Within-ejaculate haploid selection reduces disease biomarkers in human sperm

Males produce millions of sperm in a single ejaculate, but only a single sperm fertilises the egg. Fertilisation is the perfect opportunity for natural selection where sperm of poor quality are eliminated, and the fittest sperm sire the offspring. However, the biomarkers of the fittest sperm are currently elusive. Here, we selected human sperm pools for fitness within ejaculates of healthy donors using in vitro assays and identify phenotypic, genomic and proteomic biomarkers of fitter sperm. Fitter sperm showed prolonged motility and incrsed morphological normality and DNA condensation, and their genomes and proteomes differed from less fit sperm. The genes diverging between sperm pools are involved in neurodevelopmental processes, cell signalling and cell proliferation and are linked to heritable diseases including neurodevelopmental disorders and cancers. The genomic signatures of haploid selection in human sperm strongly overlapped in function with the genomic signature in zebrafish sperm suggesting that the sperm functions under haploid selection are highly conserved. The five top peptides downregulated in fitter sperm across all donors are known markers for inflammation, immune function and cancer-related cell proliferation. Selecting for high-performance long-lived sperm prior to fertilisation may therefore help prevent ageing-related heritable diseases in the offspring later in life.