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J Immunol. 2018 Sep 15;201(6):1765-1774. doi: 10.4049/jimmunol.1800100. Epub 2018 Aug 10.

Nucleotide Composition of Human Ig Nontemplated Regions Depends on Trimming of the Flanking Gene Segments, and Terminal Deoxynucleotidyl Transferase Favors Adding Cytosine, Not Guanosine, in Most VDJ Rearrangements.

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Department of Clinical Biochemistry, Zealand University Hospital, Roskilde 4000, Denmark.
Department of Clinical Immunology, Odense University Hospital, Odense 5000, Denmark.
Medical Research Council Human Immunology Unit, Weatherall Institute of Molecular Medicine, University of Oxford, Oxfordshire OX3 9DS, United Kingdom.
Randall Centre for Cell and Molecular Biophysics, School of Basic and Medical Biosciences, King's College London, London SE1 1UL, United Kingdom.
Department of Otorhinolaryngology-Head and Neck Surgery, Odense University Hospital, Odense 5000, Denmark.
OPEN, Odense Patient Data Explorative Network, Odense University Hospital, Odense 5000, Denmark; and.
Clinical Department, University of Southern Denmark, Odense 5000, Denmark.
Department of Clinical Immunology, Odense University Hospital, Odense 5000, Denmark;


The formation of nontemplated (N) regions during Ig gene rearrangement is a major contributor to Ab diversity. To gain insights into the mechanisms behind this, we studied the nucleotide composition of N regions within 29,962 unique human VHDJH rearrangements and 8728 unique human DJH rearrangements containing exactly one identifiable D gene segment and thus two N regions, N1 and N2. We found a distinct decreasing content of cytosine (C) and increasing content of guanine (G) across each N region, suggesting that N regions are typically generated by concatenation of two 3' overhangs synthesized by addition of nucleoside triphosphates with a preference for dCTP. This challenges the general assumption that the terminal deoxynucleotidyl transferase favors dGTP in vivo. Furthermore, we found that the G and C gradients depended strongly on whether the germline gene segments were trimmed or not. Our data show that C-enriched N addition preferentially happens at trimmed 3' ends of VH, D, and JH gene segments, indicating a dependency of the transferase mechanism upon the nuclease mechanism.

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