Molecular analysis of the <i>ICAM4</i> gene in an autochthonous East African population

Yin, Qinan; Srivastava, Kshitij; Schneider, Jordan B.; Gebremedhin, Amha; Makuria, Addisalem Taye; Flegel, Willy A.

doi:10.1111/trf.15217

Cited by 3 publications

(4 citation statements)

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“…In clinical diagnostics for patients, long-range haplotypes harboring novel or rare SNVs can only be detected when the haplotype is sequenced at full-length [ 92 ]. Using Sanger sequencing, we have previously characterized the ERMAP [ 93 ], ICAM4 [ 94 ], and ACKR1 [ 23 ] blood group genes at the haplotype level and identified prevalent long-range reference alleles, a time consuming and low throughput approach. We showed in this study how long contiguous stretches of homozygosity (LCSH) can serve to generate a database of long haplotypes, as defined by full length nucleotide sequences rather than the concatenation of known SNVs.…”

Section: Discussionmentioning

confidence: 99%

Cataloguing experimentally confirmed 80.7 kb-long ACKR1 haplotypes from the 1000 Genomes Project database

et al. 2021

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Background Clinically effective and safe genotyping relies on correct reference sequences, often represented by haplotypes. The 1000 Genomes Project recorded individual genotypes across 26 different populations and, using computerized genotype phasing, reported haplotype data. In contrast, we identified long reference sequences by analyzing the homozygous genomic regions in this online database, a concept that has rarely been reported since next generation sequencing data became available. Study design and methods Phased genotype data for a 80.6 kb region of chromosome 1 was downloaded for all 2,504 unrelated individuals of the 1000 Genome Project Phase 3 cohort. The data was centered on the ACKR1 gene and bordered by the CADM3 and FCER1A genes. Individuals with heterozygosity at a single site or with complete homozygosity allowed unambiguous assignment of an ACKR1 haplotype. A computer algorithm was developed for extracting these haplotypes from the 1000 Genome Project in an automated fashion. A manual analysis validated the data extracted by the algorithm. Results We confirmed 902 ACKR1 haplotypes of varying lengths, the longest at 80,584 nucleotides and shortest at 1,901 nucleotides. The combined length of haplotype sequences comprised 19,895,388 nucleotides with a median of 16,014 nucleotides. Based on our approach, all haplotypes can be considered experimentally confirmed and not affected by the known errors of computerized genotype phasing. Conclusions Tracts of homozygosity can provide definitive reference sequences for any gene. They are particularly useful when observed in unrelated individuals of large scale sequence databases. As a proof of principle, we explored the 1000 Genomes Project database for ACKR1 gene data and mined long haplotypes. These haplotypes are useful for high throughput analysis with next generation sequencing. Our approach is scalable, using automated bioinformatics tools, and can be applied to any gene.

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Section: Discussionmentioning

confidence: 99%

Cataloguing experimentally confirmed 80.7 kb-long ACKR1 haplotypes from the 1000 Genomes Project database

et al. 2021

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“…All individuals have been genotyped for five blood group systems 27 while 18 individuals have been red cell genotyped for another 12 blood group systems 26 . Blood samples from 60 other volunteer blood donors were collected from a distinct East African region as published previously, transported to NIH under the NCT01282021 protocol, and genomic DNA was extracted 28,29 …”

Section: Methodsmentioning

confidence: 99%

“…26 Blood samples from 60 other volunteer blood donors were collected from a distinct East African region as published previously, transported to NIH under the NCT01282021 protocol, and genomic DNA was extracted. 28,29…”

Section: Study Subjectsmentioning

confidence: 99%

CD59 gene: 143 haplotypes of 22,718 nucleotides length by computational phasing in 113 individuals from different ethnicities

Srivastava,

Yin,

Makuria

et al. 2024

Transfusion

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BackgroundCD59 deficiency due to rare germline variants in the CD59 gene causes disabilities, ischemic strokes, neuropathy, and hemolysis. CD59 deficiency due to common somatic variants in the PIG‐A gene in hematopoietic stem cells causes paroxysmal nocturnal hemoglobinuria. The ISBT database lists one nonsense and three missense germline variants that are associated with the CD59‐null phenotype. To analyze the genetic diversity of the CD59 gene, we determined long‐range CD59 haplotypes among individuals from different ethnicities.MethodsWe determined a 22.7 kb genomic fragment of the CD59 gene in 113 individuals using next‐generation sequencing (NGS), which covered the whole NM_203330.2 mRNA transcript of 7796 base pairs. Samples came from an FDA reference repository and our Ethiopia study cohorts. The raw genotype data were computationally phased into individual haplotype sequences.ResultsNucleotide sequencing of the CD59 gene of 226 chromosomes identified 216 positions with single nucleotide variants. Only three haplotypes were observed in homozygous form, which allowed us to assign them unambiguously as experimentally verified CD59 haplotypes. They were also the most frequent haplotypes among both cohorts. An additional 140 haplotypes were imputed computationally.DiscussionWe provided a large set of haplotypes and proposed three verified long‐range CD59 reference sequences, based on a population approach, using a generalizable rationale for our choice. Correct long‐range haplotypes are useful as template sequences for allele calling in high‐throughput NGS and precision medicine approaches, thus enhancing the reliability of clinical diagnostics. Long‐range haplotypes can also be used to evaluate the influence of genetic variation on the risk of transfusion reactions or diseases.

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“…There is also first studies highlighting polymorphisms in adhesion molecules, e.g. for ICAM4, among African ethnicities ( 138 ). It will be interesting to see if polymorphisms in adhesion molecules involved in MS pathogenesis may influence susceptibility to MS in the African population.…”

Section: Genetic Factorsmentioning

confidence: 99%

How Does the Immune System Enter the Brain?

Mapunda

Tibar²,

Regragui³

et al. 2022

Front. Immunol.

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Multiple Sclerosis (MS) is considered the most frequent inflammatory demyelinating disease of the central nervous system (CNS). It occurs with a variable prevalence across the world. A rich armamentarium of disease modifying therapies selectively targeting specific actions of the immune system is available for the treatment of MS. Understanding how and where immune cells are primed, how they access the CNS in MS and how immunomodulatory treatments affect neuroinflammation requires a proper knowledge on the mechanisms regulating immune cell trafficking and the special anatomy of the CNS. The brain barriers divide the CNS into different compartments that differ with respect to their accessibility to cells of the innate and adaptive immune system. In steady state, the blood-brain barrier (BBB) limits immune cell trafficking to activated T cells, which can reach the cerebrospinal fluid (CSF) filled compartments to ensure CNS immune surveillance. In MS immune cells breach a second barrier, the glia limitans to reach the CNS parenchyma. Here we will summarize the role of the endothelial, epithelial and glial brain barriers in regulating immune cell entry into the CNS and which immunomodulatory treatments for MS target the brain barriers. Finally, we will explore current knowledge on genetic and environmental factors that may influence immune cell entry into the CNS during neuroinflammation in Africa.

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Molecular analysis of the ICAM4 gene in an autochthonous East African population

Cited by 3 publications

References 6 publications

Cataloguing experimentally confirmed 80.7 kb-long ACKR1 haplotypes from the 1000 Genomes Project database

Cataloguing experimentally confirmed 80.7 kb-long ACKR1 haplotypes from the 1000 Genomes Project database

CD59 gene: 143 haplotypes of 22,718 nucleotides length by computational phasing in 113 individuals from different ethnicities

How Does the Immune System Enter the Brain?

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