Researchers determine new classification system for DNA architecture across the lifespan

This work was generated from several initially independent research efforts. For some time now, scientists on the DNA Zoo team have been trying to classify how chromosomes fold to fit into the nucleus of cells of different species across the tree of life.

DNA Zoo is an international consortium that includes institutions such as Baylor College of Medicine, the Center for Theoretical Biological Physics (CTBP) at Rice University, the University of Western Australia and SeaWorld, supported by the National Science Foundation.

First, the team conducted in situ Hi-C on 24 species, representing all chordate subphyla, the seven vertebrate classes, seven of the nine major animal phyla, as well as plants and fungi. Together, these genomic assemblies provide a comprehensive overview of nuclear organization since the last common ancestor of all eukaryotes.

The maps revealed four features of the nuclear architecture found on the chromosomes:

  • increased frequency of contact between loci on the same chromosome
  • prominent contacts between centromeres
  • prominent contacts between telomeres
  • X shape on the chromosome map

To identify these characteristics impartially, the team developed an aggregated chromosome analysis (ACA), a method in which the contact cards for each chromosome are rescaled and summed, then used to score each characteristic. The characteristics have been divided into two groups, based on their coexistence. Type I included clustering of centromeres, clustering of telomeres, and a telomere-to-centromere axis. Type II included only the chromosomal territories.

“Whether we were looking at worms or sea urchins, sea squirts or corals, we kept seeing the same folding patterns coming,” said co-author Olga Dudchenko, PhD, a member of the Center for Genome Architecture at Baylor and CTBP. “In some species, the chromosomes are organized like the pages of a printed newspaper, with the outer margins on one side and the middle folded on the other. And then in other species, each chromosome is crumpled into a small ball.”

Science according to which the nuclear arrangement in a human cell can be transformed into that typical of a fly. “/>

Biologists from Baylor College of Medicine, the Netherlands Cancer Institute and Rice University have shown in a study that the nuclear arrangement in a human cell can be transformed into that typical of a fly. Illustration courtesy of Evgeny Gromov.

To further explore these differences, the team developed an algorithm, called 3D-DNA Phaser, to assign variants to individual homologues (related genes), producing chromosomal length haploblocks for multiple species (segments with very little recombination). . The analysis revealed that features of the genome’s architecture appear and disappear over billions of years, as the lineages switch between types.

The team found that type I species lacked a subunit of the condensin II complex, which promotes mitotic chromosome compaction. They also noted that Type I architectural features and the loss of Condensation II subunits appear to have co-evolved repeatedly over time. Analysis showed that condensin II strengthens chromosomal territories or counteracts type I characteristics.

Humans exhibit a type II genomic architecture, with strong chromosomal territories and no type I characteristics.

Meanwhile, an independent team in the Netherlands had discovered something unexpected.

“I was experimenting with a protein called condensin II, which we knew plays a role in cell division,” said author Claire Hoencamp, a doctoral student at the Dutch Cancer Institute. “But we observed the strangest thing: when we mutated the protein in human cells, the chromosomes completely reorganized themselves. It was baffling!”

The two teams met at a conference where they realized they had stumbled upon a way to convert human cells from one nuclear type to another.

“When we looked at the genomes studied at the DNA Zoo, we found that evolution had been our experience many times before! When mutations in one species break down condensin II, they usually reverse the entire architecture of the nucleus, ”Rowland said.

“So we had a puzzle,” said senior author Erez Lieberman Aiden, PhD, associate professor of molecular and human genetics at Baylor and co-director of DNA Zoo. “The data implied that during evolution, species can switch from one type to another. We asked ourselves: what is the control mechanism? Would it be possible to change one type of nucleus into one? other in the laboratory? “

To explore this possibility, they performed Hi-C in situ on Hap1 cells lacking the condensin II CAP-H2 subunit. These cells exhibited weaker chromosomal territories and much stronger contacts between centromeres. Immunofluorescence microscopy revealed that in cells, centromeres are grouped together. Thus, the disruption of condensin II transforms the folding of the human genome into a type I configuration.

“Our simulations showed that by destroying Condensin II, you could rearrange a human nucleus to resemble a fly nucleus,” said José Onuchic, PhD, co-director of CTBP, which includes collaborators at Rice, Baylor, Northeastern University. and other institutions. in Houston and Boston.

“We started with an incredibly broad survey of 2 billion years of nuclear evolution,” said author Sumitabha Brahmachari, PhD, postdoctoral researcher in Onuchic’s lab at CTBP. “And we’ve found that it all comes down to a simple mechanism, which we can simulate and summarize, on our own, in a test tube. This is an exciting step on the road to a new kind of genome engineering – in 3D! “

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