Human bodies are teeming with trillions of microbial cells that comprise the microbiome, many of them bacteria. Although they may be small, some of these bacteria maintain health, but others promote sickness. These differences often come down to the genes in each bacterial genome, but it can be challenging to find and sequence rare strains.
Gang Fang, a geneticist at the Icahn School of Medicine at Mount Sinai, has proposed a new solution called mEnrich-seq that draws on his decade of bacterial epigenomic research to distinguish different species’ DNA for metagenomic studies. In an interview with The Scientist, Fang describes his vision for how mEnrich-seq can help scientists answer hard questions about humans’ bacterial companions.
What are some challenges associated with studying the human microbiome with metagenomics?
We have a lot of technologies to understand the microbiome in many different ways, but there is a common problem. If a bacterial species is abundant in a sample, then we can learn almost anything about it, but if the abundance of a species is really low, it is very hard to study. There may even be two or three coexisting strains of the same species, and the important strain may not be the one that is relatively more abundant. These different strains are often very similar in terms of their genomes, so it is extremely hard to differentiate between them.
What motivated you to develop mEnrich-seq?
If a target is rare, most of the sequencing throughput will be consumed by the more abundant species. The moment we sequence, we have already lost this battle, so we needed a new strategy before sequencing. The natural epigenetic barcodes in bacteria give us a unique way to solve this problem. Even though different species and strains have similar genomes, they often encode different DNA methyltransferases, which determine their DNA methylation patterns. Bacteria do this to differentiate between self and foreign DNA. We can use this to differentiate between species’ or strains’ genomes based on the global methylation pattern.
If we want to target a certain genome and we know its methylation pattern, we can rationally choose restriction enzymes that will cut at a certain sequence called the methylation motif. The enzymes will digest the vast majority of the background DNA that does not have this matching methylation. With mEnrich-seq, we can enrich bacteria of interest over 100-fold.
By Aparna Nathan, PhD
Article can be accessed on: The Scientist