How does a point mutation come about

Gene mutations - how they cause hereditary diseases

Toxins in food, aggressive metabolic products and high-energy UV rays - all of these can change the DNA, the carrier of our genetic material. Cell division also harbors dangers: DNA replication is a complicated process and does not always go perfectly.

Inherited gene mutations cause more than 4000 diseases. These hereditary diseases are usually rare, as those affected often do not live long enough to be able to pass on the gene mutations. Few forms are treatable, although curative gene therapies have advanced in recent years.

Protection through hereditary diseases?

But some hereditary diseases are astonishingly common: In tropical Africa, one in 250 newborns gets sickle cell anemia. If left untreated, this means certain death, usually at a very young age - inheritance is virtually impossible.

Why did sickle cell anemia spread anyway? It is only fatal if the gene mutation is inherited from both parents. However, a single copy is a blessing: it protects against malaria, which kills nearly a million people every year7. Protection against malaria was evolutionarily more beneficial than the death of many children.

Just recently, researchers discovered another example: A gene variant common in Africa is one of the causes of a serious kidney disease8. But at the same time, the gene mutation helps to fight the pathogen that causes sleeping sickness. The following may apply to many hereditary diseases: for some they are a death sentence, but for others they save lives.

Classes of gene mutations

Depending on the type and extent of damage, mutations are divided into different classes: The most common point mutations, deletions, triplet expansions and copy number variations on.

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1. Point mutations

Replacing a single base in the DNA sequence - a point mutation - can have serious consequences. Sickle cell anemia is caused by a point mutation that changes the blood pigment hemoglobin: it loses its stability and tends to clump. The red blood cells deform into a sickle and are broken down prematurely - the result is anemia.

2. Deletions

Some diseases are based on the loss of gene areas (called deletion in technical terms). The lack of three bases in the gene sequence of a protein that transports chloride across the outer shell of the cells causes cystic fibrosis1. As one of the consequences, thick mucus builds up in the lungs, which encourages frequent and severe bacterial infections.

Hundreds of bases are missing from certain forms of muscular dystrophy2, an often fatal breakdown of muscle tissue. The length of the missing gene segments is variable, and a larger loss does not necessarily lead to a more severe course of the disease: the crucial question is whether the affected gene can maintain at least part of its function.

3. Triplet expansions

The multiplication of a short DNA sequence triggers Huntington's disease3 (Triplet expansion). A sequence of three bases is repeated in the huntingtin gene: 10 to 30 repetitions are normal, but beyond this the protein production is changed in such a way that unusual aggregates arise in nerve cells4. The brain is so badly damaged that it inevitably leads to death.

The more triplet repetitions there are, the earlier the disease can set in and the more severe the course. The disease also develops spontaneously: the father is still healthy, but the inherited gene has more than 35 repetitions for an unknown cause - as a result, the child develops Huntington's disease.

4. copy number variations

Whole sections of the genome can have different copy numbers (so-called copy number variations or CNVs5). Thousands or even millions of bases are missing or have multiplied. Many genes can be affected at the same time, and the regulation of genome sections that are actually intact is also impaired.

These CNVs are an important part of our genetic uniqueness: Two human genomes differ by an average of more than 1000 CNVs, which is almost 1% of the entire sequence6. CNVs have also recently been linked to diseases such as autism or schizophrenia.

1 Information page of the cystic fibrosis e.V. (Link)
2 Children's network, Duchenne muscular dystrophy (Link)
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Short and sweet

  • Point mutation - replacement of a single base
  • Deletion - loss of a single base or large areas of the gene
  • Triplet Expansion - Multiplication of a sequence from three DNA bases
  • CNV (copy number variation) - whole genes or larger genome sections are multiplied
  • some gene mutations can - if inherited from father and mother - trigger hereditary diseases, but otherwise protect against other diseases