Human Knockout Genes

Why in news?

A recent study from Pakistan has identified naturally occurring ‘human knockout genes’ on an unprecedented scale.

• Knockout gene – A gene whose function is effectively switched off because loss-of-function (LoF) mutations disrupt its activity.
• Human knockout genes – When both copies (maternal and paternal) of a gene carry disruptive variants, the person may have little or no functional protein from that gene.
  • Consanguinity increases the likelihood of inheriting the same rare recessive variant from both parents.

• Medical importance – It helps identify
  • Whether a gene causes disease when lost.
  • Whether gene loss has beneficial effects.
  • Whether a gene is a good or bad drug target.
• Lacking functional copies of APOC3 had substantially lower fasting triglyceride concentrations and a smaller rise in triglycerides after consuming a fat-rich meal.
  • olezarsen, a medicine designed to reduce APOC3 production.
• loss of the gene PLA2G7 substantially reduced Lp-PLA2 levels (high levels of which are associated with an increased risk of coronary artery disease).
  • darapladib, designed to inhibit the same enzyme, had already failed to improve outcomes in large cardiovascular trials.
• Recent study – Analysis of 1,73,303 people identified human knockouts involving 6,476 genes, demonstrating the value of population-scale genomics.
  • The study also demonstrated the value of ‘recall by genotype’.

• Lessons for medicine
  • The clinical implications go beyond rare genetic diseases.
  • Loss of the gene CIDEB was associated with lower liver enzyme concentrations and a lower risk of fatty liver disease, making the pathway potentially interesting for drug development.
  • The gene LRRK2 is an important therapeutic target in Parkinson’s disease.

• India relevance – India has similar reasons for investing in population-specific genomics.

• GenomeIndia has already sequenced 10,000 genomes from 83 population groups, providing an important reference map of Indian genetic variation.
• Key limitation – A person may naturally live their whole life without a working gene, but a drug may only block that gene partly and only after adulthood.
• Significance – Researchers naturally can observe what happens when a particular gene is absent.

Reference

The Hindu| Human Knockout Genes