APOBEC3 Family of Genes

Throughout human history, we have constantly battled invisible pathogenic foes. Humans have sophisticated, built-in systems for fighting off viruses — this is how we have survived as a species.

One of the enzyme families involved in responding to viruses is called APOBEC3. It has a unique way of stopping viruses from replicating. Essentially, it causes mutations in the viral DNA, rendering the virus inactive. Once in a while, though, the mutations can increase the virulence of a virus.

What is APOBEC3?

Apolipoprotein B Editing Complex (APOBEC3) is a family of enzymes called cytidine deaminases, which play an important role in responding to viral infections.

The APOBEC3G gene encodes an enzyme that is a part of the innate defense mechanism against retroviral infections as well as a few other types of viruses.

Retroviruses insert their viral RNA into the genome of the host cell’s DNA to be transcribed. While typical viruses use the host’s cellular mechanisms to convert viral RNA into proteins, retroviruses do things differently and use reverse transcriptase to produce DNA from the viral RNA. That DNA is then incorporated into the host cell’s genome. (While this sounds pretty wild, we actually have a lot of old viral DNA in our human genome.)

Once the retrovirus is incorporated into the host cell’s nuclear DNA, the virus proteins can be transcribed and translated, just like our regular genes are transcribed and translated. The viral proteins then can assemble new copies of the virus.

Retroviruses include HIV, but HIV has evolved the Viral infectivity factor protein (Vif), which counteracts the effects of APOBEC3G.

APOBEC3G is also part of the defense mechanism against poxviruses such as monkeypox virus and other DNA viruses that utilize reverse transcription.

Human T-lymphotropic virus, herpes simplex 1, RSV, mumps, HPV, measles, and Epstein-Barr virus are also acted upon by members of the APOBEC3 family.[ref][ref][ref]

The APOBEC3 family of proteins also inhibits coronavirus infections, although the mechanism of action there is not yet determined.[ref] Some researchers think that APOBEC3-driven mutations are causing most of the variation in the SARS-CoV-2 virus.[ref]

What does APOBEC3 do?

APOBEC3G interferes with reverse transcriptase by causing mutations in the creation of the viral DNA. Specifically, it causes mutations converting G (guanine) to A (adenine) in the viral DNA. The mutations then may cause the virus to not function or not replicate well.[ref]

While the mutations in the viral DNA caused by APOBEC3G can cause the virus no longer to be infectious, it can also sometimes cause mutations that still allow the virus to function, just differently than before. In other words, APOBEC3G can cause variants in a virus.

Overall, researchers found that approximately 22% of human viral species are shaped by APOBEC3-causing mutations that result in positive evolutionary pressure in the virus.[ref]

In addition to causing hypermutations in retroviruses, researchers think that APOBEC3G also inhibits viral replication by other means. Cell studies show that APOBEC3G can inhibit infection by parvoviruses without hypermutating their genomes.[ref]

Interferon is one of the first innate immune system signals produced in a viral infection. APOBEC3G is upregulated in response to interferon. It is also produced in T cells, B cells, and macrophages, and B cells can release it in exosomes.[ref]

APOBEC3 in cancer:

HPV (human papillomavirus) is the primary cause of cervical cancer. While most HPV infections are harmless and clear up spontaneously, persistent HPV infections can lead to cancer in certain circumstances. Recently, researchers discovered that women with cervical cancer had higher levels of APOBEC3G than women who had HPV without getting cancer.[ref]

Researchers think that APOBEC3s are causing mutations in cancer cells by wrongly targeting the cell genome in cancers initiated by viruses. One study explains: “For example, high-risk papillomaviruses, whose viral genomes carry an APOBEC3 footprint, indirectly promote cell transformation due to the sustained APOBEC3 mutagenic activity.”[ref]


Genetic variants in APOBEC3:

Researchers have found that the APOBEC3 family of genes has diverse variants in population groups worldwide. It may be because specific variants have been selected by combating viruses that are endemic in certain parts of the world.[ref]

Unfortunately, only a few of these variants are covered by 23andme or AncestryDNA data.

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APOBEC3G gene: encodes the APOBEC3G enzyme, which targets retroviruses and causes mutations in the virus.

Check your genetic data for rs8177832 (23andMe v4, v5):

  • A/A: typical
  • A/G: higher APOBEC3; decreased HIV-1 risk; decreased risk of chronic hepatitis B
  • G/G: higher APOBEC3; decreased HIV-1 risk[ref][ref]; decreased risk of chronic hepatitis B[ref]

Members: Your genotype for rs8177832 is .

APOBEC3F gene: encodes the APOBEC3F enzyme, which also targets retroviruses and causes mutations in the virus.

Check your genetic data for rs2076101 (23andMe v4, v5):

  • A/A: typical HIV response
  • A/G: lower viral load in HIV with slower progression to AIDS
  • G/G: lower viral load in HIV with slower progression to AIDS[ref]

Members: Your genotype for rs2076101 is .

APOBEC3A gene: encodes the APOBEC3A enzyme, which edits RNA in viruses and host cells. One edited RNA is succinate dehydrogenase B (SDHB) which is involved in mitochondrial energy production and oxygen sensing. Mutations in SDHB are linked to a couple of types of cancer.[ref]

Check your genetic data for rs12628403 (23andMe v5):

  • C/C: increased relative risk of breast cancer in some populations[ref][ref][ref]
  • A/C: increased relative risk of breast cancer in some populations
  • A/A: typical

Members: Your genotype for rs12628403 is .

 


Lifehacks:

Stating the obvious:
Go to the doctor if you think you have a virus such as HIV or monkeypox.

Inhibiting cancer:
Sulforaphane inhibits APOBEC3G. Researchers think this could be of benefit to pancreatic cancer.[ref]

Boosting viral protection:
APOBEC3 proteins depend on zinc as a cofactor.[ref] This may be one more way that zinc is vital in fighting off viruses.

Related article: Zinc and Your Genes


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VMAT2 gene: The God Gene and Neurotransmitters
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Genetic susceptibility to viruses
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Genetics, Chronic Fatigue Syndrome, and Long Covid
Take a look into the science of the lingering effects of viruses, including chronic fatigue syndrome and long-haul viruses.

References:

An, Ping, et al. “Role of APOBEC3F Gene Variation in HIV-1 Disease Progression and Pneumocystis Pneumonia.” PLoS Genetics, vol. 12, no. 3, Mar. 2016, p. e1005921. PubMed, https://doi.org/10.1371/journal.pgen.1005921.

Bogdanova, Natalia, et al. “Hereditary Breast Cancer: Ever More Pieces to the Polygenic Puzzle.” Hereditary Cancer in Clinical Practice, vol. 11, no. 1, Sept. 2013, p. 12. PubMed Central, https://doi.org/10.1186/1897-4287-11-12.

Chen, Zhishan, et al. “Integrative Genomic Analyses of APOBEC-Mutational Signature, Expression and Germline Deletion of APOBEC3 Genes, and Immunogenicity in Multiple Cancer Types.” BMC Medical Genomics, vol. 12, Sept. 2019, p. 131. PubMed Central, https://doi.org/10.1186/s12920-019-0579-3.

Compaore, Tegwinde Rebeca, et al. “APOBEC3G Variants and Protection against HIV-1 Infection in Burkina Faso.” PloS One, vol. 11, no. 1, 2016, p. e0146386. PubMed, https://doi.org/10.1371/journal.pone.0146386.

He, Xiu-Ting, et al. “Association between Polymorphisms of the APOBEC3G Gene and Chronic Hepatitis B Viral Infection and Hepatitis B Virus-Related Hepatocellular Carcinoma.” World Journal of Gastroenterology, vol. 23, no. 2, Jan. 2017, pp. 232–41. PubMed, https://doi.org/10.3748/wjg.v23.i2.232.

Iqbal, Khurshid, et al. “Correlation of Apolipoprotein B MRNA-Editing Enzyme, Catalytic Polypeptide-like 3G Genetic Variant Rs8177832 with HIV-1 Predisposition in Pakistani Population.” Current HIV Research, vol. 16, no. 4, July 2018, pp. 297–301. PubMed Central, https://doi.org/10.2174/1570162X16666181018155827.

Luo, Yiqiao, et al. “Sulforaphane Inhibits the Expression of Long Noncoding RNA H19 and Its Target APOBEC3G and Thereby Pancreatic Cancer Progression.” Cancers, vol. 13, no. 4, Feb. 2021, p. 827. PubMed Central, https://doi.org/10.3390/cancers13040827.

Mourier, Tobias, et al. “Host-Directed Editing of the SARS-CoV-2 Genome.” Biochemical and Biophysical Research Communications, vol. 538, Jan. 2021, pp. 35–39. PubMed Central, https://doi.org/10.1016/j.bbrc.2020.10.092.

Park, Charny, et al. “Integrative Molecular Profiling Identifies a Novel Cluster of Estrogen Receptor-Positive Breast Cancer in Very Young Women.” Cancer Science, vol. 110, no. 5, May 2019, pp. 1760–70. PubMed, https://doi.org/10.1111/cas.13982.

Poulain, Florian, et al. “Footprint of the Host Restriction Factors APOBEC3 on the Genome of Human Viruses.” PLOS Pathogens, vol. 16, no. 8, Aug. 2020, p. e1008718. PLoS Journals, https://doi.org/10.1371/journal.ppat.1008718.

Sadeghpour, Shiva, et al. “Human APOBEC3 Variations and Viral Infection.” Viruses, vol. 13, no. 7, July 2021, p. 1366. PubMed Central, https://doi.org/10.3390/v13071366.

Sadler, Holly A., et al. “APOBEC3G Contributes to HIV-1 Variation through Sublethal Mutagenesis.” Journal of Virology, vol. 84, no. 14, July 2010, pp. 7396–404. PubMed Central, https://doi.org/10.1128/JVI.00056-10.

Sharma, Shraddha, et al. “APOBEC3A Cytidine Deaminase Induces RNA Editing in Monocytes and Macrophages.” Nature Communications, vol. 6, Apr. 2015, p. 6881. PubMed Central, https://doi.org/10.1038/ncomms7881.

Stavrou, Spyridon, and Susan R. Ross. “APOBEC3 Proteins in Viral Immunity.” Journal of Immunology (Baltimore, Md. : 1950), vol. 195, no. 10, Nov. 2015, pp. 4565–70. PubMed Central, https://doi.org/10.4049/jimmunol.1501504.

Sui, Shuang, et al. “Correlation of APOBEC3G Polymorphism with Human Papillomavirus (HPV) Persistent Infection and Progression of Cervical Lesions.” Medical Science Monitor : International Medical Journal of Experimental and Clinical Research, vol. 25, Sept. 2019, pp. 6990–97. PubMed Central, https://doi.org/10.12659/MSM.916142.


About the Author:
Debbie Moon is the founder of Genetic Lifehacks. Fascinated by the connections between genes, diet, and health, her goal is to help you understand how to apply genetics to your diet and lifestyle decisions. Debbie has a BS in engineering and an MSc in biological sciences from Clemson University. Debbie combines an engineering mindset with a biological systems approach to help you understand how genetic differences impact your optimal health.