What about the genes which aren’t currently associated with disease? We find that 4 of them have excess loss-of-function variants in healthy populations, suggesting that they are over transmitted to offspring but are at least partially tolerated [15/n]

Assessing the % of sperm per individual that have a likely disease mutation in their exome, we find a striking ~3-fold enrichment over expectation. Currently, we can attribute ~55% of this enrichment to known driver mutations under positive selection [13/n]

The novel genes are mostly known cancer and developmental disorder genes, but unlike previously known genes, most are enriched for loss-of-function (LOF) mutations rather than missense hotspots and they are linked to diverse pathways [12/n]

We detected >35k coding mutations in sperm, equivalent to yields from sequencing >20k trios (!). Using dN/dS tests, we replicate 9 of 13 previously known genes and identify 31 novel genes under positive selection in sperm [10/n]

Next, we investigated positive selection of driver mutations during spermatogenesis. This effect was uncovered and has been extensively characterised by the Wilkie and @gorielylab.bsky.social groups. A summary figure of theirs here [7/n]

Applying NanoSeq to 81 sperm samples from men of the TwinsUK research cohort aged 24-75 we find mutation accumulation in sperm consistent with testis sequencing (Moore et al, 2021) and gold-standard rates from trio sequencing (Sasani et al, 2019) [6/n]

Trio sequencing studies have revealed much about the rates of mutation accumulation in germ cells. However, like other polyclonal tissues, assessing mutations directly in germ cells like sperm has been challenging… [4/n]

Mutations accumulate in all cells over time, but those that occur in reproductive cell lineages like sperm and eggs are transmitted to offspring as germline de novo mutations [3/n]