‡ Indicates co-first authorship
Annotations are in the spirit of the San Francisco Declaration On Research Assessment (SF DORA)
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SELECTED PEER-REVIEWED PUBLICATIONS, ANNOTATED
Altemose N (2022). [Review]
A classical revival: Human satellite DNAs enter the genomics era. Seminars in Cell and Developmental Biology, 128, 2-14.
https://doi.org/10.1016/j.semcdb.2022.04.012 [open-access preprint available]
- Many open questions remain about the epigenetics and regulation of the newly assembled repetitive heterochromatic regions of the human genome. However, existing methods for mapping protein-DNA interactions utilize short DNA sequencing reads that cannot be reliably mapped to repetitive regions. To address this, we developed a sequencing method for mapping protein-DNA interactions on long, single, native molecules of DNA that retain endogenous CpG methylation information. Then, we applied this method to produce the first high-resolution maps of histone variants and centromere proteins across human centromeres. We joined forces with Aaron Straight’s group at Stanford, who are experts in centromere biology and who were working on a similar method.- This work was described in a news & views article in the same issue: Ahmad, K. Mapping beads on strings. Nat Methods (2022). https://rdcu.be/cOftR
Altemose N, Logsdon GA, Bzikadze AV, Sidhwani P, Langley SA, Caldas GV, Hoyt SJ, Uralsky L, Ryabov FD, Shew CJ, Sauria MEG, Borchers M, Gershman A, Mikheenko A, Shepelev VA, Dvorkina T, Kunyavskaya O, Vollger MR, Rhie A, McCartney AM, Asri M, Lorig-Roach R, Shafin K, Lucas JK, Aganezov S, Olson D, Gomes de Lima L, Potapova T, Hartley GA, Haukness M, Kerpedjiev P, Gusev F, Tigyi K, Brooks S, Young A, Nurk S, Koren S, Salama SR, Paten B, Rogaev EI, Streets A, Karpen GH, Dernburg A, F, Sullivan BA, Straight AF, Wheeler TJ, Gerton JL, Eichler EE, Phillippy AM, Timp W, Dennis MY, O’Neill RJ, Zook JM, Schatz MC, Pevzner PA, Diekhans M, Langley CH, Alexandrov IA, Miga KH (2021).
Complete genomic and epigenetic maps of human centromeres. Science, 375, eabl4178.
https://doi.org/10.1126/science.abl4178 [free to read]
- As a side project during my PhD, I joined the efforts of the Telomere-To-Telomere (T2T) Consortium to produce the first complete sequence assembly of a human genome, including repetitive heterochromatic regions. I helped lead our efforts to characterize some of the most challenging regions of the genome to assemble, which contain the repetitive sequences in which I became an expert as an undergraduate. I developed an algorithm for visualizing and quantifying the underlying repeat structure in these formerly missing regions of the genome, discovered unexpected inversions and deletion polymorphisms, and wrote the manuscript along with the corresponding authors.- This work was covered by many different journals and media outlets, including:- Zimmer C (2021). Scientists finish the human genome at last. The New York Times, 23 July 2021. https://www.nytimes.com/2021/07/23/science/human-genome-complete.html?smid=url-share- Talbert P and Henikoff S (2022). The genetics and epigenetics of satellite centromeres. Genome Research, 32, 599 607. https://doi.org/10.1101/gr.275351.121- Allday E (2022). In research breakthrough, California scientists help decode entire human genome. San Francisco Chronicle, 31 March 2022. https://www.sfchronicle.com/california/article/Scientists-complete-sequencing-of-human-genome-in-17048849.php- Sanders R (2022). Now fully complete, human genome reveals new secrets. UC Berkeley News, 31 March 2022. https://news.berkeley.edu/2022/03/31/now-fully-complete-human-genome-reveals-new-secrets/
Altemose N, Maslan A, Rios-Martinez C, Lai A, White JA, Streets A (2020).
μDamID: a microfluidic approach for joint imaging and sequencing of protein-DNA interactions in single cells. Cell Systems, 11, 1-13.
https://doi.org/10.1016/j.cels.2020.08.015 [open access, transparent review]
- Here, I describe the results from my first PhD project at UC Berkeley. Measuring protein-DNA interactions in single cells is critical for understanding key biological processes like embryonic development, stem cell differentiation, meiosis, and genome misregulation in disease. To enable the collection of joint imaging and protein-DNA mapping data from the same single cells, I designed, built, and tested a microfluidic device that allows the user to isolate, image, sort, and amplify DNA from single cells to measure both the nuclear localization and sequence identity of specific protein-DNA interactions genome-wide.
Li R‡, Bitoun E‡, Altemose N‡, Davies RW, Davies B, Myers SR (2019).
A high-resolution map of non-crossover events reveals impacts of genetic diversity on mammalian meiotic recombination. Nature Communications, 10, 1-15.
https://doi.org/10.1038/s41467-019-11675-y [open access, transparent review]
- In this article, we present the highest-resolution map ever of mammalian non-crossover gene conversion events, which are difficult to detect and study despite their high frequency in each meiosis. To accomplish this, we bred hybrid transgenic mice over 5 generations and deeply sequenced genomic DNA from over 100 offspring. Because these mice have high sequence diversity, we were able to detect short non-crossover gene conversions with unprecedented sensitivity and spatial resolution and discovered several new, fundamental properties of mammalian meiotic recombination. Most importantly, we found strong evidence that the protein PRDM9 not only positions DNA double-strand breaks across the genome, but also guides their repair by binding to both homologous chromosomes. This study represents one of my major research projects from Oxford, which I started in my final years. Reviewers called this work a “tour de force” and a “valuable resource for the community.”
Altemose N, Noor N, Bitoun E, Tumian A, Imbeault M, Chapman R, Aricescu AR, Myers SR (2017).
A map of human PRDM9 binding provides evidence for novel behaviors of PRDM9 and other zinc-finger proteins in meiosis. eLife, 6, e28383.
https://doi.org/10.7554/eLife.28383 [open access, transparent review]
- This paper encompasses several additional branches of my thesis work from Oxford. By building a high-resolution binding map of the meiotic recombination protein PRDM9 in a human cell line and comparing it to measurements of histone modifications, gene expression, and meiotic recombination rates, we discovered several novel properties of PRDM9 with consequences for fertility, genome evolution, and speciation. We made the surprising discovery that PRDM9 frequently binds gene promoters and can even activate the expression of a small number of genes, expanding its known functions and evolutionary constraints. We also found that PRDM9 can bind different DNA motifs with different subsets and arrangements of its zinc fingers, and we showed that its zinc fingers are responsible for forming PRDM9 multimers. To perform these analyses, we developed a new ChIP-seq peak-calling algorithm as well as a new ab initio motif-finding algorithm that allows for joint discovery of multiple binding motifs with variable internal spacing. Our binding map, biological insights, and methods have proven useful for other groups.
Davies B‡, Hatton E‡, Altemose N, Hussin JG, Pratto F, Zhang G, Hinch AG, Moralli D, Biggs D, Diaz R, Preece C, Li R, Brick K, Green CM, Camerini-Otero RD, Myers SR, and Donnelly P (2016).
Re-engineering the zinc fingers of PRDM9 reverses hybrid sterility in mice. Nature, 530(7589), 171–176.
https://doi.org/10.1038/nature16931 [free to read on PubMed Central]- This study proposes the first molecular mechanism of speciation in any mammal, resulting from a collaboration between four research groups (Ben Davies, R. Dan Camerini-Otero, Simon Myers, Peter Donnelly). Using maps of PRDM9 binding and double-strand break formation, we discovered that PRDM9-related hybrid infertility can be explained by PRDM9 binding unequally to each homologous chromosome at each binding site. My contribution stems from an entire chapter of my thesis work. I helped design all experiments, led the breeding of hybrid mice, performed and analyzed the PRDM9 binding experiments, and generated the fourth and final main text figure. My data and analyses proved essential for illuminating the proposed mechanism and reaching the main conclusion of the paper. Our results have inspired further investigations into this speciation mechanism by others. A news and views summary of the article is available at: https://www.nature.com/articles/nature16870
Altemose N, Hayden KE, Maggioni M, Willard HF (2014).
Genomic characterization of large heterochromatic gaps in the human genome assembly. PLoS Computational Biology, 10(5), e1003628.
https://doi.org/10.1371/journal.pcbi.1003628 [open access]
- This study represents the first comprehensive genome-wide study of Human Satellites 2 and 3, which are poorly understood repetitive sequences that comprise 1-3% of the human genome and correspond to the largest gaps in the hg38 reference sequence. As an undergraduate, I developed new computational methods to cluster and map these missing sequences genome-wide for the first time, and I provided resources, including a pseudo-reference, for their further study. By applying these resources, I discovered that a repetitive region of the Y chromosome can vary from 7 to 98 million base pairs among males, demonstrating that a large share of human genetic variation is still missing from the human reference assembly. The pseudo-reference that I published alongside this paper has been used by other groups to image and measure expression from these regions of the genome. Its conclusions and predictions have held up well in the new Telomere-To-Telomere assembly.
ADDITIONAL PEER-REVIEWED PUBLICATIONS
Nurk S‡, Koren S‡, Rhie A‡, Rautiainen M‡, Bzikadze AV, Mikheenko A, Vollger MR, Altemose N, Uralsky L, Gershman A, Aganezov S, Hoyt SJ, Diekhans M, Logsdon GA, The Telomere-To-Telomere Consortium (74 authors), Surti U, McCoy RC, Dennis MY, Alexandrov IA, Gerton JL, O’Neill RJ, Timp W, Zook JM, Schatz MC, Eichler EE, Miga KH, Phillippy AM (2022). The complete sequence of a human genome. Science, 375, eabj6987, https://doi.org/10.1126/science.abj6987 [free to read]
Gershman A, Sauria MEG, Guitart X, Vollger MR, Hook PW, Hoyt SJ, Jain M, Shumate A, Razaghi R, Koren S, Altemose N, Caldas GV, Logsdon GA, Rhie A, Eichler EE, Schatz MC, O’Neill RJ, Phillippy AM, Miga KH, Timp W (2022). Epigenetic patterns in a complete human genome. Science, 375, eabj5089, https://doi.org/10.1126/science.abj5089 [free to read]
Hoyt SJ, Storer JM, Hartley GA, Grady PGS, Gershman A, de Lima LG, Limouse C, Halabian R, Wojenski L, Rodriguez M, Altemose N, Rhie A, Core LJ, Gerton JL, Makalowski W, Olson D, Rosen J, Smit AFA, Straight AF, Vollger MR, Wheeler TJ, Schatz MC, Eichler EE, Phillippy AM, Timp W, Miga KH, O’Neill RJ (2022). From telomere to telomere: The transcriptional and epigenetic state of human repeat elements. Science, 375, eabk3112, https://doi.org/10.1126/science.abk3112 [free to read]
Gupta A, Shamsi F, Altemose N, Dorlhiac GF, Cypess AM, White AP, Yosef N, Patti ME, Tseng Y-H, Streets A (2022). Characterization of transcript enrichment and detection bias in single-nuclei RNA-seq for mapping of distinct human adipocyte lineages. Genome Research, 32, 242-257, https://doi.org/10.1101/gr.275509.121 [open-access preprint available]
Grist S, Geldert A, Gopal A, Su A, Balch H, Herr A, Rampazzi S, Smullin S, Starr N, Rempel D, Agarwal P, Altemose N, Chen T, Hu G, Tung M, Pillarisetti A, Robinowitz D, Shless J (2021). Current understanding of ultraviolet-C decontamination of N95 filtering facepiece respirators. Applied Biosafety, eprint. https://doi.org/10.1089/apb.20.0051 [open access]
Nakatsuka N, Patterson N, Patsopoulos N, De Jager P, Altemose N, Tandon A, Beecham AH, McCauley JL, Isobel N, Hauser S, Hafler DA, Oksenberg JR, Reich D (2020). Two genetic variants explain the association of European ancestry with multiple sclerosis risk in African-Americans. Scientific Reports, 10, 16902. https://doi.org/10.1038/s41598-020-74035-7 [open access]
Lai A, Altemose N, White JA, Streets AM (2019). On-ratio PDMS bonding for multilayer microfluidic device fabrication. Journal of Micromechanics and Microengineering, 29(10), 107001. https://doi.org/10.1088/1361-6439/ab341e [open-access preprint available]
Williams AL, Genovese G, Dyer T, Altemose N, Truax K, Jun G, Patterson N, Myers SR, Curran JE, Duggirala R, Blangero J, Reich D, Przeworski M, on behalf of the T2D-GENES Consortium (2015). Non-crossover gene conversions show strong GC bias and unexpected clustering in humans. eLife 4. https://doi.org/10.7554/eLife.04637 [open access]
Hinch AG, Altemose N, Noor N, Donnelly P, Myers SR (2014). Recombination in the human pseudoautosomal region PAR1. PLoS Genetics 10(7), e1004503–e1004503. https://doi.org/10.1371/journal.pgen.1004503 [open access]
Miga KH, Newton Y, Jain M, Altemose N, Willard HF, Kent WJ (2014). Centromere reference models for human chromosomes X and Y satellite arrays. Genome Research 24(4), 697–707. https://doi.org/10.1101/gr.159624.113 [open access]
Genovese G, Handsaker R, Li H, Altemose N, Lindgren AM, Chambert K, Pasaniuc B, Price AL, Reich D, Morton CC, Pollak MR, Wilson JG, McCarroll SA (2013). Using population admixture to help complete maps of the human genome. Nature Genetics 45, 406-414. https://doi.org/10.1038/ng.2565 [free to read on PubMed Central]