Genetic Jigsaw: Piecing Together the Human Pangenome

Dr. Eimear Kenny, an esteemed professor specializing in Medicine, Genetics, and Genomic Sciences at the Icahn School of Medicine at Mount Sinai, has played a pivotal role in the establishment of a more comprehensive human pangenome reference. This groundbreaking project, led by the international Human Pangenome Reference Consortium, currently incorporates the genomes of 47 individuals, with a target of expanding to 350 genomes by 2024. The overarching objective of this endeavor is to more accurately represent the genetic diversity of the human population, facilitating improved disease diagnosis, treatment, and the reduction of health disparities.

Dr. Eimear Kenny, a highly regarded researcher and educator in the fields of Medicine, Genetics, and Genomic Sciences at the Icahn School of Medicine at Mount Sinai, has made substantial contributions to the international Human Pangenome Reference Consortium, leading to the development of a more inclusive human pangenome reference.

Over two decades ago, Dr. Kenny, who had recently completed her undergraduate studies and begun her first computational genomics position, witnessed the announcement of the near-complete sequencing of the human genome. At the time, this accomplishment was considered the fundamental blueprint for all humans and aimed to expedite the diagnosis and eventual treatment of common and rare diseases, as part of the Human Genome Project.

Fast forward to the present, and Dr. Kenny, now a Professor of Medicine, Genetics, and Genomic Sciences at the Icahn School of Medicine at Mount Sinai, stands among an elite group of scientists whose invaluable contributions have led to the creation of the new human “pangenome” reference. This reference consists of a collection of genome sequences that encompass a significantly broader spectrum of human diversity.

Details regarding these groundbreaking advancements were elucidated in multiple papers published in the prestigious journal Nature last month. The efforts were spearheaded by the international Human Pangenome Reference Consortium, an organization funded by the National Human Genome Research Institute (NHGRI), which operates under the umbrella of the National Institutes of Health. Dr. Kenny serves as a Principal Investigator and lead scientist within the consortium.

The novel pangenome reference serves as a compendium of diverse genomes against which an individual’s genome sequence can be compared. Analogous to a subway system map, the pangenome graph presents numerous potential paths for a sequence to follow, symbolized by distinct colors.

A genome represents the collection of DNA instructions that govern the development and functioning of every living organism. While genome sequences exhibit slight variations among individuals, the genomes of any two humans are more than 99 percent identical on average. These subtle differences contribute to each person’s uniqueness and provide valuable insights into their health, aiding in disease diagnosis, outcome prediction, and personalized medical interventions.

“For the past two decades, we have relied on a single human reference genome, which has been an incredibly powerful resource. This reference has driven the sequencing of millions, if not hundreds of millions, of human genomes worldwide,” explains Dr. Kenny, Professor of Medicine, Genetics, and Genomic Sciences at the Icahn School of Medicine at Mount Sinai, and a co-author of the published work. “However, its limitations lie in the fact that most of the reference sequence represents only a single individual on the planet. Consequently, rarer sequences or those unique to specific populations are not adequately represented. Therefore, it became imperative for us to reimagine the human reference genome and ensure that it truly reflects the diversity of individuals across the globe. This is precisely what we have accomplished.”

The newly established pangenome reference currently incorporates the genome sequences of 47 individuals, with an aim to expand this number to 350 by mid-2024. Given that each person carries two sets of chromosomes, the existing reference already encompasses 94 distinct genome sequences, with a goal of reaching 700 distinct genome sequences upon project completion.

“Both basic researchers and clinicians who utilize genomics require access to a reference sequence that encompasses the remarkable diversity found within the human population. This inclusive reference will benefit all individuals, helping to mitigate the perpetuation of health disparities,” emphasizes Eric Green, MD, PhD, Director of NHGRI. “The creation and enhancement of a human pangenome reference align with NHGRI’s commitment to pursuing global diversity in all aspects of genomics research. This commitment is vital for advancing genomic knowledge and implementing genomic medicine in an equitable manner.”

Dr. Kenny, also the Founding Director of the Institute for Genomic Health at Icahn Mount Sinai, leads research at the intersection of genomics, medicine, and computer science. Her primary objective is to accelerate the integration of genomic information into routine clinical care, thereby enhancing human health outcomes. She employs machine learning techniques and vast databases of genomic data to uncover novel genetic variants that impact disease risk. Additionally, she oversees large-scale clinical trials focused on implementing genomic medicine within diverse populations.

Her expertise has yielded significant advancements. “As part of this consortium, my role entailed contributing to this international scientific effort and, more specifically, assisting in the selection of genomes that would comprise the new pangenome reference. This ensures that the resource is optimally beneficial for individuals worldwide,” she explains.

Dr. Kenny co-led a team that employed population genetics approaches, community engagement, and outreach to include genomes from diverse populations in the pangenome. This approach addresses issues of underrepresentation and bias in genomics research, leading to improved accuracy and generalizability of research findings across different populations.

The completion of the Human Genome Project in 2003 covered approximately 92 percent of the total human genome sequence. Recent technological advancements, such as long-read DNA sequencing, which can analyze longer stretches of DNA at a time, have helped researchers fill in the remaining gaps to achieve the first complete human genome sequence. These developments were documented in a series of six papers published in the April 1, 2022, issue of Science, along with accompanying papers in other prominent journals. The findings from these studies have been incorporated into the current pangenome reference.

“I am thrilled by the technological advancements in genomics that we have witnessed today. This new era of long-read sequencing, alongside other capabilities, enables us to obtain significantly higher resolution of genomic sequences and, more importantly, accurately identify larger genomic variants known as structural variants. Previously, these structural variants were challenging to detect using short-read technology. As a result, we can now accelerate the identification of medically relevant variants while dramatically reducing sequencing costs,” affirms Dr. Kenny.

Furthermore, a more comprehensive understanding of these variants will help ascertain whether certain genes are genuinely rare or if their prevalence is concentrated in specific regions of the world.

“Another crucial aspect of our work is our commitment to creating a resource that truly represents global diversity. We must acknowledge that individuals worldwide require resources that are best suited to their needs,” emphasizes Dr. Kenny.

For more information on this groundbreaking achievement, refer to the following resources:

• Human Pangenome Reference: A Deeper Understanding of Worldwide Genomic Diversity
• A Crystal Clear Image of Human Genomic Diversity
• Release of the New Human Pangenome Reference

The published papers that detail the project’s progress include:

• “A draft human pangenome reference” by Wen-Wei Liao et al., published in Nature on May 10, 2023 (DOI: 10.1038/s41586-023-05896-x).
• “Increased mutation rate and gene conversion within human segmental duplications” by Mitchell R. Vollger et al., published in Nature on May 10, 2023 (DOI: 10.1038/s41586-023-05895-y).
• “Recombination between heterologous human acrocentric chromosomes” by Andrea Guarracino et al., published in Nature on May 10, 2023 (DOI: 10.1038/s41586-023-05976-y).
• “Pangenome graph construction from genome alignment with minigraph-cactus” by Glenn Hickey et al., published in Nature Biotechnology on May 10, 2023 (DOI: 10.1038/s41587-023-01793-w).

Frequently Asked Questions (FAQs) about human pangenome reference

More about human pangenome reference

• Human Pangenome Reference: A Deeper Understanding of Worldwide Genomic Diversity
• A Crystal Clear Image of Human Genomic Diversity
• Release of the New Human Pangenome Reference
• Nature: “A draft human pangenome reference”
• Nature: “Increased mutation rate and gene conversion within human segmental duplications”
• Nature: “Recombination between heterologous human acrocentric chromosomes”
• Nature Biotechnology: “Pangenome graph construction from genome alignment with minigraph-cactus”