Diversity in the preimmune immunoglobulin repertoire of SHR lines susceptible and resistant to end-organ injury.

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We used next-generation sequencing to identify IGH genetic variation in two closely related hypertensive rat lines that differ in susceptibility to end-organ disease (SHR-A3 and SHR-B2). The two SHR lines differ extensively at the IGH locus from the rat reference genome sequence (RRGS) and from each other, creating 306 sequence unique IGH genes. Compared to IGH genes mapped in the RRGS, 98 are null gene alleles (31 are null in both SHR lines, 45 are null in SHR-A3 only, and 23 are null in SHR-B2 only). Of the 306 divergent gene sequences, 126 result in amino acid substitution and, among these, SHR-A3 and SHR-B2 differ from one another at the amino acid level in 96 segments. Twelve pseudogenes in the RRGS had changes displacing the stop codon and creating probable functional genes in either or both SHR-A3 and SHR-B2. A further 5 alleles that encoded functional RRGS genes or open reading frames were converted to pseudogenes in either or both SHR-A3 and SHR-B2. These studies reveal that the pre-immune immunoglobulin repertoire is highly divergent among SHR lines differing in end organ injury susceptibility and this may modify immune mechanisms in hypertensive renal injury.