April 2024
Project 8p Research Newsletter
💬 Research Question of the Month
Plots like the one above have become as commonplace in scientific journals as abstract expressionist paintings in modern art museums. Each dot represents an individual cell. Each color signifies an individual cell type. The multi-color murmurations are clusters of cells that express the same genes. What everyone struggles with is how to convert those arresting patterns into actionable insights.
Do you have pointers or tips for extracting concrete biological meaning from complex multidimensional datasets? Please drop feedback in the comments!
🔬Research Highlight
Project 8p initiated a collaboration with Dr Francesca Telese at the UCSD to tackle that thorny question. Dr Yanning Zuo, a postdoctoral fellow in the Telese lab, joined the 8p Research Roundtable last month to present updates on a comprehensive bioinformatics analysis of a massive, first-of-its-kind, single-cell RNA sequencing (scRNASeq) experiment on a 8p family trio of cortical brain organoids.
The organoids were grown for up to nine months in culture by brain organoid pioneer Dr. Alysson Muotri, whose lab is also located at UCSD. Dr. Muotri’s 8p Research Roundtable talk from January 2023 can be viewed here. Recall that his lab performed a preliminary analysis on the 8p brain organoid scRNASeq dataset that revealed a striking result that comes with a
”single-proband, single-clone” proviso.
A peculiar population of Reelin-expressing neurons was present in the 8p hero brain organoids but not in brain organoids derived from either parent. Are these the fabled Cajal-Retzius neurons that are thought to exclusively express Reelin? Or are they something else entirely?
The goal of our collaboration with the Telese lab is to complete an unbiased, well-controlled analysis of the data and let the results inform the next set of experiments. Here’s a snapshot of the initial results from 75,111 high quality nuclei, from which 30 cell subtypes were identified after QC.
At 6 months, a population of glioblasts is significantly expanded in the 8p hero (JE3) brain organoids at the expense of neural progenitor cells (NPCs), radial glia, neuroblasts and interneurons. At 9 months, the proportions of Reelin-positive excitatory neurons and choroid cells are increased in the 8p hero brain organoids.
Zooming in on those Reelin-positive cells, Yanning unexpectedly found that their gene expression profile suggested that they are more similar to cerebellar granule cells than canonical Cajal-Retzius cells. If we were dealing with bona fide Cajal-Retzius cells, we’d expect the following genes to be expressed: RELN, NHLH2, CALB2, LHX5, BARHL2, NR2F2. However, the data show that none of those genes are co-expressed with RELN in the GC-1 and GC-2 (Granule Cell) populations of interest.
Instead, the genes that are co-expressed alongside RELN include: UNC5C, a marker of cerebellar origin; PAX6, a marker granule cell progenitors; NEUROD1, a marker of mature granule cells.
Watch Yanning’s talk on the Project 8p YouTube channel and be sure to stick around for the Q&A at the end.
📄 Recent Articles and Publications
Let us know if you’ve read or published a paper or article recently that you think the 8p community should know about!
The variation and evolution of complete human centromeres. Logsdon G., et al. Nature. April 2024. https://www.nature.com/articles/s41586-024-07278-3
The last unexplored tracts of the human genome are chromosomal centromeres, the megabases-long structural anchor point on a chromosome where microtubules attach and pull apart chromosomes pairs during cell division. Led by 8p researcher Dr. Glennis Logsdon, this study using long-read DNA sequencing to compare the centromeres of all chromosomes — including chromosome 8 — from two humans and found surprising variation in centromere length and composition even in this limited sample size.Complete chromosome 21 centromere sequences from a Down syndrome family reveal size asymmetry and differences in kinetochore attachment. Mastrorosa F., et al. BioRxiv. February 2024. https://www.biorxiv.org/content/10.1101/2024.02.25.581464v1
Drs. Glennis Logsdon and Evan Eichler are on a roll in 2024 when it comes to cutting-edge centromere research. This study focuses on the centromeres of chromosome 21 in the context of Down syndrome. As we learn more about the origins of genomic imbalance in meiosis, it becomes possible to imagine ways to prevent chromosomal mishaps from happening in the first place.A high-resolution transcriptomic and spatial atlas of cell types in the whole mouse brain. Yao Z., et al. Nature. December 2023. https://www.nature.com/articles/s41586-023-06812-z
This tour d’force foundational study performed by scientists at the Allen Institute for Brain Science shows what is possible with current gene expression profiling platform technologies. The Allen Brain Cell Atlas data can be accessed through this portal: https://knowledge.brain-map.org/abcatlas. Project 8p is funding a proof-of-concept scRNA-seq cell atlas project in Dr. Hiruy Meharena’s lab with plans in the works to expand to additional 8p hero samples.
💜 Family Corner
Join us at the 2024 Project 8p Family and Science Conference!
Register now to explore the latest research and clinical recommendations while connecting with families, forging lasting connections and support networks. Let's come together for empowerment, education, and our 8p Heroes! See you there!
📆 Upcoming Events
Project 8p Research Roundtable, April 22nd, 1:30 PM EST on Zoom. Email barbara@project8p.org to attend.