Thread by @M_B_Miller

Excited to share our paper “Somatic genomic changes in single Alzheimer’s disease neurons”, published today in @nature!
nature.com/articles/s4158…
[1/19]

@Nature This was a wonderful collaboration with August Huang @tuihuaorjinhua, mentored by @ChrisAWalsh1 @EAliceLee2 and @_MikeLodato, with contributions from many others across multiple institutions. @BostonChildrens @BrighamWomens @HHMInews @harvardmed @UMassChan @broadinstitute
[2/19]

@Nature @tuihuaorjinhua @ChrisAWalsh1 @EAliceLee2 @_MikeLodato @BostonChildrens @BrighamWomens @HHMINEWS @harvardmed @UMassChan @broadinstitute Somatic mutations in the genome of cells are a major part of how we think about cancer, but recent studies found that somatic mutations also occur in “normal” cells, and build up in neurons and in other cells as we age.
[3/19]

@Nature @tuihuaorjinhua @ChrisAWalsh1 @EAliceLee2 @_MikeLodato @BostonChildrens @BrighamWomens @HHMINEWS @harvardmed @UMassChan @broadinstitute We wondered how the process of somatic mutation might play out in diseases of aging, like #Alzheimer's disease, and whether this could teach us about other aspects of disease in the brain.
[4/19]

@Nature @tuihuaorjinhua @ChrisAWalsh1 @EAliceLee2 @_MikeLodato @BostonChildrens @BrighamWomens @HHMINEWS @harvardmed @UMassChan @broadinstitute We looked at neurons isolated from human brain, focusing on large NeuN+ excitatory neurons that are known to be important and vulnerable in #Alzheimer's disease.
[5/19]

@Nature @tuihuaorjinhua @ChrisAWalsh1 @EAliceLee2 @_MikeLodato @BostonChildrens @BrighamWomens @HHMINEWS @harvardmed @UMassChan @broadinstitute To study somatic mutations, we performed whole-genome sequencing on single #neurons from the #brain, using two different genome amplification methods, allowing us to detect mutations present in individual cells, which were broadly distributed across the genome.
[6/19]

@Nature @tuihuaorjinhua @ChrisAWalsh1 @EAliceLee2 @_MikeLodato @BostonChildrens @BrighamWomens @HHMINEWS @harvardmed @UMassChan @broadinstitute We found that neurons in #Alzheimer's disease accumulated more somatic SNVs than controls. The number of extra SNV was equivalent to more than a decade of normal aging.
[7/19]

@Nature @tuihuaorjinhua @ChrisAWalsh1 @EAliceLee2 @_MikeLodato @BostonChildrens @BrighamWomens @HHMINEWS @harvardmed @UMassChan @broadinstitute To better understand what was causing the somatic mutations in #Alzheimer's disease, we used mutation signature analysis, a powerful method that can disentangle upstream causes of somatic mutations. #COSMIC
[8/19]

@Nature @tuihuaorjinhua @ChrisAWalsh1 @EAliceLee2 @_MikeLodato @BostonChildrens @BrighamWomens @HHMINEWS @harvardmed @UMassChan @broadinstitute Neurons in #Alzheimer's disease showed increased mutations in Signature C, which has been observed previously in rare neurodegenerative diseases related to DNA misrepair. C>A mutations also pointed to genomic effects of #oxidative stress, which we found to be elevated.
[9/19]

@Nature @tuihuaorjinhua @ChrisAWalsh1 @EAliceLee2 @_MikeLodato @BostonChildrens @BrighamWomens @HHMINEWS @harvardmed @UMassChan @broadinstitute AD neurons also showed similar burdens as controls of Signature A mutations, which known to build up in normal #aging. In this way, the neurons seem to have a set of disease-related mutations superimposed on "normal" mutations of aging.
[10/19]

@Nature @tuihuaorjinhua @ChrisAWalsh1 @EAliceLee2 @_MikeLodato @BostonChildrens @BrighamWomens @HHMINEWS @harvardmed @UMassChan @broadinstitute We also found that the expression level of genes impacted how many mutations landed in them, suggesting that the process of gene transcription affects the generation of mutations. This depended on the signature, pointing to distinct mutational mechanisms.
[11/19]

@Nature @tuihuaorjinhua @ChrisAWalsh1 @EAliceLee2 @_MikeLodato @BostonChildrens @BrighamWomens @HHMINEWS @harvardmed @UMassChan @broadinstitute In addition to teaching us about upstream mechanisms in #Alzheimer's disease, we also examined the potential downstream effects of genome-wide accumulation of somatic mutations, how they may lead to cell death.
[12/19]

@Nature @tuihuaorjinhua @ChrisAWalsh1 @EAliceLee2 @_MikeLodato @BostonChildrens @BrighamWomens @HHMINEWS @harvardmed @UMassChan @broadinstitute From our findings in #Alzheimer's disease neurons, and observations in Cockayne syndrome and xeroderma pigmentosum, we wonder if somatic mutation accumulation may be a common feature of neurodegeneration, limiting a cell's ability to use its full genome.
[13/19]

@Nature @tuihuaorjinhua @ChrisAWalsh1 @EAliceLee2 @_MikeLodato @BostonChildrens @BrighamWomens @HHMINEWS @harvardmed @UMassChan @broadinstitute We wonder if cells have a certain ceiling of somatic mutations that they can tolerate, and Alzheimer's disease may add on to mutations acquired during aging, reducing the time before a cell reaches such a ceiling.
[14/19]

@Nature @tuihuaorjinhua @ChrisAWalsh1 @EAliceLee2 @_MikeLodato @BostonChildrens @BrighamWomens @HHMINEWS @harvardmed @UMassChan @broadinstitute We are also intrigued by great work by @martincorena group using the NanoSeq method that found no increase, in fact a slight decrease, in mutations in AD. NanoSeq uses bulk strand-specific sequencing of 15,000 cells, while we used single-neuron strand-independent methods.
[15/19]

@Nature @tuihuaorjinhua @ChrisAWalsh1 @EAliceLee2 @_MikeLodato @BostonChildrens @BrighamWomens @HHMINEWS @harvardmed @UMassChan @broadinstitute @martincorena Comparing these findings inspires questions: which brain cell types show somatic mutation accumulation in AD? How much heterogeneity exists in populations of cells? How do genomic insults manifest, in terms of single- and double-strand effects?
[16/19]

@Nature @tuihuaorjinhua @ChrisAWalsh1 @EAliceLee2 @_MikeLodato @BostonChildrens @BrighamWomens @HHMINEWS @harvardmed @UMassChan @broadinstitute @martincorena I have learned so much about the #brain, #genomics, and #neurodegeneration through this project. Amazing experience working with the brilliant August Huang @tuihuaorjinhua and @_MikeLodato across continents and through #covid. Excited to see what we can learn next!
[17/19]

@Nature @tuihuaorjinhua @ChrisAWalsh1 @EAliceLee2 @_MikeLodato @BostonChildrens @BrighamWomens @HHMINEWS @harvardmed @UMassChan @broadinstitute @martincorena This project benefited from great mentorship @ChrisAWalsh1 @EAliceLee2 @_MikeLodato, important collaborators in the Walsh lab Zinan Zhou, Sam Kirkham, Jenn Ziegenfuss, @HannahC_Reed, Jennifer Neil, Lariza Rento, @StevenCRyu, Chanthia Ma...
[18/19]

@Nature @tuihuaorjinhua @ChrisAWalsh1 @EAliceLee2 @_MikeLodato @BostonChildrens @BrighamWomens @HHMINEWS @harvardmed @UMassChan @broadinstitute @martincorena @HannahC_Reed @StevenCRyu Great clinico-pathological collaborators were an important part of this work! Brad Hyman, Derek Oakley, Matthew Frosch, and Heather Ames @gemistocyte. And thanks to computational collaborators @junhokimkr, @emauryg, and Joe Luquette!
[19/19]