11 May 2020
Back to basics: it’s all in the DNA…sort of
Written by Nobel Laureate Professor Peter Doherty
Maybe you’ve paid $100 or more, ordered a kit, taken a mouth-swab, dropped that into the clear liquid in the tube provided, sealed it up and mailed it back to Ancestry DNA, LivingDNA, MyHeritageDNA, 23and Me, or one of the other commercial operations that analyse human genomes. Using strategies that depend on robotics and high-tech equipment, these “ancestral DNA” companies look at a million or so “sequencing snapshots” of the three billion base pairs aligned along the 23 chromosomes of the human genome.
They also check the mitochondrial DNA we inherit from our mother. Dad provides the sperm DNA that fertilises the maternal oocyte, while the baby gets an equal contribution of Mum’s genes plus a bit extra carried in the oocyte’s mitochondrial “energy machine.” Via that mechanism, all of us can be traced back to “mitochondrial Eve”, who lived about 200,000 years ago.
Comparing your genetic information with the massive data bases available, these commercial “gene detectives” might have told you that your ancestors likely included someone from the South of France, India the “new world” of the Americas, or some other unexpected location. Perhaps your spirits were lifted by this discovery that you are more mysterious than you thought! When I got my results back, the data put me firmly in the most predictable of all Caucasian/Australian groups, Anglo/Irish. Still, both lineages could have included some berserking and pillaging Viking, which raises the possibility of some drama way back in time, but also increases the likelihood of my developing Dupuytren's contracture!
So, three billion base pairs: what’s that about? Back in the 1950’s, Jim Watson and Francis Crick (played by Jeff Goldblum and Tim Piggot Smith in the BBC movie The Race for the Double Helix) built a model from rods, bits of wire, cardboard cut-outs and other lab stuff available at Cambridge University’s Cavendish Laboratory that showed how our genetic code is organised as a double helix of two complementary DNA strands. Before that, we’d known a lot about the genetics of inheritance, but had no understanding of the underlying chemistry.
The backbone of the real DNA (deoxyribose nucleic acid) double helix “twisted staircase” is made of sugar (D, deoxyribose) and phosphate, while the paired nitrogen bases of very simple molecules, the nucleotides, adenosine and thymine, guanine and cytosine (A-T, G-C) pair make up the nucleic acid (NA) polymer that defines the biological basis of who we are. These sequences of different A-T, G-C base pairs are what researchers in the area of human genomics read out in full, and the ancestral DNA companies “interrogate” in part.
Back to COVID-19: thinking in terms of genomics, we could regard what happens to us as a set of complex interactions between the genes, proteins and so forth encoded by our 3,000,000,000 base pairs versus the 30,000 of the SARS-CoV-2 virus. If, as I discussed last week, our pathogen was Corynebacterium diptheriae, we’d be up against 2,500,000 invading base pairs. What we share with bacteria is that our genetic material is encoded as DNA. That’s also the case for some of the viruses, like the adenoviruses and poxviruses we’ve mentioned previously, but it’s not true for HIV, the influenza viruses or the coronaviruses.
These are all RNA (ribose nucleic acid) viruses, which means that thymine (T) is replaced by uracil (U). The RNA base pairing is thus A-U, G-C. The 30,000 base pair SARS-CoV-2 is big for an RNA virus, with HIV being 9,200 and flu 13,500. All these tiny viruses can, of course, kill us. How do they do that? Answers re COVID-19 will emerge as we compare the genomes of people who lived or died following infection, though that analysis may wait until we’ve dealt with the pandemic.
Viruses are not as simple as they seem. No virus can grow or move independently. It has to invade then multiply in living cells. The pathogenic SARS-CoV-2 RNA virus takes over and uses DNA-directed machinery in the cells of our respiratory epithelium. As SARS-CoV-2 infects and turns more and more of our lung cells into virus-producing factories, it sources the necessary energy via our mitochondria. To transmit, SARS-CoV-2 depends on us coughing and spluttering while walking about. Just think how many human gene products in our eyes, nerves, brains, muscles and so forth are being exploited by the virus to ensure its continued propagation, and thus survival. Why does it kill us? That’s a whole other story!
And, of course, as we follow, and seek to understand, the COVID-19 pandemic we will be tracking mutations, the addition or loss of nucleotide bases in the SARS-CoV-2 genome, as we progressively sequence new virus isolates. That will tell us a lot about how SARS-CoV-2 is moving through our population, and alert us to any potentially problematic changes as we push on to develop specific vaccines and drugs. So, that’s just a few basics of bases. There’s a way to go as we move forward to dissect the complexities of the disease we call COVID-19.