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

TL;DR

This study shows that two genes from ancient retroviruses help maintain reproductive health in humans and mice, especially as they age.

Contribution

The study identifies PNMA1 and PNMA4 as retrotransposon-derived genes that are crucial for reproductive capacity and aging.

Findings

PNMA1 and PNMA4 expression declines with age in human ovaries.

Mice lacking Pnma1 or Pnma4 become subfertile and show hormonal and metabolic issues by six months.

Variants of PNMA1 and PNMA4 are linked to reproductive and metabolic traits in humans.

Abstract

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 during aging. Analysis of donated human ovaries shows that expression of both genes declines normally with age, while several PNMA1 and PNMA4 variants identified in genome-wide association studies are causally associated with low testosterone, altered puberty onset, or obesity. 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. These findings expand our understanding of factors that maintain human reproductive health and lend insight into the domestication of retrotransposon-derived genes.

Figures