Phenotype Heritability in Holobionts: An Evolutionary Model.

Many complex diseases are expressed with high incidence only in certain populations. Genealogy studies determine that these diseases are inherited with a high probability. However, genetic studies have been unable to identify the genomic signatures responsible for such heritability, as identifying the genetic variants that make a population prone to a given disease is not enough to explain its high occurrence within the population. This gap is known as the missing heritability problem. We know that the microbiota plays a very important role in determining many important phenotypic characteristics of its host, in particular the complex diseases for which the missing heritability occurs. Therefore, when computing the heritability of a phenotype, it is important to consider not only the genetic variation in the host but also in its microbiota. Here we test this hypothesis by studying an evolutionary model based on gene regulatory networks. Our results show that the holobiont (the host plus its microbiota) is capable of generating a much larger variability than the host alone, greatly reducing the missing heritability of the phenotype. This result strongly suggests that a considerably large part of the missing heritability can be attributed to the microbiome.

Modeling the Role of the Microbiome in Evolution.

There is undeniable evidence showing that bacteria have strongly influenced the evolution and biological functions of multicellular organisms. It has been hypothesized that many host-microbial interactions have emerged so as to increase the adaptive fitness of the holobiont (the host plus its microbiota). Although this association has been corroborated for many specific cases, general mechanisms explaining the role of the microbiota in the evolution of the host are yet to be understood. Here we present an evolutionary model in which a network representing the host adapts in order to perform a predefined function. During its adaptation, the host network (HN) can interact with other networks representing its microbiota. We show that this interaction greatly accelerates and improves the adaptability of the HN without decreasing the adaptation of the microbial networks. Furthermore, the adaptation of the HN to perform several functions is possible only when it interacts with many different bacterial networks in a specialized way (each bacterial network participating in the adaptation of one function). Disrupting these interactions often leads to non-adaptive states, reminiscent of dysbiosis, where none of the networks the holobiont consists of can perform their respective functions. By considering the holobiont as a unit of selection and focusing on the adaptation of the host to predefined but arbitrary functions, our model predicts the need for specialized diversity in the microbiota. This structural and dynamical complexity in the holobiont facilitates its adaptation, whereas a homogeneous (non-specialized) microbiota is inconsequential or even detrimental to the holobiont's evolution. To our knowledge, this is the first model in which symbiotic interactions, diversity, specialization and dysbiosis in an ecosystem emerge as a result of coevolution. It also helps us understand the emergence of complex organisms, as they adapt more easily to perform multiple tasks than non-complex ones.