AIRRC5 - Somatic diversification of rearranged Ab gene segments by templated mutagenesis (G. Dale)
100 بار بازدید -
4 سال پیش
-
Session from the "AIRR Community
Session from the "AIRR Community Meeting V – Zooming in to the AIRR Community!" (December 8-10, 2020)
The meeting covers progress reports from the AIRR-C Working Groups & Sub-committees, two scientific sessions (including four short talks chosen from the posters), two interactive poster sessions and four live software tool demonstrations.
https://www.antibodysociety.org/the-a...
Somatic diversification of rearranged antibody gene segments by genome-wide templated mutagenesis
Gordon Dale
PhD Candidate, Emory University School of Medicine
The ability of the humoral immune system to generate antibodies capable of specifically binding a myriad of antigens is critically dependent on the somatic hypermutation program. This program induces both templated mutations (i.e. gene conversion) and untemplated mutations. In humans, somatic hypermutation is widely believed to result in untemplated point mutations. Using a MatLab nested Monte-Carlo script called TRACE (Template Recognition via monte Carlo Experiments) we demonstrate detection of large-scale templated events that occur in human somatically mutated IgHV sequences. We find that such mutations are templated intrachromosomally from IgHV genes and interchromosomally from IgHV pseudogenes as well as other homologous regions unrelated to IgHV genes. These donor regions are used in multiple individuals, and predominantly originate from chromosomes 14, 15, and 16. In addition, we find that exogenous sequences placed at the IgH locus, such as LAIR1 also undergo templated mutagenesis and that homology appears to be the major determinant for donor choice. Further, we find that donor tracts originate from areas in proximity with open chromatin, that are transcriptionally active, and are brought into physical proximity with the IgH locus during the germinal center reaction. These donor sequences are also inserted into the Ig gene segment via putative double strand breaks associated with overlapping AID hotspots. Together, these studies suggest that diversity generated during the germinal center response is driven by untemplated point mutations as well as templated mutagenesis using local and distant regions of the genome.
The meeting covers progress reports from the AIRR-C Working Groups & Sub-committees, two scientific sessions (including four short talks chosen from the posters), two interactive poster sessions and four live software tool demonstrations.
https://www.antibodysociety.org/the-a...
Somatic diversification of rearranged antibody gene segments by genome-wide templated mutagenesis
Gordon Dale
PhD Candidate, Emory University School of Medicine
The ability of the humoral immune system to generate antibodies capable of specifically binding a myriad of antigens is critically dependent on the somatic hypermutation program. This program induces both templated mutations (i.e. gene conversion) and untemplated mutations. In humans, somatic hypermutation is widely believed to result in untemplated point mutations. Using a MatLab nested Monte-Carlo script called TRACE (Template Recognition via monte Carlo Experiments) we demonstrate detection of large-scale templated events that occur in human somatically mutated IgHV sequences. We find that such mutations are templated intrachromosomally from IgHV genes and interchromosomally from IgHV pseudogenes as well as other homologous regions unrelated to IgHV genes. These donor regions are used in multiple individuals, and predominantly originate from chromosomes 14, 15, and 16. In addition, we find that exogenous sequences placed at the IgH locus, such as LAIR1 also undergo templated mutagenesis and that homology appears to be the major determinant for donor choice. Further, we find that donor tracts originate from areas in proximity with open chromatin, that are transcriptionally active, and are brought into physical proximity with the IgH locus during the germinal center reaction. These donor sequences are also inserted into the Ig gene segment via putative double strand breaks associated with overlapping AID hotspots. Together, these studies suggest that diversity generated during the germinal center response is driven by untemplated point mutations as well as templated mutagenesis using local and distant regions of the genome.
4 سال پیش
در تاریخ 1399/09/27 منتشر شده
است.
100
بـار بازدید شده