotated these genes and wANNOVAR sep- Objective: Prostate cancer (PCa) is a complex heterogene- arated South Asian (SAS) populations – specific genetic ous disease and a major health risk to men throughout the factors at MAF threshold <0.05. world. The potential tumorigenic genetic hallmarks asso- Results: The study reports 195 genes as potential contribu- ciated with PCa include sustaining proliferative signaling, tors to prostate cancer in SAS populations. Some of iden- resisting cell death, aberrant androgen receptor signal- tified genes are PYGO2, RALBP1, RFX5, SLC22A3, VPS53, ing, androgen independence, and castration resistance. HMCN1 and KIF1C. Despite numerous comprehensive genome-wide associa- Conclusion: The identified genetic elements may assist in tion studies (GWAS), certain genetic elements associated development of population-specific screening and man- with PCa are still unknown. This situation demands more agement strategies for PCa. Moreover, this approach may systematic GWAS studies in different populations. This also be used to retrieve potential genetic elements associ- study presents a computational strategy for identification ated with other types of cancers. of novel and uncharacterized genetic factors associated Keywords: Prostate cancer (PCa); South Asians with incidence of PCa in South Asian populations. populations (SAS); Genome wide associations (GWAS); Microarray expressions; Minor allele frequency (MAF). *Corresponding authors: Kalsoom Sughra and Naeem Mahmood Öz Ashraf, University of Gujrat – Hafiz Hayat Campus, Department of Biochemistry and Biotechnology, Gujrat, Pakistan, e-mail: [email protected] (K. Sughra); Amaç: Prostat kanseri (PCa) karmaşık heterojen bir [email protected]. https://orcid.org/0000-0003-3614- hastalıktır ve dünyadaki erkekler için önemli bir sağlık ris- 0702 (N. M. Ashraf) kidir. PCa ile ilişkili potansiyel tümörijenik genetik işaret- Muhammad Zubair Mahboob and Nada Mushtaq: University of ler proliferatif sinyalleşmeyi sürdürmeyi, hücre ölümüne Gujrat, Department of Biochemistry and Biotechnology, Gujrat, direnmeyi, anormal androjen reseptör sinyalini ve and- Pakistan Arslan Hamid: University of Stuttgart, Department of Sciences, rojen bağımsızlığını ve kastrasyon direncini içerir. Çok Stuttgart, Germany sayıda kapsamlı genom çapında ilişkilendirme çalışmasına Sana Batool and Hina Batool: University of the Punjab, School of (GWAS) rağmen, PCa ile ilişkili bazı genetik unsurlar hala Biological Sciences, Lahore, Pakistan bilinmemektedir. Bu durum, farklı popülasyonlarda daha Nadia Zeeshan: University of Gujrat – Hafiz Hayat Campus, sistematik GWAS çalışmaları gerektirmektedir. Bu çalışma Department of Biochemistry and Biotechnology, Gujrat, Pakistan Güney Asya popülasyonlarında PCa insidansıyla ilişkili Muhammad Ali: Department of Biotechnology, Abbottabad Campus, COMSATS Institute of Information Technology, yeni ve daha önce karakterize edilmemiş genetik faktörle- Abbottabad, Pakistan rin tanımlanması için hesaplamalı bir strateji sunmaktadır. Muhammad Zubair Mahboob et al.: Data-mining approach for screening of rare genetic elements 849 Gereç ve Yöntem: PCa ile ilgili genetik çalışmalarda GWAS is PTEN whose inactivation has reported in 70% of Cauca- kataloğu ve Gene Expression Omnibus (GEO) kullanıldı. sians but only 34% in Chinese patients [9]. Açıklama, Görselleştirme ve Entegre Keşif Veri Tabanı Similarly, several other genetic loci including MTA-1, (DAVID), bu genleri fonksiyonel olarak açıkladı ve wAN- MYBL2, FLS353, BRCA1, BRCA2, HOXB13, NKX3.1, APPL2, NOVAR, Güney Asya (SAS) popülasyonlarını, MAF eşi- TPD52, LTC4S, ALDH1A3 and AMD1 have also been reported ğinde <0.05 eşdeğer genetik faktörleri ayırdı. multiple times as the risk factors for PCa in the various pop- Bulgular: Çalışma, SAS popülasyonlarında prostat kanse- ulations of the world [10, 11]. Although some of the genetic rine potansiyel katkıda bulunan 195 gen olduğunu bildir- elements including IRX4, FOXP4, RFX6, C2orf43, TLR-4, mektedir. Tanımlanan genlerin bazıları PYGO2, RALBP1, MMP2, TIMP2, SRD5A2, SMARCA2 and FAM111A are reported RFX5, SLC22A3, VPS53, HMCN1 ve KIF1C’dir. frequently in the South Asian populations, however, many Sonuç: Tanımlanan genetik unsurlar PCa için popülas- underlying genetic risk factors still need to be divulged in yona özgü tarama ve yönetim stratejilerinin geliştirilme- these populations [12–15]. Since the past few years, the extra- sine yardımcı olabilir. Ayrıca, bu yaklaşım, diğer kanser cellular vesicles from the body fluids are being analyzed türleriyle ilişkili potansiyel genetik elementleri elde etmek to discover the novel cancer biomarkers [16]. All available için de kullanılabilir. methods for the identification of culprit genetic elements corresponding to a particular disease are, however, time- Anahtar Sözcükler: Prostat kanseri (PCa); Güney Asya consuming, arduous, and also needs enormous funding. Popülasyonları (SAS); Genom Çapında İlişkiler (GWAS); Recent advancements in the field of computational Mikroarray Ekspresyonları; Minör Alel Frekansı (MAF). biology have made it possible to predict the genetic asso- ciation of complex diseases. The present study, therefore, make use of the multiple computational tools for the Introduction efficient identification of the population-specific genetic elements associated with the prostate cancer in the SAS Prostate gland, a part of the male reproductive system is populations. Genome-wide association and microarray responsible for proper nourishment of sperms. Prostate- expression data constitute the primary data used in this related disorders especially prostate cancer (PCa) is known study. Total five South Asians populations registered in to succumb the majority of men in the world. Although the 1000 Genomes browsers have been considered rele- the incidence and mortality of PCa vary among different vant in this study. These include Bengali from Bangladesh populations, in Western societies it is the second leading (BEB), Gujarati Indian from Houston Texas (GIH), Indian cause of cancer death in men [1, 2]. Similarly, men of Telugu from the UK (ITU), Punjabi from Lahore Pakistan Caribbean, African and Saharan African origin have been (PJL), Sri Lankan Tamil from the UK (STU). found to be at higher risk of PCa [3, 4]. Formerly Asian men The novel genetic loci identified through this compu- were at the lower risk of PCa, however, during the past few tational study can assist in the designing the genotyping decades, it is on a steady increase in the Asian countries. arrays for early diagnosis and management of the PCa Currently, the PCa is the sixth leading cause of mortality in and therefore may help in the development of population- Asian men [5, 6]. Prostate cancer is, therefore, becoming a specific targeted therapy for PCa in the SAS populations. real public health issue in many populations of the world. The study, therefore, would undoubtedly help to curtail Due to the vivid increase of the prostate cancer in the gap in the rapid disease progression and control in the the South Asian (SAS) populations, there is a consider- SAS populations. able concern to identify the genetic causes of this high prevalence. Till now, prostate-specific antigen (PSA) rep- resents the gold standard biomarker for diagnosis of PCa [7]. However, multiple genome-wide association studies Material and methods have shown that several genetic elements may also play a The main steps used to carry out this study were as follows; critical role in the development of the complex disease in various populations and therefore are useful for the effi- cient diagnosis of the diseases within these populations. Selection of relevant studies from GWAS In fact, numerous genetic elements associated with PCa- and GEO risk in distinct populations are also made known. Among these genetic elements, TMPRSS2-ERG fusion has a preva- Two literature-based databases Genome-wide association lence of about 50% [8]. Another prominent genetic factor studies (GWAS Catalog), and Gene Expression Omnibus 850 Muhammad Zubair Mahboob et al.: Data-mining approach for screening of rare genetic elements Prostate cancer Prostate cancer mortality Functional annotation of gene lists Prostate cancer (early onset) Prostate-specific antigen level Prostate cancer (gene x gene Serum prostate-specific antigen “GWAS genes list” and “Differentially Expressed Genes interaction) levels list” were functionally annotated using Database for Prostate cancer aggressiveness Androgen levels Annotation, Visualization, and Integrated Discovery (DAVID). This server correlates genes and protein lists with Figure 1: Terms assigned to retrieve PCa-associated
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    The Kinesin Superfamily Handbook Transporter, Creator, Destroyer Edited by Claire T. Friel First edition published 2020 ISBN: 978-1-138-58956-8 (hbk) ISBN: 978-0-429-49155-9 (ebk) 4 The Kinesin-3 Family Long-Distance Transporters Nida Siddiqui and Anne Straube CC BY-NC-ND 4.0 The Kinesin Superfamily Handbook The Kinesin-3 Family 4 Long-Distance Transporters Nida Siddiqui and Anne Straube CONTENTS 4.1 Example Family Members .............................................................................. 41 4.2 Structural Information .................................................................................... 41 4.3 Functional Properties ...................................................................................... 43 4.3.1 Autoinhibition of Kinesin-3 Motors and Their Activation .................45 4.4 Physiological Roles .........................................................................................46 4.4.1 Preference for Subsets of Microtubule Tracks .................................... 47 4.5 Involvement in Disease ...................................................................................48 Acknowledgements ..................................................................................................49 References ................................................................................................................49 The Kinesin-3s are a family of cargo transporters. They typically display highly processive plus-end-directed motion, either as dimers or in teams, formed via interaction with