NEW FINDINGS — GENETICS AND GENOMICS
When the initial human genome sequence was released in 2001, the scientific From genome to pangenome
community celebrated the completion of such a monumental and collaborative body of work. However, it became
apparent to scientists that gaps existed in the reference genome. The individuals who donated samples for the first genome were not representative of the diversity across the globe. Also, most of the reference genome came from one person, further limiting its diversity. The Human Pangenome Reference Consortium (HPRC) set out to address the limitations of the original genome by creating a pangenome of many diverse human genomes. The first draft of the human pange- nome was released in early 2023 and is being hailed as a tremendous advancement to the original sequence. The project included samples from 47 genetically diverse individuals, covering over 99% of the human DNA sequence. The pangenome is more than 99% accurate. The pangenome fills gaps in the reference sequence produced by the Human Genome Project, including adding more than 100 million bases. The pangenome reference also opens a window to identifying large genomic variants called structural DNA variants, which have been nearly impossible to find. The HPRC hopes to increase the number of individuals in the pangenome to 350 in 2024 and ultimately grow that number to 700 by the project's conclusion. The human pangenome reference is the next step in deepening our understanding of the human genome and how variations within it may contribute to health and disease risk. n REFERENCE: Liao, WW., Asri, M., Ebler, J. et al. A draft human pangenome reference. Nature (2023) 617, 312–324 . doi.org/10.1038/s41586-023-05896-x
Cells remember better in 3D Human cells contain our entire genome which holds instructions for thousands of protein and RNA molecules. However, a single cell typically expresses only a fraction of its genes, allowing different types of cells to arise in multicellular organisms. Epigenetics tags, which are tiny chemical markers on DNA, heavily influence a cell’s fate by telling it to become a muscle cell, for example. DNA wraps around histone proteins inside the cell nucleus, forming tightly packed chromatin. Histones under- go various modifications that regulate gene expression, creating an "epigenetic memory" crucial for preserving a cell's identity. Research shows that epigenetic modifications greatly influ- ence the 3D structure of chromosomes. A recent computational model-based study observed marked regions collapsing into dense clusters. The study suggests that a cell's 3D genome folding determines which parts receive chemical modifications. Some marks are lost during cell
division, but 3D folding helps restore them, pre- serving the cell's identity. Chemical marks during cell division aid in rees- tablishing genome folding, allowing memory pres- ervation through multiple divisions. “Reader-writer"
Example of nucleotides of DNA wrapped around the core built from histone proteins.
enzymes, specialized in adding these modifications, read existing marks and write new ones nearby. If the chromatin
has a 3D structure, marks accumulate in regions already modified by the parent cell. Evidence also suggests that the 3D dissemi- nation of marks can link neighboring regions, even if they are not directly next to one another along the DNA strand. Without this 3D structure, enzyme activity changes, hindering the preservation of epigenetic memory and potentially affecting cell differentiation. n REFERENCES: Jeremy A. Owen et al., Design principles of 3D epigenetic memory systems. Science (2023) 382, eadg3053. doi:10.1126/science.adg3053 Top figure courtesy of Leonid Mirny, PhD, Massachusetts Institute of Technology https://news.mit.edu/2023/how-cell-identity-preserved-when-cells-divide-1116
More details can be found in the Everyday DNA blog post: Pangenomes, The More the Merrier.
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