What Happens When Both Copies of a Gene Are Missing in a Person

If both copies of a gene are broken, the gene cannot make its normal protein. What that does to a person depends on which gene and which measurement you use. In 10,503 Pakistani adults, homozygous predicted loss-of-function mutations are estimated to knock out 1,317 genes. Some effects were obvious on a blood test, others were hidden until a specific challenge, such as absent PLA2G7 enzyme activity or a blunted post-meal triglyceride rise in APOC3 knockouts.

A genetic variant is not self-explanatory. Its meaning appears only when the gene is read next to the right blood test or challenge.

What happens if both copies of a gene are broken

Human genes usually come in two copies, one from each parent. A loss-of-function mutation can stop one copy from producing a working protein. If the other copy still works, the cell may produce enough protein. When both copies carry loss-of-function mutations, the gene is effectively knocked out. Predicted means the DNA sequence looks like it will break the protein, but someone still has to measure the actual biological effect.

In this study, consanguinity increased the chance of inheriting two broken copies. Relatives are more likely to carry the same rare broken copy, so their children have a higher chance of homozygosity. The team sequenced protein-coding regions from 10,503 adults in the Pakistan Risk of Myocardial Infarction Study, or PROMIS. They found 49,138 rare predicted loss-of-function variants with minor allele frequency below 1%. Those variants are estimated to knock out 1,317 genes, each in at least one person. Then they checked more than 200 biochemical and disease traits.

Why two broken copies are not always obvious

As a general biological principle, not a specific finding from this study: a missing gene product can be invisible for a long time. Some genes have backup pathways. Others only matter during a specific challenge, after a meal, during an infection, or with a second genetic hit. If the right test is not in the panel, the knockout looks like nothing. This study's measurements were broad but not infinite.

Also as a general principle, if a gene codes for an enzyme, a knockout can remove that enzyme activity. If it codes for a receptor or signalling protein, the effect may only appear when the pathway is stressed. That is why the same phrase, both copies broken, can mean nothing on a routine panel and a lot on a challenge test.

The common mistake is to read a predicted loss-of-function variant as a verdict. It is a hypothesis about protein function. The phenotype is the missing half.

What the effects looked like in real data

Several knockouts produced a clear signal in a blood test:

• PLA2G7 knockout meant absent soluble lipoprotein-associated phospholipase A2 activity, not just low activity.
• CYP2F1 knockout was associated with higher plasma interleukin-8, an inflammatory cytokine.
• TREH knockout was associated with lower apoB-containing lipoprotein subfractions.
• A3GALT2 or NRG4 knockouts were associated with markedly reduced plasma insulin C-peptide.
• SLC9A3R1 knockout was associated with changes in mediators of calcium and phosphate signalling.
• APOC3 knockouts were linked to a blunted triglyceride rise after an oral fat load.

Each of these only became meaningful because the study measured the relevant trait.

APOC3: why a challenge test matters

In the oral fat challenge, APOC3 homozygous predicted loss-of-function carriers had a markedly blunted rise in plasma triglycerides compared with family controls.

Compared with family members without the mutation, people with both APOC3 copies knocked out had a markedly blunted rise in plasma triglycerides after the fat load. That is a real gene effect. It is not a disease. It is a different response to food. Heterozygous APOC3 deficiency has been linked to coronary protection, but this paper reports only a marked blunting of the post-meal triglyceride rise in homozygous carriers compared with family controls.

A broken gene does not always mean a disease

No. Not every knockout showed a detectable effect on the traits measured in this study. That can mean the gene is genuinely redundant. It can also mean the right measurement has not been done yet. The effect may also be too small to detect in 10,503 people. A human knockout is a starting point for understanding the gene, not a diagnosis.

These participants were Pakistani adults from a study designed around cardiometabolic risk. High consanguinity made homozygous knockouts much more common than in most other populations. The findings do not transfer gene-for-gene to everyone. Some predicted loss-of-function variants may not always fully abolish protein function in every carrier. The trait list was broad but not infinite. Rare effects, childhood effects, or effects that need a different exposure may have been missed.

What to do with your own DNA

A DNA kit result often reports a single variant as defective. This study shows that no variant means anything until you know whether the second copy is also broken and what trait to measure. A useful next step is to check the gene, the second copy, and any relevant lab result together, rather than treating one reported variant as a diagnosis.