Widespread haploid-biased gene expression in mammalian spermatogenesis associated with frequent selective sweeps and evolutionary conflict

Abstract

11Mendel's first law dictates that alleles segregate randomly during meiosis and are dis-12 tributed to offspring with equal frequency, requiring sperm to be functionally independent 13 of their genetic payload. Developing mammalian spermatids have been thought to accom-14 plish this by freely sharing RNA from virtually all genes through cytoplasmic bridges, 15 equalizing allelic gene expression across different genotypes. Applying single cell RNA * Corresponding author: rfriedman@ohanabio.com sequencing to developing spermatids, we identify a large class of mammalian genes whose 17 allelic expression ratio is informative of the haploid genotype, which we call genoinforma-18 tive markers (GIMs). 29% of spermatid-expressed genes in mice and 47% in non-human 19 primates are not uniformly shared, and instead show a confident allelic expression bias 20 of at least 2-fold towards the haploid genotype. This property of GIMs was significantly 21 conserved between individuals and between rodents and primates. Consistent with the 22 interpretation of specific RNA localization resulting in incomplete sharing through cyto-23 plasmic bridges, we observe a strong depletion of GIM transcripts from chromatoid bodies, 24 structures involved in shuttling RNA across cytoplasmic bridges, and an enrichment for 25 3 UTR motifs involved in RNA localization. If GIMs are translated and functional in the 26 context of fertility, they would be able to violate Mendel's first law, leading to selective 27 sweeps through a population. Indeed, we show that GIMs are enriched for signatures of 28 positive selection, accounting for dozens of recent mouse, human, and primate selective 29 sweeps. Intense selection at the sperm level risks evolutionary conflict between germline 30 and somatic function, and GIMs show evidence of avoiding this conflict by exhibiting 31 more testis-specific gene expression, paralogs, and isoforms than expression-matched con-32 trol genes. The widespread existence of GIMs suggests that selective forces acting at the 33 level of individual mammalian sperm are much more frequent than commonly believed. 34 2 Author's summary 35Mendel's first law dictates that alleles are distributed to offspring with equal frequency, 36 requiring sperm carrying different genetics to be functionally equivalent. Despite a small 37 number of known exceptions to this, it is widely believed that sharing of gene products 38 through cytoplasmic bridges erases virtually all differences between haploid sperm. Here, 39 we show that a large class of mammalian genes are not completely shared across these 40 bridges, therefore causing sperm phenotype to correspond partly to haploid genotype. We 41 term these genes "genoinformative markers" (GIMs) and show that their identity tends 42 2 to be conserved from rodents to primates. Because some GIMs can link sperm genotype 43 to function, they can be thought of as selfish genetic elements which lead to natural se-44 lection between sperm rather than between organisms, a violation of Mendel's first ...

Battle of the Sex Chromosomes: Competition between X and Y Chromosome-Encoded Proteins for Partner Interaction and Chromatin Occupancy Drives Multicopy Gene Expression and Evolution in Muroid Rodents

“…Interestingly, a recent analysis of spermatid-expressed transcripts at the single-cell level has identified thousands of genes which are not equally shared among spermatids, called GIMs for GenoInformative Markers ( Bhutani et al. 2019 ).…”

“…Comparison of SLX/SLXL1/SLY/SSTY1 target genes with GIMs was performed using the list of common 2,424 target genes ( supplementary table S4 , Supplementary Material online) and data from Bhutani et al. (2019) accessible at bioRxiv: https://www.biorxiv.org/ (last accessed April 30, 2020) .…”

Sex and suicide: The curious case of Toll-like receptors

“…A recent preprint of a single-cell sequencing study has provided evidence for the sink-source model proposed above, suggesting that as many as 29% of all spermatid-expressed autosomal genes may show some degree of incomplete sharing [27]. Importantly, as predicted from the model, nuclear and NMD-targeted RNAs are more likely to escape sharing (Robin Friedman, personal communication), and the chromatoid body is enriched for fully shared mRNAs.…”

Within-ejaculate sperm competition

“…This view has recently been challenged as the evidence for gene expression at the post-meiotic haploid stage is steadily increasing (e.g. [40,43,57]; for reviews see [7][8][9]). While haploid gene expression is not the only way haploid selection among sperm can operate, it certainly increases the opportunity for evolution through within-ejaculate competition.…”

“…The different survival of X-and Y-sperm in the female reproductive tract of mammals including humans has been suggested several times, but these observations are currently still anecdotal. The recent findings of a wide range of genes showing biased gene expression across haploid spermatids in house mice and the cynomolgus primate Macaca fascicularis, with the same genes showing signs of directional selection in primate and human populations [40], suggest that a rather large number of genes could actually be involved in determining sperm phenotypes. Again, the function of these genes and their effect on sperm phenotype are currently unclear.…”