Deepesh Oli

Asgard Archaea, Cytoskeleton protein, Eukaryogenesis, Structural Biology

PhD student, Biomolecular Science and engineering,
VISTEC

[Deepesh Oli @deepesho]

This must be one of the interesting research about Pakistan Genome Resource, a South Asian biobank with high familial relatedness.

[Veera Rajagopal  @doctorveera]

Pakistan Genomic Resource (PGR), founded by Danish Saleheen, is the world's largest genetic database of human knockouts. It has been quietly building since 2017, from 10,000 individuals (Saleheen et al. Nature 2017) to nearly 200,000 today.

A new paper in Nature by Koch et al. reports a new analysis of 173,303 Pakistanis from PGR, offering genetic insights from natural inbreeding experiments in humans.

Koch et al. Nature 2026
https://t.co/Uk9YaeN1Ev

In biology, to understand what a gene does, you delete it, a standard experiment. Knock out the gene in a mouse and see what breaks: organ fails, behaviour changes, animal dies. Thirty years of biology built this way. It works, until it doesn't. Because, you know, mice are not humans.

To know the function of a gene in humans, you need a similar experiment. But that's unethical, you cannot deliberately delete a gene in a human. Except you don't have to, because nature has already been doing that experiment.

Occasionally, a person inherits a broken copy of a gene from both parents and is born with no working version at all--a human knockout. The problem is finding them. In most of the world's populations, where mating is largely random, these events are nearly invisible. For a gene-inactivating variant at 0.1% frequency, you'd expect one homozygous individual in every million people.

That math collapses in populations like Pakistan, where consanguineous marriage has been practised for centuries. In first-cousin marriages, the odds of observing a human knockout for the same 0.1% variant rise to roughly 1 in 16,000, a 63-fold enrichment. And the rarer the variant, the larger the advantage: ~630-fold for a 0.01% variant, ~6,300-fold for a 0.001% variant. The variants too rare to ever be seen in European biobanks become findable here.

Sequencing more than 170,000 individuals from highly consanguineous communities, the authors report a mind blowing statistic: at least one living human knockout was observed for 6,476 genes, which is nearly 1/3rd of the entire protein-coding genome!

What do we find when we finally have the human knockouts?

Studying the phenotypes in the human knockouts helps us confirm or refute our understanding of the gene's function based on animal studies. A few examples I highlight below.

PRDM9
PRDM9 might be one of the most popular genes among animal biologists. It encodes a protein that controls where chromosomes break and recombine during sperm and egg formation. Deleting the gene has caused infertility in every animal. PRDM9 was classified as the first hybrid sterility gene in vertebrates, so fundamental that crosses between mouse species with different PRDM9 alleles can't produce a fertile offspring. PGR now has 4 human PRDM9 knockouts : three women, one man. All fertile, with 2 to 7 children each. A 14-year biological fact, overturned by four families in Pakistan.

LRRK2
LRRK2 is a well-established Parkinson's disease risk gene. Activating mutations in LRRK2 are among the most common risk factors for Parkinson's. LRRK2 is a therapeutic target with many companies exploring ways to switch off this gene in the brain to treat Parkinson's. Large-scale sequencing studies have found individuals with partial loss of LRRK2, who did not show any concerning health issues, predicting adverse effects of LRRK2 inhibition in humans. Animal knockouts though warned of kidney damage. Now PGR has two LRRK2 knockouts, both with kidney disease, confirming animal studies.

RXFP1
RXFP1 encodes the receptor for a pregnancy hormone called relaxin, which has long been studied in rodents. Animal studies suggested it played a critical role in cardiovascular adaptation and connective tissue remodelling, fuelling relaxin-targeted drug development, which failed in late-stage trials. PGR found 16 RXFP1 knockouts, expanded to 26 via recall-by-genotype, all tested with cardiac imaging. None had consistent cardiovascular or reproductive deficits, retrospectively explaining the failure of relaxin-targeted drug programmes that might have spent millions of dollars. Mouse physiology failed to inform humans in the case of relaxin.

Gene constraint insights
Existing large-scale biobanks are predominantly European-based outbred populations, which shaped our understanding of gene constraints largely based on intolerance to partial loss of function. Now PGR, a South Asian-based cohort enriched for consanguineous communities, is beginning to offer insights into gene constraints based on intolerance to complete loss of function.

PGR showed that nearly 1/3rd of human genes tolerate complete loss of function. As much as the genes for which knockouts were found, the genes for which knockouts weren't found can offer biological insights.

The authors find genes depleted for knockouts in PGR are enriched for genes essential for cell survival, known Mendelian disease genes (both dominant and recessive) and genes broadly expressed across human tissues.

A fascinating insight is significant enrichment for knockouts in tissue-specific genes (OR=2.39). Human knockouts confirm what drug developers have always thought: tissue-specific genes are much safer therapeutic targets than broadly expressed genes.

The above insight should be read with caveats. The sample size of PGR is small, hence not saturated for human knockouts. It's likely the number of genes will increase as the sample size grows. There is a survivorship bias, like any other volunteer-based cohort. Absence of a gene knockout here doesn't mean biological impossibility. It means incompatibility with being a 'healthy' adult volunteer. If you build a cohort based on a hospital-based pediatric rare disease South Asian cohort, you'd expect to see knockouts that never appeared in PGR.

South Asian populations represent nearly a quarter of humanity, yet they have been largely absent from the genomic revolution. PGR shows what absence has been costing the field: overturned biological assumptions, failed trials, missed targets. The biology was always there. We just weren't looking in the right place.

[Deepesh Oli @deepesho]

@Nature I generally use Claude co-work for my structural biology work. Fable 5 doesn't even reply for my first prompt. It suggests me to switch to other model. No idea what it does.

[Deepesh Oli @deepesho]

Claude did automation in excel, PowerPoint and now in word. Faster than any of its competitors.

[Claude @claudeai]

Claude for Word is now in beta.

Draft, edit, and revise documents directly from the sidebar. Claude preserves your formatting, and edits appear as tracked changes.

Available on Team and Enterprise plans.

[Deepesh Oli @deepesho]

AI bubble or boom 🤯

[prinz @deredleritt3r]

Anthropic revenue (annualized):

- January 2025: $1B
- May: $3B
- June: $4B
- August: $5B
- October: $7B
- December: $8B to $10B

-February 2026: $14B
-March 2026: $19B
-April 2026: $30B (WTF???)

[Deepesh Oli @deepesho]

Now Claude is on its own race. No active competition.

[Claude @claudeai]

Computer use is now in Claude Code.

Claude can open your apps, click through your UI, and test what it built, right from the CLI.

Now in research preview on Pro and Max plans.

[Deepesh Oli @deepesho]

🚨 The AI Scientist is now in Nature.
AI that autonomously: generates ideas → runs experiments → writes papers → peer reviews itself.
One AI-written paper passed ICLR peer review. Zero human input.
Science will never be the same.

https://t.co/ZOvRzfG6Tp

#AIScientist #Nature

[Deepesh Oli @deepesho]

AI and the PhD student: friend or foe? I used AI to summarize this article. 😁
https://t.co/fKNeWNlnO1

[Deepesh Oli @deepesho]

How can we use Claude code for academia.

[Jeremy Nguyen ✍🏼 🚢 @JeremyNguyenPhD]

Claude Code for Academics

"A gentle introduction in how to use Claude Code for Academics."
presentation slides and github repo from Alessandro Spina

link in reply

[Deepesh Oli @deepesho]

Privileged to attend a lecture by @ProfTomEllis at @VISTEC_Thailand on Eukaryotic synthetic Genomes & Engineered Living Materials (ELMs). Basics to cutting-edge, all in 3 hours session. Thank you Prof. Ellis for an incredible lecture!
#SyntheticBiology #ELMs #VISTEC

[Patrick Hsu @pdhsu]

Evo 2, our fully open-source biological foundation model trained on trillions of DNA tokens spanning the entire tree of life, is out in @Nature today

We & the scientific community have done a lot with this @arcinstitute @nvidia model in the last year! 🧵👇

[Deepesh Oli @deepesho]

Villin's severing mechanism:
V1 and V4 domains compete with D-loop interactions, inducing F→G conformational transitions. This destabilizes longitudinal contacts and explains calcium-activated filament severing—a mechanism likely shared across actin-depolymerizing factors.

[Deepesh Oli @deepesho]

First-ever structure of an actin nucleus!
A new paper from my lab (not a co-author) just came out in Science Advances, revealing how three actin subunits assemble the critical “seed” for filament formation and how villin stabilizes this nucleus.1/6
Read:https://t.co/fXe84mN7sS

[Deepesh Oli @deepesho]

Key strucutral insights:
Actin A3 adopts F-actin conformation.
A1 (pointed end) shows pointed-end subunit conformation.
A2 (lateral) remains in G-actin-like state.
Villin's HP domain bridges A1 and A2 at their lateral junction.
This primes the nucleus for directional elongation!

[Deepesh Oli @deepesho]

Documentary about the great invention #AlphaFold , available on YouTube.

[Google DeepMind @GoogleDeepMind]

To celebrate five years of #AlphaFold, we’re making The Thinking Game available on YouTube. 🧬

Get a candid look at the triumphs, the challenges and the pivotal moments that led to a breakthrough on a 50-year-old grand challenge in biology.

Stream for free on @YouTube → https://t.co/sZv7r2VpQh

[Deepesh Oli @deepesho]

@simonmaechling Hi

[Deepesh Oli @deepesho]

@AnthropicAI Thats a great news.

[Deepesh Oli @deepesho]

First interim prime minister of Nepal chosen through Discord (a gaming communication platform) by Gen Z of Nepal.

[Rohit @neorohit]

Sushila Karki

- First female chief justice of Nepal

- First female prime minister (interim) of Nepal

- First prime minister in the world to be chosen through a Discord poll