Preface to Genomic Quirks

Imagine a physician trying to diagnose a patient’s condition. The patient’s symptoms appear mysterious, leaving the doctor stumped and the patient helpless. How can the doctor dig deeper to obtain a diagnosis?

Doctors use various tools to dig deeper. They use X-rays, MRI scans, CT scans and ultrasound scans to view our internal organs. They even view individual cells from these organs under a microscope by drawing a few drops of body fluid or by conducting surgical biopsies. But none of these helps when the cause of disease lurks deeper—at a molecular level.

In and around each of our tens of trillions of cells are a large number of molecules. Reactions between these molecules keep us going. Not surprisingly, some of our health problems are consequences of these molecules not behaving as we expect them to. However, probing these molecules for abnormal behavior is not easy for two simple reasons: they are really tiny, and they are way too many in number.

In this soup of molecules, the pride of place is occupied by the Genome. Let us spend a few minutes on the genome before we return to the plight of our doctor and his/her patient. The genome is our parents’ gift to us. Many other molecules in our body are derived from the genome in an indirect way, making it the master molecule. As a molecule (or actually a collection of molecules), it has its own distinctive form and function. Nevertheless, in our simple-minded view, it is just a book of characters—six billion characters that allow us to resemble our parents among a vast array of other functions.

The specific characters in your genomic book may be different from those in mine. And therein lies a fundamental question. What do these six billion characters tell us about ourselves? Can they predict the future trajectory of our health? Can they predict if we will grow up to be good athletes, scientists or orators? The answer is less dramatic than we might hope. For instance, identical twins are born with supposedly identical genomes. Yet, one twin may develop autism, schizophrenia, diabetes or cancer while the other does not. This serves as a reminder that genomic characters are not the sole determiners of our fate. Rather, they act in concert with various environmental factors and with sheer random chance. Even when they act by themselves, they tend to do so collectively in large groups, making it hard for us to predict their combined effect. For instance, the height of an individual is probably determined by hundreds if not thousands of genomic characters working in concert.

Yet, there are a few quirky characters which drive home their agenda almost single-handedly. A few actually means a few hundred thousand, but nevertheless a small fraction of the entire pool of six billion characters. Typographical errors in such characters, though rare, can have a dramatic effect. Indeed, the root cause of our patient’s illness may well lie in such an error. How can our doctor ever pinpoint this error in the midst of six billion characters?

For that, we have some remarkable technological advancements in recent years to thank. These make it possible for us to read the tiny genomic book of our patient, at modest costs. Indeed, even five years ago, this wouldn’t have been possible, and this book couldn’t have been written.

Returning to the plight of our doctor and her patient: today, the doctor can simply order a genome sequencing test if the suspected cause of illness is an abnormal genomic character. A request for this test, accompanied by some saliva or blood or biopsy tissue from the patient, arrives at a specialized genomics laboratory, such as the one at Strand Life Sciences. A few days later, the doctor receives a report from the laboratory describing any abnormal genomic characters found. Simple, isn’t it?

Well, what happens in the interim is anything but simple. A very elaborate quest for the offending character is conducted in the laboratory. Since requests from hundreds of patients might arrive at any given point, several such quests are run simultaneously. The complexity and gravity of these quests then makes the laboratory seem very much like a war room. In this genomics war room, molecular biologists in lab coats, or their robot equivalents, scurry around transferring samples from one receptacle to another. In this process, genomic molecules are extracted from the patient’s sample, chopped into small fragments, and subjected to a multitude of manipulations. Eventually, the genome sequence comes out, but rather indirectly—in the form of millions to billions of tiny fragment sequences that amount to gigabytes of data. High-performance computers then piece these fragments back together, like a jigsaw puzzle. A comparison between this assembled jigsaw and that for a normal person yields a long list of variants, i.e., characters that are likely suspects. Computers then scour vast amounts of biomedical literature for information that helps zoom into the most relevant of these suspects, typically a handful in number. Finally, trained geneticists rack their brains to identify the ones that hold a clue to the patient’s condition. If all goes well, one or two clear candidates emerge and are reported back to the doctor. But things don’t always go well.

Many parts of the genomic jigsaw puzzle look very similar, forcing bioinformaticians to strain and spot subtle differences in order to make progress. Variants about which very little is known are found sometimes, forcing geneticists to go out on a limb and make educated guesses to establish culpability. No variants of note are found sometimes, leaving everyone scratching their heads and prompting a relook at the gigabytes of data at hand. Some variants are hidden more subtly under these mounds of data and need new algorithms to uncover. Inconsistencies on account of noisy data arise occasionally and have to be reconciled. Anxious doctors and patients call in the meantime enquiring for results. These results sometimes call for difficult decisions to be made. All in all, a recipe for frequent huddles, frustrating roadblocks, and ecstatic aha moments.

The nine stories in this book provide glimpses into this genomics war room. Each story deals with a distinct patient suffering from a distinct illness, the root cause of which lies in a distinct genomic quirk and often requires a distinct algorithm to unravel.

The first story is my personal one and deals with a relatively minor quirk of vision—color blindness. Serious illness is never a pleasant topic to discuss, hence the decision to use this relatively minor condition to provide a friendly introduction to the genome before we encounter graver conditions in subsequent stories. Tracking down the cause of my color blindness takes us through the science of color perception and the vagaries of some cut-and-paste events that happen to the genome as it passes down the generations from parents to children.

The second story deals with a family in which several members face loss of central vision in their 30s and 40s. Why are some members of the family affected but not the others? Our detective quest takes us through the mechanics of how our eyes respond to light and some

rather unexpected side effects of this process.

The setting of the third story moves from the eye to the heart. Here, we are confronted with siblings who suffer heart failure in their 30s. Why does this happen so uncharacteristically early in life? Are the other siblings also at risk? Our search takes us on a tour of the various factors that support the heart’s tireless, rhythmic beats: electrical impulses, powerful muscle contractions, and the adhesive structures that hold things firmly in place in the midst of all this energetic movement. In pinning down the root cause, we are confronted with our first taste of genomic uncertainty. How confident are we that our answer is correct?

The challenge of genomic uncertainty is taken to its peak in the fourth story—distraught parents whose two children have passed away of mysterious causes when they were just a year old. Our detective mystery finds itself in uncharted genomic territory as it tackles a character which has never previously been observed. Is this indeed the character responsible for the tragic fate of the two children? While we are still debating this fact, the stakes on the answer are raised considerably because the couple is now expecting their next child. Would this child encounter the same fate?

The fifth story presents a most curious phenomenon—children whose organs are out of place. Our detective quest, after some false starts, hits a real conundrum: the children’s genomes appear not to have been inherited from their parents as they should be. How could this happen? Much head-scratching then offers a solution: a rare genomic event that lies concealed under mounds of data.

The sixth story involves a patient whose hemoglobin (the red pigment in our blood) cannot carry and deliver the regular quota of oxygen to various parts of the body. This relatively well-known

condition is expected to be a cakewalk for our detectives. Yet, our search draws a blank. This prompts some deeper digging, eventually uncovering the genomic cause where it was least expected, and exposing us to some fascinating genomic jumps in the process.

The seventh story switches gears to cancer. Typically, cancer is a disease of age. One in two or three persons will be diagnosed with cancer at some point in life, more likely in their later years. In contrast, the cancer patient in this story is barely a few years old. How does cancer strike so early? The quest for the genomic cause again draws a blank. Some huddles then suggest a new line of attack. And out pops the answer, but not before it leads us through the delicate balance between division, differentiation, and death that tips a normal cell over to a cancer cell.

The eighth story reminds us that the genome in our cells is constantly under attack, and constantly being defended. The patient in this case has a compromised defense, which leads to both immediate challenges as well as an increased future risk of cancer. The only suspect in our hunt appears to have a strong alibi though. More dogged investigation then breaks this alibi and provides a glimpse into some intricate genomic surgeries that happen in nature.

The final story presents a middle-aged cancer patient and a fundamentally different detective quest. Doctors try many different treatments for the cancer. Each time it bounces back. The goal of the detective quest is to determine the next step in this game of moves and countermoves. Will it succeed?

These are but a few among several stories that have come our way. All are real stories, of real patients whose lives have (often) been impacted gravely due to the genomic quirks described in these stories. These stories only touch upon but do not dwell upon this grave impact; the greater focus remains on the genome and on the detective quest for the genomic cause. Regardless, the gravity of impact is always acting as the backdrop and any attempt at simplification or lightness for lucidity is not intended to disrespect it in any way.

With that introduction, we can launch into our stories. “What!” you might say. No introductory rant on the biology of it all: the genome, chromosomes, DNA, RNA, introns, exons, cells, nuclei, etc.? Indeed, there is much science and engineering that these stories are based on. Each story attempts to connect the world of clinical practice, built upon centuries of careful observation of external form, to the world of molecular biology, with its deep internal secrets. The path between these two worlds passes through the mind-bending world of computer algorithms, which distills large amounts of data down to its essence. The interplay between these three worlds is fascinating, as you will hopefully see. However, the last thing a writer wants is to lose the reader to an extensive overdose of dry facts. Therefore, these facts are woven into the stories themselves in a novel experiment at combining hard science with entertaining storytelling. A glossary of terms is at hand though, at the end of the book, just in case you need a place to look things up quickly.

On that note, and without further ado, let us dive into our stories of genomic typographical errors and their impact on patient lives.

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