This July marks the 25th anniversary of the Time cover story announcing that sequencing of the human genome was nearly complete. This was the culmination of an international collaboration started in 1990, often referred to as “decoding the book of life,” and predicted by many to be the key to unlocking secrets of human identity, health and evolution.
Prior to the completion of the Human Genome Project, it was believed that humans had around 100,000 protein-coding genes. However, an early revelation from completing the project was that humans have far fewer genes than previously thought — approximately 20,000-25,000 protein-coding genes. In fact, the protein-coding regions (exons) make up only about 1-2% of the human genome.
To me, this highlights a pillar of human genetics: the more we learn, the more we realize we don’t know.
Each landmark discovery in genetics leads to multiple new questions. Attempts to answer questions born from the Human Genome Project has led to a deeper understanding of our DNA and redefined the use of genetic testing in the clinic. Despite this, today there is more we don’t understand about our DNA than ever before.
The vast majority of our DNA doesn’t code for proteins; this DNA was previously thought to be “junk” DNA. We now understand this “non-coding” DNA is essential to genome function, as it regulates gene activity through various mechanisms, though our current understanding of its complexity is superficial.
The clinical impact of discoveries and technological advances in genetics over the past 25 years cannot be understated. However, a gap between the newest genetic discoveries and its use for patient care will always be present. This gap contributes to confusion for both patients and providers about how, if at all, to integrate genetic testing into health care. Below is an overview of the capabilities and limitations of current genetic testing in clinical care.
Current Utility in Clinic:
- Diagnostic genetic testing can identify DNA changes that disrupt gene function and lead to clinical symptoms:
- Karyotyping generates a picture of all chromosomes in an individual’s cells, identifying large-scale genetic changes, such as extra or missing chromosomes.
- Chromosome microarray scans chromosomes for extra or missing pieces without detecting changes in the DNA sequence.
- Exome sequencing evaluates protein-coding regions (exons) to identify rare DNA changes that disrupt gene function and cause clinical symptoms.
- Genome sequencing evaluates both protein-coding and non-coding regions, though current understanding of clinically relevant non-coding DNA changes is superficial.
- Epigenetic testing evaluates methylation patterns of genetic conditions with an associated unique epigenetic signature (about 90 conditions currently).
- Predictive genetic testing identifies DNA changes that increase specific health risks and/or provides guidance on risk-reducing interventions:
- Hereditary cancer gene panel testing identifies DNA changes in genes increasing risk of developing cancer in the future.
- Prenatal carrier screening identifies DNA changes in genes for some inherited disorders in which offspring are at risk if both parents are carriers for the same disorder.
- Pharmacogenetic testing identifies DNA changes in genes that affect the metabolism of medications and/or genes that affect medication’s effect on the body.
Limited Current Utility in Clinic with Promising Potential:
- “Polygenic Risk Score” testing is designed to estimate a genetic susceptibility to a specific condition with potential of driving early intervention or prevention.
Limitations of Genetic Testing in Clinic:
- Generally, testing cannot reveal future health problems with certainty.
- Unknown impact of every DNA change. Diagnostic testing may reveal DNA changes with uncertain effect on gene function, potentially leading to anxiety from the unknown.
- Testing cannot explain or predict complex traits, such as personality or cognitive potential.
- Testing cannot rule out a genetic cause of symptoms with certainty.
The discoveries in human genetics since the Human Genome Project illustrate the capacity for many more discoveries in the future. The capacity of diagnostic genetic testing to identify a genetic cause of rare diseases continues to improve, with increasing opportunities for targeted therapies for those affected. The impact of predictive genetic testing is shaping the conceptualization of precision medicine.
As we continue to unravel secrets of our genetics, the cycle of one discovery generating new questions is simultaneously humbling and comforting. While our genetics provide a framework to understand our biology, it does not allow us to predict the future with certainty, nor does it dictate the person we become.