A study published in Nature analyzed the genomes of more than 10,000 adults from Pakistan to identify naturally occurring "knockout" genes, where both copies of a gene carry loss-of-function variants.
The research leveraged the high rate of consanguineous marriage in Pakistan, which increases the likelihood that offspring inherit two identical disabled copies of a gene from a shared ancestor.
Scientists found 1,843 genes that were completely inactivated in at least one participant who appeared healthy at the time of examination.
The team cross-referenced these knockouts with clinical data, including blood biomarkers and disease histories, to assess whether the missing genes caused detectable harm.
Many of the inactivated genes were previously considered essential for survival based on mouse models, suggesting significant differences in gene function between species.
The study also identified knockouts in genes that are current drug targets, offering a way to anticipate potential side effects of inhibiting those proteins in humans.
Researchers emphasized that the participants were adults, so the analysis cannot rule out effects on embryonic development or late-onset conditions.
The authors described the cohort as a "genetic knockout resource" that can help prioritize genes for therapeutic development and improve the interpretation of rare variants in clinical diagnostics.
What we can learn from nature switching off human genes
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