Did We Fail to Crack the Human Genome Code?

The Human Genome Project successfully sequenced our DNA, but did it truly decode the genome? We’ve struggled to grasp its full complexity—especially when it comes to non-coding regions, DNA structures, epigenetic marks, and 3D genome organization. These layers challenge our early assumptions and call for a much deeper understanding beyond just the sequence.

It’s been over two decades since we celebrated the completion of the Human Genome Project. But the question remains—did we really achieve what we set out to do? The simple answer is: yes, we did complete the sequencing. But did we truly crack the genome code? The answer is probably no.

Why did we decide to sequence the entire genome, especially when the cost of the initial sequencing was roughly eight times higher than that of the Apollo 11 program, which successfully put a human on the moon? The answer lies in one word: cancer. By the 1980s, it was widely accepted that cancer was caused by mutations in genes, which could lead to the up- or down-regulation of gene expression. The idea was simple—identify the mutated part of the genome, reverse the change, and voilà! Cancer would be cured.

So if we managed to read all the bases and assemble the entire genome, where did we go wrong? The problem wasn’t with the sequencing itself, but rather with how simplistically we thought about the genome. We assumed that once we had the full sequence, we would be able to pinpoint the mutations and understand which proteins were dysfunctional. However, it is now well established that only about 2–3% of our genome consists of protein-coding genes. The remaining 97–98% is non-coding—often referred to as “junk DNA.” So what happens when we find a mutation in the so-called junk DNA? The short answer: we tend to dismiss it.

Another major issue lies in how we read the genome sequence. We all know the genome is composed of just four letters: A, T, G, and C. When we sequence DNA, we’re essentially reading what comes after each letter—T, G, C, or maybe another A. Yes, we can assemble the 3.1 billion letters, but does that mean we understand the genome’s complexity? Absolutely not.

Let me illustrate this with a simple analogy. If I show you a paragraph (see below) in an image that lacks proper spacing and punctuation, would you be able to read it easily? Now compare that to reading a well-formatted paragraph below it. What’s the difference? The second one has words forming sentences, spaces separating those words, and common punctuation marks—like periods, commas, question marks, and quotation marks—that help us make sense of the text. So, where are the punctuation marks in our genome? If they exist, where are they—and why aren’t we reading them?

This is a paragraph taken from one of my favourite book 'The Old Man and the Sea'

In fact, the genome does have punctuation-like elements. Structures such as cruciform DNA, Z-DNA, R-loops, and supercoiled DNA all contribute to how a cell reads and interprets genetic information. Then there’s the epigenetic landscape, which acts like a highlighter, marking important regions of the genome that deserve special attention.

So, if we map all the alternative DNA structures, identify the supercoiling context of each region, and catalog all the epigenetic marks—will we finally understand the genome? Probably not. Because on top of all that, we also have to consider the three-dimensional architecture of the genome—how DNA is folded and organized in 3D space.

Make no mistake, sequencing the genome was a monumental achievement—arguably the greatest in modern biology. Without it, we’d still be doing research in the dark ages. We are all deeply grateful for that progress. But just because we can sequence and read the genome's letters doesn’t mean we understand the language of the genome. There’s still a long journey ahead.