Pangenome Project Sheds Light on Down Syndrome-related Chromosome Abnormality

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Until recently, the study of human genomes has relied almost exclusively on a single reference genome to which others are compared to identify genetic variations. But a single reference genome cannot represent human diversity, and operating that way introduces a pervasive bias.

At the end of 2021, researchers at the UC Santa Cruz Genomics Institute introduced Giraffe, a tool that efficiently maps new genome sequences to a “pangenome,” representing many diverse human genome sequences. 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 draft reference includes the genome sequences of 47 people, and the consortium aims to increase the number to 350 by mid-2024.

Now, less than two years later, the same team has made their first big breakthrough using the pangenome—they solved the most common type of chromosomal abnormality in humans, which is linked to Robertsonian translocations and down syndrome.

According to their study published in Nature, the researchers discovered the recombination of five acrocentric chromosomes, which have centromeres closer to one end rather than in the center.

Humans have two copies of most chromosomes: one inherited from their mother, and the other from their father. Recombination, or the exchange of genetic material between chromosomes, is thought to occur between equivalent chromosome pairs. However, the researchers discovered different acrocentric chromosomes can recombine with each other to exchange DNA through their shorter arms.

This discovery was key to solving the most common type of chromosomal abnormality in humans— Robertsonian translocation. Robertsonian translocation occurs when a portion of the short arm of chromosome 14 is inverted relative to the other acrocentric chromosomes, and recombination results in a chromosomal abnormality. A Robertsonian chromosome is a fusion of two acrocentric chromosomes in a head-to-head orientation. This can cause an abnormal number of chromosome copies, which causes reproductive issues for carriers of Robertsonian translocations.

“The presence of the extra chromosome copy will cause fertility issues and is related to Down syndrome,” said study author Erik Garrison, assistant professor at the University of Tennessee Health Science Center (UTHSC). “We were able to actually provide a molecular description of why this is happening, resolving a question about the cause of Robertsonian translocations that has been open for 50 years. This will have ramifications for potential treatment, and it will help carriers understand the cause of their genetic condition.”

The scientists say their work will unlock a new wave of sequence-based cytogenetic research, and also paves the way toward researching previously overlooked genome regions.

“We show that these regions behave unusually genetically, and new approaches will be needed to leverage the information they contain into biomedical studies at the population level,” said Vincenza Colonna, also an assistant professor at UTHSC.

Overall, the pangenome project is in its infancy. The team hopes to add 300 in the next year, and thousands over the next few years. The more people added from different backgrounds, the more valuable the tool becomes. The data can even help animal researchers create their own pangenome to study species with far more variation than humans.

 

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