We started with single-cell RNA-Seq on human and mouse testes, which revealed that the previously reported widespread expression in this tissue indeed comes from the germ cells and not the soma cells.pic.twitter.com/J2JijzGRNE
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We started with single-cell RNA-Seq on human and mouse testes, which revealed that the previously reported widespread expression in this tissue indeed comes from the germ cells and not the soma cells.pic.twitter.com/J2JijzGRNE
As a spermatocyte is differentiating it expresses over 90% of its genes! This seemed so strange to us, particularly since transcription can lead to DNA damage and much of the expression comes when the cell is haploid, i.e. no back-up and going into the next generation.pic.twitter.com/3N8vlkSqRy
Bo and I came up with the crazy hypothesis that this expression may have evolved to systematically insert mutations into the population, to increase genetic variation for evolution. We decided to test this idea by cross-referencing with DNA variations in the population.
But studying the results we were surprised by the exact opposite of the predicted result: genes expressed during spermatogenesis have not more but in fact fewer mutations than those that are unexpressed. We then realized that transcription-coupled repair (TCR) could be at play.pic.twitter.com/7pNrqMCzsm
We found that genes expressed during spermatogenesis display lower mutation rates on the transcribed strand. In other words, the widespread gene expression in the male testes may function exclusively to correct mutations by a process we termed ‘transcriptional scanning’.pic.twitter.com/skrQs9f11o
Moreover, this effect is fine-tuned by the level of gene expression during spermatogenesis.pic.twitter.com/E39HfJKPKr
You might then ask, ‘why are not 100% of the genes expressed, instead of just 90%?’. When we studied this small group of unexpressed genes we found that it is enriched for sensory and immune/defense system genes. These functions are known to have evolved fast in the human lineagepic.twitter.com/fXLyHxKVvn
Collectively, we propose that transcriptional scanning shapes germline mutations and modulates mutation rates in a gene-specific manner, maintaining DNA sequence integrity for the bulk of genes but allowing for faster evolution in a specific subset.pic.twitter.com/icZZaiuqtb
Very cool hypothesis! I remember discussing why so many genes are expressed in the testis when I was an undergrad...haven’t read (yet) but whats the mutation profile at regulatory elements?
It's a very cool hypothesis, but unfortunately I don't see how it's testable. Given that transcription coupled repair is a thing, then anything expressed in the germline will show lower mutation rates.
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