Science Spotlight

Centromeric proteins find their own niche

From the Malik Lab, Basic Sciences Division

“It may be said that natural selection is daily and hourly scrutinizing, throughout the world, every variation, even the slightest; rejecting that which is bad, preserving and adding up all that is good; silently and insensibly working, whenever and wherever opportunity offers, at the improvement of each organic being in relation to its organic and inorganic conditions of life. We see nothing of these slow changes in progress, until the hand of time has marked the long lapse of ages, and then so imperfect is our view into long past geological ages, that we only see that the forms of life are now different from what they formerly were.”

Charles Darwin, The Origin of Species

Variation and selective pressure are two key, indispensable principles underlying evolution by means of natural selection. Variation in the gene sequences of organisms is generated by errors in DNA replication that result in mutations or gene amplification events. Gene duplications arise in the genomes as a product of erroneous amplification events. Selective pressure would then dictate whether a gene variant or duplicated gene is maintained or lost. It would follow thus that genes that are essential for the survival of an organism undergo stringent scrutiny because their function must be maintained.

But nature, full of paradoxes, never ceases to perplex us and the evolution of centromeric proteins is one such paradox. The centromeres are a specialized component of each chromosome that ensure proper segregation of chromosomes into new cells during cell division and are therefore essential. However, despite being essential, centromeric proteins and DNA have been shown to evolve rapidly. Research in the Malik lab (Basic Sciences Division) seeks to understand this paradox. Using Drosophila species as a model, former MCB graduate student, Dr. Lisa Kursel, investigated in a previous study the evolution of centromeric histones (CenH3s) and identified several independent duplication and specialization events of the Cid gene, which encodes for the CenH3 protein in Drosophila

Kursel and Malik proposed that Cid might be under selective pressure to perform multiple functions including mitotic and meiotic cell divisions and centromere inheritance in sperm. This can lead to intralocus conflict which occurs when two or more functions are performed by the same gene. And just as it is in the life of human beings, it does pay off (sometimes) to avoid conflict. As such, a duplication event in an essential gene not only provides a unique opportunity for specialization, more importantly it can resolve intralocus conflict.

Kursel and Malik hypothesized that the retention of specialized Cid paralogs was driven by the pressure to resolve an intralocus conflict. And as nature is often guilty of self-plagiarism -although never held accountable for it- Kursel and Malik wondered if intralocus conflict driving CenH3 specialization is a recurring theme in evolution. Kursel worked with Frances Welsh, a former summer intern in the lab. Together, they took advantage of recent mosquito genome sequencing efforts and analyzed CenH3 evolution and specialization in several mosquito species. They published their findings in Molecular Biology and Evolution.

The authors conducted a phylogenomic analysis of centromeric proteins in mosquito genomes and found that most mosquito species encode two CenH3 genes, mosqCid1 and msoqCid2. They found that both duplicates have been co-retained for over 150 million years which makes it the oldest CenH3 duplication event known so far. An additional mosqCid3 gene was found in the Aedes species, a result of an independent gene duplication of mosqCid1. The mosqCid paralogs encoded divergent N-terminal tails and showed tissue-specific expression patterns, reminiscent of the divergent selective constrains that drove the evolution of their Drosophila Cid counterparts.

Fluorescently-labelled mosqCid proteins localize to centromeres in dividing cells. MosqCid proteins tagged using green florescent protein (GFP) were expressed in mosquito cells in culture.
Fluorescently-labelled mosqCid proteins localize to centromeres in dividing cells. MosqCid proteins tagged using green florescent protein (GFP) were expressed in mosquito cells in culture. From publication

Kursel and colleagues extended their analyses to other centromeric proteins, including chaperones that deposit CenH3s at centromeres. They found that Anopheles mosquitoes encode not one but two paralogs of Cal1, a CenH3 chaperone. Therefore, the authors identify several examples of ancient co-retention of centromeric proteins, further supporting the notion that intralocus conflict could provide the selective pressure underlying functional specialization.

“The most exciting aspect of Lisa’s thesis”, Malik added, “is that it highlights how gene duplications provide a way out of the impasse of centromeric proteins having to simultaneously perform multiple, potentially incompatible functions. Thus, organisms such as humans, whose centromeric proteins are encoded by single genes, must pay a price in terms of a functional compromise of their centromeric functions.”

This study was supported by funding from the National Institutes of Health and the Howard Hughes Medical Institute. H.S.M. is an Investigator of the Howard Hughes Medical Institute.

Kursel, L. E., Welsh, F. C., & Malik, H. S. 2020. Ancient Coretention of Paralogs of Cid Centromeric Histones and Cal1 Chaperones in Mosquito Species. Molecular Biology and Evolution. http://doi.org/10.1093/molbev/msaa056