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Reposted by Matthew Neville

Craig Anderson @craigandersn.bsky.social · 1d

Mutations in Time and Space is headed to Cambridge, UK for 2026!

You can check out the exciting list of invited speakers here: coursesandconferences.wellcomeconnectingscience.org/event/mutati...

See you at the Wellcome Genome Campus, on 13–15 April?

Nice one! ;-) #MITS26

Mutations in Time and Space — 20260413

Mutations in Time and Space

coursesandconferences.wellcomeconnectingscience.org

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Matthew Neville @mattneville.bsky.social · 5d

Large % of findings replicating a @gorielylab.bsky.social discovery or prediction!

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Reposted by Matthew Neville

Inigo Martincorena @imartincorena.bsky.social · 6d

Our latest work is out in Nature today. In this paper, we introduce an improved version of NanoSeq, a duplex sequencing protocol with <5 errors per billion bp in single DNA molecules, and use it to study the somatic mutation landscape of oral epithelium in >1000 people www.nature.com/articles/s41...

Somatic mutation and selection at population scale - Nature

A new version of nanorate DNA sequencing, with an error rate lower than five errors per billion base pairs and compatible with whole-exome and targeted capture, enables epidemiological-scale studies of somatic mutation and selection and the generation of high-resolution selection maps across coding and non-coding sites for many genes.

www.nature.com

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Reposted by Matthew Neville

Vladimir (Vova) Seplyarskiy @vseplyarskiy.bsky.social · 6d

Our paper on clonal expansions in Sperm is out in Nature www.nature.com/articles/s41...
If you are interested in working at an intersection of Mendelian genomics/Population genetics/Clonal expansions +Cancer genetics/ and of course mutagenesis, please rich out about postdoc in my lab

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Matthew Neville @mattneville.bsky.social · 6d

Good question! We see ~1 in 50 sperm at age 30 carry a known disease mutation for kids up to ~1 in 20 by 60.
But most sperm, even at 60, have no such mutation. So for me, individual level takeaway is knowledge of increasing risks (just like mom’s age) for decision making and not 60yr old sperm = bad

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Matthew Neville @mattneville.bsky.social · 6d

Thanks Aylwyn - appreciated some useful early discussions about it with you!

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Matthew Neville @mattneville.bsky.social · 6d

Thanks Sandra!!

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Reposted by Matthew Neville

Michael Le Page @mjflepage.bsky.social · 6d

The risk of older fathers fathers passing on disease-causing mutations 🧬 to their children is higher than we thought 🧪

The reason - mutant sperm stem cells that turn selfish and divide faster than normal 1/

www.newscientist.com/article/2499...

Selfish sperm see older fathers pass on more disease-causing mutations

Older men are more likely to pass on disease-causing mutations to their children because of the faster growth of mutant cells in the testes with age

www.newscientist.com

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Matthew Neville @mattneville.bsky.social · 6d

Huge thanks to @kerrinsmall.bsky.social and TwinsUK volunteers, @r-rahbari.bsky.social who dreamed up and supervised the project, @mehurles.bsky.social who co-supervised this project, the Martincorena & Rahbari teams and many others. Questions and feedback welcome! [17/17]

Matthew Neville @mattneville.bsky.social · 6d

These findings show the power of sperm sequencing for understanding positive selection and offspring disease risk. They also raise many new questions that we’re excited to follow up on, stay tuned for more sperm sequencing... [16/n]

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Matthew Neville @mattneville.bsky.social · 6d

What about the genes which aren’t currently associated with disease? We find that 4 of them have excess loss-of-function variants in healthy populations, suggesting that they are over transmitted to offspring but are at least partially tolerated [15/n]

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Matthew Neville @mattneville.bsky.social · 6d

This suggests that positive selection in spermatogenesis is driving a much broader disease risk in ageing fathers than previously appreciated. We caution however that not all disease mutations in sperm will necessarily appear in live births at the same rate [14/n]

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Matthew Neville @mattneville.bsky.social · 6d

Assessing the % of sperm per individual that have a likely disease mutation in their exome, we find a striking ~3-fold enrichment over expectation. Currently, we can attribute ~55% of this enrichment to known driver mutations under positive selection [13/n]

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Matthew Neville @mattneville.bsky.social · 6d

The novel genes are mostly known cancer and developmental disorder genes, but unlike previously known genes, most are enriched for loss-of-function (LOF) mutations rather than missense hotspots and they are linked to diverse pathways [12/n]

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Matthew Neville @mattneville.bsky.social · 6d

Many of the same novel genes are also uncovered by @vseplyarskiy.bsky.social, Shamil Sunyaev and co looking directly at over-transmitted DNMs in trios. Paper also out today! [11/n] www.nature.com/articles/s41...

Hotspots of human mutation point to clonal expansions in spermatogonia - Nature

A systematic statistical genetics approach discovers CES drivers as hotspots of human de novo mutation and shows that clonal expansions in germline may both modulate the prevalence of disorders and lead to false-positive disease associations.

www.nature.com

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Matthew Neville @mattneville.bsky.social · 6d

We detected >35k coding mutations in sperm, equivalent to yields from sequencing >20k trios (!). Using dN/dS tests, we replicate 9 of 13 previously known genes and identify 31 novel genes under positive selection in sperm [10/n]

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Matthew Neville @mattneville.bsky.social · 6d

Can we investigate this at scale in sperm? An updated NanoSeq protocol unlocks our ability to deeply sequence coding regions in sperm. See the method and incredible insights into somatic evolution from @imartincorena.bsky.social and team also out today: [9/n] www.nature.com/articles/s41...

Somatic mutation and selection at population scale - Nature

A new version of nanorate DNA sequencing, with an error rate lower than five errors per billion base pairs and compatible with whole-exome and targeted capture, enables epidemiological-scale studies of somatic mutation and selection and the generation of high-resolution selection maps across coding and non-coding sites for many genes.

www.nature.com

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Matthew Neville @mattneville.bsky.social · 6d

To date 13 genes have been linked to this effect. Critically, all 13 are causal for severe developmental disorders, leading to increases (up to 1,000-fold) in the sporadic birth prevalence of these disorders, with a strong correlation to elevated age of the father [8/n]

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Matthew Neville @mattneville.bsky.social · 6d

Next, we investigated positive selection of driver mutations during spermatogenesis. This effect was uncovered and has been extensively characterised by the Wilkie and @gorielylab.bsky.social groups. A summary figure of theirs here [7/n]

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Matthew Neville @mattneville.bsky.social · 6d

Applying NanoSeq to 81 sperm samples from men of the TwinsUK research cohort aged 24-75 we find mutation accumulation in sperm consistent with testis sequencing (Moore et al, 2021) and gold-standard rates from trio sequencing (Sasani et al, 2019) [6/n]

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Matthew Neville @mattneville.bsky.social · 6d

Error-corrected duplex sequencing approaches such as NanoSeq have overcome challenges of polyclonality by achieving single-molecule accuracy and error rates compatible with the low mutation rate of sperm [5/n]
www.nature.com/articles/s41...

Somatic mutation landscapes at single-molecule resolution - Nature

NanoSeq is used to detect mutations in single DNA molecules and analyses show that mutational processes that are independent of cell division are important contributors to somatic mutagenesis.

www.nature.com

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Matthew Neville @mattneville.bsky.social · 6d

Trio sequencing studies have revealed much about the rates of mutation accumulation in germ cells. However, like other polyclonal tissues, assessing mutations directly in germ cells like sperm has been challenging… [4/n]

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Matthew Neville @mattneville.bsky.social · 6d

Mutations accumulate in all cells over time, but those that occur in reproductive cell lineages like sperm and eggs are transmitted to offspring as germline de novo mutations [3/n]

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Matthew Neville @mattneville.bsky.social · 6d

If you saw preprint, biggest two updates are: Much improved discussion + variant calls now accessible

If you'd like an accessible summary check out this great article from @mjflepage.bsky.social in New Scientist:

For science thread read on! [2/n]
institutions.newscientist.com/article/2499...

institutions.newscientist.com

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Matthew Neville @mattneville.bsky.social · 6d

Now published! Our paper on:
(1) Accurate sequencing of sperm at scale
(2) Positive selection of spermatogenesis driver mutations across the exome
(3) Offspring disease risks from male reproductive aging
[1/n]
www.nature.com/articles/s41...

Sperm sequencing reveals extensive positive selection in the male germline - Nature

A combination of whole-genome NanoSeq with deep whole-exome and targeted NanoSeq is used to accurately characterize mutation rates and genes under positive selection in sperm cells.

www.nature.com

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