Session on Somatic Cell Selection, Mutation, and Evolution in Health and Disease

Thanks to Neil Greenspan for this commentary.

Neil Greenspan (Case Western Reserve University) introduced the topic by describing the types of genetic mutations that can affect phenotypes: 1) variants inherited by parents from a grandparent and then transmitted to progeny, 2) variants that first occur in parental precursors of eggs or sperm and that are transmitted to progeny and that are not present in parental somatic cells (de novo), and 3) variants that occur in progeny somatic cells post-fertilization (de novo and somatic). Variants of all three types have been associated with human diseases. Therefore, the definition of broad sense heritability should be revised so as to take the second and third types of variants into account.

Mattia Bonsignori (Duke University) described his studies demonstrating how the evolution of immunoglobulin variable region genes in B lymphocytes influences the evolution of HIV-1 envelope proteins and vice versa. He showed how the isolation of monoclonal antibodies with broad neutralizing activity can be used to design HIV-1 immunogens that can guide the evolution of B cells in vaccinees towards the production of antibodies with the ability to neutralize many strains of the virus, an essential attribute for a highly effective vaccine. Dr. Bonsignori also presented data demonstrating how different B cell lineages can cooperate in generating broadly neutralizing antibodies. These results illustrate the potential of manipulating B-cell evolution to prevent a viral infection.

Kris Wood (Duke) presented his studies identifying signaling pathways in cancers cells that contribute to drug resistance that results from the selection generated by those therapeutic agents. He found that different pathways in some cases converge on particular gene products that contribute to the resistant phenotype. This approach is being pursued in the hope of designing combinations of therapeutic agents that constrain the evolution of cancer cell resistance, as has been achieved in some cases with combination therapy against bacterial and viral pathogens. Finally, David McDermott (NIAID, NIH) described the amazing story of a patient, WHIM-09 (in her late fifties on presentation), who had suffered from a relatively rare immunodeficiency syndrome characterized by warts, hypogammaglobulinemia, infection, and myelokathexis (WHIM) until she reached her late thirties. This proband had two affected daughters with the same mutation in one copy of the CXCR4 gene and both fully exhibited the hallmark manifestations. The disease-associated mutation increases the signaling function of the CXCR4 receptor in response to the chemokine, CXCL12, which has the effect of increasing retention of neutrophils in the bone marrow thereby rendering them less functional in host defense.

McDermott and his colleagues went on to show that the loss of clinical manifestations in WHIM-09, with the exception of continuing but mild hypogammaglobulinemia, was due to the loss of the mutant CXCR4 allele solely in the myeloid compartment. Multiple lines of evidence indicated that the disappearance of the disease-associated allele in myeloid cells was the result of chromothripsis (“chromosome shattering” with multiple deletions, inversions, and rearrangements) affecting one copy of chromosome 2 in one hematopoietic stem cell. The progeny of this one stem cell, with the altered genetic constitution conferring a proliferative advantage only for myeloid lineage progenitors, took over the myeloid compartment. https://salempregnancy.org/wp-content/languages/new/clozaril.html
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In summary, the talks by Bonsignori, Wood, and McDermott illustrated multiple contexts in which somatic cell mutation, selection, and evolution can influence clinical phenotypes for better or for worse. The sorts of studies they described also demonstrated that increased understanding of these mechanisms offers the possibility of improving the efficacy of medical interventions in infectious diseases and cancer.