Ruth B. McCole
Postdoctoral Scholar

PhD Genetics and Developmental Research, King’s College London, UK (2011).

BA Natural Sciences, University of Cambridge, UK (2005).

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My work centers on a profound enigma in the field of genomics: the existence of ultraconserved elements (UCEs). These are regions of the human genome that display extreme and unexplained similarity in their DNA sequences when compared to other vertebrates. The Wu laboratory has proposed that UCEs function to maintain genome integrity via a homology-based mechanism. I am investigating this and other models by delineating the functions and properties of UCEs using a variety of approaches including human disease genetics, population genetics, and microscopy.

UCEs, copy number variation, and cancer

A number of publications from the Wu lab (Chiang et al. 2008; Derti et al. 2006; McCole et al. 2014) have described an interesting relationship between UCEs and copy number variants (CNVs). We have found that UCEs are depleted from copy number variants (CNVs) in healthy cells, since we discovered that regions disrupted by CNVs overlap UCEs much more seldom than is expected. These results imply that UCEs may be dosage sensitive, wherein altering UCE copy number is deleterious to cells or individuals.

My publication in the journal PLoS Genetics (McCole et al. 2014) addressed the process underlying the dosage sensitivity of UCEs in order to gain insights into the way that UCE dosage affects cells. My study demonstrated that, in contrast to CNVs inherited by healthy individuals, cancer-specific CNVs are, as a rule, not depleted for UCEs and may even be enriched. Furthermore, by discovering that CNVs arising anew in the healthy, as opposed to diseased, body are depleted of UCEs, I obtained evidence that healthy cells may be responsive to changes in UCE dosage in a way that is disrupted in cancer cells. After examining data representing CNVs over time in cell culture, I then postulated that selection against UCE-disrupting CNVs in healthy cells acts rapidly. This raised the exciting possibility of exploring in cell culture how UCE dosage sensitivity may explain ultraconservation. In sum, my work linking UCEs, copy number variation, and cancer suggests that an understanding of the different responses of healthy and cancer cells to changes in UCE dosage could be harnessed to address genomic instabilities in cancer.

UCEs and neurodevelopment

My investigation of the relationships between UCEs, CNVs, and cancer left unexplored the critical question of whether alterations of UCE dosage, per se, are associated with disease, or whether alterations of the position of UCEs in the genome due to dosage-balanced chromosome rearrangements such as inversions, translocations, and complex rearrangements are also associated with deleterious phenotypes.

In collaboration with the Talkowski Lab (Massachusetts General Hospital, Harvard Medical School, Broad Institute), I am addressing this important issue from the perspective of neurodevelopment, taking advantage of new datasets detailing the positions of balanced chromosome rearrangements in individuals with neurodevelopmental disorders and related phenotypes. I am exploring the potential links between genome fragility and structural rearrangements in both cancer and NDD, including the speculative model that UCEs may be involved in detecting structural genomic aberrations in healthy cells, and that both neurodevelopmental disorders and cancers are possible consequences that arise when this UCE-based mechanism is compromised.

The DNA composition of UCEs

Together with Wren Saylor, a research assistant in the Wu laboratory, I am characterizing the profile of UCEs from the perspectives of DNA sequence and epigenetic modification. The Wu lab has previously discovered that UCEs show a particular profile of AT content, with high levels of AT bases within the UCE itself, but a sharp drop in AT content at the boundaries of the UCEs. We are exploring these profiles in more detail, as well as studying CpG positions and methylation profiles. We aim to build a detailed picture of UCEs as they would be perceived by DNA- or chromatin-binding proteins in the nucleus.

Imaging UCEs

I am leveraging super-resolution and conventional imaging technologies to visualize UCE regions in the nucleus, working together with Wren Saylor and Guy Nir, a fellow postdoc in the Wu laboratory. Our goal is to delineate the chromosome structure at these regions and to describe how UCEs are positioned in three dimensions within the mammalian nucleus.

Science outreach

As an affiliate of the Personal Genetics Education Project (PgEd) at Harvard Medical School, I am consulting with film-makers Carylanna Taylor and Jacob Okada of First Encounter Productions on their feature film, currently being produced under the title 'Little Narwhal'. The film brings to life the work of a scientist faced with a genetic puzzle involving human cultures, love, and fertility. Inspired by our interactions, Carylanna and Jacob included me in the script as a collaborator of one of the main characters, and I was recently very honored to accept a small cameo in the film, playing myself!

Wu Laboratory publications on UCEs

Abnormal dosage of ultraconserved elements is highly disfavored in healthy cells but not cancer cells.
McCole, R. B., Fonseka, C. Y., Koren, A., & Wu, C.-T.
PLoS Genetics, 10(10), e1004646 (2014).

Ultraconserved Elements: Analyses of Dosage Sensitivity, Motifs and Boundaries.
Chiang, C. W. K., Derti, A., Schwartz, D., Chou, M. F., Hirschhorn, J. N., & Wu, C. T.
Genetics, 180(4), 2277‐2293 (2008).

Mammalian ultraconserved elements are strongly depleted among segmental duplications and copy number variants.
Derti, A., Roth, F. P., Church, G. M., & Wu, C.-T.
Nat Genet, 38(10), 1216‐1220 (2006).

My publications

Abnormal dosage of ultraconserved elements is highly disfavored in healthy cells but not cancer cells.
McCole RB, Fonseka CY, Koren A, Wu CT.
PLoS Genet. 2014 Oct 23;10(10):e1004646. doi: 10.1371/journal.pgen.1004646. PMID: 25340765

Genes with monoallelic expression contribute disproportionately to genetic diversity in humans.
Savova V, Chun S, Sohail M, McCole RB, Witwicki R, Gai L, Lenz TL, Wu CT, Sunyaev SR, Gimelbrant AA.
Nat Genet. 2016 Mar;48(3):231-7. PMID: 26808112

Single-molecule super-resolution imaging of chromosomes and in situ haplotype visualization using Oligopaint FISH probes.
Beliveau BJ, Boettiger AN, AvendaƱo MS, Jungmann R, McCole RB, Joyce EF, Kim-Kiselak C, Bantignies F, Fonseka CY, Erceg J, Hannan MA, Hoang HG, Colognori D, Lee JT, Shih WM, Yin P, Zhuang X, Wu CT.
Nat Commun. 2015 May 12;6:7147. PMID: 25962338

Genomewide and parental allele-specific analysis of CTCF and cohesin DNA binding in mouse brain reveals a tissue-specific binding pattern and an association with imprinted differentially methylated regions.
Prickett AR*, Barkas N*, McCole RB*, Hughes S, Amante SM, Schulz R, Oakey RJ. Genome Res. 2013 Jun 26. [Epub ahead of print]
Genome Res. 2013 Oct;23(10):1624-35. PMID: 23804403 [*Co-first authors.]

Versatile design and synthesis platform for visualizing genomes with Oligopaint FISH probes
Beliveau BJ, Joyce EF, Apostolopoulos N, Yilmaz F, Fonseka CY, McCole RB, Li JB, Senaratne TN, Williams BR, Rouillard JM, Wu CT.
Proc Natl Acad Sci USA. 2012. 109(52):21301-6. PMID: 23236188

Short interspersed element (SINE) depletion and long interspersed element (LINE) abundance are not features universally required for imprinting.
Cowley M, de Burca A, McCole RB, Chahal M, Saadat G, Oakey RJ, Schulz R.
PLoS One. 2011 Apr 20;6(4):e18953. PMID: 21533089

A case-by-case evolutionary analysis of four imprinted retrogenes.
McCole RB, Loughran NB, Chahal M, Fernandes LP, Roberts RG, Fraternali F, O'Connell MJ, Oakey RJ.
Evolution. 2011 May;65(5):1413-27.PMID: 2116679

Transcript- and tissue-specific imprinting of a tumour suppressor gene.
Schulz R, McCole RB, Woodfine K, Wood AJ, Chahal M, Monk D, Moore GE, Oakey RJ.
Hum Mol Genet. 2009 Jan 1;18(1):118-27. PMID: 8086640

Unwitting hosts fall victim to imprinting.
McCole RB, Oakey RJ.
Epigenetics. 2008 Sep;3(5):258-60. PMID: 18948747. Review.

Lateral line, otic and epibranchial placodes: developmental and evolutionary links?
Baker CV, O'Neill P, McCole RB.
J Exp Zool B Mol Dev Evol. 2008 Jun 15;310(4):370-83. PMID: 17638322. Review.

A molecular analysis of neurogenic placode and cranial sensory ganglion development in the shark, Scyliorhinus canicula.
O'Neill P, McCole RB, Baker CV.
Dev Biol. 2007 Apr 1;304(1):156-81. PMID: 17234174. Erratum in: Dev Biol. 2009 Aug;332(1):186-8.