Beyond the genome: Unveiling human genetic diversity through the ‘Pangenome’

May 21, 2023

The human genome has been extensively studied and sequenced in the past few decades, resulting in a wealth of information about our genetic makeup. However, recent research has shown that the human genome is not as static as previously thought. In fact, there is a vast amount of genetic diversity that is not captured by the reference genome. This is where the concept of a ‘pangenome’ comes in.

In the vast, awe-inspiring realm of genomics, we’ve embarked on a new journey – one that pushes us beyond the familiar territory of the single reference genome, into the uncharted landscape of the pangenome. A pangenome is a comprehensive collection of all the genes and genetic variations present in a species. Unlike the reference genome, which is based on a single individual or a small group of individuals, the pangenome takes into account the genetic diversity present in a population. Representing the entire set of genes in a species, the pangenome promises a richer, more diverse understanding of our genetic heritage.

This approach has been used to study the genetic diversity of many organisms, from bacteria to plants, and now it is being applied to humans. As we explore this new frontier, we’re not only illuminating the corners of human genetic variation but also revolutionising fields from personalised medicine to health equity.

The genesis of genomic studies: A brief history

Our journey begins with the advent of genomic studies. Here are some key events in the history of genomics:

  • The Discovery of DNA (1869) by Friedrich Miescher

  • The Double Helix Structure (1953) by James Watson and Francis Crick

  • The Genetic Code (1960s) cracked by scientists like Marshall Nirenberg and Har Gobind Khorana

  • Recombinant DNA Technology (1970s) by Paul Berg, Herbert Boyer, and Stanley Cohen

  • Polymerase Chain Reaction (PCR) (1983) by Kary Mullis

  • CRISPR-Cas9 (2012) by Jennifer Doudna and Emmanuelle Charpentier

Human Genome Project, completed in 2003, provided us with the first comprehensive view of the human genome. However, this ‘reference genome’ was primarily based on a few individuals, thereby representing an ‘average’ sequence that didn’t capture the full spectrum of human genetic diversity. Our understanding of genomics dramatically speeded up with the development of high-throughput sequencing (NGS) technologies and was further enriched by subsequent projects like the 1000 Genomes Project, which began to uncover the vast extent of genetic variation among humans. These projects set the stage for the next big leap in genomics: the human pangenome.

The limitations of the current human reference genome

While the reference genome was a monumental achievement, it’s far from perfect. It was primarily constructed using DNA from a limited number of individuals of European descent, which means it may not accurately reflect genetic variations found in other ethnic groups.This underrepresentation of the global population limits our understanding of disease predispositions in different ethnic groups and hampers the development of effective treatments for everyone. Additionally, the reference genome overlooks many genetic variations, such as insertions, deletions, duplications, inversions, and translocations, many of which can have significant effects on gene function and health. Complex regions like regions with repetitive sequences and many SNPs and other genetic variations are often not well-represented in the reference genome. The creation of a human pangenome, which includes genomes from individuals of diverse ethnic backgrounds, aims to address these limitations and provide a more comprehensive view of human genetic diversity.

The ‘Pangenome’: A new approach to understanding genetic diversity

A pangenome is a comprehensive collection of all the genes and genetic variations present in a species. Unlike the reference genome, which is based on a single individual or a small group of individuals, the pangenome takes into account the genetic diversity present in a population. It expands our view from a single reference genome to a comprehensive collection of genomes representing the full spectrum of human genetic diversity. The concept of a pangenome was initially developed in the field of bacterial genomics and now it is being applied to humans. However, creating a human pangenome is a much larger task than creating a bacterial pangenome, due to the complexity and size of the human genome. Therefore, this is a task that requires significant resources and collaboration among researchers worldwide.

Assembling the pangenome: A collaborative scientific endeavour

Creating a human pangenome is a monumental and collaborative scientific endeavour. The first step in creating a pangenome is the selection of diverse samples. This means collecting DNA from individuals of diverse ethnic backgrounds, genders, and geographical locations to capture as much genetic variation as possible. Once the samples are collected, the DNA is sequenced, assembled and annotated. The final step is to integrate all of these individual genomes into a single pangenome. This involves identifying regions of the genome that are shared among all individuals (the “core” genome) and regions that vary among individuals (the “dispensable” or “flexible” genome). Throughout this process, there’s a huge amount of data to be managed, and challenges to overcome. Different laboratories around the world have to coordinate their efforts, share data, and agree on standards and protocols. It’s a truly collaborative scientific endeavour that requires expertise in fields ranging from molecular biology to computer science.

Human Pangenome Reference Consortium

The Human Pangenome Reference Consortium (HPRC) is a vital collaborative effort initiated in 2019, uniting over a dozen research institutions from the United States and Europe in a mission to create a more comprehensive and diverse reference of the human genome. This consortium, funded by the National Human Genome Research Institute, includes eminent institutions such as the Coriell Institute of Medical Sciences, Stanford University, Yale School of Medicine, and the Santa Cruz Genomics Institute under the University of California. The HPRC aims to sequence and assemble genomes from individuals from diverse populations, offering a more representative depiction of the genomic landscape of diverse human populations. Serving as the nexus for these multifaceted projects is the Human Pangenome Reference Center at Washington University, which coordinates and streamlines the consortium’s collective efforts.

The pangenome and its potential impact on personalised medicine

The recently published human pangenome is a collection of high-quality genome sequences from 47 people of diverse ancestries from Africa, Asia, and North and South America. It’s the first phase of a larger project that aims to sequence 350 people by 2024 to capture a broad range of human genetic diversity. This pangenome holds transformative potential for personalised medicine. It provides a more accurate basis for understanding how different genetic variants influence health and disease, thus enabling doctors to diagnose genetic diseases more effectively and tailor treatments to a patient’s unique genetic makeup. Furthermore, it can revolutionise pharmacogenomics (a field that studies how people’s genetic variations affect their responses to drugs) by predicting patients’ drug responses more accurately, leading to personalised drug prescriptions and dosages. Importantly, the pangenome can help reduce health disparities by ensuring that all ethnicities are represented in genetic research.

In summary, the assembly of a human pangenome represents a significant advance in our ability to understand and apply genetic information in a medical context. It has the potential to pave the way for truly personalised medical treatments, and to ensure that these benefits are shared equitably across all populations.

The future of genomics with the pangenome

The pangenome will allow us to map the full spectrum of human genetic diversity, providing a more comprehensive understanding of our species. It will broaden our knowledge base from a single reference genome to a diverse panorama of genomes that truly represent humanity’s genetic heterogeneity. With the pangenome as a resource, the future of medicine could be profoundly personalised. Doctors might be able to tailor treatments based on a patient’s unique genetic profile, increasing the efficacy of treatments and reducing adverse side effects. This could revolutionise the treatment of diseases ranging from cancer to cardiovascular disease, and beyond. Besides, a pangenome could provide a more detailed understanding of many rare diseases, potentially leading to new diagnostic tools and treatments. It will enhance genetic testing such as prenatal genetic tests, carrier screenings, and tests for predicting the risk of developing specific diseases. The huge amount of data generated by pangenome projects will require sophisticated computational tools to analyze. This could lead to advances in bioinformatics and machine learning algorithms, as well as increased demand for experts in these fields.

In conclusion, the pangenome represents a new frontier in genomics. It could revolutionize our understanding of human genetics and have profound impacts on medicine, public health, and biological research. However, it’s important to note that these are projections and the actual impact will depend on numerous factors, including scientific, technological, and societal developments.

Conclusion

The pangenome, our most recent, powerful tool, grants us an unattainable view of human genetic diversity. As we continue to explore this new frontier, we not only illuminate corners of human genetic variation but also promise to revolutionize fields from personalized medicine to health equity.

However, the pangenome also presents its own set of unique challenges. As we stand on the precipice of this new frontier, we must navigate complex questions of ethics, data privacy, and resource allocation. Furthermore, the vast data generated by pangenome projects will require significant advancements in bioinformatics and machine learning, necessitating collaboration across disciplines.

Nonetheless, the potential benefits of the pangenome are immense, promising a future where healthcare is personalized, every individual’s unique genetic makeup guides their medical journey, and health equity becomes a reality. As our journey into the pangenome unfolds, it’s clear that the story of human genetics is still being written. We are reminded that our diversity isn’t just our history—it’s also our strength, and our future.

In the end, the human pangenome is more than a scientific endeavour; it is a testament to our shared humanity, a recognition of our collective diversity, and a bold step towards a future of health equity and personalised care. As we turn the page to this new chapter, we remain eager to uncover what the pangenome holds for the future of genomics.

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