Towards a More Perfect Genome

The human reference genome is still evolving and improving. 

The original human genome, when issued to great fanfare in 2000, was an incomplete draft, covering only 92% of the sequence. It caught the most important parts, surely- most of the protein-coding genes- but sequencing technology was not up to the task of doing a complete job. To understand why, imagine the genome as a jigsaw puzzle. The number of pieces corresponds to the sequencing technology- the number of consecutive nucleotides (nt) that can read from the genome at one go. The dominant technology then (and still now) is short read sequencing, which reads about 200 nt at a time, from a randomly sheared up pile of DNA from the genome. Perhaps 300 or 400 if lucky. This means that the 3 billion nucleotide genome is chunked into ~15 million pieces, and that our one-foot jigsaw puzzle has 4,000 pieces per side, each one about 0.08 mm on a side. That is very small. Imagine trying to put together a puzzle like that! Computers are helpful, but they can only do so much.

And like a really hard jigsaw puzzle, our genome has large areas of uniform color- those sky-blue regions and large clouds. Those are the repetitive sequences, which, all together, make up about half of the genome. These are mostly defunct transposons, but also pure repetitive DNA that makes up structural features like centromeres and telomeres. For instance, the sequence GAATGn (where "n" stands for any nucleotide), goes on repetitively for 28 million nucleotides on chromosome 9. That is not an easy puzzle to solve, using tiny sequence reads, no matter how much computer power you have.

A map of some of the repetitive areas of the genome, focusing on centromeres. Panel A gives a color code for different kinds of repetitive sequence. Panel C gives compositions of the centromere of each chromosome, which are highly variable and different in length as well. Centromeres are underlain by piles of genomic junk, really, with a few key functional sequences.

So the original project did what it could and released the draft, which was both a huge accomplishment and a large boon to biology ever since. This draft has been patched up several times with improvements. In 2022, finally, a complete genome emerged, which advertised itself as end-to-end, or "T2T", for telomere to telomere. This genome still has a gap on the Y chromosome, which is a degenerate mess. But otherwise, it fills in all gaps, brings in a hundred more protein-coding genes, two thousand other genes, and fixes innumerable other sequencing errors. What got us to this point?

The new technology was long-read sequencing, which is an amazing advance based on threading a single DNA molecule through a tiny pore (a nanopore, which is actually a bacterial protein). You can read the electrical resistance as each base passes through. Each base is ever-so-slightly different electrically, making it possible to figure out the sequence, step-by-step. These methods have been refined to the point that they can read 100,000 nucleotides routinely, and even attain four million nucleotides at a single go. That is revolutionary for closing difficult, repetitive genome gaps.

Reading sequence, sequentially, as it passes through a tiny pore.

This long-read nanopore sequencing also benefits from using relatively unprocessed, native molecules (not extensively amplified/copied) helps to reduce errors, though this method has its own error problems, mostly due to the fact that taking electrical readings off the pore is extremely sensitive and tricky. It is also hard to scale up, mostly due to the slow process of threading DNA through those pores, so long-read sequencing has not challenged the huge bulk sequencers for lowest-cost or greatest scale. But when you have to finish a sequence, one that is problematic, with low complexity, long-read sequencing is perfect. 

Lastly, what is all that junk DNA doing in our genomes? Mostly, it is honest-to-goodness junk, just carried along out of inertia and lack of selective attention (though there is the story of piRNAs). Transposons can occasionally re-activate and create new mutations, but there are way too many of them to get rid of. They also can gain significant functions, giving rise to new, functional genes and regulatory controls over other genes. So they are a sort of a junk heap / pick-n-pull that can be very useful from time to time. The satellite sequences in the image above are concentrated in structural areas like the centromere, where they do not have classical "gene" type functions, but facilitate equally important processes like genome division and distribution to new cells. 

Unfortunately, as we learned from the draft genome, it is not a holy grail full of secrets that will, of themselves, solve our medical mysteries and confer immortality. Its use is as an armature on which we can hang the accumulating knowledge of biology. Each nucleotide in the genome has its own story, of how it got there, what processes it plays in, and how it can affect our health and happiness. The system built upon the sequence is far more involved and interesting than just the sequence.

• More on taxes and inequality.
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Origins of The Trumpocene: Something in the Air?

I have a theory about our predicament.

How did we get here? With a madman as president, a cabinet of incompetants and sycophants, a supine legislature barely able to keep the lights on, and a dominant block of voters that see nothing wrong with it? This president has, for no discernable reason, decided to wage a trade war against basically the entire world, with special emphasis on our closest friend, Canada. This president launched an idiotic war against Iran that has destroyed our military and diplomatic status, and isn't doing much for our economy either. This president has launched vendettas against anyone with brains, such as colleges, medical researchers, military, diplomatic and intelligence professionals. And this president has made past corruption scandals look like penny ante with shameless shakedowns, pump-and-dumps, and quid-pro-quos reaching into the billions.

It's not good, and stands at the end of a political tradition with far higher accomplishments. We used to expect complete sentences, coherent thoughts, and reasoned policies. All that is now out the window. The civil war era and the revolutionary era were both characterized by excellent, sometimes great writing, lengthy and reasoned debates, and careful argument. Just think of the Federalist papers, the Lincoln-Douglas debates, and other works of Abraham Lincoln. Even into the end of the 20th century, we accomplished great things, and had elevated goals, such as fostering a world-leading research enterprise, and addressing poverty. 

Today, politics revolves around zingers and memes, and we can hardly hold things together while our madman in chief burns down one institution after another. But therein lies a clue- what is in the air? What is making us crazy? As we pass the September 11 anniversary, we recall, inter alia, the devastating effects of pollution around ground zero. Among its many health effects are cognitive impairment and dementia. There is a large literature on the cognitive impairments caused by particulate pollution, particularly in the young. That is a clue.

Long ago, someone had the bright idea to add lead to gasoline. Lead was already known as a neurological poison, but cars were king, and already exquisitely dangerous, so it hardly seemed significant to add an entirely different kind of risk to the fuel mix. Lead was never added to diesel fuel, as diesel is supposed to auto-combust from engine compression. But gasoline is supposed to, instead, be ignited by the spark plug, not compression. An "octane" rating was even devised to make higher-lead gasoline more attractive at the pump. 

Leaded gasoline proceeded to pollute our landscapes, increasingly as car use rose during the 20th century. Urban areas were particularly hard-hit, though agricultural areas can also be highly polluted. There is a well-supported theory connecting this pollution with rises in crime in the US, and later declines as lead was removed from gasoline and gradually the environment. The phaseout of lead was gradual, so if we take its peak in the mid-70's to 80's, then the generation exposed to the most lead in childhood would have been at prime criminal age in the mid-90's. That is one reason why crime has been dropping since that time. But prime criminal age is only one stage of life. Our political system is run by older adults, and the prime voting age is more like fifties and sixties. Thus a peak of criminality in the mid 90's due to the cognitive ravages of lead would correspond to a peak of political influence right about now. 

This is not to say that our president is suffering from lead poisoning. He has other, and far more serious issues with psychopathy and Hitler/Putin worship. (Though he is remarkably touchy about not being very bright.) But the political generation that elected him and forms his base- our political generation- may well be afflicted, explaining to some degree why our political environment is so degraded right now. We are not entirely up to scratch. 

But it isn't just about lead. Particulate pollution is pervasive, from all sorts of fossil fuel burning. We used to think nothing of cooking with natural gas, but it is a major source of indoor pollution. Coal burning spewed vast amounts of mercury, another neurotoxin, among many other pollutants. The bottom line is that the clean energy transition can not come soon enough, if not for our planet, then for our political sanity. 

• Alternative ruminations on origins.
• To Russia, with love.
• Truly bottom of the barrel.
• The Supreme Court may be afflicted as well.
• Our real strength.

Institutions of Truth

Society is built up around institutions, which come in several varieties.

We gather together to do more than we can possibly so alone, into families, tribes, and nations. As human capabilities increased through time, and our populations increased, ever-more diverse and specialized groups assembled to deal with the incredibly complex opportunities at the technological and social frontier. Putting astronauts on the moon required a vast organization with all sorts of skills, but especially technical skills. Such an institution runs on truth. Managers need to get truthful statements from the financial bean counters, the astronauts need to have confidence in the testing and engineering operations, the engineers need to count on the vendors and technicians for quality products and work. 

As a scientist, I often think of my own community as the epitome of truth-seeking and moral righteousness. But all human communities are truthful in their own way, though rarely so explicitly and doggedly. The legal system, for example, is predicated on a search for truth. Granted, it uses an adversarial system that relies on each side bending the truth to its interests, which is an ethic and practice that can easily get out of hand. Even politics is a sort of truth-finding system, not in its speechifying and rhetoric, but in gauging the feelings of an electorate- how it views its problems and who it thinks might solve them, assuming that voting is truly secret and civically engaged. It has been fascinating to see the lies of our current president, so meaningful to his base, functioning as permission to be their worst selves- racist, greedy, incontinent, misogynist, hateful, ignorant.

The news media is an explicitly truth-seeking and publishing enterprise, but can be compromised, both by its market incentives and by political pressures and interests. Markets and business are likewise truth-seeking, not in that they always tell the truth, but that they are predicated on finding a ground truth of what makes money- what is the most efficient and useful thing to be done at this moment. And connected with this is advertising, apparently one of the best ways to make money, and the financial foundation of the news media. Advertising is a curious phenomenon. Its practitioners are paid to tell lies, but only little lies, that skirt the boundaries of fraud. Their art is more typically to insinuate their lies rather than state them outright. That pretty women will flock to the owner of this watch or that car, or that betting at this casino will make you both handsome and rich. 

The arts dispense with explicit truths entirely, and tell human truths though imagined stories. The mark of great art is that it cuts to the heart of the human condition using all its artifice and archetypes. The Matrix is a great example of a wildly creative and frankly insane story that poses the central moral dilemma- can we take the truth, and can we- do we even want to- overcome pleasant illusions to get there?

At the bottom of it all is religion, which offers spiritual purpose and community, founded on pure fantasy. It used to be, in pagan times, that religions were not taken so literally and seriously. Each cult coexisted with the others, and none claimed to be more than an art of the archetypes whereby people could get in touch with a sense of binding social and philosophical purpose. A civic pleasure and ceremonial. But then came Christianity, child of the collision between Judaism and Egyptian and Greek philosophies. Christianity claimed a true historical story, even though it was fabricated more or less out of whole cloth. It claimed absolute truth, certain life after death, and salvation for something... apparently, the human condition was not good enough and had to be redeemed, by blood and death. It certainly was dramatic, but truth? Only on some campy (and masochistic) emotional level.

This institution has had incredibly pervasive effects on our view of truth, and it has taken hundreds of years to extricate ourselves from its presumptions and bizarre claims. Even now there is a rump movement of biblical literalists who are wreaking evil on our politics and society. All in the name of a hot mess of fabrications and primitive morals. We need to take a closer look at the role that truth plays in our day-to-day lives and society, in our moral lives and imaginations. 

• Progress on post-viral syndromes.