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The RHCE*CeRN allele: molecular junction characterization and frequency distribution in Sub-Saharan African

Assia Hadjkali1, Caroline Izard1,2, Laurine Laget1,2

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The CeRN allele, a hybrid RHCE-D-CE gene, was found to involve only exon 4, with a high frequency in The Gambia, particularly among the Fula ethnic group. This finding aids in understanding genetic architecture for diagnostics and transfusion therapy.

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Area of Science:

  • Genetics
  • Molecular Biology
  • Population Genetics

Background:

  • The CeRN (RHCE*02.10) allele arises from hybrid RHCE-D-CE genes, potentially involving exon 4 alone or with part of exon 3.
  • Existing methods cannot differentiate between the two reported CeRN allele variants.
  • Understanding the precise genetic structure and frequency of the CeRN allele is crucial for accurate diagnostics and transfusion practices.

Purpose of the Study:

  • To determine the existence of both reported CeRN alleles.
  • To elucidate the genetic sequence of the CeRN allele.
  • To ascertain the allelic frequencies of CeRN in relevant populations.

Main Methods:

  • Analysis of 17 heterozygous and 10 homozygous CeRN samples.
  • Utilized classical PCR with Sanger sequencing and Oxford Nanopore Next-Generation Sequencing (NGS) with long-range PCR.
  • Investigated CeRN allelic frequency in sub-Saharan populations using data from the 1000 Genomes Project and the International Genome Sample Resource.

Main Results:

  • A single CeRN allele sequence was identified, comprising exon 4 only, with an RHCE-RHD gene junction approximately 400 base pairs upstream of exon 4.
  • The CeRN allele was detected in Gambian ethnic groups, reaching a maximum allelic frequency of 6.0% in the Fula population.
  • The CeRN allele involving exon 4 and part of exon 3 was not observed, suggesting it is either rare or absent in the studied populations.

Conclusions:

  • The study confirmed a single CeRN allele structure (exon 4 only) and identified a high allelic frequency in specific Gambian populations, particularly the Fula.
  • The observed homogeneity and high frequency suggest a single genetic founder event within the Fula ancestral group.
  • The findings have significant implications for refining molecular diagnostics and transfusion strategies, especially in regions with high prevalence of abnormal hemoglobin, and demonstrate the utility of low-coverage whole-genome sequencing for complex variant analysis.