Thread by @ATJCagan

Thrilled to finally be able to share our new preprint on the mutational landscape of human somatic and germline cells! #Panbodymap

We integrated histology and genomics to reveal the genomic diversity that develops within our own bodies as we age

biorxiv.org/content/10.110…

[1/15]

As we age our cells accumulate DNA damage, we often only become aware of this damage when it leads to diseases such as cancer but recent research has revealed a dynamic landscape of mutation and selection even within seemingly normal cells. [2/15]

It’s becoming increasingly clear that our bodies are constantly evolving cellular landscapes, but most of the territory remains uncharted. A better understanding could help answer several fascinating questions relevant to cancer, ageing and evolution. [3/15]

Integrating histology and genomics we sequenced >500 whole genomes from 29 microanatomical structures from both the soma and the germline from 3 individuals. [4/15]

We found variation in the clonal composition of different microanatomical structures, reflected in their variant allele fraction distributions. This informs us about the underlying cellular dynamics of different tissues. [5/15]

We quantified the mutation burden and found remarkable levels of variation between tissues - crypts of the digestive tract receive 52 SBS/year while spermatogonia receive only 2.6 SBS/year! [6/15]

To understand the cause of these mutations we extracted mutational signatures and found both the ubiquity of SBS1, SBS5 & SBS40 across all cell types as well as more sporadic and cell specific signatures [7/15]

We explored how telomere length, considered a hallmark of ageing, varies between tissues [8/15]

To further explore the remarkably low mutational burden in the male germline we sequenced 162 microbiopsies of seminiferous tubules from an additional 11 men. The haploid mutation rate was strikingly similar to that inferred from trio studies [9/15]

But what enables the spermatogonia, engaged in highly proliferative spermatogenesis, to maintain such a low mut rate? Assuming SBS1 is associated with cell division, we infer that the basal spermatagonial stem cells may actually divide only a few times per year at most [10/15]

This low division rate can explain the low rate of SBS1 but not the low rates of SBS5+40. Maybe being in a quiescent state + expressing high fidelity repair mechanisms enables them to minimise DNA damage. Future work will be needed to solve this mystery of the germline! [11/15]

Using this dataset we also compared mutational biases between the germline and soma and observe some striking differences between the two [12/15]

Setting out on this endeavour involved an extraordinary team including @luiza_moore , @TimCoorens , @RasheshSanghvi , @MDC_Neville , @MathijsSanders , Thomas Oliver, @redtbutler, @imartincorena , Peter Campbell, Mike Stratton , @R_Rahbari and many more. [13/15]

We also present another preprint using these individuals to build large phylogenetic trees giving insights into human development. See more here:

biorxiv.org/content/10.110…

Tweetorial:

https://twitter.com/TimCoorens/status/1332270537716994048?s=20

[14/15]

Finally, this research would have been impossible without the generosity of the individuals and their families who donated so that we might see further. I’m tremendously grateful to them. I look forward to more insights into our remarkable bodies in the future [15/15]

For another take on the paper see this tweetorial

https://twitter.com/luiza_moore/status/1332273233517797376?s=20

by joint first author @luiza_moore