Mona khan

PhD | Human Genetics | Ex QAU | Ex-UofT | opinions are my own

[Mona khan @MemoonaRasheed2]

Almost 3 decades back, my parents moved to more resourceful city so that their future children can have better access to education. Today their daughter defended her PhD thesis
Its Dr. Rasheed officially
@AcademicChatter #phdvoice #PhDone #phdlife #WomenInSTEM @hapyresearchers

[Mona khan @MemoonaRasheed2]

Some clicks from my Juneteenth road trip. Beautiful roads, flowing water, and quiet moments. My heart still belongs there.

[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.

[Mona khan @MemoonaRasheed2]

@b_r_khan_ I made it twice using recipe from food fusion.
Give it a try

[Mona khan @MemoonaRasheed2]

@b_r_khan_ Happy EU day

[Cyborg 🇵🇰🍁 @cyborg_reborn]

After Islamabad, they’re now flooding Lahore with these useless, shadeless palm trees.

No shade in brutal summer heat, not suited to the local climate, and most will likely be dead within a year.

[PhD_Genie @PhD_Genie]

Getting an administrative task during the research...

[Mona khan @MemoonaRasheed2]

@i_bot404 Chemistry k curriculum main chapter b hai how crude oil is refined 😁
Bhai sahab nai miss ki hongi classes

[Zafar Mirza @zfrmrza]

We are sitting on a generalised epidemic of AIDS in Pakistan. UNAIDS estimates that Pakistan has the fastest-growing number of AIDS cases in Asia.

What BBC film has revealed in Tunsa THQ is a tip of the iceberg. Same practices are rampant in all districts of the country. All blood borne diseases as a result are on the rise in Pakistan due to absolutely irresponsible health care practices including, reuse of disposable syringes by health care workers and drug addicts; unscreened blood transfusions; unprotected sex; unhygienic use of shaving instruments and so on. We have the largest population with Hepatitis C infection in the world ie around 10 million.

After RatuDero outbreak of AIDS among young children, I sat up a Taskforce for safe injection which produced a National Action Plan for Injection Safety and we banned the import, manufacture, sale and use of reusable disposable syringes and we promoted their replacement with auto-destruct syringes. The breakdown of governance, lack of implementation of policies, and complete lack of accountability has not made the desired effect on the ground though local manufacture has shifted predominantly to auto-destruct syringes.

There are health budget issues, supply chain issues and unfilled posts in public sector health facilities where only poor and gullible people go for lack of affordability. Tunsa is a wake up call, like Ratu Dero (2020) outbreak was, like Jalalpur Jatan (2009) outbreak was, and many other outbreaks. After a spike in media discussions and governments defending the issue gradually dies down.

Our successive governments have failed to make health care their priority which is evident from the very low spending on health care. In this case, very young children are suffering and dying due to AIDS due to health care workers criminal behaviour of using same infected syringes on multiple children. Those who survive have to take lifelong medication - a life long suffering and liability on society. Look at the clip below. It is horrendous. This is scandalous.

For God sake take care of people’s health and make it a fiscal priority. We have to take a moral and financial responsibility for people’s health care, rather than continue to be dependent on Global Fund, GAVI and others. These are our children, our people and they are our responsibility.

[Sabah Bano Malik @sabahbanomalik]

A Punjab government hospital caused an outbreak of HIV because it was reusing needles - the same Punjab government that just got a brand spanking new private jet.

[Mona khan @MemoonaRasheed2]

@b_r_khan_ Karma 🤪🤪🤪

[Mona khan @MemoonaRasheed2]

@b_r_khan_ Oh no

[Mona khan @MemoonaRasheed2]

@GongR1ght Pakistan doesn’t have a public transport and the metro lines in Islamabad/RWP/Lahore don’t cover all parts of the city.

[yang goi @GongR1ght]

you can make public transport free but I’m pretty sure Pakistanis will still not use it because Pakistan is an extremely classist society which carries a huge stigma for someone using public transport. Orange Line metro in Lahore is world class but very few people in Pakistan will use it.

People in Pakistan think it’s a shame to use public transport.

[Mona khan @MemoonaRasheed2]

@MaheeraGhani It’s natural to miss family or place where one grew up.
If you don’t like to view such content, just scroll down. Don’t shame people for expressing what they feel 🙂

[Mona khan @MemoonaRasheed2]

@b_r_khan_ So pretty

[FIGHT FINISHED!!! @Natsgrl1]

⁦@capitalweather⁩ Cherry Blossoms at 6PM on approach to DCA

[feelings ღ @eternaltxts]

we’ve lost the art of tucking a flower into a girl’s hair

[Mona khan @MemoonaRasheed2]

@WasayJalil Credits @ReelWind_

[Mona khan @MemoonaRasheed2]

@mahparasafdar @sindh_sukk33564 Come on
Its a 4 mins video
Some faces are difficult to reproduce with AI. @ReelWind_ has done a great job with conception and execution
All these people who are criticizing can try and do better job themselves

[Mona khan @MemoonaRasheed2]

@b_r_khan_ @Osman_malik5 I am dead laughing 😅😅😅