Matthew Neville
@mattneville.bsky.social
Postdoctoral scientist @ Sanger Institute in Cambridge, UK. Sperm sequencing, de novo mutation, and somatic evolution.
Large % of findings replicating a @gorielylab.bsky.social discovery or prediction!
October 9, 2025 at 12:46 PM
Large % of findings replicating a @gorielylab.bsky.social discovery or prediction!
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
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
October 9, 2025 at 7:22 AM
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
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
Thanks Aylwyn - appreciated some useful early discussions about it with you!
October 9, 2025 at 7:00 AM
Thanks Aylwyn - appreciated some useful early discussions about it with you!
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]
October 8, 2025 at 3:51 PM
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]
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]
October 8, 2025 at 3:51 PM
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]
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]
October 8, 2025 at 3:51 PM
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]
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]
October 8, 2025 at 3:51 PM
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]
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]
October 8, 2025 at 3:51 PM
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]
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]
October 8, 2025 at 3:51 PM
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]
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
October 8, 2025 at 3:51 PM
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...
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]
October 8, 2025 at 3:51 PM
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]
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
October 8, 2025 at 3:51 PM
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...
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]
October 8, 2025 at 3:51 PM
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]
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]
October 8, 2025 at 3:51 PM
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]
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]
October 8, 2025 at 3:51 PM
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]
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...
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
October 8, 2025 at 3:51 PM
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...
www.nature.com/articles/s41...
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]
October 8, 2025 at 3:51 PM
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]
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]
October 8, 2025 at 3:51 PM
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]
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...
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
October 8, 2025 at 3:51 PM
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...
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...