Glennis Logsdon, Ph.D.

Centromeres are specialized regions on each chromosome that mediate the segregation of sister chromatids during cell division. Errors in this process can cause aneuploidy, or an imbalance in chromosome number, which can result in cancer, infertility, and birth defects. Although centromeres are essential chromosomal regions, their sequence has remained unresolved in the human genome for the past two decades. The lack of complete centromeric sequences has limited our understanding of the role these regions play in essential cell biological processes required to maintain genome integrity and sustain life. During her postdoctoral training, Dr. Logsdon developed wet- and dry-lab methods to determine the first complete sequence of a human autosomal centromere (Logsdon et al., Nature, 2021). This work led to the complete sequence of all human centromeres (Altemose, Logsdon et al., Science, 2022) and, ultimately, the completion of the human genome (Nurk et al., Science, 2022).

The complete sequence of each human centromere provides an unprecedented opportunity to determine their variation and evolution for the first time. As such, the Logsdon Lab aims to uncover the genetic and epigenetic variation of centromeres among the human population and in diseased individuals, develop a model of human centromere variation, and use this model to study their basic biology and function. In addition, the Logsdon Lab plans to reconstruct the evolutionary history of centromeres over the last 25 million years using phylogenetic and comparative approaches with both human and non-human primate species. Finally, the Logsdon lab will apply our discoveries of centromeres to design and engineer new ones on human artificial chromosomes (HACs). This effort will build on Dr. Logsdon’s previous success in engineering HACs (Logsdon et al., Cell, 2019) and has the potential to revolutionize scientific research and medicine through the design of custom chromosomes and genomes. Together, our lab’s research will advance our understanding of the complex biology of human centromeres and will generate HACs that have the potential to fundamentally transform scientific research and medicine. Below, we provide an overview of each of these three research areas.

1. Centromere variation among the human population

With advances in long-read sequencing technologies and genome assembly algorithms, we are now in an era where the systematic assembly of centromeres is becoming a reality. The complete assembly of centromeres enables the study of their sequence and structural variation for the first time, and it allows for the precise mapping of histones and other centromeric proteins that were previously unmappable. As such, we are standing on the precipice of uncovering the complex biology of centromeres through the discovery of their genetic and epigenetic landscapes. The Logsdon Lab will lead the effort in this area by sequencing and assembling hundreds of human genomes from both healthy and diseased individuals, determining their centromeric genetic and epigenetic variation, and experimentally testing how this variation impacts centromere function. This work is foundational and will greatly advance our understanding of centromere biology and its role in chromosome segregation during cell division. This work will be done in close collaboration with the Human Pangenome Reference Consortium (HPRC) and the Human Genome Structural Variation Consortium (HGSVC).

a. Logsdon GA, Rozanski AN, Ryabov F, Potapova T, Shepelev VA, Catacchio CR, Porubsky D, Mao Y, Yoo D, Rautiainen M, Koren S, Nurk S, Lucas JK, Hoekzema K, Munson KM, Gerton JL, Phillippy AM, Ventura M, Alexandrov IA, Eichler EE. The variation and evolution of complete human centromeres. Accepted at Nature. Available on bioRxiv. doi: 10.1101/2023.05.30.542849

b. Logsdon GA, Vollger MR, Hsieh P, Mao Y, Liskovykh MA, Koren S, Nurk S, Mercuri L, Dishuck PC, Rhie A, …, Miga KH, Phillippy AM, Eichler EE. The structure, function and evolution of a complete human chromosome 8. Nature. 2021 April 7. doi: 10.1038/s41586-021-03420-7. PMCID: PMC7877196

c. Altemose N, Logsdon GA*, Bzikadze AV*, Sidhwani P*, Langley SA*, Caldas GV*, Hoyt SH, Uralsky L, Ryabov FD, Shew CJ, …, Eichler EE, Phillippy AM, Timp W, Dennis MY, O’Neill RJ, Schatz MC, Pevzner PA, Diekhans M, Langley CH, Alexandrov IA, Miga KH. Complete genomic and epigenetic maps of human centromeres. Science. 2022 April 1. doi: 10.1126/science.abl4178. PMCID: PMC9233505

*Authors contributed equally

d. 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, …, Eichler EE, Miga KH, Phillippy AM. The complete sequence of a human genome. Science. 2022 April 1. doi: 10.1126/science.abj6987. PMCID: PMC9186530

2. Centromere evolution among primate species

Centromeres are among the most rapidly evolving regions of the genome, with a mutation rate at least four-fold greater than the unique portions (Logsdon et al., Nature, 2021). This rapid evolution leads to variation in a‑satellite sequence and structure, and it contributes to the emergence of new a-satellite repeats. The forces that shape the evolution of human centromeres are not well understood, and this is largely due to a lack of complete sequence assemblies of centromeres from other primates. The Logsdon Lab will fill this gap in knowledge by sequencing and assembling centromeres from diverse primate species and using these assemblies to reconstruct the evolutionary history of centromeres over the last 25 million years. We will initially focus on the bonobo, chimpanzee, gorilla, orangutan, and macaque species but plan to expand to other primates that comprise the lesser apes and New World monkeys. This work will be done in close collaboration with the Telomere-to-Telomere (T2T) Consortium, which is planning to generate the first complete reference genomes for nearly all primates. We will also work with our long-standing collaborators who have expertise in primate centromere evolution and pangenomics.

a. Mao Y, Harvey WT, Porubsky D, Munson KM, Hoekzema K, Lewis AP, Audano PA, Rozanski A, Yang X, Zhang S, . . ., Logsdon GA, . . ., Eichler EE. Structurally divergent and recurrently mutated regions of primate genomes. Accepted at Cell. Available on bioRxiv. doi: 10.1101/2023.03.07.531415

b. Logsdon GA, Vollger MR, Hsieh P, Mao Y, Liskovykh MA, Koren S, Nurk S, Mercuri L, Dishuck PC, Rhie A, …, Miga KH, Phillippy AM, Eichler EE. The structure, function and evolution of a complete human chromosome 8. Nature. 2021 April 7. doi: 10.1038/s41586-021-03420-7. PMCID: PMC7877196

c. Sulovari A, Li R, Audano PA, Porubsky D, Vollger MR, Logsdon GA, Human Genome Structural Variation Consortium, Warren WC, Pollen AA, Chaisson M, Eichler EE. Human-specific tandem repeat expansion and differential gene expression during primate evolution. PNAS. 2019 October 28. doi: 10.1073/pnas.1912175116. PMCID: PMC6859368

3. Engineered centromeres on human artificial chromosomes

Human artificial chromosomes (HACs) have the potential to revolutionize scientific research and medicine through the development of numerous radical advancements, such as engineered viral immunity and cancer resistance in cell lines as well as cost-effective vaccine and pharmaceutical development. The Human Genome Project-Write is leading the way in this area by proposing to synthesize human chromosomes and genomes from scratch, building on previous successes in budding yeast. Among the many potential hurdles in translating success from yeast to human, perhaps the greatest is the centromere. Unlike yeast, human centromeres are comprised of hundreds of thousands of a-satellite repeats, which have been challenging to sequence and assemble for the past two decades. The lack of complete assemblies of these regions has hindered our ability to identify sequences that can form a centromere on a HAC, such as those associated with centromeric chromatin and the kinetochore. Because the Logsdon Lab will resolve the sequence of hundreds of human centromeres, we are in an ideal position to identify sequences that may be able to form a centromere on a HAC. Therefore, we plan to identify centromere-competent DNA sequences from natural human centromeres and test them for centromere formation and long-term stability on a HAC. This work will lay the groundwork for the construction of future synthetic human chromosomes and genomes that may fundamentally transform scientific research and medicine.

a. Gambogi CW, Mer E, Brown DM, Arora UP, Yankson G, Gavade JN, Logsdon GA, Heun P, Glass JI, Black BE. Efficient formation of single-copy human artificial chromosomes. Accepted at Science. Available on bioRxiv. doi: 10.1101/2023.06.30.547284

b. Gambogi CW, Dawicki-McKenna J, Logsdon GA, Black BE. The unique kind of human artificial chromosome: bypassing the requirement for repetitive centromere DNA. Exp Cell Res. 2020 April 1. doi: 10.1016/j.yexcr.2020.111978. PMCID: PMC7253334

c. Logsdon GA, Gambogi CW, Liskovykh MA, Barrey EJ, Larionov V, Miga KH, Heun P, Black BE. Human artificial chromosomes that bypass centromeric DNA. Cell. 2019 July 25. doi: 10.1016/j.cell.2019.06.006. PMCID: PMC6657561