The haplotype-resolved genome and epigenome of the aneuploid HeLa cancer cell line

Andrew Adey, Joshua N. Burton, Jacob O. Kitzman, Joseph B. Hiatt, Alexandra P. Lewis, Beth K. Martin, Ruolan Qiu, Choli Lee, Jay Shendure

Research output: Contribution to journalArticle

152 Citations (Scopus)

Abstract

The HeLa cell line was established in 1951 from cervical cancer cells taken from a patient, Henrietta Lacks. This was the first successful attempt to immortalize human-derived cells in vitro. The robust growth and unrestricted distribution of HeLa cells resulted in its broad adoption - both intentionally and through widespread cross-contamination - and for the past 60 years it has served a role analogous to that of a model organism. The cumulative impact of the HeLa cell line on research is demonstrated by its occurrence in more than 74,000 PubMed abstracts (approximately 0.3%). The genomic architecture of HeLa remains largely unexplored beyond its karyotype, partly because like many cancers, its extensive aneuploidy renders such analyses challenging. We carried out haplotype-resolved whole-genome sequencing of the HeLa CCL-2 strain, examined point- and indel-mutation variations, mapped copy-number variations and loss of heterozygosity regions, and phased variants across full chromosome arms. We also investigated variation and copy-number profiles for HeLa S3 and eight additional strains. We find that HeLa is relatively stable in terms of point variation, with few new mutations accumulating after early passaging. Haplotype resolution facilitated reconstruction of an amplified, highly rearranged region of chromosome 8q24.21 at which integration of the human papilloma virus type 18 (HPV-18) genome occurred and that is likely to be the event that initiated tumorigenesis. We combined these maps with RNA-seq and ENCODE Project data sets to phase the HeLa epigenome. This revealed strong, haplotype-specific activation of the proto-oncogene MYC by the integrated HPV-18 genome approximately 500 kilobases upstream, and enabled global analyses of the relationship between gene dosage and expression. These data provide an extensively phased, high-quality reference genome for past and future experiments relying on HeLa, and demonstrate the value of haplotype resolution for characterizing cancer genomes and epigenomes.

Original languageEnglish (US)
Pages (from-to)207-211
Number of pages5
JournalNature
Volume500
Issue number7461
DOIs
StatePublished - 2013
Externally publishedYes

Fingerprint

Aneuploidy
HeLa Cells
Haplotypes
Papillomaviridae
Genome
Cell Line
Neoplasms
Chromosomes
Gene Dosage
Proto-Oncogenes
Loss of Heterozygosity
Karyotype
Point Mutation
PubMed
Uterine Cervical Neoplasms
Carcinogenesis
RNA
Gene Expression
Mutation
Growth

ASJC Scopus subject areas

  • General

Cite this

Adey, A., Burton, J. N., Kitzman, J. O., Hiatt, J. B., Lewis, A. P., Martin, B. K., ... Shendure, J. (2013). The haplotype-resolved genome and epigenome of the aneuploid HeLa cancer cell line. Nature, 500(7461), 207-211. https://doi.org/10.1038/nature12064

The haplotype-resolved genome and epigenome of the aneuploid HeLa cancer cell line. / Adey, Andrew; Burton, Joshua N.; Kitzman, Jacob O.; Hiatt, Joseph B.; Lewis, Alexandra P.; Martin, Beth K.; Qiu, Ruolan; Lee, Choli; Shendure, Jay.

In: Nature, Vol. 500, No. 7461, 2013, p. 207-211.

Research output: Contribution to journalArticle

Adey, A, Burton, JN, Kitzman, JO, Hiatt, JB, Lewis, AP, Martin, BK, Qiu, R, Lee, C & Shendure, J 2013, 'The haplotype-resolved genome and epigenome of the aneuploid HeLa cancer cell line', Nature, vol. 500, no. 7461, pp. 207-211. https://doi.org/10.1038/nature12064
Adey A, Burton JN, Kitzman JO, Hiatt JB, Lewis AP, Martin BK et al. The haplotype-resolved genome and epigenome of the aneuploid HeLa cancer cell line. Nature. 2013;500(7461):207-211. https://doi.org/10.1038/nature12064
Adey, Andrew ; Burton, Joshua N. ; Kitzman, Jacob O. ; Hiatt, Joseph B. ; Lewis, Alexandra P. ; Martin, Beth K. ; Qiu, Ruolan ; Lee, Choli ; Shendure, Jay. / The haplotype-resolved genome and epigenome of the aneuploid HeLa cancer cell line. In: Nature. 2013 ; Vol. 500, No. 7461. pp. 207-211.
@article{2303f4d65f3e4ce0bb0c18f2b7629571,
title = "The haplotype-resolved genome and epigenome of the aneuploid HeLa cancer cell line",
abstract = "The HeLa cell line was established in 1951 from cervical cancer cells taken from a patient, Henrietta Lacks. This was the first successful attempt to immortalize human-derived cells in vitro. The robust growth and unrestricted distribution of HeLa cells resulted in its broad adoption - both intentionally and through widespread cross-contamination - and for the past 60 years it has served a role analogous to that of a model organism. The cumulative impact of the HeLa cell line on research is demonstrated by its occurrence in more than 74,000 PubMed abstracts (approximately 0.3{\%}). The genomic architecture of HeLa remains largely unexplored beyond its karyotype, partly because like many cancers, its extensive aneuploidy renders such analyses challenging. We carried out haplotype-resolved whole-genome sequencing of the HeLa CCL-2 strain, examined point- and indel-mutation variations, mapped copy-number variations and loss of heterozygosity regions, and phased variants across full chromosome arms. We also investigated variation and copy-number profiles for HeLa S3 and eight additional strains. We find that HeLa is relatively stable in terms of point variation, with few new mutations accumulating after early passaging. Haplotype resolution facilitated reconstruction of an amplified, highly rearranged region of chromosome 8q24.21 at which integration of the human papilloma virus type 18 (HPV-18) genome occurred and that is likely to be the event that initiated tumorigenesis. We combined these maps with RNA-seq and ENCODE Project data sets to phase the HeLa epigenome. This revealed strong, haplotype-specific activation of the proto-oncogene MYC by the integrated HPV-18 genome approximately 500 kilobases upstream, and enabled global analyses of the relationship between gene dosage and expression. These data provide an extensively phased, high-quality reference genome for past and future experiments relying on HeLa, and demonstrate the value of haplotype resolution for characterizing cancer genomes and epigenomes.",
author = "Andrew Adey and Burton, {Joshua N.} and Kitzman, {Jacob O.} and Hiatt, {Joseph B.} and Lewis, {Alexandra P.} and Martin, {Beth K.} and Ruolan Qiu and Choli Lee and Jay Shendure",
year = "2013",
doi = "10.1038/nature12064",
language = "English (US)",
volume = "500",
pages = "207--211",
journal = "Nature",
issn = "0028-0836",
publisher = "Nature Publishing Group",
number = "7461",

}

TY - JOUR

T1 - The haplotype-resolved genome and epigenome of the aneuploid HeLa cancer cell line

AU - Adey, Andrew

AU - Burton, Joshua N.

AU - Kitzman, Jacob O.

AU - Hiatt, Joseph B.

AU - Lewis, Alexandra P.

AU - Martin, Beth K.

AU - Qiu, Ruolan

AU - Lee, Choli

AU - Shendure, Jay

PY - 2013

Y1 - 2013

N2 - The HeLa cell line was established in 1951 from cervical cancer cells taken from a patient, Henrietta Lacks. This was the first successful attempt to immortalize human-derived cells in vitro. The robust growth and unrestricted distribution of HeLa cells resulted in its broad adoption - both intentionally and through widespread cross-contamination - and for the past 60 years it has served a role analogous to that of a model organism. The cumulative impact of the HeLa cell line on research is demonstrated by its occurrence in more than 74,000 PubMed abstracts (approximately 0.3%). The genomic architecture of HeLa remains largely unexplored beyond its karyotype, partly because like many cancers, its extensive aneuploidy renders such analyses challenging. We carried out haplotype-resolved whole-genome sequencing of the HeLa CCL-2 strain, examined point- and indel-mutation variations, mapped copy-number variations and loss of heterozygosity regions, and phased variants across full chromosome arms. We also investigated variation and copy-number profiles for HeLa S3 and eight additional strains. We find that HeLa is relatively stable in terms of point variation, with few new mutations accumulating after early passaging. Haplotype resolution facilitated reconstruction of an amplified, highly rearranged region of chromosome 8q24.21 at which integration of the human papilloma virus type 18 (HPV-18) genome occurred and that is likely to be the event that initiated tumorigenesis. We combined these maps with RNA-seq and ENCODE Project data sets to phase the HeLa epigenome. This revealed strong, haplotype-specific activation of the proto-oncogene MYC by the integrated HPV-18 genome approximately 500 kilobases upstream, and enabled global analyses of the relationship between gene dosage and expression. These data provide an extensively phased, high-quality reference genome for past and future experiments relying on HeLa, and demonstrate the value of haplotype resolution for characterizing cancer genomes and epigenomes.

AB - The HeLa cell line was established in 1951 from cervical cancer cells taken from a patient, Henrietta Lacks. This was the first successful attempt to immortalize human-derived cells in vitro. The robust growth and unrestricted distribution of HeLa cells resulted in its broad adoption - both intentionally and through widespread cross-contamination - and for the past 60 years it has served a role analogous to that of a model organism. The cumulative impact of the HeLa cell line on research is demonstrated by its occurrence in more than 74,000 PubMed abstracts (approximately 0.3%). The genomic architecture of HeLa remains largely unexplored beyond its karyotype, partly because like many cancers, its extensive aneuploidy renders such analyses challenging. We carried out haplotype-resolved whole-genome sequencing of the HeLa CCL-2 strain, examined point- and indel-mutation variations, mapped copy-number variations and loss of heterozygosity regions, and phased variants across full chromosome arms. We also investigated variation and copy-number profiles for HeLa S3 and eight additional strains. We find that HeLa is relatively stable in terms of point variation, with few new mutations accumulating after early passaging. Haplotype resolution facilitated reconstruction of an amplified, highly rearranged region of chromosome 8q24.21 at which integration of the human papilloma virus type 18 (HPV-18) genome occurred and that is likely to be the event that initiated tumorigenesis. We combined these maps with RNA-seq and ENCODE Project data sets to phase the HeLa epigenome. This revealed strong, haplotype-specific activation of the proto-oncogene MYC by the integrated HPV-18 genome approximately 500 kilobases upstream, and enabled global analyses of the relationship between gene dosage and expression. These data provide an extensively phased, high-quality reference genome for past and future experiments relying on HeLa, and demonstrate the value of haplotype resolution for characterizing cancer genomes and epigenomes.

UR - http://www.scopus.com/inward/record.url?scp=84881401766&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84881401766&partnerID=8YFLogxK

U2 - 10.1038/nature12064

DO - 10.1038/nature12064

M3 - Article

VL - 500

SP - 207

EP - 211

JO - Nature

JF - Nature

SN - 0028-0836

IS - 7461

ER -