Achilles Dugaiczyk

The Molecular Clock Runs at Different Rates Among Closely Related Members of a Gene Family

Abstract. The serum albumin gene family is composed of four members that have arisen by a series of duplications from a common ancestor. From sequence differences between members of the gene family, we infer that a gene duplication some 580 Myr ago gave rise to the vitamin D–binding protein (DBP) gene and a second lineage, which reduplicated about 295 Myr ago to give the albumin (ALB) gene and a common precursor to α-fetoprotein (AFP) and α-albumin (ALF). This precursor itself duplicated about 250 Myr ago, giving rise to the youngest family members, AFP and ALF. It should be possible to correlate these dates with the phylogenetic distribution of members of the gene family among different species. All four genes are found in mammals, but AFP and ALF are not found in amphibia, which diverged from reptiles about 360 Myr ago, before the divergence of the AFP-ALF progenitor from albumin.Although individual family members display an approximate clock-like evolution, there are significant deviations—the rates of divergence for AFP differ by a factor of 7, the rates for ALB differ by a factor of 2.1. Since the progenitor of this gene family itself arose by triplication of a smaller gene, the rates of evolution of individual domains were also calculated and were shown to vary within and between family members. The great variation in the rates of the molecular clock raises questions concerning whether it can be used to infer evolutionary time from contemporary sequence differences.

Structural integrity of the human albumin gene in congenital analbuminemia

The human serum albumin gene was analyzed by restriction endonuclease mapping of chromosomal DNA isolated from a patient with congenital analbuminemia. Following digestion with a variety of restriction endonucleases, the DNA from this individual produced the same fragments with homology to a serum albumin cDNA probe as did a control DNA specimen. Therefore, the genetic condition of congenital analbuminemia is not caused by any gross structural rearrangement or deletion of the gene itself, but may result from an abnormality in the genes fine structure, perhaps affecting regulation or processing of the primary RNA transcript.

Structure of the gorilla α-fetoprotein gene and the divergence of primates

Abstract The sequence of the gorilla α-fetoprotein gene, including 869 base pairs of the 5′ flanking region and 4892 base pairs of the 3′ flanking region (24,607 in total), was determined from two overlapping lambda phage clones. The sequence extends 18,846 base pairs from the Cap site to the polyadenylation site, and it reveals that the gene is composed of 15 exons, which are symmetrically placed within three domains of α-fetoprotein. The deduced polypeptide chain is composed of a 19-amino-acid leader peptide, followed by 590 amino acids of the mature protein. The RNA polymerase II binding site, TATAAAA, and the promoter element, CCAAC, are positioned at −21 and −65 from the Cap site, respectively. The polyadenylation signal, AATAAA, is located in the last exon, which is untranslated. The sequence for the gorilla α-fetoprotein gene was compared with that of the previously published human α-fetoprotein gene ( P. E. M. Gibbs, R. Zielinski, C. Boyd, and A. Dugaiczyk, 1987 , Biochemistry 26: 1332–1343). Four types of repetitive sequence elements were found in identical positions in both species. However, one Alu and one Xba DNA repeat within introns 4 and 7, respectively, of the human gene are absent from orthologous positions in the gorilla. The Alu and the Xba DNA repeats probably emerged in the human genome after the human/gorilla divergence and became established novelties in the human lineage. There are 363 21,523 mutational changes between human and gorilla, amounting to 1.69% DNA divergence between the two primate species. The value of 1.69% is lower than the 2.27% obtained from melting temperatures of hybrids between human and gorilla genomic DNA (C. G. Sibley and J. E. Ahlquist, 1984, J. Mol. Evol. 26: 99–121). At the protein level, Homo sapiens differs from Gorilla gorilla only at 4 of 609 amino acid positions (0.665) in the α-fetoprotein sequence. This difference signifies a lower rate of molecular divergence for the α-fetoprotein gene in primates, as compared to rodents.

Genomic expansion across the albumin gene family on human chromosome 4q is directional.

Abstract The albumin gene family arose in a series of duplication events which gave rise to symmetry in its structure. The four genes are tandemly linked on human chromosome 4q in the order: 5′ ALB-5′ AFP-5′ ALF-5′ DBP-centromere, and their introns display a symmetrical and repetitive pattern that is shared by members of the gene family. These repetitive motifs provide an internal reference, allowing observations of evolutionary changes within a single line (human) of evolutionary descent. The four genes and three intergenic regions between them increase in size as they get closer to the centromere. An invasion by multiple repetitive DNA elements may account, in part, for this expansion.

Structure and Evolution of the Serum Albumin Gene Family

Abstract The serum albumin gene family is comprised of three known members: serum albumin, α-fetoprotein, and a vitamin D-binding α-globulin, also known as the group-specific component (Gc) protein. In humans, the three genes map within q11-22 of chromosome 4. Despite their close linkage and great similarity in structure, their mode and tempo of evolution appears to be distinctly different. The rate of evolutionary change of α-fetoprotein approaches that of pseudogenes. Albumin evolves at a slower rate, although still faster than hemoglobin. At some time after the mammalian radiation, the introns of the human albumin gene were invaded by Alu repetitive DNA sequences.

The Structure and Regulation of the Natural Chicken Ovomucoid Gene

The molecular mechanism by which steroid hormones regulate specific gene expression has been an area of acute interest during the past several years. One particularly attractive model system for studying this hormonal regulation has been the hen oviduct (O’Malley et al. 1969). A number of laboratories, in addition to our own, have utilized this model system for investigations of eucaryotic molecular biology (Oka and Schimke 1969; Palmiter and Schimke 1973; Palmiter et al. 1976; Cox 1977; Hynes et al. 1977; Garapin et al. 1978b; Mandel et al. 1978). Administration of estrogen to the newborn chick stimulates oviduct growth and differentiation and results in the appearance of a number of new specific intracellular proteins (O’Malley et al. 1969; Hynes et al. 1977; Palmiter 1973; Chan et al. 1973; Harris et al. 1973, 1975; Sullivan et al. 1973; O’Malley and Means 1974). The synthesis of one of these proteins, ovalbumin, has been studied extensively. Ovalbumin mRNA has been purified (Rosen et al. 1975), and a full-length dsDNA copy synthesized (Monahan et al. 1976b) and cloned in a bacterial plasmid (McReynolds et al. 1977). More recently, ovalbumin genomic DNA sequences have been isolated from restriction enzyme digests of hen DNA and cloned (Woo et al. 1978). The other three major proteins under estrogenic control in the oviduct tubular gland cell, ovomucoid, conalbumin and lysozyme, have been less extensively studied (Palmiter 1972; Hynes et al. 1977).