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Genome Sequencing of Idiopathic Pulmonary Fibrosis in Conjunction with a Medical School Human Anatomy Course Genome Sequencing of Idiopathic Pulmonary Fibrosis in Conjunction with a Medical School Human Anatomy Course Akash Kumar1,2,3, Max Dougherty1,2,3., Gregory M. Findlay1,2,3., Madeleine Geisheker1,2., Jason Klein1,2,3., John Lazar1,2., Heather Machkovech1,2,3., Jesse Resnick1,2., Rebecca Resnick1,2., Alexander I. Salter1,2., Faezeh Talebi-Liasi1., Christopher Arakawa1,2, Jacob Baudin1,2, Andrew Bogaard1,2, Rebecca Salesky1, Qian Zhou1, Kelly Smith4", John I. Clark5", Jay Shendure3", Marshall S. Horwitz4*" 1 University of Washington School of Medicine, Seattle, Washington, United States of America, 2 Medical Scientist Training Program (MSTP), University of Washington, Seattle, Washington, United States of America, 3 Department of Genome Sciences, University of Washington, Seattle, Washington, United States of America, 4 Department of Pathology, University of Washington, Seattle, Washington, United States of America, 5 Department of Biological Structure, University of Washington, Seattle, Washington, United States of America Abstract Even in cases where there is no obvious family history of disease, genome sequencing may contribute to clinical diagnosis and management. Clinical application of the genome has not yet become routine, however, in part because physicians are still learning how best to utilize such information. As an educational research exercise performed in conjunction with our medical school human anatomy course, we explored the potential utility of determining the whole genome sequence of a patient who had died following a clinical diagnosis of idiopathic pulmonary fibrosis (IPF). Medical students performed dissection and whole genome sequencing of the cadaver. Gross and microscopic findings were more consistent with the fibrosing variant of nonspecific interstitial pneumonia (NSIP), as opposed to IPF per se. Variants in genes causing Mendelian disorders predisposing to IPF were not detected. However, whole genome sequencing identified several common variants associated with IPF, including a single nucleotide polymorphism (SNP), rs35705950, located in the promoter region of the gene encoding mucin glycoprotein MUC5B. The MUC5B promoter polymorphism was recently found to markedly elevate risk for IPF, though a particular association with NSIP has not been previously reported, nor has its contribution to disease risk previously been evaluated in the genome-wide context of all genetic variants. We did not identify additional predicted functional variants in a region of linkage disequilibrium (LD) adjacent to MUC5B, nor did we discover other likely risk- contributing variants elsewhere in the genome. Whole genome sequencing thus corroborates the association of rs35705950 with MUC5B dysregulation and interstitial lung disease. This novel exercise additionally served a unique mission in bridging clinical and basic science education. Citation: Kumar A, Dougherty M, Findlay GM, Geisheker M, Klein J, et al. (2014) Genome Sequencing of Idiopathic Pulmonary Fibrosis in Conjunction with a Medical School Human Anatomy Course. PLoS ONE 9(9): e106744. doi:10.1371/journal.pone.0106744 Editor: Antje Prasse, Medical School Hannover, Germany Received March 5, 2014; Accepted August 2, 2014; Published September 5, 2014 Copyright: ß 2014 Kumar et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. Data Availability: The authors confirm that, for approved reasons, there are some access restrictions on the data underlying the findings. Full genome sequence data, additional gross and microscopic images, radiographic images, and clinical history and laboratory data are unsuitable for deposit due to reasons of patient confidentiality. The data are available upon request and requests may be sent to Dr. Jay Shendure ([email protected]). Funding: This study was funded by University of Washington School of Medicine institutional funds designated for educational activities for medical students. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. Competing Interests: The authors have declared that no competing interests exist. * Email: [email protected] . These authors contributed equally to this work. " KS, JIC, JS and MSH are joint senior authors on this work. Introduction To address emerging implications for applying clinical geno- mics, students earning concurrent M.D. and Ph.D. degrees in the Recently, several studies have supported the value of clinical University of Washington Medical Scientist Training Program genome sequencing, particularly when there is diagnostic uncer- (MSTP) participate in a new course, also open to a limited number tainty [1–4]. As clinical genome sequencing becomes more widely of M.D.-only students, in which a cadaver undergoes whole available, it is likely to provide useful information, even when there genome sequencing in association with dissection in the human is no family history of disease. However, interpretation of genomic anatomy lab. The cadaver selected for the inaugural exercise had data has not yet been widely incorporated into medical school been an otherwise healthy male with non-familial idiopathic curricula, and how such studies can best be employed to inform pulmonary fibrosis (IPF). medical practice remains a subject of intense interest [5]. PLOS ONE | www.plosone.org 1 September 2014 | Volume 9 | Issue 9 | e106744 IPF Cadaver Genome Interstitial lung diseases can be difficult to clinically and Analysis of variants in the vicinity of rs35705950 (MUC5B) pathologically characterize [6]. Many cases are diagnosed as To assess the possibility of causal variants underlying the idiopathic, highlighting a need to develop better understanding of MUC5B GWAS signal in LD with rs35705950, we used the their pathogenesis. Current evidence suggests that IPF follows a recently described CADD method [21] to generate ‘‘C-scores’’ for ‘‘two-hit’’ disease model where hereditary factors alter underlying each of the patient’s variants within 1 Mb of rs35705950 disease susceptibility to environmental stressors such as cigarette (Chr11:1,241,221). LD data from the SNP Annotation and Proxy smoke, asbestos, or silica [7,8]. Familial IPF kindred and genome- Search (SNAP) [22] did not identify any variants in the CEU wide association studies (GWAS) have identified several genetic population in high LD (r-squared .0.6) with rs35705950 within variants that alter disease susceptibility [9–15]. Interestingly, many 1 Mb. Nonetheless, we ranked variants by C-scores, which are an of the variants described in the literature are known to be involved integrated measure of ‘‘deleteriousness’’ outputted on a ‘‘phred- in host defense, cell adhesion, maintenance of genomic integrity, like’’ scale from 0 to 99 [21]. We additionally investigated a region and preservation of lung architecture. To cite one prominent within 20 kB of rs35705950 to identify any rare (AF,2%) variants example, a single nucleotide polymorphism (SNP) in the promoter that overlapped with DNase hypersensitive or putative transcrip- of the MUC5B gene was recently reported to up-regulate tion factor binding sites. expression of the gene and is both genetically linked and associated with IPF [10–14,16]. Didactics As an exercise in medical education, we interpret the cadaver’s A group of 15 first year medical students, including 12 genome sequence in concert with gross and microscopic anatom- combined M.D./Ph.D. students from the Medical Scientist ical examination and discuss its potential relevance for diagnosis Training Program (MSTP), plus a more senior MSTP student and management of IPF. (AK) who functioned as a teaching assistant, met in the Human Anatomy Lab and classroom for a total of 8 hours dispersed Materials and Methods through 5 sessions. In smaller groups, the students, under the supervision of the teaching assistant, prepared DNA samples for Ethics genomic sequencing. Students were then paired off to complete Written informed consent for body donation for research and remaining bioinformatic analysis and jointly draft the manuscript education was obtained through the University of Washington using a shared document online over the ensuing academic School of Medicine Willed Body Program. All research was quarter. Instructors and students met as a group in 3 additional conducting according to Declaration of Helsinki principles. sessions spanning a total of 5 hours in order to refine and revise the manuscript. Genome sequencing Tissue samples were obtained postmortem from the unem- Results balmed cadaver. A cube of liver tissue approximately 1 cm on a side was dissected from the liver and frozen at 280uC to be used in Clinical history the preparation of DNA for sequencing. 17 mg of genomic DNA The patient was a 61 year-old man of European-American was extracted using Qiagen DNeasy Blood & Tissue Kit from this ancestry without significant prior medical history who enjoyed sample. Shotgun sequencing libraries were prepared using the good health until approximately eight months before he expired, KAPA library preparation kit (Kapa Biosystems) following when he developed flu-like symptoms marked by progressive dry manufacturer’s instructions. DNA was sequenced on an Illumina cough and dyspnea. He first sought medical attention when, two HiSeq 2000 with paired-end 100 bp reads. The raw sequence data months
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