Evolution of immunogenetic components encoding ultralong CDR H3

Area of Science:

• Immunology
• Genomics
• Evolutionary Biology

Background:

• Vertebrate antibody diversity arises from V, D, and J gene segments, creating variable CDR3 sequences.
• Cattle exhibit fewer VDJ segments, necessitating alternative strategies for antibody diversity, such as ultralong-encoding IGHV and IGHD gene segments.
• These ultralong segments generate elongated CDR H3 regions and unique paratope microdomains for broad antigen epitope binding.

Purpose of the Study:

• To investigate the evolutionary timeline of ultralong-encoding immunoglobulin heavy variable (IGHV) and immunoglobulin heavy diversity (IGHD) gene segments in Bovidae species.
• To determine when the genetic duplication responsible for the TTVHQ motif in ultralong IGHV segments emerged.

Main Methods:

• Genome sequencing and analysis of twelve Bovidae species.
• Identification of specific 8-bp duplications within IGHV segments.
• mRNA analysis from bison spleen to assess the expression of ultralong CDR H3 antibody transcripts.

Main Results:

• The 8-bp duplication encoding the TTVHQ motif in ultralong IGHV segments was found in six Bovid species within the Bos and Bison genera.
• Ultralong-encoding IGHD gene segments were identified in the same species, excluding the domestic yak, and were confined to the Bos and Bison clade.
• Bison spleen mRNA analysis revealed a rich repertoire of expressed ultralong CDR H3 antibody transcripts, indicating their use in host defense.

Conclusions:

• The genetic duplication for ultralong IGHV segments and the emergence of ultralong IGHD segments likely occurred in a common ancestor of the Bos and Bison genera.
• This evolutionary event is estimated to have happened 5-10 million years ago, providing a unique mechanism for antibody diversity in these lineages.