RNA Innovation Seminar: Sundeep Kalantry, Ph.D., Professor of Human Genetics, U-M Medical School

“Evolution of Mammalian Dosage Compensation”
Sundeep Kalantry, Ph.D.

Professor,
Human Genetics,
University of Michigan Medical School

In-person: Kahn Auditorium, BSRB | Hybrid link

Abstract:
The sex chromosomes pose an inequality between XX females and XY males. In therian mammals, the Y chromosome contains few unique genes, whereas the X chromosome harbors ~1000 protein-coding genes and many more noncoding loci. Excessive expression of X-linked genes in females can cause abnormal development and lethality. To equalize X-linked gene expression to that of males, females evolved X-chromosome inactivation as a dosage compensation mechanism. X-inactivation results in the silencing of most genes on one of the two Xs in females. In eutherian (‘placental’) mammals, X-inactivation requires the Xist long noncoding RNA that is expressed from and accumulates on the inactive X chromosome. Xist RNA recruits proteins that silence genes on the inactive-X. That dosage compensation requires X-inactivation and that X-inactivation requires the Xist RNA are tenets of mammalian sex chromosome biology.

Despite much work, however, whether dosage compensation requires Xist RNA and X-inactivation remains unclear. Dosage compensation is believed to have originated in therian mammals when the Y chromosome differentiated from the X chromosome. To prevent loss of genes that favored male sexual differentiation, discrete segments of the Y chromosome are thought to have undergone a series of inversions to suppress recombination with the X chromosome. Suppression of recombination is believed to have led to degeneration of genes on the Y chromosome. Due to the loss of Y-linked genes in males, females are believed to have ultimately evolved X-inactivation as a dosage compensation mechanism. Since the Y chromosome lost its gene content gradually, the need to dosage compensate X-linked genes is likely to also have arisen in a piecemeal manner. The step-wise differentiation of the X and Y chromosomes, therefore, is incompatible with chromosome-wide dosage compensation by Xist RNA and X-inactivation.

How dosage compensation can occur in the absence of Xist and X-inactivation is not known. The first Y chromosome segment to undergo differentiation from the X chromosome preceded the divergence of eutherian from metatherian mammals. Yet, Xist evolved later and only in eutherians and not in metatherians. Dosage compensation of genes in this ancestral segment of the X chromosome, therefore, is likely to have occurred prior to the advent of Xist. The ancestral form of dosage compensation is unknown but we hypothesize is still functional. We further hypothesize that this ancestral mechanism of dosage compensation was subsequently co-opted to regulate Xist when Xist arose for chromosome-wide dosage compensation through X-inactivation.

In testing the above hypotheses, we find that dosage compensation can occur in the absence of Xist and X- inactivation. We further identify an ancestral X-linked gene in the Xist- and X inactivation-independent dosage compensation mechanism. Together, our data provide insights into the origins of sex differences, mechanistically define the evolution of mammalian dosage compensation, and broadly inform how cells balance gene expression despite changes in chromosome copy number.

Bio:
Our long-standing focus is to understand mechanisms that underlie mammalian X chromosome dosage compensation, including X chromosome inactivation. X-inactivation ensures similar levels of X-linked gene expression between female and male mammals by silencing genes on one of the two X chromosomes in females. Notably, X-inactivation is also a model of sexually dimorphic epigenetic regulation, since two identical X chromosomes in female cells become transcriptionally divergent.  The study of dosage compensation promises to elucidate the origins of sex differences and inform how cells balance gene expression despite changes in chromosome copy number

Links:
Kalantry Lab