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

Abstract

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.

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

“…Due to the inherent uncertainty of computational phasing, 28 the analysis was performed with MaCH program settings of 2000 rounds and 500 states 28 . CD59 haplotypes were extracted from the 2504 unrelated individuals of the 1000 Genome Project Phase 3 cohort (chr11:33,702,782–33,725,810; hg38) as described previously 33 and used as reference haplotypes. Heterozygosity at a single site or complete homozygosity allowed for the unambiguous assignment of a haplotype as described previously 34 …”

How Does the Immune System Enter the Brain?

“…ACKR1 mediates inflammatory chemokine shuttling across the BBB and enhances transcellular T-cell diapedesis across the BBB during EAE ( 62 , 63 ). Lack of ACKR1 ameliorates development of EAE and it remains to be shown if individuals lacking functional ACKR1 are protected from MS. Alternatively, also different ACKR1 haplotypes could affect susceptibility to MS. To this end over 900 ACKR1 haplotypes were identified ( 136 ). There is in fact evidence that a strong selective pressure for malaria resistance in the Ethiopian population correlates with the development and maintenance of certain ACKR1 haplotypes ( 137 ).…”