You are a unique combination of thousands of small changes in the human genome. Biologists call the specific DNA letters at a location in the genome a genotype. Where does your ACE2 genotype fit in the context of ACE2 genotypes for known human genomes?
Your rs2106809 genotype is AG
NOTE: we use the 1000 Genomes nomenclature for the broad population categories.
AFR = African SAS = South Asian, EAS = East Asian, EUR = European, AMR = Admixed American
Your Biology Snapshot explained the main effect of your particular genotype on your ACE2 gene and how your ACE2 genotype might affect coronavirus infection. If you want to get into details, follow us on a tour of the science behind your unique ACE2 genotype. The ACE2 acronym will be defined before this is all done! Let's draw a simple cartoon cell to set the stage. If you learned about control of protein expression from Your MTHFR Story and want to jump straight to ACE2's role in coronavirus infection, click here.
What is a gene? In the strict sense, a gene is a string of DNA letters that codes for an RNA molecule. DNA is famously known from crime shows and sci-fi movies as the three letter acronym for deoxyribonucleic acid. RNA is the less glamorous acronym for ribonucleic acid. Note the shared part of each molecule, nucleic acid. Nucleic acids are the information storage molecules of life on Earth. Nucleic acids are long strings of individual nucleotides hooked together. DNA is the stable long term information storage molecule that is passed from parent cells to daughter cells. RNA is a relatively unstable nucleic acid that participates in information transfer and even biochemical reactions. For our purposes, we will focus on RNA's role in information transfer in cells with a nucleus. Remember: a gene is a string of DNA letters that spell an RNA molecule!
rs2106809 is a commonly studied location in the human ACE2 gene. What are these peculiar "rs" numbers? Biologists studying genetic variations in human populations all agreed to name locations in the genome by reference SNP IDentification numbers, or rsIDs. SNP is the fancy biologist acronym for Single Nucleotide Polymorphism. Polymorphism means "many forms" and, in this case, refers to places in the genome where the nucleotide spelling is different across individuals.
How scientists discovered this place in the ACE2 gene will be covered in a future update to this Story. For now, it's enough to know that changes in the DNA letters at this position have consequences for the spelling of the RNA made from the ACE2 gene. Even more importantly for you, is the nucleotide letters you inherited at this position from your parents. You can inherit two alleles, or slightly different copies of the same gene. For the purposes of explaining ACE2, alleles are different DNA nucleotide letters at the same rsID location. Humans inherit one allele from each parent. The actual allele combination you inherited is also known as your genotype. Some genes, like ACE2, are on the X chromosome. For chromosomal males, genes on the X chromosome are hemizygous, they have one copy. Chromsomal females are functionally hemizygous, they have two copies but one is turned off (usually). GenEd doesn't need to know your chromosomal sex, we cover both in our materials. According to the data you uploaded, you inherited "AG" at rs2106809. The importance of your inherited genotype will make more sense as we continue the tour of ACE2 biology . . .
It took biologists a while to figure out why our genes are organized in this interrupted pattern of expressing regions ("exons") and intervening regions ("introns"). Exons are the part of the gene translated into protein language of amino acids. Our cells use a process called splicing to choose exons that are appropriate for the same protein in different developmental stages or tissues. This allows a single gene to code for multiple varieties of the same protein and turn those variants on and off at the right time! The alleles you inherited from your parents at this position are copied into exon RNA that will be translated into ACE2 protein.
Biologists are still working hard to figure out the details of how the mRNA moves from the nucleus to the cytoplasm. Note that your unique spelling at rs2106809 is now two levels away from the original DNA storage in the nucleus. Here, in the cytoplasm, the ACE2 mRNA is bound by the ribosome. The ribososome reads the genetic code of nucleotide letters into the protein language of amino acid letters. Biologists call this process translation.
The ACE2 protein, Angiotensin Converting Enzyme 2, is a membrane exopeptidase. This is a lot to unpack, so let's take it one letter and one word at a time. Angiotensin I is a peptide produced by activity of the Renin-Angiotensis System (RAS). The RAS will be covered in greater detail in a future story, we promise. What's a peptide? Peptides are messenger molecules bigger than amino acids, but smaller than full blown proteins. The original ACE, ACE1, converts inactive Angiotensin I (Ang-I) to active Angiotensin II (Ang-II) by cutting off two amino acids at the very end of Angiotensin I. Think about this for a second. Cells in one part of the body can make an inactive form of a peptide, it can circulate in the body to where it is needed, and then ACE1 can cleave it to the active form. Active forms are great, but you wouldn't want too much Ang-II. Active Ang-II is a vasoconstrictor. Too much Ang-II? This is one of the causes of hypertension, or high blood pressure. What turns off Ang-II? ACE2!! ACE2, enmeshed in the membrane of Ang-II target cells, uses its exopeptidase activity to cleave off one more amino acid from Ang-II, deactivating its ability to tighten up blood vessels. An exopeptidase is an enzyme that cuts amino acids off of peptides or proteins from the ends of the target peptide or protein. Endopeptidases are the opposite: they cut amino acids in the middle of peptides or proteins. Put this all together, and you can see that ACE1 and ACE2 are partners in regulating blood pressure. We'll see lots of this yin-yang type of regulation, homeostasis, as we learn about more complicated gene networks here at GenEd.
Because it plays such an important role in maintaing blood pressure homeostasis, ACE2 is considered highly conserved. This means that ACE2 has been maintained throughout evolutionary history. We were not the first living things to notice ACE2's importance. Some viruses, like the coronaviruses SARS and 2019-nCoV, capitalize on the importance of ACE2 by using it to gain entry to the interior of their target cells, pneumocytes. The coronavirus Spike, or S, protein evolved to "hook" ACE2 and begin the process of fusing the viral membrane with the lung cell's membrane. Scientific studies show that ACE2-dependent coronaviruses infect pneumocytes best when they are in the part of their life cycle with the most ACE2 protein at the pneumocyte membrane.
Because you inherited 'AG' at rs2106809, and because these letters were spliced into your particular ACE2 mRNA, carried to the ribosome, and turned into ACE2 protein, your cells have increased expression of ACE2 protein relative to cells of people with AA at rs2106809. While epidemiology studies disagree on the importance of individual SNPs in ACE2 to coronavirus infection, we believe it is important for people to have this kind of information so they can read the current literature and decide for themselves. See where your particular genotype fits in the population statistics in the Context section above.
- Depending on their reading of the literature about ACE2 and your ACE2 status, your healthcare provider may say one of three things:
- 1) Your provider may say that ACE2 has nothing to do with coronavirus infection and you should follow CDC guidelines.
- 2) Your provider may say that not enough is known about the individual risk of coronavirus infection on the basis of ACE2 genotype.
- 3) Your provider may work with you to plan ahead for any increased risk of ACE2-dependent coronavirus exposure.
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