Common 5' -globin RFLP haplotypes harbour a surprising level of ancestral sequence mosaicism

• Published in: Human genetics 2003-07, Vol.113 (2), p.123
• Main Authors: Webster, Matthew T, Clegg, John B, Harding, Rosalind M
• Format: Article
• Language: English
• Subjects: Analysis; Ethylenediaminetetraacetic acid; Genes; Genetic aspects; Genetic polymorphisms; Genomes; Genomics
• ISSN: 0340-6717; 1432-1203
• DOI: 10.1007/s00439-003-0954-0

Blocks of linkage disequilibrium (LD) in the human genome represent segments of ancestral chromosomes. To investigate the relationship between LD and genealogy, we analysed diversity associated with restriction fragment length polymorphism (RFLP) haplotypes of the 5[variant prime] β-globin gene complex. Genealogical analyses were based on sequence alleles that spanned a 12.2-kb interval, covering 3.1 kb around the ψβ gene and 6.2 kb of the δ-globin gene and its 5[variant prime] flanking sequence known as the R/T region. Diversity was sampled from a Kenyan Luo population where recent malarial selection has contributed to substantial LD. A single common sequence allele spanning the 12.2-kb interval exclusively identified the ancestral chromosome bearing the "Bantu" βs (sickle-cell) RFLP haplotype. Other common 5[variant prime] RFLP haplotypes comprised interspersed segments from multiple ancestral chromosomes. Nucleotide diversity was similar between ψβ and R/T-δ-globin but was non-uniformly distributed within the R/T-δ-globin region. High diversity associated with the 5[variant prime] R/T identified two ancestral lineages that probably date back more than 2 million years. Within this genealogy, variation has been introduced into the 3[variant prime] R/T by gene conversion from other ancestral chromosomes. Diversity in δ-globin was found to lead through parts of the main genealogy but to coalesce in a more recent ancestor. The well-known recombination hotspot is clearly restricted to the region 3[variant prime] of δ-globin. Our analyses show that, whereas one common haplotype in a block of high LD represents a long segment from a single ancestral chromosome, others are mosaics of short segments from multiple ancestors related in genealogies of unsuspected complexity.