Jacey Pridgen

MD/PhD candidate @BCMHouston | Goodell Lab | Somatic mosaicism, clonal hematopoiesis & TP53/Li-Fraumeni | Aspiring oncologist | Views my own

[Jacey Pridgen @Jacey_Pridgen]

Overall, this is a monumental amount of work and just the tip of the iceberg for what @SMaHTnetwork will do next!

Links to all papers are here!

Commentary: https://t.co/38x4q5cK6n
Preprint: https://t.co/kVLMGxNPUM
Benchmarking: https://t.co/QTAHtqWZgg 11/n

[Jacey Pridgen @Jacey_Pridgen]

3. For structural variants and mobile elements, read length beats depth

At ~60X, long reads caught ~80% of SVs at 5-20% VAF vs ~30% for short reads 8/n

[Jacey Pridgen @Jacey_Pridgen]

The surprise: somatic epimutations.

Fiber-seq found heritable, haplotype-specific chromatin changes with no change in DNA sequence

In one line they outnumbered somatic SNVs ~20-fold, and many look clonal 10/n

[Jacey Pridgen @Jacey_Pridgen]

2. The reference genome is the wrong genome

A near-T2T donor-specific assembly recovered 343 Mb missing from GRCh38, and 16% of somatic SNVs fell in those regions

Pangenome-based assemblies are a cheaper middle ground 7/n

[Jacey Pridgen @Jacey_Pridgen]

1. Deeper isn't always better

~300X is needed to catch variants below 2% VAF

Sequencing deeper didn't improve detection much, but sequencing several tissues at moderate depth beat one tissue at >1200X 6/n

[Jacey Pridgen @Jacey_Pridgen]

For the people who like the nitty-gritty, across the 17 papers (several published @CellCellPress and @CellGenomics), there were four major lessons: 5/n

[Jacey Pridgen @Jacey_Pridgen]

Dozens of technologies and tools were benchmarked to find the best way detect this mosaicism that is found within us all, with the main paper published @CellCellPress today 2/n

[Jacey Pridgen @Jacey_Pridgen]

Many questions are now open:

How much "Mendelian" disease is missed by early mosaicism?

Do epimutations drive clonal expansion? Does somatic mosaicism drive aging?

Through this work, we now have the more tools to begin to uncover these answers 4/n

[Jacey Pridgen @Jacey_Pridgen]

In a recent preprint from the group, these tools have now been applied across 20 tissues from 25 donors, to see where variants were found and if they was consistent across tissues

tldr: they're not 3/n

[Jacey Pridgen @Jacey_Pridgen]

Not two cells in our body have exactly the same DNA, making us all genetic mosaics! @SMaHTnetwork is trying to understanding what this mosaicism is doing

Excited to say that our commentary @Goodell_Lab "The Silent Variation Within Us" about SMaHT's first papers is out now! 1/n