Daniel Malawsky

Human geneticist @sangerinstitute, Former Gates Cambridge & Churchill Scholar @Cambridge_Uni

[Daniel Malawsky @DMalawsky]

Excited to share our new work on the common and rare variant genetic architecture of cognitive ability across childhood and adolescence, using data from @CO90s, @CLScohorts, and @uk_biobank.
https://t.co/EBmPZjY9r5

[Emilie Wigdor @EmilieWigdor]

📣 Preprint 🧵: we profiled post-mortem human BA22 (speech cortex) in autism across 100 donors using single-nucleus multiomics (~500,000 nuclei), integrating RNA + chromatin accessibility. Shout-out to my co-first authors @VarunSuresh007 and @YUHANHAO2: https://t.co/mXFNdh0NSs

[Daniel Malawsky @DMalawsky]

@htanudisastro @hilsomartin @GenSocUK Thank you!

[Daniel Malawsky @DMalawsky]

@timothycbates @hilsomartin @GenSocUK Thank you!

[Loïc Yengo @LoicYengo]

We are pleased to announce that our new study explaining the missing heritability of many phenotypes using WGS data from ~347,000 UK Biobank participants has just been published in @Nature. Please check out our manuscript here: https://t.co/PK2DIpshOQ.

[Abdel Abdellaoui @dr_appie]

Studying the genetics of intelligence measures can help us understand the neurobiology of cognition and neurodevelopmental conditions 🧬🧠

We estimated missing intelligence test scores in @uk_biobank to reduce bias and boost power.

Preprint: https://t.co/M3832KD7sE

Thread 👇

[Alex Strudwick Young @AlexTISYoung]

In March last year, at the age of 35, I was diagnosed with advanced stage III rectal cancer with a metastasis in my liver. This was a shock: I had no family history, and none of the doctors suspected it. In fact, I'd had a negative occult blood test when I went to ER with severe digestive symptoms a few months before.

The first lesson I learnt from this was that there's no substitute for the proper diagnostic procedures: if you have any bleeding, get a colonoscopy, even if you don't have family history.

I was treated with total neoadjuvant therapy at UCLA. I had 6 weeks of combination radiation and chemotherapy (Xeloda). The photo shows me after completing that first step of my treatment along with my parents in Yosemite. My mother has already survived two breast cancers, and my father had recently had a knee replacement (at the age of 70), so getting all three of us to the top of Sentinel Dome felt like an achievement.

The chemoradiation was followed by 6 rounds of combination chemotherapy: oxaliplatin infusions followed by two weeks of Xeloda. I tolerated this unusually well. During this period, I managed to hike up to over 11,000ft multiple times in the Sierras, and I wrote the main text of a 72 author meta-analysis paper and submitted it to Nature where it has passed first round reviews (currently working on revisions).

I showed a good clinical response, with the tumor in my rectum nearly completely disappearing and the liver metastasis shrinking substantially.

At the end of October I had surgery: I was under for 9 hours, and they cut out a large bit of my rectum, 1/3rd of my liver, and gave me a temporary ileostomy. Waking up from this was probably the strangest experience of my life: I felt more machine than man, and I had wild hallucinations form such a large dose of anesthesia.

It took a while to feel OK after that surgery. However, I still had the ostomy. I had that reversed at the end of January in another surgery, which took a greater toll on me than I expected.

There's a cumulative effect of having so many major medical interventions, and it reveals anything weak in body or mind. Surprisingly, my mind held up well during this process. This was thanks to the love and support I received from friends and family and the great care I received from UCLA — in particular Dr Anand (medical oncology), Dr Kazanjian (colorectal surgery), Dr Agopian (liver surgery), and the radiation oncology team.

I only just started to feel like I was starting to feel OK again and I got bad news: I got a positive circulating tumor DNA test (ctDNA), the signatera test from natera. Unfortunately, the second test I had done recently showed the level of ctDNA in my blood is increasing. This means disease recurrence is almost certain, likely within a year from the first positive test.

Since then I've been put on celecoxib based on recent data indicating this can reduce risk of disease recurrence, although it doesn't seem to agree to well with my digestion. I've had CT, MRI, colonoscopy and there's been nothing to see, but it's only a matter of time. My oncologist thinks it is very likely (90%+) that it will be a local recurrence in my liver, which should be fairly easy to cure. But there's a small chance it is something worse, even potentially incurable. This is the reality of cancer for many patients: years of uncertainty.

It's still not clear why this happened. Genetic testing returned nothing. My polygenic risk score (PRS) — something close to my own research — gave me totally average risk, at least according to 23andMe. I've always been slim, fit, eaten a pretty healthy diet. I was even raised vegetarian by hippy parents. I probably drank and partied more than is medically advised, but nothing extreme.

However, there's been a well-documented uptick in cases like mine. A recent paper indicated this may be due to colobactin, a bacterial mutagen associated with E. coli among other bacteria. I may look at my Tempus tumor data to see if the somatic mutation in the APC gene they found (the only driver mutation) has a signature matching colobactin.

If anyone knows anyone with a worthwhile expert opinion on how to manage my situation I'd be interested to hear!

[Daniel Malawsky @DMalawsky]

Thanks for taking an interest in our work! As you note, I’d caution against extrapolating from the effects of damaging rare variants in constrained genes. These are specifically ascertained for phenotypic effects consistent with reduced fitness, so they may not reflect rare variants more broadly.
That said, reconciling twin- and molecular-based estimates of genetic influences on cognitive and behavioural traits may well require new modelling approaches. Later in the paper (and thread), we show that PGI-by-age effects increase nonuniformly across the IQ distribution, as seen in our quantile regression results.
I also ran some simulations suggesting that even without true amplification, nonuniform increases in genetic effects across phenotypic quantiles can generate apparent “amplification” in twin models that assume homogeneous genetic effects.
All that is to say, we still have a long way to go in fully understanding the Wilson effect and missing heritability in cognitive and behavioural traits. I think these two papers complement each other well in pursuit of this goal!

[Mackenzie Dion @Mackenzie_then]

Excited to share 2p-prime, a novel physical pathway for multiphoton fluorescence generation that enables optical sectioning and excitation at red wavelengths with simple systems like continuous wave lasers.

I founded @tripletimaging with @jdwong_campos to fully realize the potential of this tech and introduce a new paradigm for multiphoton fluorescence.

We’re exciting real intermediary states, specifically driving forbidden triplet transitions, using picosecond and continuous wave lasers. Links to two pre-prints + explanation in the thread where we demonstrate 2p-prime with ps and CW lasers in dyes and living cells expressing fluorescent proteins.

David thought of this idea, inspired by optical control of forbidden state transitions in atomic systems from his past life in quantum computing in the Monroe lab and as an early employee at @IonQ_Inc.

In the limit, our approach could be optimized to replace all fluorescence microscopes with simple LED systems that can do rapid volumetric imaging with capabilities akin to existing 2p systems in optical sectioning, contrast, depth, and resolution. Low power, high throughput multiphoton imaging could enable moonshots like functional imaging of every synapse on a neuron or single cell resolution across an entire mouse cortex — datasets which are inaccessible now due to high powers required by ultrafast lasers.

Fundamental insights may generate broad possibilities, and we’re investigating applications across multiple industries like diagnostics and 2p lithography.

This is a white space in photophysics. No indicators have been designed or evolved for this process. We’re optimistic we’ll keep lowering power levels as indicators are optimized for these transitions, e.g. enhanced spin-orbit coupling.

[Emilie Wigdor @EmilieWigdor]

📣Big news! Our tag-team effort on common variants in rare neurodevelopmental conditions is now out in @Nature! 📣
Co-first authoring with the brilliant @qinqin_huang🌟—proof that teamwork does make the dream work. 💪 https://t.co/D9grX4obEW

[Alex Strudwick Young @AlexTISYoung]

New work from Richard Border and others (including myself and @andywdahl) that develops a computationally efficient software package, xftsim, for forward simulation of complex intergenerational dynamics including both genetic and cultural transmission from parents to offspring.

The paper examines commonly used methods in human genetics including LD score regression and population and family-based GWAS under a comprehensive set of scenarios.

Population based GWAS and LD score regression exhibit strong biases under assortative mating with cultural (sometimes called 'vertical') transmission from parents to offspring, a phenomenon closely related to indirect genetic effects.

As expected from theory, family-based methods are robust to complex intergenerational dynamics, but can produce biased estimates under certain sample ascertainment regimes.

[Alex Strudwick Young @AlexTISYoung]

https://t.co/pqWNSLcJYx

[Daniel Malawsky @DMalawsky]

@ksamocha @EmilieWigdor @qinqin_huang https://t.co/JksDFFssnq

[Daniel Malawsky @DMalawsky]

Excited to share our new work on the common and rare variant genetic architecture of cognitive ability across childhood and adolescence, using data from @CO90s, @CLScohorts, and @uk_biobank.
https://t.co/EBmPZjY9r5

[Daniel Malawsky @DMalawsky]

Also check out related work like @ksamocha‘s fascinating preprint and @EmilieWigdor and @qinqin_huang soon to be published paper on the contributions of inherited rare and common variants to neurodevelopmental disorder risk.

https://t.co/JksDFFssnq
https://t.co/FVCAlbKUgM