Zinan Zhou

Unsplash image of the Earth, mostly the nightside with a tracery of city lights on every continent.

OK, this is wild.

In September 2023, geophysicists across the world started monitoring a very odd signal coming from the ground under them.

It was picked up in the Arctic. And Antarctica. It was detected everywhere, every 90 seconds, as regular as a metronome, for *nine days*.

What the HELL?

1/

Human-chimpanzee tetraploid system defines mechanisms of species-specific neural gene regulation A major challenge in human evolutionary biology is to pinpoint genetic differences that underlie human-specific traits, such as increased neuron number and differences in cognitive behaviors. We used human-chimpanzee tetraploid cells to distinguish gene expression changes due to cis -acting sequence variants that change local gene regulation, from trans expression changes due to species differences in the cellular environment. In neural progenitor cells, examination of both cis and trans changes – combined with CRISPR inhibition and transcription factor motif analyses – identified cis -acting, species-specific gene regulatory changes, including to TNIK , FOSL2 , and MAZ , with widespread trans effects on neurogenesis-related gene programs. In excitatory neurons, we identified POU3F2 as a key cis -regulated gene with trans effects on synaptic gene expression and neuronal firing. This study identifies cis -acting genomic changes that cause cascading trans gene regulatory effects to contribute to human neural specializations, and provides a general framework for discovering genetic differences underlying human traits. ### Competing Interest Statement C.A.W. is on the SAB of Bioskyrb Genomics (cash, equity) and Mosaica Therapeutics (cash, equity), and is an advisor to Maze Therapeutics (equity), but these have no relevance to this work. The remaining authors declare no competing interests.

We just posted two preprints on uncovering the genetic bases of species-specific differences in neural progenitors, excitatory neurons, and upon neuronal stimulation using the human-chimpanzee tetraploid system. Please check them out!
www.biorxiv.org/content/10.1...
www.biorxiv.org/content/10.1...

Recurrent patterns of widespread neuronal genomic damage shared by major neurodegenerative disorders Amyotrophic lateral sclerosis (ALS), frontotemporal dementia (FTD), and Alzheimer's disease (AD) are common neurodegenerative disorders for which the mechanisms driving neuronal death remain unclear. ...

10/ Check out the full paper for all the details!
🔗 doi.org/10.1101/2025...

9/ Our findings suggest TOP1-mediated RER is a mutagenic process shared by major neurodegenerative conditions. Could modulating TOP1 activity slow neurodegeneration? More research is needed!

8/ Why does this matter?
If TOP1-mediated mutagenesis is a common driver of neurodegeneration, targeting this pathway could open new therapeutic avenues for ALS, FTD, and AD.

7/ Gene expression analysis suggests that deficiencies in RNase H2 and ribonucleotide reductase—two key regulators of cellular and genomic ribonucleotides—may contribute to this widespread DNA damage.

6/ High levels of ID4-like Indels in neurons correlated with increased single-strand DNA breaks, further implicating TOP1-mediated mutagenesis in neuronal genomic instability.

5/ TOP1-mediated RER generates single-strand breaks and single-strand 2-bp deletions as intermediates. Using duplex sequencing, we confirmed these double-strand deletions and identified single-strand deletions with the same pattern—likely precursors to double-strand deletions.

4/ Consistent with TOP1-mediated RER, we identified hallmark features of TOP1-driven Indels:
1. Enrichment of a TNT motif at deletion sites
2. Preferential deletion of CT dinucleotides
3. Correlation between somatic Indels & gene expression levels

3/ Strikingly, diseased neurons exhibited an excess of 2-bp deletions and a mutational signature resembling COSMIC ID4—a signature linked to topoisomerase 1 (TOP1)-mediated ribonucleotide excision repair (RER).

2/ Using single-cell whole-genome sequencing of neurons from ALS, FTD, AD, and control brains, we found significantly increased burdens of somatic SNVs and Indels in all three disease conditions.

1/ Neurodegenerative diseases like ALS, FTD, and AD have distinct genetic & pathological features, but could they share a common mechanism of genomic instability? 🤔

Recurrent patterns of widespread neuronal genomic damage shared by major neurodegenerative disorders Amyotrophic lateral sclerosis (ALS), frontotemporal dementia (FTD), and Alzheimer's disease (AD) are common neurodegenerative disorders for which the mechanisms driving neuronal death remain unclear. ...

We uncovered a shared pattern of neuronal somatic mutations across ALS, FTD, and AD.
🔗 doi.org/10.1101/2025...
Huge thanks to co-first authors Joe Luquette & @guanlandong.bsky.social , and everyone in the Park, Lagier-Tourenne, Lee, and Walsh labs!