Very recent evolution of a new cell type

[sfmatheson]

https://www.nature.com/articles/s41586-024-07423-y

A few notable points in this new paper in Nature.

• This new cell type appears to have evolved very recently (~20,000 years ago).
• The steroid hormone at the center of the story “has long been considered to be an inactive metabolite of progesterone.”
• Somewhat unexpectedly, straightforward mutation/variation in transcription factors is not apparently at the root of the evolutionary change. From the Discussion:

…genetic variation affecting transcription factors has long been hypothesized to drive the evolution of novel cell types, but empirical evidence to support this hypothesis is scant. […] We found that genetic variation affecting Gadd45a—a nuclear protein that affects DNA methylation and cell differentiation—probably contributes to the development of the zona inaudita cell, and that genetic variation modulating the expression of tenascin N—an ECM protein—is a likely cause of the gain of a novel enzymatic function of this cell type. Transcription factors are likely to be involved in the development of the zona inaudita cell, as several transcription factors including Batf, Hif1a, Runx2, Tsc22d3 and Tshz3 are also markers of this cell type. However, our genetic mapping experiments indicate that interspecific genetic variation at or near these transcription factor genes is not a major force driving the emergence of the zona inaudita; thus, their expression in the zona inaudita is probably in response to upstream genetic variation in other genes, including Gadd45a.

News & Views piece accompanying paper:

https://www.nature.com/articles/d41586-024-01356-2

Glad to provide PDFs on request.

[misterme987 (Andrew P.)]

Very cool! Thank you for sharing. How different is this new cell from previously existing cell types?

[sfmatheson]

@misterme987

How different is this new cell from previously existing cell types?

I would describe it as a new cousin of other adrenal cortex cells. Its most obvious distinguishing feature (genetically) is expression of the enzyme that converts progesterone into the “new” hormone previously thought to be inactive. They found almost 200 other genes expressed at higher (>2-fold) levels than in other adrenal cell types. And interestingly, these cells form an anatomically distinct and unique layer in the adrenal of the oldfield mice. The evidence points to a new cell type and not just an existing cell type that’s making a new protein, but this does depend on how one defines “cell type.”

This is Fig 3f, showing the unique cell layer (they named it Zona inaudita)