A groundbreaking analysis of 173,303 exomes and genomes from the Pakistan Genome Resource (PGR) has been published in Nature, revealing a wealth of insights into human genetics and its implications for drug development. The study, which represents the largest genetic investigation of a South Asian population to date, highlights the unique genetic landscape of Pakistan and its potential to accelerate medical breakthroughs globally.
The research identified approximately 34,000 individuals with "human knockouts," meaning they have a complete loss of function in at least one gene. This high prevalence, roughly 3.5 times greater than in European-ancestry databases, is attributed to the high rate of consanguineous marriages in Pakistan, a factor that increases the likelihood of inheriting two copies of a non-functional gene. Danish Saleheen, the study leader and professor at Columbia University, emphasized the value of this resource, stating, "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."
This extensive dataset is crucial for understanding why many drugs developed using mouse models fail in human clinical trials. The study demonstrated that genes considered essential in mice can be variable in humans, providing human-specific data for drug safety and efficacy. For instance, the PGR revealed that the RXFP1 gene, implicated in heart disease in mice, functions differently in humans, explaining past drug trial failures. Conversely, it showed that individuals lacking functional CIDEB genes are protected from liver disease, suggesting a safe therapeutic target.
The PGR also allows for "recall-by-genotype" studies, enabling researchers to re-examine individuals and their families for in-depth medical evaluations. This capability offers unprecedented detail into the effects of gene deletions, as individuals with varying genotypes within the same family often share similar environmental exposures. This approach has already provided critical safety signals, such as the potential kidney disease risk associated with LRRK2 inhibitors for Parkinson's disease, a finding supported by preclinical rodent models.
With nearly half of the identified variants being unique to the PGR compared to existing databases, the resource underscores the vast potential of studying underrepresented populations. The ongoing expansion of this cohort promises further discoveries into gene function, disease susceptibility, and the translation of preclinical findings into effective human therapies.
