THE LOGSDON LAB
We use long-read sequencing to study the
variation, evolution, and function of human centromeres
and their role in health & disease
What are centromeres,
and why are they so fascinating?
Centromeres are specialized regions on each chromosome that mediate the segregation of chromosomes during cell division. Errors in chromosome segregation 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.
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 Human Genome Structural Variation Consortium (HGSVC).
The first view of human centromere variation among two complete sets of centromeres. These centromeres show a remarkable level of variation in the size and structure of their a-satellite HOR arrays, as indicated by the colorful regions shown between each pair of chromosomes. Additionally, 16 out of 23 centromeres show variation in the location of the kinetochore, marked by the presence of nucleosomes containing the histone H3 variant, CENP-A (dark red dot), with six having kinetochores separated by over 500 kbp of sequence. Adapted from Logsdon et al., bioRxiv, 2023.
Centromere evolution among primate species
The complete sequence, structure, and epigenetic landscape of six sets of centromeres from four primate species (human, chimpanzee, orangutan, and macaque). Comparative analysis of these six sets of centromeres reveal diverse a-satellite HOR organization and structures and distinct species-specific differences. Adapted from Logsdon et al., bioRxiv, 2023.
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 use 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, who 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 evolutionary biology.
Engineered centromeres on human artificial chromosomes
Human artificial chromosomes (HACs) and genomes 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
Metaphase chromosome spreads containing a human artificial chromosome (HAC; green). HACs are engineered mini-chromosomes that acquire a functional centromere and are stably maintained in human cells. A functional centromere is indicated by the presence of the centromeric histone H3 variant CENP-A (red). Scale bar = 10 microns. Adapted from Logsdon et al., Cell, 2019.
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.
In the news
Photo credit: Michael Abbey/Science Source
Photo credit: Oxford Nanopore Technologies
Photo credit: Kendra Hoekzema
Image credit: George Retseck/The Scientist
Glennis Logsdon, Ph.D.
Dr. Logsdon is an Assistant Professor in the Department of Genetics and a core member in the Epigenetics Institute at the University of Pennsylvania Perelman School of Medicine. She completed her postdoctoral training at the University of Washington School of Medicine Department of Genome Sciences with Dr. Evan Eichler in 2022, where she studied the sequence, structure, and evolution of human centromeres using long-read sequencing and computational approaches. Before that, she obtained her Ph.D. in Biochemistry and Molecular Biophysics in 2018 from the University of Pennsylvania Perelman School of Medicine, where she studied centromere establishment on human artificial chromosomes with Dr. Ben Black. She is involved with several national consortia, including the Telomere-to-Telomere (T2T) consortium, Human Pangenome Reference Consortium (HPRC), and Human Genome Structural Variation Consortium (HGSVC). She also works with non-profit, patient-led organizations, such as Project 8p, to better understand complex structural variation in the human genome.
Lab mascot/morale booster
Pepe is a 3-year-old mini goldendoodle who likes to hang out with lab members and visitors. He enjoys cuddles, pets, and treats and is incredibly friendly, social, and loving. By nature, Pepe is hypoallergenic, non-shedding, and fun to be around.
The Logsdon lab has multiple open positions!
Postdoctoral fellow (Human centromere variation)
A postdoctoral position is available in January 2024 in the Logsdon Lab to characterize genetic and epigenetic variation from human and nonhuman phased whole-genome assemblies using long-read sequencing technologies. The position focuses on understanding human diversity, structural variation, epigenetic regulation, and transcription of some of the most complex regions of the genome that have eluded standard human genetic analyses: the centromeres. In addition to developing an independent research program, the successful applicant will work with international consortia, including the Human Pangenome Reference Consortium (HPRC), Telomere-to-Telomere (T2T) consortium, and Human Genome Structural Variation Consortium (HGSVC). The position seeks an individual with expertise in population/evolutionary genetics and bioinformatics/computational genomics.
Applicants must have a Ph.D. in the field of bioinformatics or genetics, already have or be within six months of their doctorate degree, and have demonstrable expertise in bioinformatics/genome sequence analysis. The position is for a minimum of three years.
Please send a cover letter, CV, and contact information of three references to Glennis (firstname.lastname@example.org).
The Logsdon Lab is looking for a Bioinformatics Specialist to join our team. The successful candidate will develop, implement, and execute computational methods and tools to assess the organization of human and primate centromeres using both short- and long-read sequencing technologies. Familiarity with existing bioinformatics-specific software tools, especially data mining of whole-genome sequencing data, is required. Experience in genomics research is necessary for performance of this job. The ideal candidate will independently perform scientific investigative procedures applying professional judgment, interpreting experimental results, guiding lab members through bioinformatics methods and analyses, and preparing research reports for presentation or publication.
Please send a cover letter with a link to a recent code sample that demonstrates your programming ability and technique as well as contact information of three references to Glennis Logsdon (email@example.com).
The Logsdon Lab is looking for a Research Specialist to work with new long-read DNA and RNA sequencing technologies. Projects will include using long-read sequencing technology to investigate the role of genomic structural variation in human disease, performing DNA and RNA sequencing of individuals with unsolved genetic disorders, and collaborating with a diverse group of investigators to design and implement long-read sequencing projects. The position will be actively involved in development of cutting-edge techniques in next-generation and long-read DNA and RNA sequencing, for projects both within the laboratory and with outside collaborators. The Research Specialist will actively contribute to ongoing laboratory research projects and work with local and international collaborators to design and implement long-read sequencing projects on the Oxford Nanopore Technologies (ONT) platform. They will work collaboratively with other lab members and assist graduate students and postdoctoral fellows with ongoing research projects. They will independently perform scientific investigative procedures under limited supervision and complete assigned tasks on time to achieve tight production deadlines. The successful candidate will have strong multitasking skills and an interest in scientific inquiry on the technical scale in addition to broader thinking.
Please send a cover letter, CV, and contact information of three references to Glennis (firstname.lastname@example.org).
The Logsdon Lab is also recruiting several graduate students at the University of Pennsylvania! We are affiliated with the following graduate groups/programs:
If interested in rotating in our lab, please email Glennis with a brief statement of your interest and CV at email@example.com.