What we can learn from nature switching off human genes

Nature has illuminated a remarkable phenomenon: individuals who seemingly function normally despite both copies of a gene failing to perform its role. A groundbreaking study from Pakistan, published in the prestigious journal Nature, has uncovered this natural form of gene inactivation on an unprecedented scale. Among a staggering 1,73,303 participants, roughly one in five possessed at least one gene where both gene copies had lost their functionality.

This amounted to the identification of such knockouts across 6,476 genes, which constitutes nearly one-third of the roughly 20,000 protein-coding genes present in human DNA.

Each of these individuals serves as an intriguing case study, akin to a natural experiment conducted by nature herself. The human genome, akin to a comprehensive manual for constructing, operating, and sustaining the human body, is composed of 23 pairs of chromosomes and DNA sequences written using only four chemical letters - A, T, G, and C. Within this genetic code, genes act as individual instructions or recipes, each encoded by a specific arrangement of these DNA letters.

Proteins, which are essential for a myriad of functions such as digesting food, transporting substances, constructing tissues, transmitting signals, and functioning as antibodies against infections, are directly derived from these instructions.

The study delves into the genetic intricacies of consanguineous marriages, which are prevalent in several Pakistani communities. Nearly two-thirds of marriages are between relatives, and almost half are between first cousins. In such close-knit lineages, individuals may inherit identical stretches of DNA from a shared ancestor, leading to the occurrence of rare loss-of-function variants in two copies instead of just one.

This unique genetic backdrop makes Pakistan an invaluable laboratory for studying the functions of specific genes.

Researchers can investigate individuals where a particular protein is largely or entirely absent and pose critical questions: does its absence lead to disease, have little discernible impact, or could it potentially be advantageous? Understanding these dynamics also aids in predicting the effects of medications designed to inhibit the same protein.

The importance of this approach was demonstrated in a 2017 Nature study by Danish Saleheen, which analyzed the protein-coding regions of 10,503 adults from the Pakistan Risk of Myocardial Infarction Study. The researchers identified 1,843 participants carrying variants affecting both copies of at least one gene, involving 1,317 genes.

Comparative analysis of these genetic findings with over 200 biochemical and disease-related traits underscored the utility of 'recall by genotype'. This approach involves identifying participants with unusual genotypes, contacting them for further study, examining their relatives, and performing specialized tests tailored to the affected gene.

One compelling example is the APOC3 gene, which produces a protein involved in triglyceride metabolism. Individuals lacking functional copies of APOC3 exhibited significantly lower fasting triglyceride levels and a reduced rise in triglycerides following a high-fat meal. This observation provided tangible human evidence supporting the therapeutic potential of reducing APOC3 activity.

Consequently, olezarsen, a medication aimed at decreasing APOC3 production, was approved by the United States Food and Drug Administration in December 2024 for the treatment of familial chylomicronaemia syndrome, a severe inherited disorder of triglyceride metabolism.

Moreover, the study sheds light on the limitations and contradictions of genetic targets. For instance, the loss of the gene PLA2G7 resulted in reduced levels of Lp-PLA2, an enzyme associated with an increased risk of coronary artery disease. However, this reduction did not translate into improved cardiovascular outcomes, as evidenced by large cardiovascular trials.

The approval of darapladib, designed to inhibit the same enzyme, serves as a cautionary tale, highlighting that genetic insights must be translated into clinical efficacy.

The Pakistan Genome Resource, as reported in June 2026, extends the scope of this genetic exploration. Researchers analyzed data from 1,73,303 participants across 23 cities, encompassing 1,66,625 exomes and 6,678 whole genomes. They linked this genetic information to medical histories and laboratory biomarkers, identifying 34,364 individuals carrying predicted loss-of-function variants affecting both copies of at least one gene.

Of these, 6,476 genes were represented by at least one such individual. Genes crucial for embryonic development, DNA repair, and energy production were notably resistant to knockout, suggesting their indispensable roles in human development and physiology.

The clinical implications of these findings extend far beyond rare genetic disorders. For instance, the loss of the CIDEB gene was linked to lower liver enzyme concentrations and a reduced risk of fatty liver disease, indicating potential avenues for drug development in managing liver health. Conversely, the gene LRRK2, a key therapeutic target in Parkinson's disease, was found in Pakistani data to be associated with impaired kidney function, raising concerns about the renal impacts of prolonged pharmacological inhibition.

This resource also challenges assumptions derived from animal experiments, with mice lacking PRDM9 revealing unexpected outcomes that underscore the complexity of translating genetic findings from model organisms to humans.