Deciphering the limits, mechanisms and evolution of developmental robustness using the paradigm of C. elegans seam cell patterning.

稳健性是指系统在存在扰动时保持性能的能力。这在工程中是一个非常重要的原则，在工程中，桥梁、飞机或互联网等系统的设计都能承受各种干扰并保持功能。健壮性是生命系统的一个同样重要的属性。然而，生物稳健性的研究和理解很少。事实上，值得注意的是，生物系统是如何进化成在存在内部和外部扰动的情况下具有再生性的。尤其是发育，对遗传和环境的变化是非常强大的，这有助于受精卵转变为多细胞个体。人类发育健壮性的一个非常显著的例子是五个手指头的存在，这个数字对个体间遗传组成的变化或环境的差异非常健壮。然而，健壮的系统并不是万无一失的，也会犯错误，所以多指或少指的情况虽然很少见，但仍然会发生。这种情况代表着发育错误，并使我们能够量化特定发育特征的稳健性限度。稳健性是一种确保表型稳定性的属性，因此，它对系统行为和进化非常重要。疾病也可以被视为强健机制的崩溃。因此，理解使生物系统变得健壮的一般原理是生物学中的一个基本问题。为了找到类似基本问题的满意答案，一种常见的做法是求助于模型系统，在那里我们可以轻松而快速地执行许多精细的实验。我们最喜欢的系统是一种小型线虫，秀丽线虫，它以其简单、快速和高度可重复性的发育而闻名。我们建议专注于线虫的一组表皮细胞，即所谓的Seam细胞，并将该组织作为研究动物发育稳健性的模型系统。这些细胞引起了人们的极大关注，因为它们具有干细胞特性，因此它们在幼虫阶段不对称分裂，一个子细胞保持增殖状态，而另一个子细胞分化成专门的组织，如神经元。作为这些分裂的结果，野生线虫成虫两性的每侧有16个缝隙细胞。我们想要描述这个系统对遗传(突变)和环境变化的发育稳健性的限制。我们的初步数据表明，有可能在不影响Seam细胞平均数量的情况下发现增加Seam细胞数量变异的突变，因此我们希望确定这些基因的本质是什么，这些基因有助于确保表型稳健性。我们将开发和测试已识别的基因如何在表型稳健性中发挥作用的假设，并研究它们的作用是针对Seam细胞还是更普遍地在整个动物水平上对系统稳健性起作用。最后，我们将通过研究布里奇萨线虫的稳健性机制的进化，解决我们的结果可以外推到其他系统的程度。布里奇萨线虫是一种与优雅线虫有亲缘关系的线虫物种。我们的方法可能使我们能够深入了解发育稳健性的遗传机制和进化，并得出一些关于关键调控因子对数量变化的稳健性程度以及基因对发育结果稳定的相对贡献的一般原则。我们的目标是开发广泛的假设，这些假设将为对稳健的药物靶向感兴趣的生物医学科学家和致力于设计稳健的生物网络的合成生物学家提供信息。

Robustness is the ability of a system to maintain performance in the presence of perturbations. It is a very important principle in engineering, where systems like bridges, aeroplanes or the internet, are designed to withstand a variety of perturbations and retain functionality. Robustness is an equally important property of living systems. However, biological robustness is poorly studied and understood.It is in fact remarkable how biological systems have evolved to perform reproducibly, in the presence of internal and external perturbations. Development, in particular, is highly robust to genetic and environmental variation and this is instrumental for the transformation of a fertilised egg into a multicellular individual. A very striking example of developmental robustness in humans is the presence of five hand digits, a number that is very robust to variation in the genetic composition among individuals or differences in the environment. However, robust systems are not infallible and make mistakes, so cases of poly- or oligodactyly, although rare, do still occur. Such cases represent developmental errors and allow us to quantify the limits of robustness of a particular developmental trait. Robustness is a property that ensures phenotypic stability, and as such, it is very important for system behaviour and evolution. Disease can also be viewed as a breakdown of robustness mechanisms. Therefore, understanding the general principles of what makes a biological system robust is a fundamental problem in biology. To find satisfactory answers to similar basic questions, a common practice is to turn to model systems, where we can easily and rapidly perform a lot of fine experiments. Our favourite system is a small nematode, Caenorhabditis elegans, which is well-known for its simple, fast and highly reproducible development. We propose to focus on a group of epidermal cells of C. elegans, the so-called seam cells, and develop this tissue as a model system to study developmental robustness in animals. These cells have attracted substantial attention because they have stem cell properties, so they divide asymmetrically during larval stages and one daughter cell maintains the proliferating status, whereas the other daughter differentiates into a specialised tissue, such as neurons. As a result of these divisions, wild-type C. elegans adult hermaphrodites have 16 seam cells per lateral side. We would like to characterise the limits of the developmental robustness of this system to genetic (mutations) and environmental variation. Our preliminary data indicate that it is possible to identify mutations that increase seam cell number variation without affecting the mean number of seam cells, so we hope to identify what is the nature of these genes that contribute to ensure phenotypic robustness. We will develop and test hypotheses about how the identified genes play a role in phenotypic robustness and study whether their action is specific for the seam cells or more general to systemic robustness at the whole-animal level. Finally, we will address to what extent our results can be extrapolated to other systems, by studying the evolution of robustness mechanisms in C. briggsae, which is a related nematode species to C. elegans.Our approach will likely enable us to gain insights into the genetic mechanisms and evolution of developmental robustness and derive some general principles about the degree of robustness to quantitative variation in critical regulators and the relative contribution of genes to stabilisation of developmental outcomes. Our goal is to develop broad hypotheses that will be informative to both biomedical scientists interested in robust drug targeting and synthetic biologists who aim at engineering robust biological networks.