How 170,000 Pakistani Genomes Could Transform Drug Development
核心洞察
A landmark analysis of 173,303 genomes from Pakistan, published in Nature, identified 34,000 "human knockouts" with complete loss of function in at least one gene, offering unprecedented insights into human genetics.
The Pakistan Genome Resource is 3.5 times more efficient at identifying human genetic knockouts than European ancestry databases, with one in five individuals missing at least one gene.
The study revealed that genes considered essential based on mouse models are actually variable in humans, explaining why many experimental drugs that succeed in mice fail in clinical trials.
A comprehensive analysis of 173,303 genomes from Pakistan, published today in Nature, is reshaping how scientists understand human genetics and drug development. By identifying 34,000 individuals who are "human knockouts"—people with complete loss of function of at least one gene—the study reveals critical variation in the human genome that could shape new treatments while illuminating why drugs developed in mice often fail in humans.
The Pakistan Genome Resource represents the largest genetic study to date of a South Asian population, which includes approximately 2 billion people globally. "South Asians have been severely underrepresented in genome studies—comprising just 2% of global genomic databases despite representing 25% of the world's population," said study leader Danish Saleheen, professor of medical sciences and director of global genomics at Columbia University Vagelos College of Physicians and Surgeons (搜索). "But the distinctive characteristics of South Asian genomes, shaped by population history and cultural practices like consanguineous marriage, can power global medical breakthroughs that benefit patients everywhere."
The Knockout Advantage
The study has identified knockouts of nearly 6,500 genes—approximately one third of all protein-coding genes—across 34,000 individuals. About one person out of every five in the Pakistan Genome Resource is a human knockout, compared to only about one in 14 people in largely European ancestry databases. This makes the resource 3.5 times more efficient at identifying human genetic knockouts than European ancestry databases.
"We simply can't obtain answers to many questions with the more limited European-centric databases," Saleheen said.
The genomes also contain information needed to uncover the functions of two thirds of human genes that remain a mystery even 25 years after the completion of the Human Genome Project.
Bridging the Mouse-to-Human Translation Gap
A crucial finding of the study is that genes considered "essential" to life and intolerant to changes, based on mouse models, are actually variable in humans—a discovery with profound implications for pharmaceutical development.
"Mouse genes often have different functions than their human counterparts," Saleheen explained. "What we would prefer to do is identify people who are born without working copies of these genes and see if that has an effect on their health."
These human knockouts are rare in genome databases like the UK Biobank and the NIH's All of Us, which predominantly contain genomes of people with European ancestry. "Consequently, many experimental drugs that seem promising in mice fail in clinical trials. That costs billions of dollars in losses every year," Saleheen said.
Key Genetic Discoveries with Therapeutic Implications
The database has already yielded significant findings. The RXFP1 (搜索) gene, implicated in heart disease and other conditions in mice, works differently in humans, explaining why drugs developed to target the gene failed in clinical trials.
More promisingly, the study showed that people without functional CIDEB (搜索) genes are protected from liver disease, suggesting that chronic CIDEB inhibitors could be a potentially safe treatment to prevent fatty liver disease (搜索).
The study also revealed important safety signals. Inhibiting a pain receptor targeted for migraine treatment will not cause serious side effects, but LRRK2 (搜索) inhibitors in development for Parkinson's disease (搜索) may increase the risk of kidney disease (搜索), suggesting that kidney function should be monitored in patients taking those drugs.
A Unique Study Design
What sets the Pakistan Genome Resource apart is the ability to conduct comprehensive follow-up examinations. "What's unique about our Pakistan study is we can go back to participants and conduct comprehensive medical exams to see what kind of effects the gene deletion may have on the individual," Saleheen said.
Because many generations often live together, researchers can also examine family members who may have partial or full function of a given gene. "We can study people with all the three genotypes who have the same diet, the same environmental exposures, so we're able to quantify the effect of that genotype in much more detail. That isn't possible in any other study in the world," Saleheen added.
The Power of Population History
Since the 1960s, when studies of American Amish populations provided a wealth of data on inherited conditions, researchers have known that populations with a high rate of marriages between first cousins are uniquely suited to genetic discovery. In Pakistan, marriages between first cousins have been common for hundreds of years, and about one-third of individuals in the Pakistan Genomic Resource are from first-cousin marriages. When children are born to two closely related parents, they are more likely to inherit the same genetic mutations from each other, including mutations that inactivate genes.
The study also reveals that South Asian populations carry genetic ancestry components shared with both European and African populations, suggesting that insights gained from the Pakistan Genome Resource have broad applicability across multiple human populations.
"The pharmaceutical industry has been facing the issue of side effects for several decades," Saleheen said. "Our database could prevent companies from spending millions of dollars on drug candidates doomed to fail or give them confidence to move ahead."