The consequences of how our immune system works ripple out through much of human biology – a surprising amount of who and what we are has been influenced by our never-ceasing struggle to survive disease. It’s the wonder of it all that’s most important, and the reason why I wrote this book. But there’s also the pragmatic issue of what our compatibility gene inheritance means to each of us in everyday life. Zoom in on a couple of particularly important examples – my wife and me. What diseases might we be more or less susceptible to? And, possibly even more important, according to the results from those smelly T-shirt experiments, just how compatible are we?
To find out, we each dribbled into small plastic tubes and sent them off for analysis. Before the answers came back, we had a couple of days to consider what the impact of the results might be. If our genes said that we are especially compatible, would that add to our relationship in any way? If the results come back that we are not ideally compatible, should I call a lawyer? Is love so blind that genes can be overlooked? Should we even find out about our compatibility genes, given that how long we have to live can be influenced by the versions we have? Our house became a waiting room. There was a sense that something intimate was about to be exposed.
Our spit arrived at Anthony Nolan – a UK charity that helps match transplantation donors and recipients. The tubes were bar-coded and shuffled down a series of robotic instruments that first isolated the DNA and then made copies of our compatibility genes. Small beads, each having a different short piece of DNA attached, are added to a solution containing our genes; beads with DNA just right to bind to one of our compatibility genes are picked out by a sensor, revealing which versions of these genes we have. This is how personal secrets are exposed in the twenty-first century.
So my wife, Katie, has the class I HLA genes A*02, A*03, B*07, B*27, Cw*01, Cw*07, and her class II genes are the variants classified as DRB1*01, DRB1*07, DRB4*01, DQA1*01, DQA1*02, DQB1*05 and DQB1*03. My own class I genes are those named A*30, A*68, B*44, B*13, Cw*06, Cw*05, while my class II genes are named DRB1*08, DRB1*11, DRB3*02, DQA1*04, DQA1*05, DQB1*03 and DQB1*04. A quick glance at the two lists by Steve Marsh – Deputy Director for Research at Anthony Nolan – reveals that I am very rare and my wife is rather common.
Immediately, it springs to mind that Wedekind’s T-shirt experiment indicated that women prefer the scent of dissimilar versions of compatibility genes. By that reckoning – if my genes are exceptionally rare – everyone would find me sexually attractive. Well, that’s a result I hadn’t expected. Why didn’t I know this when I was younger?
Trying to stay focused on the science – lost opportunities aside – I ask Marsh: just how rare am I? Marsh accesses an international database used for seeking transplant donors which lists the compatibility genes of 18 million people. Out of all these, there are just four like me. Four out of 18 million; I’m truly special (knew it). Even these four individuals – one in Germany and three in the US – may not be exactly like me. More precise analysis of the DNA would be done if we were really seeking a match for bone-marrow transplantation, because minor variations in compatibility genes weren’t included in the analysis. After Marsh tells me these results, he looks at me and says plainly: just don’t get ill. Any delusions of grandeur I had from thinking about my desirable scent are quashed by the realization that it’s not going to be easy if I ever really do need to find a transplant donor.
When I say that my wife is common, sure her genes are more common than mine – but out of the 18 million in the database, there are only 185 people with genes like hers. Not quite the one in a million I always thought she was, but one in 100,000. Marsh himself has a particularly common set of compatibility genes, but even his only match a couple of hundred people out of the 18 million. The commonest set of HLA genes in the UK still only occurs with a frequency of less than 0.5 per cent. What makes you so special? Your immune system.
Looking at the issue in another way, nearly 6 per cent of people are without any match. That is, out of the 18 million people in the international database, over one million are uniquely defined by their compatibility genes. This puts the issue of sexual attractiveness in perspective. Aside from the controversy surrounding the experiments using smelly T-shirts and the like, even if it’s true that women prefer the scent of men with compatibility genes dissimilar to their own, we’re all pretty different.
Dating agencies that test HLA types to find your perfect soul-mate use computer algorithms which take into account the extent to which one version of a gene differs from another – that is, they don’t just say A*02 is different from A*03, but they also assess how different these two variants are. But, overall, there’s no evidence that this will help something as complex as a successful marriage. Genes are important – a carrot seed will never produce a turnip – but they are not the be all and end all. It’s what you do with your genetic inheritance that counts. And my wife and I are compatible through shared experiences and magic.
As we discussed, there’s a geographical structure to HLA types, and so the versions of compatibility genes we have also tell us about our ancestry. Since sets of compatibility genes are often inherited together, it can be established which of our genes are likely to have come together from each of our parents. For example, it is likely that I inherited A*68, B*44 and DRB1*08 from one parent and A*30, B*13 and DRB1*11 from the other parent, as these sets of genes are often found together in people. We can then examine where these sets of genes are usually found in the world.
My wife’s HLA genes are found most frequently in Western Europe, consistent with her family being from that part of the world for as far back as we know. But something quite unexpected is the discovery that some of my wife’s HLA genes are those that were found in Neanderthal DNA. Put simply, it is highly likely that my wife’s ancestors bred with archaic humans. Nothing like that for me; I am so much more refined. And I look forward to discussing my wife’s Neanderthal inheritance with her family at our next Christmas lunch.
For me, it turns out that one group of my HLA genes, A*30, B*13 and DRB1*11, are frequently found in Europe, particularly Eastern Europe, while my other set, A*68, B*44 and DRB1*08, are common in India or Australia. This explains why my set of compatibility genes is so rare. It’s not that any of the individual genes are unusual, but the combination of them is rare because they are usually found in different parts of the world. The Eastern European versions of my genes are likely to come from my maternal grandfather, who was born in Poland. And I have indeed been told that my natural father was born in India. I haven’t seen my genetic father since I was a baby, because my parents divorced when I was very young. Before this moment, I had never considered that I have a genetic inheritance common in India. Something intimate has indeed been exposed.
Of course, these genes are best established as being important for our health. So what do our versions say about our own susceptibility or resistance to diseases? From the specific examples we’ve discussed, it is striking that my wife has inherited HLA-B*27; the version of HLA-B that would help if she ever suffered an infection with HIV but which also increases her susceptibility to the auto-immune disease ankylosing spondylitis. What does this mean practically? Nothing that’s immediately life-changing, because the risk of ankylosing spondylitis is still extremely small. But if she ever develops back pain, the fact that she has HLA-B*27 would come to mind, and we might benefit from an early diagnosis should this auto-immune disease ever really develop.
Overall, nobody has a better or worse set of compatibility genes: there’s no hierarchy in the system. The fact that we differ is what’s important; the way our species has evolved to survive disease requires us to be different. This knowledge is, for me, the greatest gift that contemporary biology has given to society.
Bill Clinton, campaigning to be US president in 1992, emphasized how a country’s finances underlie so much else: It’s the economy, stupid was his catchphrase. If there’s an analogous aspect of human physiology, a system of paramount importance which underpins a great deal of who and what we are, it’s the immune system, stupid. It’s our overarching system. We are each a fragment of a vast genetic tapestry forged from the way our species evolved to survive disease.