6.1: Introduction

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With the magnitude and diversity of bacterial populations in human body, human microbiome has many common properties with natural ecosystems researched in environmental biology. As a field with a large number of quantitative problems to tackle, bacterial genomics offers an opportunity for computational biologist to be actively involved in the progress of this research area.

There are approximately 10¹⁴ microbial cells in an average human gut, whereas there are only 10¹³ human cells in a human body in total. Furthermore, there are 10¹² external microbial cells living on our skin. From a cell count perspective, this corresponds to 10 times more bacterial cells in our body than our own cells. From a gene count perspective, there are 100 times more genes belonging to the bacteria living in/on us than to our own cells. For this reason, these microbial communities living in our bodies are an integral part of what makes us human and we should research upon these genes that are not directly encoded in our genome, but still have a significant effect on our physiology.

Evolution of microbiome research

Earlier stages of microbiome research were mostly based on data collection and analysis of surveys of bacterial groups present in a particular ecosystem. Apart from collecting data, this type of research also involved sequencing of bacterial genomes and identification of gene markers for determining different bacterial groups present in the sample. The most commonly used marker for this purpose is 16S rRNA gene, which is a section of the prokaryotic DNA that codes for ribosomal RNA. Three main features of 16S gene that makes it a very effective marker for microbiome studies are: (1) its short size (∼1500 bases) that makes it cheaper to sequence and analyze, (2) high conservation due to exact folding requirements of the ribosomal RNA it encodes for, and (3) its specificity to prokaryote organisms that allows us to differentiate from contaminant protist, fungal, plant and animal DNAs.

A further direction in early microbial research was inferring rules from generated datasets upon microbial ecosystems. These studies investigated initially generated microbial data and tried to understand rules of microbial abundance in different types of ecosystems and infer networks of bacterial populations regarding their co-occurrence, correlation and causality with respect to one another.

A more recent type of microbial research takes a predictive approach and aims to model the change of bacterial populations in an ecosystem through time making use of differential equations. For example, we can model the rate of change for the population size of a particular bacterial group in human gut as an ordinary differential equation (ODE) and use this model to predict the size of the population at a future time point by integrating over the time interval.

We can further model change of bacterial populations with respect to multiple parameters, such as time and space. When we have enough data to represent microbial populations temporally and spatially, we can model them using partial differential equations (PDEs) for making predictions using multivariate functions.

Data generation for microbiome research

Data generation for microbiome research usually follows the following work-flow: (1) a sample of microbial ecosystem is taken from the particular site being studied (e.g. a patient’s skin or a lake), (2) the DNAs of the bacteria living in the sample are extracted, (3) 16S rDNA genes are sequenced, (4) conserved motifs in some fraction of the 16S gene (DNA barcodes) are clustered into operational taxonomic units (OTUs), and (5) a vector of abundance is constructed for all species in the sample. In microbiology, bacteria are classified into OTUs according to their functional properties rather than species, due to the difficulty in applying the conventional species definition to the bacterial world.

In the remainder of the lecture, a series of recent studies that are related to the field of bacterial genomics and human microbiome studies are described.