Evolutionary Constraints in the beta-Globin Cluster: The Signature of Purifying Selection at the delta-Globin (HBD) Locus and Its Role in Developmental Gene Regulation

• Type: Article in International Scientific Journal
• Date: 2013

Authors

Ana Moleirinho (Author) Other; Susana Seixas (Author) Other; Alexandra M Lopes (Author) Other; Celeste Bento (Author) Other; Maria J Prata (Author) FCUP; Antonio Amorim (Author) FCUP

Journal

Title: Genome Biology and Evolution

Vol. 5

Pages: 559-571

ISSN: 1759-6653

Publisher: Oxford University Press

Indexing

ISI Web of Knowledge - 14 Citations

Scopus - 14 Citations

Scientific classification

FOS: Natural sciences > Earth and related Environmental sciences

Other information

Authenticus ID: P-005-3FN

DOI: 10.1093/gbe/evt029

Abstract (EN): Human hemoglobins, the oxygen carriers in the blood, are composed by two alpha-like and two beta-like globin monomers. The beta-globin gene cluster located at 11p15.5 comprises one pseudogene and five genes whose expression undergoes two critical switches: the embryonic-to-fetal and fetal-to-adult transition. HBD encodes the delta-globin chain of the minor adult hemoglobin (HbA(2)), which is assumed to be physiologically irrelevant. Paradoxically, reduced diversity levels have been reported for this gene. In this study, we sought a detailed portrait of the genetic variation within the beta-globin cluster in a large human population panel from different geographic backgrounds. We resequenced the coding and noncoding regions of the two adult beta-globin genes (HBD and HBB) in European and African populations, and analyzed the data from the beta-globin cluster (HBE, HBG2, HBG1, HBBP1, HBD, and HBB) in 1,092 individuals representing 14 populations sequenced as part of the 1000 Genomes Project. Additionally, we assessed the diversity levels in nonhuman primates using chimpanzee sequence data provided by the PanMap Project. Comprehensive analyses, based on classic neutrality tests, empirical and haplotype-based studies, revealed that HBD and its neighbor pseudogene HBBP1 have mainly evolved under purifying selection, suggesting that their roles are essential and nonredundant. Moreover, in the light of recent studies on the chromatin conformation of the beta-globin cluster, we present evidence sustaining that the strong functional constraints underlying the decreased contemporary diversity at these two regions were not driven by protein function but instead are likely due to a regulatory role in ontogenic switches of gene expression.

Language: English

Type (Professor's evaluation): Scientific

No. of pages: 13