The retrotransposon - derived capsid genes PNMA1 and PNMA4 maintain reproductive capacity

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The human genome contains 24 gag -like capsid genes derived from deactivated retrotransposons conserved among eutherians. Although some of their encoded proteins retain the ability to form capsids and even transfer cargo, their fitness benefit has remained elusive. Here we show that the gag -like genes PNMA1 and PNMA4 support reproductive capacity. Six-week-old mice lacking either Pnma1 or Pnma4 are indistinguishable from wild-type littermates, but by six months the mutant mice become prematurely subfertile, with precipitous drops in sex hormone levels, gonadal atrophy, and abdominal obesity; overall they produce markedly fewer offspring than controls. Analysis of donated human ovaries shows that expression of both genes declines normally with aging, while several PNMA1 and PNMA4 variants identified in genome-wide association studies are causally associated with low testosterone, altered puberty onset, or obesity. These findings expand our understanding of factors that maintain human reproductive health and lend insight into the domestication of retrotransposon-derived genes.

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  1. Elucidating their functions will likely require identifying the cargo that is being transported.

    This is a wonderful paper with clear results and great explanations. I'm super curious about the cargo as well. Is it common for single genes (or two in this case) to have similar effects on male AND female fertility, or are differences between males and females more common? It seems striking to me that the knockout of Pnma1 and Pnma4 dramatically reduced fertility across the board. I wonder if looking at other genes that have similar impacts in both sexes would help to understand what the cargo is potentially interacting with.

  2. 8.5% of granulosa cells expressed PNMA1 and 5.1% expressed PNMA4, possibly indicating specific granulosa subpopulations

    Is there a potential spatial component to this? If capsids are used to transmit signals, then would identifying the location of the PNMA1 and PNMA4-expressing populations in relation to nearby cell types give you potentially useful information?

  3. The in situ biochemical properties of PNMA4 are consistent with capsid formation, which may mediate the protein’s pro-fertility function.

    You found that PNMA1 and PNMA4 expression reduces with age - would you then expect capsid production also decline with age?