טכניון מכון טכנולוגי לישראל
הטכניון מכון טכנולוגי לישראל - בית הספר ללימודי מוסמכים  
Ph.D Thesis
Ph.D StudentDubovik Tatyana
SubjectDrivers of Variation in Immunity, an Environmentally
Sensitive Complex System
DepartmentDepartment of Medicine
Supervisor Professor Shai Shen-Orr
Full Thesis textFull thesis text - English Version


Abstract

Complex physiological systems such as the immune system are prone to environmental challenges, as the system senses the environment and responds to it. Such systems are likely an outcome of multiple interacting cell-types and the trait they yield is polygenic. Yet, how these genes yield a single network governing the phenotype has not been well defined, making it difficult to prioritize associations. Recently it has been proposed that regulatory networks determining complex traits have a set of “core genes” which are more directly related to the trait and hence are more important. This proposition has been contested especially with respect to the question whether such core could be identified for every trait.

Here we aimed to identify the genetic basis of variation in immune-cellular homeostasis between individuals, a heritable, yet environmentally affected trait. We analyzed immune cellular profiles with multiple phenotypic markers and characterized 11 major immune cell-types in mouse bone marrow. We identified 788 associated genes; whose polygenic information predicts phenotype. These genes form a multi-cellular network architecture that has three main attributes: common control across cell-types, specialized cell-specific programs, and between-cell synchronization. Testing gene evolutionary conservation across 600 million years, we observed a gradual increase                                                                                                                                                                                                                                                                                                                                              in network complexity in line with the division to distinct network attributes. From a functional perspective, regulatory network genes are enriched for turnover functionalities, thus supporting the previously suggested model of core genes. Furthermore, core genes are more central in trait determination and more evolutionary conserved, suggesting their role in even an ancient regulatory network. Contrasting to human studies suggests the regulatory network expands with environmental exposure history. Our findings shed light on the origin of individual immune-cellular variation and regulatory architectures that may generalize to other environmentally sensitive systems.