Metagenetics: spending our inheritance on the future
Consider a proposal
Just as genetics indelibly shaped our understanding of solitary bacterial existence, so it can transform our understanding of bacteria as they engage in community life. This will require a new application of mutant analyses in a community context. Let's call this ‘metagenetics’, to highlight the concept of an analysis that transcends individuals (‘meta’ in Greek means ‘transcendent’). Metagenetics provides a parallel with metagenomics – genetics and genomics deal with single organisms and metagenetics and metagenomics both apply to analysis of a multi-genome unit, or community.
Consider the past
The glory of the last 50 years of microbiology is founded, in large part, on genetic analysis. Every aspect of cellular bacterial life has been cracked by the use of mutants. Metabolic pathways have been defined by analyses of mutants blocked in various biochemical steps. Macromolecular synthesis, membrane function and chemotaxis yielded to the chisel of genetics. Later, the study of protein structure and function emerged based on precise, single amino acid changes generated by point mutations.
The mark of microbial genetics extends beyond understanding the working of the bacterial cell. The foundation for microbial evolution was provided by the classic Luria–Delbrück fluctuation test and the Lederbergs' replica plating experiment. Both provided irrefutable evidence that bacterial evolution depends on pre-existing mutations that are independent of selection pressure. The impact of these landmark experiments was felt throughout biology because they presented potent fortification for the Darwinian concept of evolution that pre-existing variation in populations that are acted upon by natural selection.
In the early days of bacterial genetics, classical crosses and complementation analysis were accomplished through conjugation, transformation, and transduction, fostering associations between genes, functions, and ultimately proteins. Genetics lost some of its abstract nature and advanced to a new level when it became possible to physically isolate genes by cloning. The advent of DNA sequencing generated a new depth of understanding of the nature of mutations, making mutant analysis more powerful than ever. The satisfying level of precision provided by molecular genetic analysis has created a gold standard of proof in modern microbiology. This, in turn, has generated a two-class distinction of sub-fields of microbiology. Sadly, ecology has been largely relegated to the less desirable class by many of those who study solitary bacterial life because they find the types of evidence and structure of arguments in ecological study to lack the precision to which they are accustomed. All of that can change.
Consider the future
Metagenetics will dissect ecological questions at a new level of precision. But unlike the early days of bacterial genetics, the new field of metagenetics will be buttressed by vast databases of sequence from metagenomic analysis. Metagenomics will generate hypotheses to be tested with genetics as well as the sequence information on which to base mutant construction.
Metagenetics will need to embrace both random mutagenesis, which is a way of giving voice to the bacteria, and directed mutant analysis, which is driven (and limited by) the imagination of the investigator. In the first, we will mutagenize a pure culture and then screen the random mutants for a community phenotype. In the second, we will create a defined mutant in a gene of interest and determine its phenotype in the community context. We might, for example screen a randomly mutagenized population of bacteria for the loss of ability to invade a community or we might construct a mutant lacking flagella and determine whether it is affected in the ability to invade. Both approaches will be facilitated by available genome maps, sequence information and extensive ‘-omics’ (transcriptomics, proteomics and metabolomics) data.
Metagenetics on culturable community members may not seem all that different from classical genetics except in the nature of the phenotype tested. But the bold advance will issue from development of genetic tools to study unculturable members. For example, imagine the power of knocking out all homologues of a particular gene in all members of the community? What would happen if we knocked out all of the polysaccharide biosynthesis genes in a community? Alternatively, what if we knocked them out only in one family of bacteria? Highly specific conjugal vectors and sequence-based homing devices can make these approaches reality. Metagenomics will furnish the raw material for such studies – sequence information from the unculturable members of the community that will form the basis for generating hypotheses and genetic devices to make targeted changes.
Metagenetics, in concert with the other tools of the ecologist, including statistics, modelling, microscopy, radioactive labels, chemical analysis and meta-omics, will elevate the level of rigor and precision with which we can approach community-level microbial ecology. Just as early bacterial genetics provided critical data beyond microbiology, to the entire field of evolution, microbial metagenetics may advance the entire field of ecology by answering questions at a level and with tools that are not possible in macroecological systems. The lessons from 50 years of bacterial genetics are powerful. Perhaps 50 years from now we will be reflecting on the advancement of ecology by a parallel metagenetic approach.