Sperm-specific natural selection

Sperm cells are genetically haploid, but because of the cytoplasmic bridges that link cells, they can be transcriptionally diploid. However, some gene transcripts are not shared. Bhutani et al. sequenced single sperm from mice, cattle, and macaques to determine the extent of distortion in the expression of these putatively selfish transcripts, which the authors call genoinformative markers (GIMs). Investigating the evolutionary pressures on these GIMs, they found that they exhibited signatures of positive selection yet tend to be biased toward sperm function. This observation explains why, relative to other tissues, testis shows distinctive gene expression patterns.

Science, this issue p. eabb1723

Structured Abstract

INTRODUCTION

Mendel’s first law dictates that alleles are distributed equally among progeny, which requires sperm to be functionally independent of their genetic payload. Although mammalian spermatogenesis includes a long haploid stage with extensive gene expression, gene products are shared through spermatid cytoplasmic bridges, which decreases phenotypic differences between individual haploid sperm. However, there are known exceptions to the rule of complete sharing of transcripts between spermatids, including a gene product encoded by the t haplotype in mice that has restricted localization and therefore does not cross cytoplasmic bridges. This results in functional differences between sperm depending on their genotype and leads to preferential transmission of the t haplotype, causing it to act as a selfish genetic element.

RATIONALE

Given that many mammalian transcripts have specific subcellular localization, we reasoned that many spermatid gene products would not be completely shared across cytoplasmic bridges and would therefore exhibit allele-specific bias reflecting the haploid genotype of the cell. Here, we performed single-cell RNA sequencing in four mammalian species to quantify allele-specific biases in spermatids and develop a new computational technique to jointly infer genotype and allelic expression biases (both technical and biological) in single haploid cells.

RESULTS

We show that a large class of mammalian genes exhibit allelic bias linked to the haploid genotype of the cell, which we call “genoinformative markers” (GIMs). Confident GIMs comprise 31 to 52% of spermatid-expressed genes in mice, bulls, cynomolgus macaques, and humans, and at least 62% of GIMs had at least a twofold mean allelic bias. Most GIMs identified were autosomal genes, but we did find evidence for genoinformativity in sex chromosome genes as well. Genoinformativity tends to be conserved between individuals and between homologs of different species, suggesting that it is governed by slow-evolving features. GIMs are enriched for specific subcellular localization patterns and 3ʹ untranslated region motifs and are depleted from chromatoid bodies (subcellular structures that transit across cytoplasmic bridges), consistent with the model of genoinformativity by evasion of cytoplasmic bridges. For GIMs with proteins that are also not shared across cytoplasmic bridges, sperm function may be affected by allelic differences, leading to sperm competition and sperm-level natural selection. Genes expressed in spermatogenesis are known to experience heightened selective forces on average, but a subset of GIMs experience further increases, as evidenced by statistically significant enrichment for signatures of selective sweeps, loss-of-function intolerance, and transmission ratio distortion in humans, mice, and bulls. These forces are consistent with a subset of GIMs acting as selfish genetic elements that spread alleles unevenly. For GIMs with functions both in sperm and in somatic tissues, this could cause an evolutionary conflict for genes because optimal function in highly specialized sperm cells may be detrimental in somatic cells. We identified evolutionary pressure to avoid this conflict, because GIMs are significantly enriched for testis-specific gene expression, paralogs, and isoforms.

CONCLUSION

Our work demonstrates that at least one-third of spermatid transcripts are GIMs across a variety of mammalian species. Many of the corresponding proteins may not have genoinformative expression, but we provide evolutionary evidence that a subset of GIMs show signatures of sperm-level natural selection, implying an effect of protein-level genoinformativity during mammalian evolution. This phenomenon may help to explain why testis gene expression patterns are an outlier relative to all other tissues, with a large fraction of testis-specific gene expression, paralogs, and isoforms.

Incomplete transcript sharing leads to sperm-level functional differences.

Left: Models for sharing of gene products between adjacent haploid spermatids across cytoplasmic bridges. Genes with complete sharing (top) have no differences in allelic expression; genes with no sharing (middle) lead to allele-specific gene expression and potentially phenotypic differences in mature sperm; genes with partial sharing (bottom) lead to quantitative allelic biases and potential quantitative phenotypic differences in mature sperm. Most GIMs fall into the partial sharing category. Right: Phenotypic differences between mature sperm that are linked to the genotype (top) can lead to sperm-level natural selection, which may conflict with organism-level natural selection. This creates an evolutionary pressure that may be resolved by testis-specific expression, paralogs, and alternative isoforms. This suggests a possible explanation for the high prevalence of testis-specific gene expression patterns in mammals.

Abstract

Sperm are haploid but must be functionally equivalent to distribute alleles equally among progeny. Accordingly, gene products are shared through spermatid cytoplasmic bridges that erase phenotypic differences between individual haploid sperm. Here, we show that a large class of mammalian genes are not completely shared across these bridges. We call these genes “genoinformative markers” (GIMs) and show that a subset can act as selfish genetic elements that spread alleles unevenly through murine, bovine, and human populations. We identify evolutionary pressure to avoid conflict between sperm and somatic function as GIMs are enriched for testis-specific gene expression, paralogs, and isoforms. Therefore, GIMs and sperm-level natural selection may help to explain why testis gene expression patterns are an outlier relative to all other tissues.

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