Embryonic left–right separation mechanism allows confinement of mutation‐induced phenotypes to one lateral body half of bilaterians

Abstract

A fundamental question in developmental biology is how a chimeric animal such as a bilateral gynandromorphic animal can have different phenotypes confined to different lateral body halves, and how mutation-induced phenotypes, such as genetic diseases, can be confined to one lateral body half in patients. Here, I propose that embryos of many, if not all, bilaterian animals are divided into left and right halves at a very early stage (which may vary among different types of animals), after which the descendants of the left-sided and right-sided cells will almost exclusively remain on their original sides, respectively, throughout the remaining development. This embryonic left-right separation mechanism allows (1) mutations and the mutation-induced phenotypes to be strictly confined to one lateral body half in animals and humans; (2) mothers with bilateral hereditary primary breast cancer to transmit their disease to their offspring at twofold of the rate compared to mothers with unilateral hereditary breast cancer; and (3) a mosaic embryo carrying genetic or epigenetic mutations to develop into either an individual with the mutation-induced phenotype confined unilaterally, or a pair of twins displaying complete, partial, or mirror-image discordance for the phenotype. Further, this left-right separation mechanism predicts that the two lateral halves of a patient carrying a unilateral genetic disease can each serve as a case and an internal control, respectively, for genetic and epigenetic comparative studies to identify the disease causations.

Somatic mosaicism: implications for disease and transmission genetics

“…Individuals with congenital hemidysplasia with ichthyosiform erythroderma and limb defects (CHILD) syndrome exhibit striking demarcation of affected and unaffected tissue along the midline (Figure 2A) [7]. The exact time of left-right separation in humans is unknown [8]; in mice it appears to occur near the 8-cell stage [9]. If mutant cells arise before determination and are present on both sides of the left-right axis, tissues on both sides of the individual can be affected, potentially including one or both gonads (Figure 1B).…”

Single-cell RNA sequencing reveals dynamic changes in A-to-I RNA editome during early human embryogenesis

“…Moreover, embryonic left-right separation is an important event during embryogenesis of bilaterians. In a recent study, by analyzing multiple lines of molecular and cell biology evidence, Ma concluded that embryos of bilaterians are divided into left and right lateral halves at or shortly after 8-cell stage [ 24 ].…”

The chicken left right organizer has nonmotile cilia which are lost in a stage‐dependent manner in the talpid3 ciliopathy

“…Avian gynandromorphs exhibit distinct male/female trait demarcation along the midline (Aw and Levin, 2008;Vandenberg and Levin, 2013) suggesting that the midline and, therefore, a distinct left-right axis, is established at the first cell division. Analysis of incomplete chicken gynandromorphs, however (Zhao et al, 2010), suggests that asymmetry is not established until the eight-cell stage (Ma, 2013). Subsequent to establishing the midline, it has been demonstrated that PCP signaling during the formation of the primitive streak (1-3HH; Hamburger and Hamilton, 1951), establishes the polarization of cells toward the primitive streak and, therefore, confers unique cellular identity in the left and right axis, perturbation of which disrupts subsequent asymmetrical expression of SHH (Zhang and Levin, 2009).…”