Deregulation of Y-linked protamine-like genes in sex chromosome-biased spermatid demise

J. I. Park, G. W. Bell and Y. M. Yamashita,  bioRxiv,  2022.

Meiotic drive is a phenomenon wherein a genetic element achieves a higher rate of transmission than dictated by Mendelian segregation (1-3). One proposed mechanism for meiotic drivers to achieve biased transmission is by sabotaging essential processes of gametogenesis (e.g. spermatogenesis), leading to demise of gametes that contain their opponents (1). Studies in D. simulans have recently found that a set of meiotic driver genes contain a sequence homologous to protamines (4, 5), critical proteins that package sperm chromatin (6-8). However, the underlying mechanisms of drive and the relevance of protamine-like sequences in meiotic drive remain unknown. While studying the function of Modulo, the homolog of Nucleolin in Drosophila melanogaster (9, 10), we unexpectedly discovered Y-linked protamine genes function as a meiotic driver: we found that modulo mutant's known sterility is caused by deregulation of the autosomal protamine-like gene (Mst77F) and its Y chromosome-linked homolog (Mst77Y). Modulo regulates these genes at the step of polyadenylation of the transcripts. We show that Mst77Y likely acts as a dominant-negative form of Mst77F, interfering with the process of histone-to-protamine transition, leading to nuclear decompaction. Overexpression of Mst77Y in a wild-type background is sufficient to cause nuclear decompaction and results in the biased demise of X chromosome-bearing sperm. We propose that dominant-negative protamine variants may be a common strategy found in male meiotic drive and may explain known rapid divergence of protamine genes.

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