Science Spotlight

Genetic multitasking and the resolution of cellular conflict

From the Malik Lab, Basic Sciences Division

Ask nearly any biologist, or any nature lover for that matter, and they’ll likely happily extol the incredible diversity of life on earth. Also amazing, though perhaps less appreciated, is the diversity contained within our own bodies. We possess muscle cells that contract. Brain cells that communicate with electrical signals. Immune cells that fight off invaders. Cells that sense light. Cells that secrete acid, or bile, or insulin. Bone cells. Skin cells. Even cells that can make whole new people. Where does such diversity come from?  In terms of the diversity of animals and plants, we can turn to good old Darwin for the answer: evolution has altered the genetic codes, the toolkits with which each organism is created, of different species to generate divergent forms and behaviors. But the diverse cells within our bodies all carry the same genetic code. And when it comes to generating these many different cells from the same toolkit, the flexible use of those tools is the key. This is accomplished in large part by turning on different genes in different cells – muscle genes in muscle cells, immune genes in immune cells. However, this flexibility has its limits. Most genes are turned on in several different cell types, and, while the gene, and the function it delivers, is fundamentally the same in the various cell types in which it is activated, the needs of the cells regarding how such functions should be performed can differ. How, then, can an individual gene adjust to the needs of distinct cells?  In some cases, our cells can make different versions of a gene in different cells, through processes such as alternative splicing. So too can the proteins encoded by some genes be differentially modified to alter their functions. Absent the requisite flexibility to meet cellular demands, though, a gene can present an interesting conflict: evolution may optimize the function of the gene for cell type A at the expense of cell type B, or optimize the function of the gene for cell type B at the expense of cell type A, or find a compromise. Either way, someone’s left wanting, and these cell types, belonging to the same body, would ideally not be in conflict at all. Understanding such genetic conflicts, and how evolution deals with them, is a major interest of Dr. Harmit Malik, a professor in the Basic Sciences Division at Fred Hutch and a member of the Fred Hutch/University of Washington Cancer Consortium. In a new paper published in the Journal Life Science Alliance, Dr. Malik’s group, led by former graduate student Dr. Lisa Kursel, identified a gene at the center of a conflict between cell types in the fruit fly Drosophila virilis, and described the means by which the conflict was resolved.

Because evolution generally happens on far too long a timescale to watch it in action, most stories of this process are told in reverse – we observe the results of evolution and work backwards to understand how things came to be the way they are. This story begins with a universal cellular process – cell division – and a histone protein central to this act – CenH3. “CenH3 localizes to centromeric DNA and helps recruit other components of the kinetochore, which mediates chromosome segregation”, explain the authors. Despite the ubiquity of cell division, and of CenH3’s essential role, Drs. Malik and Kursel suspected a conflict. That’s because not all cell divisions are the same. Somatic cells undergo mitosis. But germ cells – sperm and oocytes – also undergo meiosis, which has its own unique quirks. Human oocytes pause in the middle of meiosis for decades as they await sexual maturity and their turn to make the long-anticipated journey down the fallopian tubes, and CenH3 must maintain centromere structure throughout that time. Sperm are even more dramatic - after division, their chromatin is radically reorganized, and CenH3 must remain on the centromeres as nearly all other histone proteins are stripped away and replaced by sperm-specific DNA-packaging proteins; failure to do so may deprive paternal chromosomes from correctly establishing centromeres after sperm-egg fertilization. Thus, the authors reflect, “we hypothesized that disparate chromatin environments in soma versus germline [and sperm versus egg] might impose divergent functional requirements on single CenH3 genes.”

How do you go about testing such a hypothesis?  “Dissecting these [proposed] multiple functional constraints in many model organisms (such as D. melanogaster and M. musculus) is challenging because CenH3 is an essential single-copy gene in these species”, they noted. But in Drosophila virilis, a relative of the more commonly studied Drosophila melanogaster, they thought they might have a species that had found a natural solution to its conflict. This is because during its evolution, the D. virilis CenH3 gene was duplicated to create two genes – Cid1 and Cid5. Gene duplication and subfunctionalization is a classic solution to intralocus conflicts, as each of the two copies is freed up to evolve to meet the needs of a different cell type. “Thus”, they explained, “gene duplications present a unique opportunity to more precisely understand the tissue-specific functions of CenH3.”

If sperm, eggs, and somatic cells needed different things from CenH3, then the duplicate Cid1 and Cid5 genes should have evolved to act in different cell types. To test this, Dr. Kursel examined where these two genes are expressed. Cid1, she found, but not Cid5, is present in somatic cells. Both proteins were found in the ovaries and testes, but as sperm and egg maturated the authors observed a divergence: Cid5 was lost from oocytes prior to meiotic arrest, while Cid1 was lost from sperm prior to chromatin reorganization. Thus, it appears that these two proteins have functionally diverged, with Cid5 being optimized to support sperm cell maturation, and Cid1 being optimized to support both oocyte maturation and somatic cell mitosis, perhaps representing the dissolution of a conflict between male and female germ cells that may continue to this day in those organisms that contain only one CenH3 gene.

It is natural, and tempting, to consider our bodies paragons of cooperation – trillions of cells working in collaborative harmony to support the organism of which they are all a part. To recognize that they are, in many cases, racked with conflict and infighting is revelatory of the imperfectness and complexity of the evolutionary process, as well, perhaps, of the truly intricate beauty and diversity of the life it has wrought.

Cid1/Cid5 in oocyte and sperm
Divergent localizations of Cid1 (green) in the oocyte nucleus (top left) and Cid5 (magenta) in spermatids (bottom right). Image provided by Harmit Malik

This work was supported by the National Institutes of Health and the Howard Hughes Medical Institute.

Fred Hutch/UW Cancer Consortium member Harmit Malik contributed to this work.

Kursel L, McConnell H, de la Cruz AFA, Malik HS. (2021) Gametic specialization of centromeric histone paralogs in Drosophila virilis. Life Science Alliance 4 (7) e202000992; DOI: 10.26508/lsa.202000992