The “mystery of mysteries” phrase related to speciation is often attributed to Charles Darwin but was used in a February 20, 1836 letter from John Herschel to Charles Lyell, in which Herschel wrote “that mystery of mysteries the replacement of extinct species by others.” In "On the Origin of Species", Darwin wrote of facts which “seemed to throw some light on the origin of species—that mystery of mysteries, as it has been called by one of our greatest philosophers” though he did not identify Herschel at the time.
Biological species are often defined on the basis of reproductive isolation and ever since Darwin pointed out the difficulty in explaining why crosses between two species often yield sterile or inviable progeny (for instance, mules emerging from a cross between a horse and a donkey), biologists have sought answers as to why. A Science Express article suggests that the solution to this problem lies within the heterochromatin, a tightly packed, gene-poor compartment of DNA found within the genomes of all nucleated cells.
Malik and first author Joshua Bayes, Ph.D., a former graduate student in the Malik lab, focused on understanding the cellular function of a particular Drosophila gene dubbed Odysseus. The gene is so named because of its ability to cause havoc and male sterility when introduced into the genome of another species. Odysseus is a gene that is derived from a transcription factor, and it was long believed to be a protein that turned on expression of other genes in Drosophila testis.
Odysseus also had been previously shown to rapidly evolve in its DNA-binding domain. Based on this observation, Bayes and Malik reasoned that Odysseus must interact with some rapidly evolving DNA in the genome. They tested the hypothesis, first proposed by Malik and Hutchinson Center colleague Steven Henikoff, Ph.D., that such hybrid-sterility proteins may bind repetitive satellite DNA in heterochromatin. Such repeats are believed to evolve rapidly due to an "arms-race" for preferential transmission during the process of forming an egg, whereby only one of four chromosomes is non-randomly chosen to be included into the egg.
Consistent with this hypothesis, Bayes found that Odysseus proteins localize to heterochromatic DNA found next to centromeres and on gene-poor chromosomes, which leads to their decondensation. Dramatically, the hybrid-sterility-associated Odysseus from one species showed additional localization to the Y chromosome of the other species. Through experiments in cell lines and transgenic flies, Bayes further showed that Odysseus localization has rapidly evolved during recent evolution, evidence of the "arms-race" that drives rapid evolution of satellite DNA repeats. Altered expression and localization has profoundly deleterious consequences for the process of sperm formation, a process that remains a mystery and is under active study in the Malik lab.
The finding that rapidly evolving heterochromatin may underlie this phenomenon also ties in with other work in Malik's lab that explores how "mismatches" originating from rapid evolution of DNA and proteins could lead to chromosome segregation defects and aneuploidy events that are sometimes precursors in transitions to cancer.
Earlier this year Malik, a Howard Hughes Medical Institute Early Career Scientist, was awarded the Presidential Early Career Award for his unique combination of evolutionary and genetic approaches to tackle important problems like speciation and infectious disease.
Grants from the National Institutes of Health, the Mathers Foundation and the Howard Hughes Medical Institute funded this research.