رُحَیل | 𐨪𐨂𐨱𐨅𐨫

🇵🇰࿇࿈ Buddʰaṃ śaraṇaṃ gaccʰāmi |
Stellar nucleosynthesis is the process by which chemical elements are generated via fusion reactions within stars.

[رُحَیل | 𐨪𐨂𐨱𐨅𐨫 @Virosakala]

“Impermanent, alas, are all formations!
Their nature is to rise and fall.
Having arisen, they cease;
Their calming is true bliss.”

[رُحَیل | 𐨪𐨂𐨱𐨅𐨫 @Virosakala]

Haaaaahahahahahaha

[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.

[رُحَیل | 𐨪𐨂𐨱𐨅𐨫 @Virosakala]

@BmaAnirudh @e_munti I'm aware

[Asad 🇵🇰 @asadfacts]

There are some utterly fascinating, almost forgotten threads that link Punjab with Hitler and Nazi Germany.

Since most able-bodied young men from my "martial race" belt of Punjab's Potohar served in WWII, references to Hitler still linger in our vernacular till date. Even today, when we want to describe someone as "tough", we call them "German". It's fascinating to hear simple old villagers, who don't even know the country of Germany, proclaim "Oh kedda German ae" - "how German he is!" - simply because their WWII-veteran fathers defined toughness with the word "German". Additionally, there are a plethora of oral tales of Punjabi mother equating their young sons' brashness in awe with Hitler's renowned ferocity.

Moreover, one of Goebbels's vital propagandists was Haider Khan from District Rawalpindi, who oversaw Nazi propaganda for the entirety of pre-partitioned Punjab, NWFP, Delhi, and Balochistan. Furthermore, quite a few Punjabis - including Habib ur Rehman, Shubhas Bose's Chief of Staff who later led Pakistan Army's guerrilla planning for the 1948 Kashmir War and founded "GHQ Gujrat" - fought under the Axis alignment for Bose's Free India Legion.

[jin (金) @WukongReborn]

“She who arises from the abyss
of the Northwest,
riding a 9 headed black wolf.
she who is the Queen
Of Black magic; she who
defends birth, life, and
the medicine of the field
and valley; she who eats
the hearts of Wicked sorcerers
and their servitors, AHO!”

[𝚛𝚊𝚠𝚊𝚝 @rawatthekiid]

in ride the tiger, julius evola (d. 1974) wrote, “neither pleasure nor pain should enter as motives when one must do what must be done.”

[رُحَیل | 𐨪𐨂𐨱𐨅𐨫 @Virosakala]

https://t.co/qzq0p5tw50

[Maqamat @AlMaqamat_]

From Ibn Sina to space, 1980 Soviet mural in Dushanbe, Tajikistan.

[رُحَیل | 𐨪𐨂𐨱𐨅𐨫 @Virosakala]

Xi Jinping do nothing win image

[Anthropic @AnthropicAI]

The US government, citing national security authorities, has issued an export control directive to suspend all access to Fable 5 and Mythos 5 by any foreign national, whether inside or outside the United States, including foreign national Anthropic employees.

The net effect of this order is that we must abruptly disable Fable 5 and Mythos 5 for all our customers to ensure compliance.

Access to all other Claude models is not affected.

We apologize for this disruption to our customers. We believe this is a misunderstanding and are working to restore access as soon as possible.

Read our full statement: https://t.co/bwn0sximKZ

[رُحَیل | 𐨪𐨂𐨱𐨅𐨫 @Virosakala]

@JattDaPutt101 The spelling mistakes there make me think that even if it is true, some Pakistani put the plaque himself. Also, there are several of these fragments in various Pakistani museums.

[رُحَیل | 𐨪𐨂𐨱𐨅𐨫 @Virosakala]

@lowercas33 Well, good luck I suppose

[رُحَیل | 𐨪𐨂𐨱𐨅𐨫 @Virosakala]

@MlecchasHunter You can know your enemy and still eventually get exhausted. The Hindu Shahis did the best with what they had: they made alliances, used the advantage of their infantry, and came close to pushing the Ghaznavids back early on.

[Sam Dalrymple @SamDalrymple123]

Downstairs are the bronze knockers of Mansurah. Produced soon after the Ummayad conquest of Sindh, they might be the earliest Islamic art in South Asia. Naturally, however, the label just says "door knockers".

[رُحَیل | 𐨪𐨂𐨱𐨅𐨫 @Virosakala]

@Rezerois_PEAK @ScottLahori There you go
https://t.co/NiISo37ZnM

[munti @e_munti]

When the Greeks arrived at Taxila they described it as being about the size of Nineveh (a city in Iraq) & walled like a Greek city. They found the city divided by narrow streets, well-arranged, reminding them of Athens. A sovereign there ruled over what was the kingdom of Porus.

[رُحَیل | 𐨪𐨂𐨱𐨅𐨫 @Virosakala]

@uglyluhan From South India, right?

[رُحَیل | 𐨪𐨂𐨱𐨅𐨫 @Virosakala]

With downcast eyes, as one walks through a village,
With guarded senses, guarding the mind —
Wander alone, like the rhinoceros.
―The Gandharan Rhinoceros Sutra

[л @yetoshi24]

Islamic calligraphy depicting a Rhinoceros.