Research on the first ever reference to the human pangenome helps to better understand the biology of chromosomes

Researchers at the University of Tennessee Health Science Center have made a seminal discovery about chromosome biology through their work on the first reference to the human pangenome.

Recently published by the Human Pangenome Reference Consortium in the journal Nature, the pangenome draft uses complete genomic assemblies to provide a different look at the genetic makeup of humans. Researchers from UTHSC’s Department of Genetics, Genomics and Informatics created the technical tools to build the pangenome, and then used them to understand the variation in parts of the genome that could not be seen before.

The pangenome project aims to map the entirety of human genetic variation to create a comprehensive reference for geneticists to use to compare DNA sequences, which can aid in the study of connections between genes and diseases. The baseline draft includes genome sequences from 47 people, and the consortium aims to increase that number to 350 by mid-2024. The milestone comes more than 20 years after the first draft genome was released.

The first version of the reference design aimed to make a single complete version that is representative of a typical genome, which has been used in biomedical research to incredible effect over the past 20 years.”

Erik Garrison, PhD, UTHSC

According to Dr. Garrison, relating a genome to the original reference could cause biases, which were understood from the beginning but could not be technically addressed. ‘The differences between individual genomes can be quite significant. This causes a reference bias that makes most individual genomes look more like the reference than they actually are,’ he said. “The goal with the human pangenome project is to overcome this by having a reference that is a collection of many genomes.”

In addition to Dr. Garrison, the UTHSC team included Associate Professor Pjotr ​​Prins, PhD; Assistant Professor Vincenza Colonna, PhD; postdoctoral fellow Andrea Guarracino, PhD; PhD student Flavia Villani; postdoctoral fellow Silvia Buonaiuto, PhD; and IT analyst Christian Fischer.

The team’s biological discovery was published in a separate paper in Nature next to the pangenome reference draft. Dr. Guarracino, Dr. Colonna and Dr. Garrison are credited as authors.

The finding involves the recombination of five acrocentric chromosomes, which have centromeres closer to one end than the center. Humans have two copies of most chromosomes: one inherited from the mother and one from the father. Recombination, the exchange of genetic material between chromosomes, is generally believed to occur between pairs of equivalent chromosomes, but in a significant departure from this conventional understanding, UTHSC researchers have found that several acrocentric chromosomes can recombine with each other to exchange the DNA through their shorter arms.

Furthermore, the team showed that this observation was key to solving the most common type of chromosome abnormality in humans. A portion of the short arm of chromosome 14 is reversed from the other acrocentric chromosomes and recombination with it can result in a chromosomal abnormality known as a Robertsonian translocation. A Robertsonian chromosome is a fusion of two acrocentric chromosomes in an end-to-end orientation. This can cause an abnormal number of chromosome copies, which causes reproductive problems for carriers of Robertsonian translocations.

“The presence of the extra chromosome copy will cause fertility problems and is related to Down syndrome,” said Dr. garrison. “We were able to actually provide a molecular description of why this is happening by solving a question about the cause of Robertsonian translocations that has been open for 50 years. This will have ramifications for potential treatment and will help patients understand the cause. of their genetic condition”.

Dr. Guarracino suggests their methods will unlock a new wave of sequence-based cytogenetic research. “Our work addresses the limitations of previous studies and lays a solid foundation for future genomics and cytogenetics research, bringing us closer to solving the lingering mysteries of human genetic evolution,” he said.

The collaboration also paves the way for consideration of these regions in biomedical and evolutionary studies that had previously overlooked them. “We have been unable to explain the variation in the short arms of acrocentrics in previous studies of whole-genome association and human evolution,” said Dr. Column. ‘We demonstrate that these regions behave genetically in unusual ways, and new approaches will be needed to exploit the information they contain in population-level biomedical studies.’

According to the researchers, the pangenome project is only just beginning. Dr. Prins said the reference will continue to grow, adding that the more people are added to it from different backgrounds, the more valuable it becomes. The team’s work won’t just apply to the study of humans, but Dr. Prins said he could also help animal researchers create a pangenome to help study species with far more variation than humans.

“People will always come to us, because we wrote the tools,” said Dr. Prins. “If you build a pangenome of 100 individuals, it’s already quite daunting, but obviously in a few years we will add thousands. So, we will need to improve the software that can handle these things and we may also need new methods.”

UTHSC researchers will hold a three-day lecture and class this week on the UTHSC campus in Memphis and virtually share their experience. Through the hands-on workshop, participants learn the concepts of pangenome and its multiple applications. The conference will feature presentations by leading experts in the field of pangenome research.


University of Tennessee Health Sciences Center

Magazine reference:

Guarracino, A. et al. (2023) Recombination between heterologous human acrocentric chromosomes. Nature.

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