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The genomic and transcriptomic landscape of HeLa cells

Landry, Jonathan

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Abstract

HeLa is and always has been the most widely used model cell line for studying human cellular and molecular biology, and has thus defined our current understanding of human cells. However, no genomic or transcriptomic references exist for this cell line, and studies thus far have relied on the undoubtedly different human reference genome. This knowledge is essential to guide the increasing number of molecular and genetic studies being done in this cell line, both for design and interpretation. During my doctoral work, I performed deep DNA and RNA sequencing of a HeLa-Kyoto cell line and analyzed its mutational portfolio and gene expression profile. We generated a comprehensive description of the genomic and transcriptomic landscape of this cell line. A segmentation of the genome according to copy number revealed an astonishingly high level of aneuploidy and numerous large structural variations at unprecedented resolution. Remnants of catastrophic chromosome shattering, known as chromothripsis, were evident. Comparison of the HeLa expression profile to the physiological range of human gene expression reveals that several pathways, including cell cycle and DNA repair mechanisms, are 'abnormally' expressed. These results provide the first detailed account of the extent of variations in the HeLa genome, yielding insight into their impact on gene expression, cellular function, and their origins during the evolution of this cell line. This study demonstrates the importance of accounting for the strikingly aberrant characteristics of HeLa cells when designing and interpreting experiments. The important resources provided will help to reevaluate the way HeLa is used to model human biology.

Translation of abstract (German)

HeLa ist momentan die in der menschlichen Zell- und Molekularbiologie am weitesten verbreitete Modell-Zelllinie und hat unser Verständnis menschlicher Zellen maßgeblich beeinflusst. Da weder ein Referenzgenom noch ein Referenztranskriptom für HeLa verfügbar ist, verwendeten bisherige Studien das zweifelsohne unterschiedliche humane Referenzgenom zur Datenanalyse. Ein verfügbares Referenzgenom für HeLa ist essentiell um das Design und die Interpretation einer wachsenden Anzahl molekularer und genetischer Studien an dieser Zellline zu ermöglichen. In meiner Doktorarbeit habe ich DNA und RNA einer HeLa-Kyoto Zellline sequenziert und ihr Mutationsportfolio und Genexpressionsprofil analysiert, sowie eine umfassende Charakterisierung der genomischen und transkriptomischen Landschaft dieser Zellline erstellt. Die Segmentierung des Genoms nach “copy number” enthüllt ein erstaunlich hohes Maß an Aneuploidie sowie zahlreiche große strukturelle Variationen mit einer bisher nicht verfügbaren Auflösung. Die Spuren von katastrophalen chromosomalen Umlagerungsereignissen, bekannt als Chromothripsis, sind evident in dieser Segmentierung. Der Vergleich des Expressionsprofils von HeLa mit dem physiologischen Spektrum menschlicher Genexpression offenbart mehrere Signalwege, unter anderem Zellzyklus und DNA Reperaturmechanismen, deren Expressionslevel stark von diesem Spektrum abweichen. Diese Resultate liefern den ersten detaillierten Katalog genetischer Variationen in HeLa, und geben Einsicht in deren Einfluss auf Genexpression, zellulare Funktionen sowie die evolutionäre Herkunft während der Evolution dieser Zellinie. Diese Studie verdeutlicht, wie wichtig es ist, die abweichenden Charakteristika von HeLa beim Design und der Interpretation von Experimenten zu Berücksichtigen. Die von uns zur Verfügung gestellten Ressourcen werden dabei helfen, die Art und Weise in der HeLa als Modell humaner Biologie verwendet wird, neu zu bewerten.

Item Type: Dissertation
Supervisor: Wölfl, Prof. Dr. Stefan
Date of thesis defense: 6 December 2012
Date Deposited: 06 Mar 2013 13:42
Date: 27 September 2012
Faculties / Institutes: The Faculty of Bio Sciences > Institute of Pharmacy and Molecular Biotechnology
Service facilities > European Molecular Biology Laboratory (EMBL)
Subjects: 570 Life sciences
Controlled Keywords: Genomics, Transcriptomics, HeLa cell line, Resource, Variation
Additional Information: The content of this thesis is available in Landry et al., G3 2013: http://g3journal.org/content/3/8/1213 The genome sequence described in this thesis was derived from a HeLa cell line. Henrietta Lacks, and the HeLa cell line that was established from her tumor cells in 1951, have made significant contributions to scientific progress and advances in human health. We are grateful to Henrietta Lacks, now deceased, and to her surviving family members for their contributions to biomedical research. Please consult the publication. For additional requests please contact the EMBL press office: pressoffice@embl.de
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