Non-Canonical and Sexually Dimorphic X Dosage Compensation States in the Mouse and Human Germline

Mahesh N Sangrithi,Helene Royo,Shantha K Mahadevaiah,Obah Ojarikre,Leena Bhaw,Abdul Sesay,Antoine H.F.M Peters,Michael Stadler,James M.A Turner

doi:10.1016/j.devcel.2016.12.023

Abstract

SummarySomatic X dosage compensation requires two mechanisms: X inactivation balances X gene output between males (XY) and females (XX), while X upregulation, hypothesized by Ohno and documented in vivo, balances X gene with autosomal gene output. Whether X dosage compensation occurs in germ cells is unclear. We show that mouse and human germ cells exhibit non-canonical X dosage states that differ from the soma and between the sexes. Prior to genome-wide reprogramming, X upregulation is present, consistent with Ohno's hypothesis. Subsequently, however, it is erased. In females, erasure follows loss of X inactivation, causing X dosage excess. Conversely, in males, erasure leads to permanent X dosage decompensation. Sex chromosomally abnormal models exhibit a “sex-reversed” X dosage state: XX males, like XX females, develop X dosage excess, while XO females, like XY males, develop X dosage decompensation. Thus, germline X dosage compensation states are determined by X chromosome number, not phenotypic sex. These unexpected differences in X dosage compensation states between germline and soma offer unique perspectives on sex chromosome infertility.

Highlights

Male and female mammals carry the same complement of autosomes but differ with respect to their sex chromosomes: females have two X chromosomes (XX) while males have one X chromosome and one Y chromosome (XY)
Evolutionary loss of genes from the Y chromosome led to a disparity in the dosage of X chromosome versus autosomal genes, with males becoming monosomic for X-linked gene products
Our studies reveal important differences in X dosage compensation states between the germline and soma and provide fresh insight into the etiology of subfertility caused by sex chromosome abnormalities

Summary

Introduction

Male and female mammals carry the same complement of autosomes but differ with respect to their sex chromosomes: females have two X chromosomes (XX) while males have one X chromosome and one Y chromosome (XY). Susumo Ohno proposed that to rectify this imbalance, expression of X chromosome genes was increased 2-fold to match the output of the diploid autosomal complement, i.e., giving an X-to-autosome ratio (X:A) of 1 (termed Ohno’s hypothesis) (Ohno, 1967). This process, X chromosome upregulation, was acquired in females, leading to a 2-fold excess in X gene expression compared with males. X upregulation and X inactivation ensure equalization of gene dosage both within, and between, the sexes

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