June 24, 2024

Pangenome: a collective human reference genome

The team of Guarracino Liao et al. Each of these PHR’s is a jumble of sequence blocks. When the group compared the graphs of their PHRs with the “linear” reference genome, they found more similarity to the other four horizontally centered arms of T2T-CHM13 than to their counterparts there. Presumably, these clusters support heterologous recombination and ensure that the p-arms evolve together to maintain their joint role in nucleation.

The team also identified the sequences in the PHRs where the breaks occur, giving rise to Robertsonian translocations (ROBs). The acrocentric chromosomal arms fuse and most of the p arms are lost. This phenomenon mostly occurs during oocyte production, and the finding indicates that ROBs are collateral damage of heterologous recombination. Given that ROBs occur in 1 in 800 human births, we suspect that heterologous recombination between acrocentric chromosomes is common and persistent. We expect that as more genomes are added to the pangenome repertoire, it will be possible to determine how common these recombination events are.

In contrast, Folger’s team used the reference to systematically compare variance in segment repeats with variance in non-repetitive parts of the genome. They found 60 percent higher sequence diversity in duplicated segments and showed that these differ significantly between populations and individuals. Genes in such duplicated segments are subject to what is known as an ‘interstitial gene transfer’ (IGC) – in which non-homologous segments of the duplicated region exchange short sequences of DNA.

Folger and his group identified IGC events by looking for signs of sequence transitions in pangenomes and concluded that these events are probably one of the main reasons for the diversity of duplications. They found that 799 genes with protein-coding regions were affected by IGC. It is exciting to see duplications characterized in more detail, as duplicated sequences can promote the evolution of new, specialized functions of a gene.

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The team also examined the “restrictions” of sequences in the duplicated genes. In doing so, they looked specifically at that duplication during the evolution of the human lineage. ‘Restraint’ is a measure of sequence diversity – lower variation indicates that mutations at this point reduce the organism’s viability. The team found this limitation in 38 genes, including members of NOTCH2A family of genes associated with typical human changes in brain size over the course of development. The repetitive nature of segment repeats made it extremely difficult to identify a ‘limitation’ in at least 40 percent of the genes analyzed.

The authors also found that 171 genes were duplicated and moved intact to new regions of the genome. This may also mean that the mechanisms regulating these genes have been reorganized. In the future, the Pangenome Project should give experts the opportunity to more accurately assess ‘limitation’ in newly duplicated genes. Taken together, these works give a taste of how human genetic repertoire can be exploited. They show how the exchange of sequences between repetitive regions of our genome contributes to population variation and our evolution. As the reference pangenome continues to expand in the future, we expect more insights into these intriguing genomic regions.