When you choose to publish with PLOS, your research makes an impact. Make your work accessible to all, without restrictions, and accelerate scientific discovery with options like preprints and published peer review that make your work more Open.


Looking Back 20 Years After the Unveiling of the First Human Genome Sequence

I’m about to begin revising the 14th edition of my human genetics textbook. In normal times, I’d have amassed technical articles and case reports, as well as notes from meetings and interviews, choosing topics to add or ax and updating or replacing examples as the new edition takes shape.

But I haven’t thought much about genetics in 18 months, instead obsessively reading, listening, and writing about COVID-19 and SARS-CoV-2, terms that didn’t exist when the current edition was published in September 2019. The before time.

So much has changed since I published my first COVID article on January 23, 2020.

I’m relieved to focus once more on human genetics. A recent webinar from scientific publisher Elsevier, “20 Years of the Human Genome: From Sequence to Substance,” has helped me get back on track and brought back memories.

Genetics Begat Genomics

I attended meetings in the mid-1980s, when gene mapping technologies had advanced enough to make sequencing “the” human genome a possibility, and not science fiction. Discovering the precise sequence of the DNA bases A, T, C, and G of that first human genome took a decade; today it can be done in under a day, a sequence displayable on a cell phone.

The US government-funded program to sequence the human genome began in 1990, accelerating as technologies improved. Each edition of my textbook followed the progress, starting with the first edition in 1993. “The human genome” was at first a chapter tacked onto the end. Then I moved it to follow molecular genetics and mutations. Now, genomics is woven into every chapter.

The final years of the effort to sequence a human genome became a contentious race between government researchers and the private company Celera Genomics. On June 26, 2000, Francis Collins, from the National Institutes of Health, and J. Craig Venter, from Celera, flanked President Clinton in the White House rose garden to announce the great sequencing – the only open date on the calendar, so goes the lore. The effort supposedly ended in a tie.

The first drafts of a human genome sequence were published in February 2001. The Celera version was in Science, with 5 individuals contributing to that composite genome including Venter. Nature published the version from the International Human Genome Sequencing Consortium, which included the NIH group and used genome pieces from several de-identified individuals.

A fuller version was published in 2003, but all the gaps weren’t filled in until a publication on May 7, 2021. We now know that a human genome consists of 3,054,832,041 DNA base pairs.

Yet even as the first draft was nearing announcement, a global effort to catalog genetic variability had already begun, in 1999: the SNP Consortium. A single nucleotide polymorphism – SNP – is a place in the genome at which most people have one of the four DNA bases, but others have one of the other three. Cataloging the rarer SNPs quickly revealed that there is no one human genome. We’re mostly the same, but the interesting parts of our genomes, many that impact health, differ.

The Rise, Finally, of Genomic Medicine

Last month, 20 Years of the Human Genome: From Sequence to Substance, began with remarks from Eric Green, MD, PhD, director of the National Human Genome Research Institute (NHGRI genome.gov/). He defined genomic medicine as “an interdisciplinary medical specialty involving the use of genomic information.” It embraces:

genetic testing

gene variants

exome and genome sequencing

DNA and RNA as biomarkers


“big data” ‘omics: genomics, transcriptomics, epigenomics, pharmacogenomics, proteomics, and metabolomics

ethical, legal, and social implications (ELSI) of genetic and genomic research for individuals, families and communities

communication of findings

Practical applications of genome information have been a long time coming. “It’s 18 years out from the end of the genome project, 20 years from completion of the finished sequence, yet we are just starting to see genomic medical implementation. The most notable advances are in cancer genomics and pharmacogenomics, in rare genetic disease diagnostics, and diagnosing cases in ways that we never could have anticipated, faster and faster,” Green said. He mentioned the newborn ICU, where rapid access to genomic information can now provide in days diagnoses that once took months, even years, “in some cases changing and saving lives.”

Dr. Green discussed 4 insights on the impact of genomic advances since the unveiling of the first draft sequences.

1. “We are victims of our own success. We can generate human genome sequences easily and quickly. Getting an inventory of variants for an individual is straightforward, but understanding that list, and knowing for each variant what to do clinically or what to ignore, is not trivial. We often don’t know what a list of gene variants means.” Dr. Green mentioned ClinGen, an NIH-funded resource that “defines the clinical relevance of genes and variants for use in precision medicine and research.”

2. “We have changed the relevance of genomics in our world. When I got involved at the beginning, it was just a bunch of geeky scientists like me trying to map the genome. We convinced health care professionals to come under our tent. Then we started doing genomic medicine – cancer, pharmacogenomics, prenatal testing, rare disease diagnosis. Now genomics touches the health care ecosystem. Genomics is very much a part of society. Privacy, regulation, payment, all come with the responsibility of something becoming relevant.”

3. “We have a pervasive diversity problem in our field, from participants engaging as part of studies, to our workforce.” He offered the example of the many genome-wide association studies – GWAS – that teased links between genome parts and traits/illnesses. “A great majority of participants in GWAS in 2009 were European – 96% – and by 2016 it was 81%.

“We must address health equity issues as genomic medicine is implemented. But we risk exacerbating this problem because traditionally we know that first access to cutting edge genomic medicine is skewed to people with the best health care, and that’s disproportionately people of European ancestry,” Dr. Green said. The Human Pangenome Reference Center.o is compiling genome sequences that reflect all human genome variation.

4. “Beyond genomics. We are in a remarkable growth phase of genomic medicine due to technology we have for sequencing DNA. But health and environmental monitoring technologies are important too, and with those we can generate other ‘omic data to couple with genomic data.”

Dr. Green suggested that we think more broadly about genomic medicine, and say ‘decision medicine’ as a more precise accounting of individual variability. “Precision medicine is how genomic risk affects physiology, which also reflects lifestyle and environment. Through the lens of individual genetic variants, we have a powerful opportunity to advance our understanding of human health and disease.” He mentioned the NIH’s All of Us cohort of a million volunteers, adding that “the UK Biobank is way ahead of us.”

In October 2020, on the eve of the pandemic, Dr. Green and a stellar team published “10 Bold Predictions for Human Genomics by 2030.” They are:

1. Sequencing and analyzing complete human genomes will become common in research labs
2. Knowing every gene’s function
3. Considering environmental influences on genomes to predict health and disease
4. Genomics will no longer use social constructs, like race, in research
5. Science fairs will include more genomics projects
6. Genomic testing will become as commonplace in medicine as blood tests
7. It will be easy to know if a person’s gene variants are clinically important
8. Smartphones will display complete genome sequences unveiled 2 months later
9. Advances will benefit all
10. Genomics discovery and technologies will cure more genetic diseases

At the end of the webinar, Dr. Green took “a walk down memory lane” 30 years ago when the idea of sequencing “the” human genome” arose. He joked about how little attention was paid to whose genome would be sequenced.

“Were the parts being sequenced from the PI (principal investigator) or the slowest post doc who couldn’t run out quickly enough when they came with the hypodermic to draw blood? Someone said ’whoever you pick, make sure that person is normal.’

We now know that everyone is a mutant in some way and it doesn’t matter. Now we recognize the lack of insight and thoughts about implications of actually getting that first sequence of a human genome. We’ve come a long way in terms of thinking about these things, now that we have millions of genomes sequenced, but we really weren’t prepared for that first one.”

Leave a Reply

Your email address will not be published. Required fields are marked *

Add your ORCID here. (e.g. 0000-0002-7299-680X)

Related Posts
Back to top