On March 31, 2022, scientists from the Telomere-to-Telomere (T2T) consortium announced a historic first in the field of human genetics: they successfully sequenced an entire human genome, essentially completing the work started by the Human Genome Project. We spoke with PNRI scientist Rick McLaughlin, PhD, whose research focuses on noncoding or “junk” DNA, about the significance of the T2T achievement and its implications for the future of genetics research.
PNRI Communications: What’s significant about this news considering that the Human Genome Project had already mapped 92% of the human genome?
PNRI: How so?
Rick McLaughlin: It is definitely exciting to see this accomplishment. As soon as the first genome assembly was published in 2001, the field recognized that (while incredibly useful) that map was replete with unresolved patches. Some said those regions, composed mainly of heterochromatin (a highly modified and compacted state of DNA) and repeats (including the transposable elements or jumping genes that our lab studies), were unimportant junk DNA. This most recent complete assembly of a human genome enables researchers to identify the many parts of this junk that likely play central roles in human biology.
“To me, the greatest impact of this work is that we now have a confident map of all the territory of the genome where we can search for mutations that affect human health.”
RM: For example, the T2T researchers found 99 new protein-coding genes within the 8% of our genome that had been previously disregarded as junk. While a fundamental goal of genetics is to understand the function of all the genes in our genome, that’s hard to do without a complete list of the potentially “functional” pieces of our genome. And with the discovery of every new gene with an important role in human biology comes another place we now know to look for disease-causing mutations.
PNRI: Adam Phillippy, one of the lead scientists in the T2T study, said, “Within 10 years, getting a complete, perfectly accurate human genome will be a routine part of health care, and it will be cheap enough that it won’t be a second thought … You’ll have the complete genome in your pocket.” What are the other advances we have to make to reach that point?
RM: I do agree that the sequence of a patient’s genome will eventually be an actionable part of medical records, and I fervently believe this largely relies upon increased support for basic and applied research to develop affordable technologies of scale. However, I think we have some deeply anchored barriers to excavate before we can make diagnostic genome sequencing accessible in an equitable way in the U.S. and worldwide. This includes systemic deficiencies in our healthcare system and the challenge of building broad acceptance and trust of these technologies by patients.
PNRI: PNRI’s research focuses on people’s innate resilience to disease. Does this last 8% of our genetic material offer any clues or potential answers to how our genes protect us from illness?
RM: It’s such a fascinating question – why does a given mutation cause a debilitating disease in one individual while another individual with that same mutation remains unaffected? This can happen because some mutations don’t act alone; they need a partner mutation to cause disease. There is reason to believe that the hard-to-sequence regions of our genome are enriched for these partner mutations, which could either enable or resist disease. For example, some of the virus-like jumping genes called transposable elements that we study might be completely benign without an accompanying mutation in one of the genes of our immune system. In this case, we can only predict disease if we know the jumping gene is present (which we can now do with the complete genome sequence) and the immune system mutation is present. Either piece of information is, alone, insufficient.
PNRI: How does a significant advancement like this affect or inform the work you do in your lab?
RM: Our lab’s research into the evolution and diversity of transposable elements, which are a major source of hard-to-sequence DNA, will benefit immensely from these and future studies that finally resolve the sequence, location, and variation of these often-overlooked drivers of human disease.
PNRI: What’s most exciting to you about these findings?
RM: To me, the greatest impact of this work is that we now have a confident map of all the territory of the genome where we can search for mutations that affect human health. What I most look forward to is the extension of this approach to hundreds more diverse genomes to help us finally grasp the true extent of genetic variation in the human population.
PNRI: Thanks so much, Rick!