"Ever wonder why the testis expresses most genes? We propose that ‘transcriptional scanning’ in the testes reduces the germline mutation rate while enabling a select set of genes to diverge faster over evolutionary time-scales!” As Itai tweeted, our new story about genome evolution, titled as "Widespread transcriptional scanning in testes modulates gene evolution rates", is out on BioRxiv!
It has always confused people as why testis expresses so many genes, higher than any other organs including the brain, which thought to be among the most complex organs. In our recent manuscript, we proposed that such widespread transcription in male germ cells acts as a systematic mechanism to detect and remove germline DNA damages for the bulk of the genes, while selectively leaves a group of genes out to retain higher mutation rates. This mechanism represents a different layer of regulation which biases gene evolution rates. We termed such a mechanism as 'transcriptional scanning'.
In this manuscript, we firstly used unbiased single-cell RNA-seq to characterize the human spermatogenesis at the single cell transcriptome level. We were amazed by the beautiful projection of single cell transcriptomes as it clearly captures the spermatogenic lineage. We could have followed up with identifying novel genes and pathways required for spermatogenesis. However, our data also reflects the long-standing question of widespread gene expression in male germ cells. Such an interest encouraged us to focus on interpreting how the widespread gene expression in the testis affects the germline mutation rates of genes, and ultimately shapes the genome evolution rates.
Surprisingly, we found that the widespread gene expression in male germ cells leads to lower germline mutation rates through a process called transcription-coupled repair (TCR), while the unexpressed genes retain higher germline mutation rates because of the lack of such benefit. The unexpressed genes are not random, but highly enrich with defense-immune system genes, signalling genes and sensory genes, which together give higher fitness for the species at the population level.
We also found the fine-tuned mutation rates by the gene expression levels in the testis. The mutation rates get lower as the expression level increases, while when the expression level goes to the highest level, transcription-coupled damage (TCD) overwhelms the effect of transcription-coupled repair, leading to a relatively higher rates of germline mutations. Considering that around 80% of de novo germline mutations come from the males, such mechanism makes lots of sense for shaping human genome diversity and gene evolution rates. Together we propose that 'transcriptional scanning' model in male germ cells shapes the genome evolution rates in human.
Finally, we asked if this process would be conserved across evolution. The answer is yes! 'Transcriptional scanning' model predicts that genes expressed in male germ cells evolve slower, while the unexpressed genes and the most highly-expressed genes evolve faster. The results exactly recapitulate the prediction when comparing the ape genomes to human.
We all feel proud of this study, as it connects gene expression, transcription, DNA damage and repair, which all together generate an unprecedented view of how the gene expression in germ cells shapes gene evolution rates. The study opens a new door for us to understand the cross-talk between DNA damage and repair, with reference to gene expression. I really appreciate all the co-authors, without them we could never finish such an exciting work! Great team work!
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