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Researchers from the Human Pangenome Reference Consortium have released a groundbreaking collection of high-quality human genome sequences that significantly expand the representation of genetic diversity from different human populations. This landmark achievement, funded by the National Human Genome Research Institute (NHGRI), is expected to revolutionize genomics research and enhance medical diagnostics and treatments.
Published in Nature, the research presents the concept of a "pangenome" reference, encompassing genome sequences from 47 individuals. The consortium aims to increase this number to 350 by mid-2024. Considering that each person carries a unique pair of chromosomes, the current reference includes 94 distinct genome sequences. The ultimate goal is to achieve 700 distinct genome sequences, capturing the rich diversity of the human species.
The human genome serves as a blueprint of DNA instructions that govern the development and function of living organisms. While individuals' genome sequences are more than 99% identical on average, subtle variations contribute to their uniqueness and offer valuable insights into their health, enabling disease diagnosis, outcome prediction, and tailored medical interventions.
To comprehend these genomic differences, scientists create reference human genome sequences that serve as a standard for comparing, aligning, assembling, and studying other human genome sequences. The original reference, nearly two decades old, has undergone periodic updates to account for technological advancements and the discovery of new genome regions. However, it falls short of representing the vast diversity of the human species, primarily consisting of genomes from only about 20 individuals, with a significant portion derived from a single person.
Dr. Adam Phillippy, a senior investigator in the Computational and Statistical Genomics Branch at NHGRI and a co-author of the primary study, highlights the need for a more inclusive approach. "Everyone has a unique genome, so using a single reference genome sequence for every person can lead to inequities in genomic analyses. For example, predicting a genetic disease might not work as well for someone whose genome is more different from the reference genome."
Overcoming the limitations of the current reference with recent technological advancements, such as long-read DNA sequencing, has enabled researchers to address missing information and fill gaps in the human genome. The Telomere-to-Telomere (T2T) consortium, funded by the NIH, unveiled the first complete human genome sequence last year, which was incorporated into the present pangenome reference.
By employing advanced computational techniques to align the various genome sequences, the researchers constructed a novel human pangenome reference, with each assembly covering over 99% of the expected sequence and achieving more than 99% accuracy. The new reference includes an additional 100 million bases, expanding the possibilities for analyzing human genome sequences.
The pangenome reference also unlocks the ability to identify larger genomic variants known as structural variants, which were previously inaccessible due to the limitations of using a single linear reference sequence. Structural variants, involving thousands of bases, have remained largely undiscovered using traditional short-read sequencing methods.
“The human pangenome reference will enable us to represent tens of thousands of novel genomic variants in regions of the genome that were previously inaccessible,” said Wen-Wei Liao, co-first author of the publication and Yale University Ph.D. student. “With a pangenome reference, we can accelerate clinical research by improving our understanding of the link between genes and disease traits.”
Moreover, the human pangenome reference is projected to enable the representation of tens of thousands of novel genomic variants in previously unexplored regions of the genome. This advancement holds promise for accelerating clinical research and deepening our understanding of the complex relationships between genes and disease traits.
“Basic researchers and clinicians who use genomics need access to a reference sequence that reflects the remarkable diversity of the human population. This will help make the reference useful for all people, thereby helping to reduce the chances of propagating health disparities,” said NHGRI Director, Dr. Eric Green. “Creating and enhancing a human pangenome reference aligns with NHGRI’s goal of striving for global diversity in all aspects of genomics research, which is crucial to advance genomic knowledge and implement genomic medicine in an equitable way.”
More information about the pangenome and the consortium’s work can be found on the NIH website or by reading one of the original publications below:
Liao et al. A draft human pangenome reference. Nature. Doi: 10.1038/s41586-023-05896-x (2023).
Vollger et al. Increased mutation rate and gene conversion within human segmental duplications. Nature. Doi: 10.1038/s41586-023-05895-y (2023).
Guarracino et al. Recombination between heterologous human acrocentric chromosomes. Nature. Doi: 10.1038/s41586-023-05976-y (2023).
Hickey et al. Pangenome graph construction from genome alignment with minigraph-cactus. Nature Biotechnology. Doi: 10.1038/s41587-023-01793-w (2023).
Published in Nature, the research presents the concept of a "pangenome" reference, encompassing genome sequences from 47 individuals. The consortium aims to increase this number to 350 by mid-2024. Considering that each person carries a unique pair of chromosomes, the current reference includes 94 distinct genome sequences. The ultimate goal is to achieve 700 distinct genome sequences, capturing the rich diversity of the human species.
The human genome serves as a blueprint of DNA instructions that govern the development and function of living organisms. While individuals' genome sequences are more than 99% identical on average, subtle variations contribute to their uniqueness and offer valuable insights into their health, enabling disease diagnosis, outcome prediction, and tailored medical interventions.
To comprehend these genomic differences, scientists create reference human genome sequences that serve as a standard for comparing, aligning, assembling, and studying other human genome sequences. The original reference, nearly two decades old, has undergone periodic updates to account for technological advancements and the discovery of new genome regions. However, it falls short of representing the vast diversity of the human species, primarily consisting of genomes from only about 20 individuals, with a significant portion derived from a single person.
Dr. Adam Phillippy, a senior investigator in the Computational and Statistical Genomics Branch at NHGRI and a co-author of the primary study, highlights the need for a more inclusive approach. "Everyone has a unique genome, so using a single reference genome sequence for every person can lead to inequities in genomic analyses. For example, predicting a genetic disease might not work as well for someone whose genome is more different from the reference genome."
Overcoming the limitations of the current reference with recent technological advancements, such as long-read DNA sequencing, has enabled researchers to address missing information and fill gaps in the human genome. The Telomere-to-Telomere (T2T) consortium, funded by the NIH, unveiled the first complete human genome sequence last year, which was incorporated into the present pangenome reference.
By employing advanced computational techniques to align the various genome sequences, the researchers constructed a novel human pangenome reference, with each assembly covering over 99% of the expected sequence and achieving more than 99% accuracy. The new reference includes an additional 100 million bases, expanding the possibilities for analyzing human genome sequences.
The pangenome reference also unlocks the ability to identify larger genomic variants known as structural variants, which were previously inaccessible due to the limitations of using a single linear reference sequence. Structural variants, involving thousands of bases, have remained largely undiscovered using traditional short-read sequencing methods.
“The human pangenome reference will enable us to represent tens of thousands of novel genomic variants in regions of the genome that were previously inaccessible,” said Wen-Wei Liao, co-first author of the publication and Yale University Ph.D. student. “With a pangenome reference, we can accelerate clinical research by improving our understanding of the link between genes and disease traits.”
Moreover, the human pangenome reference is projected to enable the representation of tens of thousands of novel genomic variants in previously unexplored regions of the genome. This advancement holds promise for accelerating clinical research and deepening our understanding of the complex relationships between genes and disease traits.
“Basic researchers and clinicians who use genomics need access to a reference sequence that reflects the remarkable diversity of the human population. This will help make the reference useful for all people, thereby helping to reduce the chances of propagating health disparities,” said NHGRI Director, Dr. Eric Green. “Creating and enhancing a human pangenome reference aligns with NHGRI’s goal of striving for global diversity in all aspects of genomics research, which is crucial to advance genomic knowledge and implement genomic medicine in an equitable way.”
More information about the pangenome and the consortium’s work can be found on the NIH website or by reading one of the original publications below:
Liao et al. A draft human pangenome reference. Nature. Doi: 10.1038/s41586-023-05896-x (2023).
Vollger et al. Increased mutation rate and gene conversion within human segmental duplications. Nature. Doi: 10.1038/s41586-023-05895-y (2023).
Guarracino et al. Recombination between heterologous human acrocentric chromosomes. Nature. Doi: 10.1038/s41586-023-05976-y (2023).
Hickey et al. Pangenome graph construction from genome alignment with minigraph-cactus. Nature Biotechnology. Doi: 10.1038/s41587-023-01793-w (2023).