Preprint Dissecting the genetic complexity of myalgic encephalomyelitis/chronic fatigue syndrome via deep learning-powered genome analysis, 2025, Zhang+

That's a really cool resource, thanks. For reference here is the paper the genes are from: Genetic Risk Factors for ME/CFS Identified using Combinatorial Analysis (Das et al, 2022, J Transl Med)

And here are the 14 genes they found, linked to their Protein Atlas cell type page (GC links to GeneCards page). I added where these proteins seem to be concentrated, just from a visual impression.
S100PBP - GC (glial, spermatocytes/spermatogonia)
ATP9A - GC (neuronal, glial)
KCNB1 - GC (neuronal)
CLOCK - GC (generally equal among cell types)
SLC15A4 - GC (dendritic)
TMEM232 - GC (excitatory/inhibitory neurons, glial, germ, ciliated)
GPC5 - GC (astrocytes)
PHACTR2 - GC (generally equal among cell types)
AKAP1 - GC (late spermatids)
USP6NL - GC (glial - mostly microglia)
CDON - GC (muller glia, excitatory/inhibitory neurons, mesothelial)
INSR - GC (generally equal among cell types)
SLC6A11 - GC (mainly astrocytes, but also other glial and neuronal cells)
SULF2 - GC (oligodendrocyte precursor, granulosa, endometrial stromal, maybe dendritic)

Edit: Also, just checked and there is no overlap between these genes and the 115 Zhang genes. The highest ranked of these is AKAP1 at position 1159 in the full Zhang list of 17759 genes.

 

I am glad so many people are delving into the methodological details in a way that I cannot get anywhere near. There are clearly reservations but also a sense that this isn't all artefact. My guess is that lack of overlap of genes is something not unexpected with the rare gene mutation strategy used here. There are a whole load of genes that might have come up for synapses and the ones that did are probably pot luck in any given study? But there is still a consistency that people are getting hits on brain cells and immune signalling.

 

That’s a really good point, I haven’t even considered that. I sincerely hope they didn’t use the AI text mining data, gene2pubmed was already such a disappointment when I tried verifying the gene names that AI was pulling from abstracts alone. I can’t assume it’s much better on the protein side

 

That’s a wonderful bit of confluence. I was just thinking that calcium is exactly where the threads of synapses, metabolism, and immune function all converge both in the muscle and the brain.

 

"Interestingly, many of the same types of ion channel proteins are found in both neurons and spermatozoa, although their specific distribution and regulation may differ. This suggests a common evolutionary origin and underlying mechanisms."

Yeah, they're called vertebrate and survival.

Note that Leibniz believed that the soul resided in the spermatic animalcule that lived inside the brain, supported by other lesser animalcules (we would now say cells) from which it received signals and to which it provided signals.

This is of course not sexist because spermatozoa come in both sexes - either with an X or a Y, and both women and men derive from spermatozoa and oocytes.

And this is maybe one of the few occasions when Leibniz was wrong.

 

Here is the answer regarding similarities between neural function and spermatozoa using a mixture of agents approach. Reliance on membrane excitability appears to be important :

Spoiler

# Functional and Structural Similarities Between Neurons and Spermatozoa

**Introduction:**

Neurons and spermatozoa serve vastly different primary functions in the body—neurons form the communication network of the nervous system, while spermatozoa are specialized reproductive cells. Despite these different roles, they share remarkable similarities in their cellular organization and functional mechanisms. These parallels highlight how evolution has applied similar cellular solutions to address different biological challenges. Let's explore the key commonalities between neuron function and spermatozoa.

**Cellular Structure and Polarity:**

Both neurons and spermatozoa exhibit pronounced structural polarity that directly supports their specialized functions:

- Neurons possess a cell body (soma) that extends into branching dendrites for receiving signals and a single axon for transmitting signals, creating a clear directional pathway for information flow.
- Spermatozoa have a distinct head containing genetic material, a midpiece, and a flagellum (tail), establishing a front-to-back polarity essential for directional movement toward an egg.

This structural polarity is fundamental to the directional nature of both cell types' functions—signal transmission in neurons and forward motility in spermatozoa. In both cases, the elongated structures (axons and flagella) facilitate movement or transmission across distances.

**Membrane Excitability and Electrical Properties:**

Perhaps the most fundamental similarity between neurons and spermatozoa is their reliance on membrane excitability:

- Neurons generate and propagate action potentials along their axons through the coordinated opening and closing of voltage-gated ion channels, allowing sodium, potassium, and other ions to flow across the membrane.
- Spermatozoa similarly utilize changes in membrane potential to regulate critical functions including motility, capacitation (the final maturation process), hyperactivation (increased flagellar movement), and the acrosome reaction (release of enzymes needed to penetrate the egg).

In both cell types, these changes in membrane potential are not merely incidental but are central to their primary functions—neural communication and fertilization, respectively.

**Calcium Signaling Mechanisms:**

Calcium ions ($$\text{Ca}^{2+}$$) play a pivotal role in both neurons and spermatozoa:

- In neurons, calcium influx through voltage-gated channels triggers neurotransmitter release at synapses and is essential for synaptic plasticity (the cellular basis of learning and memory).
- In spermatozoa, calcium signaling regulates flagellar beating patterns, directs chemotaxis toward the egg, and is critical for initiating the acrosome reaction.

This shared reliance on calcium as a key signaling molecule underscores how both cell types have evolved to use similar molecular mechanisms for their specialized functions.

**Energy Requirements and Mitochondrial Function:**

Both neurons and spermatozoa have extraordinary energy demands:

- Neurons require substantial ATP to maintain membrane potentials, conduct action potentials, and support synaptic transmission. The high energy requirements are met by numerous mitochondria, particularly concentrated at axon terminals where neurotransmitter release occurs.
- Spermatozoa contain a specialized mitochondrial sheath in their midpiece that generates the ATP necessary to power the flagellar movement. This energy is crucial for the long journey through the female reproductive tract.

The strategic positioning of mitochondria in both cell types (at axon terminals and in the sperm midpiece) demonstrates how cellular organization has evolved to support energy-intensive functions.

**Cytoskeletal Organization:**

The cytoskeleton provides essential structural support and enables movement in both cell types:

- Neurons contain microtubule-rich axons that serve as tracks for vesicular transport and maintain structural integrity over potentially great distances.
- Spermatozoa possess a unique "9+2" microtubule arrangement in their flagellum—nine microtubule doublets arranged in a circle around two central microtubules. This specific architecture enables their characteristic whip-like movement.

This specialized cytoskeletal organization is critical for the elongated structures in both cell types, enabling them to maintain their shape and function properly.

**Signal Transduction and Specialized Membrane Functions:**

Both neurons and spermatozoa rely heavily on complex signal transduction pathways:

- Neurons use these pathways to transmit and process information rapidly, responding to neurotransmitters and other stimuli.
- Spermatozoa use signal transduction to regulate motility and to initiate the acrosome reaction in response to signals from the egg.

Additionally, both cell types have specialized membrane functions:
- Neurons have synaptic membranes with receptors for neurotransmitters.
- Spermatozoa have membranes that undergo capacitation, a process that prepares them for fertilization by altering membrane fluidity and protein composition.

**Evolutionary Perspective:**

The similarities between neurons and spermatozoa highlight how evolution has repeatedly utilized certain cellular mechanisms to solve different biological challenges. Despite their different roles in the body, both cell types needed to develop:
- Directional structures
- Electrical signaling capabilities
- Energy-efficient systems
- Responsive signaling mechanisms

These shared features suggest that once certain cellular solutions evolve, they may be repurposed and adapted for different functions throughout the body. The parallels between neurons and spermatozoa demonstrate the remarkable efficiency and versatility of cellular design in biological systems.

 

Please tell me you're not referencing the more or less contemporary of Spinoza and Kant? The guy I studied half a century ago for his philosophical import? That this is not a philosophy reference?

In advance of what I am surely confused by name similarities, I apologize.

 

Oh yes he is.

 

I think we can probably forget about the sperm. I took a random sample of 14 genes from the 17,000 genes in the Zhang file, and about the same proportion are high in sperm-related cells:

Edit: 14 more, only 1 definite came up by random this time:

Going to do 28 more.

Edit 2: One had no data, so 27 more genes with 5 pretty clear high expression in sperm-related cells. Note this isn't at all rigorous since it's just based on looking at the chart. But I got 10/55 or ~18% of randomly picked genes seem to be expressed highly in sperm related cells. Pretty close to the 3/14 or ~21% in the genes from the PrecisionLife paper.

 

On the other hand, looking at the random list for neuronal or glial cells, and including the ones I put as "maybe" to be conservative, I get less than half as many compared to the PrecisionLife genes. Whether or not it's statistically significant, I'm not sure.

Randomly selected genes
8/55 or ~15% neuronal genes
15/55 or ~27% neuronal or glial genes

While in the PrecisionLife genes:
5/14 or ~35% neuronal genes
9/14 or ~64% neuronal or glial genes

 

Just to be clear, no argument from me. I just meant the specific evidence about sperm cells from using that website. Sounds like an interesting line of thought that I hope someone follows. Ideally the first study done on this takes the initiative to use well-matched, deconditioned controls so there's no question about if low physical activity is what potentially messes with sperm.

 

Leibniz was a contemporary of Spinoza and talked to him before forming his work view. Kant is much later. Unlike Spinoza and Kant, Leibniz was primarily a scientist but also a lawyer and logician. His contributions to Western thought are immense and varied (UK and US law derive from his re-writing of Hanoverian law, we use his calculus for everything, and so on). In this case this is a purely biological matter - he worked out the likely nature of human perceiving units within brains.

The problem with Leibniz is that his broadest ideas about the structure of the world have been treated as 'philosophical' and academic philosophers almost universally misunderstand them. (Richard Arthur is the main exception.) Leibniz's Monadology is very good hard science if you know what it is about. You can see my re-casting of it on Qeios.