Newswise — The Genetics Society of America (GSA) is pleased to announce that Barbara Meyer is the recipient of the 2018 Thomas Hunt Morgan Medal, which is awarded for lifetime achievement in genetics. This honor is given in recognition of her groundbreaking work on chromosome behaviors that govern gene expression, development, and heredity.
Meyer’s studies of how chromosomes determine sex began during her postdoctoral period in the laboratory of Sydney Brenner, who later won a Nobel Prize for establishing the nematode worm Caenorhabditis elegans as an important model organism for research on development. Meyer’s early work focused on how C. elegans “counts” the number of X chromosomes and sets of autosomes to determine its sex, as well as how it adjusts to the imbalance in the number of X chromosomes between the two sexes.
In C. elegans, individuals with two X chromosomes are self-fertilizing hermaphrodites; those with only one X chromosome are males. A popular hypothesis when Meyer began her postdoctoral work was that the worms compensate for the difference in the number of copies of genes on the X chromosome between the two sexes. But it wasn’t clear whether the worms accomplished this by upregulating genes on the X chromosome in males or by downregulating genes on the X chromosome in hermaphrodites—in fact, no one had conclusively shown dosage compensation occurs at all.
As a postdoctoral researcher and after establishing her own lab, Meyer confirmed at the molecular level that the worm engages in a dosage compensation process. She then identified genes involved in the process and showed that dosage compensation works by reducing expression of X-linked genes in hermaphrodites.
Further analysis of the mechanism underlying dosage compensation produced many key insights into gene regulation. Because the sex of C. elegans individuals is determined by the ratio of X chromosomes to sets of autosomes, she knew there must be a molecular mechanism for sensing this ratio. Her lab identified a gene they named xol-1 as the master switch for sex determination: when the gene is turned off, the animals are hermaphrodites, and when it’s turned on, the animals are male. xol-1 controls both sex determination and dosage compensation in response to the ratio of X chromosomes to sets of autosomes, the sex-determination signal.
Meyer’s group found that transcription factors encoded by both the X chromosome and the autosomes battle to control whether xol-1 is transcriptionally active or inactive. After a victor emerges in this molecular tug-of-war, proper maintenance of xol-1’s state is ensured by a splicing factor—also studied in Meyer’s lab—that acts on xol-1 mRNA. Active xol-1 directs male development by inducing repression of sdc-2, a second master sex-switch gene. Without xol-1-mediated repression, sdc-2 would direct hermaphrodite development by repressing yet another gene—one that heads a sex-determination cascade that causes male development. Additionally, active sdc-2 would trigger assembly of a dosage compensation complex on both X chromosomes in the hermaphrodites.
These key findings formed the foundation of many fruitful research projects across the field, including extensive analysis in Meyer’s own lab. By characterizing the dosage compensation complex in C. elegans, the group discovered that the same protein complexes that tightly condense chromosomes and repress transcription during mitosis (condensins) can be repurposed to turn down transcription during interphase. These condensin complexes act as structural elements to remodel the higher-order structure of X chromosomes and regulate entire regions of the chromosomes.
“Her elegant genetic analysis, followed by beautiful molecular and cellular studies, have continued to yield a deep and fascinating picture of these processes,” says Cynthia Kenyon, Vice President of Aging Research at Calico Labs.
In addition to leading excellent research projects through a career spanning more than 30 years, Meyer has mentored many graduate students and postdoctoral researchers, fostering their career success. She is currently an investigator of the Howard Hughes Medical Institute and a professor at the University of California, Berkeley, where she previously served as chair of the Genetics Division in the Department of Molecular and Cell Biology and as director of the department’s graduate program.
The Thomas Hunt Morgan Medal is awarded to scientists with a rich history of achievement in genetics, encompassing their full bodies of work. The Medal honors the memory of Thomas Hunt Morgan (1866–1945), one of the most recognized figures in the history of genetics. Among his many discoveries, Morgan is known for being the first to show that chromosomes are the carriers of genetic information.