The human Deleted in Azoospermia gene family : structure, function and evolution

Abstract

The human Deleted in Azoospermia genes lie within the AZFc region of the Y chromosome that is frequently deleted in men with severe spermatogenic failure and male infertility. This thesis describes the evolution, structure and function of human DAZ genes. First, we determined that Y-linked DAZ genes arose by transposition from an autosomal ancestor during primate evolution, and were repeatedly amplified and pruned by multiple splicing mutations. This was the first example of acquisition of a male fertility factor by the Y chromosome independent of the X chromosome in any species. Then, we characterized the genomic structure and organization of four Y-linked DAZ genes in two clusters within the AZFc region. We found that each cluster has an inverted head to head pair of two DAZ genes. All DAZ genes appear capable of encoding DAZ proteins and two of these DAZ genes encode proteins with multimeric RNAbinding domains. We found transcripts from three DAZ genes. Next we determined the molecular nature of DAZ gene polymorphism in men. We deciphered 49f/a TaqI polymorphism, which corresponds to polymorphism in 2.4 kb repeats within all DAZ genes, and studied homogenization and deletion of one or the other DAZ gene cluster. We find that DAZ genes and corresponding DAZ proteins are highly polymorphic in different human Y chromosomal lineages. In the first appendix, we describe characterization of AZFc region deletions in three infertile men, two of whom have deletions of one DAZ cluster. In the second appendix, we describe partial rescue of the meiotic entry defect in Drosophila boule by overexpression of human DAZ and mouse DAZL proteins in testes of boule deficient flies. This functional assay suggests some functional conservation of DAZ and boule function. This thesis uncovers the genomic complexity, dynamic instability and evolution of a Y chromosomal gene family that is important for its role in human male fertility.