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1.  The haplotype-resolved genome and epigenome of the aneuploid HeLa cancer cell line 
Nature  2013;500(7461):207-211.
The HeLa cell line was established in 1951 from cervical cancer cells taken from a patient, Henrietta Lacks, marking the first successful attempt to continually culture human-derived cells in vitro1. HeLa’s robust growth and unrestricted distribution resulted in its broad adoption – both intentionally and through widespread cross-contamination2 – and for the past sixty years it has served a role analogous to that of a model organism3. Its cumulative impact is illustrated by the fact that HeLa is named in >74,000 or ~0.3% of PubMed abstracts. The genomic architecture of HeLa remains largely unexplored beyond its karyotype4, in part because like many cancers, its extensive aneuploidy renders such analyses challenging. We performed haplotype-resolved whole genome sequencing5 of the HeLa CCL-2 strain, discovering point and indel variation, mapping copy-number and loss of heterozygosity (LOH), and phasing variants across full chromosome arms. We further investigated variation and copy-number profiles for HeLa S3 and eight additional strains. Surprisingly, HeLa is relatively stable with respect to point variation, accumulating few new mutations since early passaging. Haplotype resolution facilitated reconstruction of an amplified, highly rearranged region at chromosome 8q24.21 at which the HPV-18 viral genome integrated as the likely initial event underlying tumorigenesis. We combined these maps with RNA-Seq6 and ENCODE Project7 datasets to phase the HeLa epigenome, revealing strong, haplotype-specific activation of the proto-oncogene MYC by the integrated HPV-18 genome ~500 kilobases upstream, and permitting 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.
PMCID: PMC3740412  PMID: 23925245
2.  ALLPATHS 2: small genomes assembled accurately and with high continuity from short paired reads 
Genome Biology  2009;10(10):R103.
Allpaths2, a method for accurately assembling small genomes with high continuity using short paired reads.
We demonstrate that genome sequences approaching finished quality can be generated from short paired reads. Using 36 base (fragment) and 26 base (jumping) reads from five microbial genomes of varied GC composition and sizes up to 40 Mb, ALLPATHS2 generated assemblies with long, accurate contigs and scaffolds. Velvet and EULER-SR were less accurate. For example, for Escherichia coli, the fraction of 10-kb stretches that were perfect was 99.8% (ALLPATHS2), 68.7% (Velvet), and 42.1% (EULER-SR).
PMCID: PMC2784318  PMID: 19796385
3.  Activation of human T cells by FcR nonbinding anti-CD3 mAb, hOKT3γ1(Ala-Ala) 
Journal of Clinical Investigation  2003;111(3):409-418.
Dimeric Fc receptor (FcR) nonbinding anti-CD3 antibodies have been developed to minimize toxicities associated with classical anti-CD3 monoclonal antibodies (e.g., OKT3). Studies with murine analogs of non-FcR–binding antibodies have shown reduced mitogenicity compared to OKT3. In a trial of an FcR nonbinding humanized anti-CD3 mAb hOKT3γ1(Ala-Ala) for treatment of patients with type 1 diabetes, we found significant increases in IL-10 and IL-5 in the serum of 63% and 72% of patients, respectively, and TNF-α and IL-6 levels that were lower than those previously reported following OKT3 therapy. The activation signal delivered by hOKT3γ1(Ala-Ala) was associated with calcium signaling and cytokine production by previously activated human cells in vitro. However, the production of IL-10, compared to IFN-γ on a molar basis, was greater after culture with hOKT3γ1(Ala-Ala) than with OKT3. Flow cytometric studies confirmed that OKT3 induced IFN-γ and IL-10 production, but hOKT3γ1(Ala-Ala) induced only detectable IL-10 production in CD45RO+ cells. Moreover, in vivo, we found IL-10+CD4+ T cells after drug treatment. These cells were heterogeneous but generally CD45RO+, CTLA-4–, and expressed CCR4. A subgroup of these cells expressed TGF-β. Thus, the non-FcR binding anti-CD3 mAb, hOKT3γ1(Ala-Ala) delivers an activation signal to T cells that is quantitatively and qualitatively different from OKT3. It leads to the generation of T cells that might inhibit the autoimmune response and may be involved in the beneficial effect on β cell destruction in Type 1 diabetes.
PMCID: PMC151852  PMID: 12569167

Results 1-3 (3)