Issue 25 Understanding Science

Beneficial mutations – beating the genetic odds

🕒 3 min

In medical terms mutations are often viewed through a negative lens, as an occurrence that mostly leads to higher disease susceptibility or causes a disease itself. But what about mutations that protect us from infections or disable a gene that plays a role in chronic disease development?

Most popular examples of protective mutations have been discovered somewhat by accident in the past. One of them is sickle cell trait, the heterozygous form (HbAS) of a mutation that affects the beta-globin chain of hemoglobin where glutamine is replaced by valine at the sixth position of the chain. This replacement leads to an abnormal shape of red blood cells that are also brittle and have a reduced capacity to carry oxygen in homozygous (HbSS) individuals. Heterozygous individuals, however, almost never present with typical symptoms of sickle cell anaemia, but they are partially protected against severe malaria caused by Plasmodium falciparum infections. It is well known that sickle cell disease is more prevalent in sub-Saharan Africa where most malaria cases occur. The exact mechanism of protection has not yet been determined, but there are multiple proposed mechanisms and further research is underway to help us better understand this phenomenon. Studies have shown that individuals with HbAS have a 50 – 90% reduction in parasite density in comparison to people with normal haemoglobin, a faster clearance of asymptomatic infection was noticed in heterozygous individuals, as well as AS genotype being underrepresented among children with severe cases of malaria.

Plasmodium spp. life cycle in healthy (HbAA) individuals (source: Nature)

Another common example is a mutation found in Northern Europeans, in a gene called CCR-5. The CCR5 co-receptor plays an important role in HIV virus entering immune cells. This mutation, known as CCR5-delta 32, causes the CCR5 co-receptor on the outside of immune cells to develop smaller than usual. In this form it no longer sits on the cells surface, thus preventing HIV from entering. One per cent of Europeans are homozygous carriers of the mutation which makes them immune to HIV infection. Heterozygous carriers have a reduced chance of infection and AIDS progression is delayed in these individuals. However, there have been reports of homozygous carriers getting infected by HIV so caution is needed, but this finding certainly opened the door for new ways of HIV protection.

Timothy Ray Brown, more famously known as ‘the Berlin patient’, is the only person to have been cured of HIV and his doctor believes it was due to a bone marrow transplant from a person that had this mutation. While being HIV positive and taking his antiretroviral therapy, Timothy was diagnosed with non-HIV related acute myeloid leukaemia. He underwent chemotherapy and a bone marrow transplant after which he didn’t resume his antiretroviral therapy but the researchers only found traces of viral genetic material which cannot replicate in his blood. Scientists believe that this and two other factors, combined or independently, helped him get rid of HIV. One of the factors is conditioning – destroying a person’s immune system to prepare them for bone marrow transplant, and the other is graft versus host disease, meaning that his new immune system destroyed his old one that held the infected cells. This way of treating HIV is certainly too aggressive and expensive for mostly poverty struck populations that deal with the virus the most but could, coupled with further research, provide new insights in the fight against HIV epidemic.

HIV replication cycle (source: NIAID)

In recent years, some scientists have started to research genomes of people we can think of as abnormally healthy, such as elderly, overweight individuals who should by all means have diabetes type II, but actually don’t. This approach could lead to some interesting and relevant findings even though it currently faces a lot of problems. The main challenge is finding the beneficial mutations because healthier people tend to use healthcare systems less, therefore there is less data available to researchers. Moreover, existing genetic databases aren’t designed to detect a lack of an illness. Beneficial mutations are also harder to prove than the disease-causing ones. However, animal studies on Ebola virus, malaria and kuru did show some positive outcomes in the past and could be helpful in fighting these serious diseases in the future.

Overall, hunting down protective mutations and using them to design drugs and predict outcomes of clinical trials will take a lot of effort, a large pool of people and detailed data on their health status but the search could result in new and better approaches in treating serious conditions or even preventing them.

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