Abstract
Although mutation and natural selection have given rise to our immune system, a well-placed mutation can also cripple it, and within an expanding population we are recognizing more and more cases of single-gene mutations that compromise immunity. These mutations are an ideal tool for understanding human immunology, and there are more ways than ever to measure their physiological effects. There are also more ways to create mutations in the laboratory, and to use these resources to systematically define the function of every gene in our genome. This review focuses on the discovery and creation of mutations in the context of mammalian immunity, with an emphasis on the use of genome-wide chemical and CRISPR/Cas9 mutagenesis to reveal gene function.
Highlights
The origins of immunity Since the emergence of unicellular life, there have been few selective pressures more abundant than infection
This review focuses on the discovery and creation of mutations in the context of mammalian immunity, with an emphasis on the use of genome-wide chemical and CRISPR/Cas[9] mutagenesis to reveal gene function
How does a pathogen infect its target cell, and how does that cell react? How does a hematopoietic stem cell give rise to a diverse range of lineages, and what allows a malignant lymphocyte to escape these boundaries of proliferation? These questions and many others may all be addressed with cellular CRISPR/Cas[9] mutagenesis
Summary
The origins of immunity Since the emergence of unicellular life, there have been few selective pressures more abundant than infection. Along with archives of targeted mouse mutants, the establishment of high-throughput phenotyping pipelines has meant that diverse phenotypes can be explored systematically in a single facility, rather than sequentially over many years in several different labs This has already led to some unexpected discoveries, with new phenotypes detected for 56 of the first 250 genes analyzed.[28] Many of these genes had been examined by specialist laboratories in the past, but certain physiological functions had never been suspected and were never examined (or reported). Mutagenizing cells immediately after enrichment ensures that mutations will persist in either a hemizygous (if haploid) or homozygous (if diploid) state, and can be used directly for recessive screens.[57,58] By combining this approach with directed hCas[9] transgene
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