Some individuals lead typical lives despite both copies of a gene, inherited from each parent, being non-functional. They often remain unaware until DNA analysis occurs. A major Pakistan-based investigation, released in Nature in June 2026, uncovered such natural human knockouts at a large scale. In 173,303 participants, roughly one in five had at least one gene with loss-of-function changes affecting both copies. The work found knockouts in 6,476 genes, nearly one-third of the approximately 20,000 human protein-coding genes. Each case offers researchers a natural experiment on gene effects.
The human genome functions like a detailed manual for building and sustaining the body. Its 23 chromosome pairs resemble chapters written in DNA using four chemical bases: A, T, G and C. Genes act as specific instructions or recipes within this sequence. Proteins handle digestion, transport, tissue formation, signaling and immune defense. Genetics examines how these instructions pass on, change or turn off naturally.
Consanguineous unions occur frequently in some Pakistani communities. National health data indicate nearly two-thirds of marriages involve relatives, with almost half between first cousins. Related parents may share rare variants from common ancestors, leading children to inherit identical DNA segments on both chromosomes. This setup allows rare loss-of-function variants to appear in two copies, making the population valuable for gene function research. Scientists can examine people lacking a protein and determine if its absence causes illness, has minimal impact or offers benefits. Results may forecast outcomes of drugs targeting the same protein.
A 2017 Nature paper by Danish Saleheen illustrated this method. Analysis of exomes from 10,503 adults in a heart attack risk study found 1,843 people with variants disabling both copies of at least one gene across 1,317 genes. These were matched against over 200 traits and biomarkers. The approach enabled recall by genotype, allowing follow-up with specific participants and tailored tests.
One case involved the APOC3 gene, which affects triglyceride processing. People without functional APOC3 copies showed much lower fasting triglycerides and reduced post-meal spikes. This evidence supported therapies lowering APOC3 activity. Olezarsen, a drug reducing APOC3 production, gained U.S. approval in December 2024 for a severe triglyceride disorder.
Genetics can also steer researchers from weak targets. Loss of PLA2G7 lowered Lp-PLA2 levels linked to heart disease risk but did not cut actual disease rates. Darapladib, an inhibitor of the same enzyme, failed in prior trials. Genetic data thus separates viable drug targets from unproven ideas.
The Pakistan Genome Resource, detailed in June 2026, scaled up this work. Data from 173,303 participants across 23 cities included 166,625 exomes and 6,678 genomes, tied to health records and lab results. About 6.6 million coding variants emerged. Nearly 47 percent were absent in non-South Asian gnomAD entries, and 30 percent missing even in South Asian subsets. This highlights unique variation in the group.
