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The haplotype-resolved genome and epigenome of the aneuploid HeLa cancer cell line
Open accessAbstract
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.
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TL;DR
The paper reports a haplotype-resolved genome and epigenome of the aneuploid HeLa CCL-2 cancer cell line, using clone dilution pool sequencing to phase variants across full chromosome arms. It finds that HeLa is relatively stable in point variation, maps aneuploidy/LOH and structural rearrangements, and shows haplotype-specific activation of MYC by an integrated HPV-18 genome at chromosome 8q24.21.
Key findings
- HeLa CCL-2 carried 4.1 × 10^6 SNVs, with 90.2% overlapping 1000 Genomes Project variants, similar to control genomes (mean 4.2 × 10^6 SNVs; 87.7% overlap), suggesting no appreciably large accumulation of somatic SNVs relative to inherited variants.
- Copy-number analysis found 61% of the genome at baseline copy number three, only 3% at CN>4 or CN<2, and LOH encompassing 15.7% of the genome, including entire chromosome arms 5p, 6q, Xp, and Xq.
- The study validated 8,165 somatic mutations with an estimated sensitivity of 61.1%, giving a point mutational frequency of 2.16 per Mb, on the lower end of frequencies observed across cancer genomes.
- A highly rearranged HPV-18 integration at chromosome 8q24.21 was reconstructed; the integrated viral genome lacks a functional E2 and is associated with strong, haplotype-specific MYC activation ~500 kb upstream (mean expression ratio 95:1).
Methods
- Haplotype-resolved whole-genome sequencing of HeLa CCL-2 used shotgun sequencing to 88X non-duplicate coverage plus mate-pair, long-read, and clone dilution pool sequencing.
- Phasing used 288 fosmid clone dilution pools, yielding 518,293 non-overlapping clones with a median insert size of 33 kb and 6.3X physical coverage of the haploid reference; haplotype blocks had an N50 of 550 kb and scaffolds covered 1.96 Gb (90.3% of the non-LOH genome) with an N50 of 44.8 Mb.
- Copy number and LOH were mapped with HMM-based read-depth analysis; RNA-Seq and ENCODE datasets were phased against HeLa CCL-2 haplotype and copy-number maps to analyze haplotype-specific expression, chromatin, and transcription factor binding.
Limitations
- The paper states that normal tissue corresponding to HeLa is unavailable, so inherited and somatic variants cannot be fully distinguished; some protein-altering variants could not be excluded as rare inherited variants or passenger mutations.
- The paper states that without estimates for parameters such as the number of doublings during tumorigenesis, cells explanted, and passages in culture, the post-aneuploidy mutational burden cannot be rescaled to a rate per base per division.
- The paper states that further studies are required to resolve the functional relevance of candidate genes and to assess whether they are recurrently altered in HPV+ cervical carcinomas; it also notes that phasing of HeLa S3 ENCODE data relied on CCL-2 maps because the strains are nearly identical, though not identical.
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“The gene-level overlap with the Sanger Cancer Gene Census (SCGC)12 was also comparable (HeLa, n = 4; controls, mean n = 8.7).”
§ The haplotype-resolved genome and epigenome of the aneuploid HeLa cancer cell line > Abstract
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- Not matchedcites [12] The Cancer Genome Project. http://www.sanger.ac.uk/genetics/CGP/ (Wellcome Trust Sanger Institute, January 2013)
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“Excluding these and sites found in the 11 control genomes, 5,282 sites (mean, 1.32 per haploid Mb) remained at which clones differed in genotype between the two or more amplified copies of the same germline haplotype, with little regional variation in the abundance (Supplementary Fig. 22).”
§ The haplotype-resolved genome and epigenome of the aneuploid HeLa cancer cell line > Abstract
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“For example, in non-LOH CN=3 regions that are necessarily 2:1 or 1:2, allelic ratios calculated for each block had distributions centered on 0.32 or 0.65, close to the expected fractions of 1/3 and 2/3 (Supplementary Fig. 14).”
§ The haplotype-resolved genome and epigenome of the aneuploid HeLa cancer cell line > Abstract
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“Moreover, on average, each haplotype copy makes a comparable contribution to the transcriptome despite uneven amplification and, in some cases, rearrangement (Figure 3c,e).”
§ The haplotype-resolved genome and epigenome of the aneuploid HeLa cancer cell line > Abstract
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“We first calculated the cumulative allelic ratio among shotgun reads for the SNVs residing in each haplotype block, which clustered closely with the underlying haplotype ratio.”
§ The haplotype-resolved genome and epigenome of the aneuploid HeLa cancer cell line > Abstract
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“Generally, various cell lines have revolutionized scientific investigations and have found applications in vaccine development, drug testing for metabolism and toxicity, generating antibodies, exploring gene functions, creating artificial tissues like synthetic skin, and producing biologic substances such as therapeutic proteins [16,19,26].”
From Cell Immortality: In Vitro Effective Techniques to Achieve and Investigate Its Applications and Challenges (2024) · cites this paper as [19]
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In the paper
§ The haplotype-resolved genome and epigenome of the aneuploid HeLa cancer cell line > Abstract
“The gene-level overlap with the Sanger Cancer Gene Census (SCGC)12 was also comparable (HeLa, n = 4; controls, mean n = 8.7).”
§ The haplotype-resolved genome and epigenome of the aneuploid HeLa cancer cell line > Abstract
“Canonical tumor suppressors and oncogenes were notably absent among the five SCGC genes with PPA variants in HeLa (BCL11B, EP300, FGFR3, NOTCH1, and PRDM16, Supplementary Tables 3–6).”
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Metadata
- Authors
- Adey, A., Burton, J. N., Kitzman, J. O., Hiatt, J. B., Lewis, A. P., Martin, B. K., Qiu, R., Lee, C., & Shendure, J.
- Affiliations
- University of Washington (US)
- Corresponding author
- Adey, Andrew
- Shendure, Jay
- ORCID
- Venue
- Nature
- Published
- 2013-08-07
- Volume
- 500
- Issue
- 7461
- Pages
- 207-211
- ISSN
- 0028-0836 (ISSN-L)
- 1476-4687
- PMC
- PMC3740412
- OpenAlex
- W1972616856
- Cited by
- 362
- References
- 43
- Citations by year
- 2026: 16 · 2025: 12 · 2024: 33 · 2023: 24 · 2022: 21 · 2021: 36 · 2020: 26 · 2019: 28 · 2018: 27 · 2017: 30 · 2016: 33 · 2015: 31 · 2014: 28 · 2013: 15
- FWCI
- 16.82
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Nature (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- RePEc: Research Papers in Economics (submittedVersion)
- Funders
- National Institute on Aging (F30AG039173)
- National Human Genome Research Institute (R01HG006283, T32HG000035)
- National Cancer Institute (R21CA160080)
- National Institute of General Medical Sciences (T32GM007266)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genomic variations and chromosomal abnormalities
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer Genomics and Diagnostics
- Health Sciences › Medicine › Epidemiology › Cervical Cancer and HPV Research
- Keywords
- haplotype-resolved genome, aneuploidy, copy number variation, loss of heterozygosity, MYC activation, somatic mutation rate, epigenome, DNA methylation, histone modifications, cell line stability
- MeSH terms
- Proto-Oncogene Mas, Aneuploidy, Uterine Cervical Neoplasms, Female, Haplotypes, HeLa Cells, Humans, Molecular Sequence Data, Mutation, Transcriptional Activation, Genome, Human, Genes, myc, Sequence Analysis, DNA, Human papillomavirus 18, DNA Copy Number Variations, Epigenomics
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
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