Polymorphic differences within HLA-C alleles contribute to alternatively spliced transcripts lacking exon 5

Femke A I Ehlers, Timo I Olieslagers, Mathijs Groeneweg, Gerard M J Bos, Marcel G J Tilanus, Christina E M Voorter, Lotte Wieten*

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review

Abstract

The human leukocyte antigen (HLA) genes are amongst the most polymorphic in the human genome. Alternative splicing could add an extra layer of complexity, but has not been studied extensively. Here, we applied an RNA based approach to study the influence of allele polymorphism on alternative splicing of HLA-C in peripheral blood. RNA was isolated from these peripheral cells, converted into cDNA and amplified specifically for twelve common HLA-C allele groups. Through subsequent sequencing of HLA-C, we observed alternative splicing variants of HLA-C*04 and *16 that resulted in exon 5 skipping and were co-expressed with the mature transcript. Investigation of intron 4 sequences of HLA-C*04 and *16 compared to other HLA-C alleles demonstrated no effect on predicted splice sites and branch point. To further investigate if the unique polymorphic positions in exon 5 of HLA-C*04 or *16 may facilitate alternative splicing by acting on splicing regulatory elements (SRE), in-silico splicing analysis was performed. While the HLA-C*04 specific SNP in exon 5 had no effect on predicted exonic SRE, the HLA-C*16 specific exon 5 SNP did alter exonic SRE. Our findings provide experimental and theoretical support for the concept that polymorphisms within the HLA-C alleles influence the alternative splicing of HLA-C. This article is protected by copyright. All rights reserved.

Original languageEnglish
Pages (from-to)232-243
Number of pages12
JournalHLA
Volume100
Issue number3
Early online date27 Jun 2022
DOIs
Publication statusPublished - Sept 2022

Keywords

  • CANDIDATE
  • CLASS-I
  • ENHANCERS
  • EXPRESSION
  • G MESSENGER-RNA
  • HLA-C
  • IDENTIFICATION
  • MECHANISMS
  • MOLECULE
  • SEQUENCE
  • VARIANT
  • alternative splicing
  • exon skipping
  • splicing regulatory elements

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