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

鲁棒性是指系统在存在扰动的情况下保持性能的能力。这是工程学中一个非常重要的原则，桥梁、飞机或互联网等系统的设计都是为了承受各种干扰并保持功能。鲁棒性是生命系统的一个同样重要的属性。然而，人们对生物鲁棒性的研究和理解却很少，事实上，生物系统如何进化到在内部和外部扰动的情况下可重复地运行是值得注意的。特别是，发育对遗传和环境变异非常敏感，这有助于受精卵转化为多细胞个体。人类发育稳健性的一个非常突出的例子是五个手指的存在，这个数字对个体之间遗传组成的变化或环境的差异非常稳健。然而，强大的系统并不是绝对可靠的，也会犯错误，所以多指或少指的情况虽然罕见，但仍然会发生。这种情况代表了发育错误，使我们能够量化特定发育特征的鲁棒性极限。鲁棒性是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。疾病也可以被看作是强健机制的崩溃。因此，理解是什么使生物系统健壮的一般原理是生物学中的一个基本问题。 为了对类似的基本问题找到满意的答案，通常的做法是转向模型系统，在那里我们可以轻松快速地进行大量精细的实验。我们最喜欢的系统是一种小型线虫，秀丽隐杆线虫，它以其简单，快速和高度可重复的发展而闻名。我们建议集中在一组表皮细胞的C。秀丽线虫，即所谓的缝细胞，并将这种组织开发为研究动物发育稳健性的模型系统。这些细胞吸引了大量的关注，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。由于这些分裂，野生型C.秀丽线虫雌雄同体成虫每侧有16个缝细胞。我们想证明这个系统对遗传（突变）和环境变化的发育鲁棒性的限制。我们的初步数据表明，有可能确定增加接缝细胞数量变异而不影响接缝细胞平均数量的突变，因此我们希望确定这些基因的性质有助于确保表型稳健性。我们将开发和测试关于所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否对接缝细胞具有特异性，或者更普遍地对整个动物水平的系统稳健性具有特异性。最后，通过研究C语言中鲁棒性机制的演变，我们将讨论我们的结果在多大程度上可以外推到其他系统。briggsae是与C.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节因子中定量变化的稳健性程度和基因对发育结果稳定性的相对贡献的一般原则。我们的目标是开发广泛的假设，这将是翔实的生物医学科学家有兴趣在强大的药物靶向和合成生物学家谁的目的是工程强大的生物网络。

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.