Dosage sensitivity of X-linked genes in human embryonic single cells

Jian-Rong Yang,Xiaoshu Chen

doi:10.1186/s12864-019-5432-8

Abstract

BackgroundDuring the evolution of mammalian sex chromosomes, the degeneration of Y-linked homologs has led to a dosage imbalance between X-linked and autosomal genes. The evolutionary resolution to such dosage imbalance, as hypothesized by Susumu Ohno fifty years ago, should be doubling the expression of X-linked genes. Recent studies have nevertheless shown that the X to autosome expression ratio equals ~ 1 in haploid human parthenogenetic embryonic stem (pES) cells and ~ 0.5 in diploid pES cells, suggesting no doubled expression for X-linked genes and refuting Ohno’s hypothesis.ResultsHere, by reanalyzing an RNA-seq-based single-cell transcriptome dataset of human embryos, we found that from the 8-cell stage until the time-point just prior to implantation, the expression levels of X-linked genes are not two-fold upregulated in male cells and gradually decrease from two-fold in female cells. Additional analyses of gene expression noise further suggest that the dosage sensitivity of X-linked genes is weaker than that of autosomal genes in differentiated female cells, which contradicts a key assumption in Ohno’s hypothesis, that most X-linked genes are dosage sensitive. Moreover, the dosage-sensitive housekeeping genes are preferentially located on autosomes, implying selection against X-linkage for dosage-sensitive genes.ConclusionsWe observed dosage imbalance between X-linked and autosomal genes, as well as relatively high expression noise from X-linked genes. These results collectively suggest that X-linked genes are less dosage sensitive than autosomal genes, putting one primary assumption of Ohno’s hypothesis in question.

Highlights

During the evolution of mammalian sex chromosomes, the degeneration of Y-linked homologs has led to a dosage imbalance between X-linked and autosomal genes
There is evidence for reduced expression noise of genes that are sensitive to dosage [31, 32], fitness effects of gene dosage [33] assessed at the genomic scale would be helpful to further test the insensitive X hypothesis
As we showed in this study, X-linked genes exhibit noisier expression, and gene-specific dosage compensation may still be suboptimal for X-linked dosage-sensitive genes

Summary

Introduction

During the evolution of mammalian sex chromosomes, the degeneration of Y-linked homologs has led to a dosage imbalance between X-linked and autosomal genes. The evolutionary resolution to such dosage imbalance, as hypothesized by Susumu Ohno fifty years ago, should be doubling the expression of X-linked genes. Ohno proposed that the expression levels of X-linked genes should be doubled to re-balance the expression dosage between X-linked and autosomal genes [1] in male cells, where only one X chromosome exists. In 2006, the first genome-wide empirical test of Ohno’s hypothesis is conducted with a set of microarray-based gene expression profiles in human somatic tissues [5], where the gene expression ratio between one active X and two autosomes (AA) is found as approximately 1, or X:AA ~ 1, lending support to Ohno’s hypothesis [5]. A number of groups are convinced that Ohno’s hypothesis is correct because the X:AA ~ 1 when only actively expressed genes are

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