Public Release:  Study suggests methylation and gene sequence co-evolve in human-chimp evolutionary divergence

High-resolution comparison of methylation 'bookmarks' across species and individuals

Cold Spring Harbor Laboratory

Cold Spring Harbor, NY -- Scientists at Cold Spring Harbor Laboratory (CSHL) and the University of Southern California (USC) today published the first quantitative evidence supporting the notion that the genome-wide "bookmarking" of DNA with methyl molecules - a process called methylation - and the underlying DNA sequences corresponding with these marks, have co-evolved in a kind of molecular slow-dance over the 6 million years since humans and chimps diverged from a common ancestor.

The team's findings in some ways defy the conventional understanding of how methylation and related processes work. Broadly known as epigenetic processes, methylation and other means by which the genome is "marked" are usually thought of as altering the way a gene is expressed (i.e., whether it is "on" or "off") without changing the underlying sequence of DNA letters -- As, Gs, Cs and Ts - that "spell out" the gene.

Yet the new research supports theories proposing that methylation changes could drive changes in DNA sequence. The CSHL-USC team specifically suggests that methylation changes, which are reversible, might allow a short-term "flexibility in phenotype" - characteristics that individuals within a species exhibit - that would be a kind of dry run for more permanent genomic changes, if a newly conferred trait proves advantageous.


The evolutionary insight about methylation is only one of a number of new perspectives that emerge from the team's research paper, which is the cover story in the September 16 issue of the journal Cell. Its publication coincides with advance publication of a sister paper in Molecular Cell by the same team, whose members also include CSHL Professor W. Richard McCombie and co-first authors of the paper, CSHL postdoc Dr. Emily Hodges and doctoral student Antoine Molaro. Hodges is lead author of the companion paper, which shows how methylation changes in human blood stem cells are involved in "cell-fate decisions" that help determine how the precursor cells differentiate into mature lineage-specific blood cells.

Cells are reprogrammed in two waves


Each of the two cell types studied represents the "output" of one of the two reprogramming waves. One type was human embryonic stem (ES) cells; this cell type is the progenitor of all so-called "somatic" cells, i.e., cells that "differentiate" into all the tissues and organs of an organism. The methylome of the ES cells used in the current study was generated in a previous study. It is used in the current study for comparative purposes, specifically, to form a comparison with male germs cells sampled from two humans and from two chimpanzees, man's closest evolutionary relative.

"These two cell types, the human ES cell and the human and chimp male germ cell, represent the output of the two re-programming waves, and as such are the basis or 'ground state' for all that will follow, over the life of the individual cell and the organism itself," explains Molaro. "The ES cells subsequently differentiate into lung, blood, heart, liver, brain cells, etc. The germ cells are of course fundamental to sexual reproduction."

Methylation in different cell types vs. within types across species


The current study provides the first quantitative evidence of a remarkable fact: the methylation patterns that characterize each class of human or chimp cells - heart, blood, liver, etc. -- are far more different from one another than are the patterns within each cell type when viewed across species. A chimp heart cell will share most of its methylation marks with a human heart cell; but the chimp heart cell's methylation patterns will share comparatively fewer points of commonality when compared with those seen in a chimp's liver cells.




Comparison of non-methylated regions, across species


HMRs have long been of interest because the DNA sequences of most of the 21,000 human genes are associated with HMRs. Therefore, HMRs - areas without methyl marks - have been used as a rough guide to where genes lie in the vast DNA landscape that is the genome, 98% of which does not consist of genes.

More specifically, most HMRs overlap with the very beginning portions of gene sequences in humans and chimps - places called promoters. This fact is of evolutionary import: places in the genome where genes are regulated tend to be unmethylated. This is the flip side of a fact that has long been known: methylation tends to block gene expression. One way is by blocking access of the cell's transcriptional machinery at promoter sites.





"Sperm Methylation Profiles Reveal Features of Epigenetic Inheritance and Evolution in Primates" appears in Cell on September 16, 2011. The authors are: Antoine Molaro, Emily Hodges, Fang Fang, Qiang Song, W. Richard McCombie, Gregory J. Hannon and Andrew D. Smith. The paper can be accessed online: doi:10.1016/j.cell.2011.08.016

The companion paper, "Directional DNA Methylation Changes and Complex Intermediate States Accompany Lineage Specificity in the Adult Hematopoietic Compartment," appears online ahead of print Sept. 16 in Molecular Cell. The authors are: Emily Hodges, Antoine Molaro, Camila O. Dos Santos, Pramod Thekkat, Qiang Song, Philip Uren, Jin Park, Jason Butler, Shahin Rafii, W. Richard McCombie, Andrew D. Smith and Gregory J. Hannon. The paper can be accessed online at: doi:10.1016/j.molcel.2011.08.026

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