As the scope of DNA sequencing is widened, more and more detailed information on the current status of the human genome will become available. Distinguishing details that are relics of irrelevant evolutionary accidents from changes important for current normal function will be difficult. Intense studies of the history of representative genetic elements is an important tool for developing ways of making this distinction, and of unraveling how the human genome reached its present form. In order to increase our understanding of the plasticity of the human genome at the molecular level, with special emphasis on the evolution of multigene families, I propose to continue my intensive study of the haptoglobin gene complex in primates and human populations. In humans the cluster has two genes; an apparently functional but unexpressed haptoglobin-related gene (Hpr) occurs at 2.2 kb downstream of the expressed haptoglobin gene (Hp). The number of genes in the haptoglobin gene family has changed during primate evolution: it is one in New World monkeys, three in Old World monkeys and apes, and two in humans. I propose four specific aims: (1) I will determine the complete nucleotide sequence of the triplicated gene cluster (Hp-Hpr-Hpp) in rhesus monkeys and compare it to the sequences in humans, chimpanzees and spider monkeys that I have accumulated to date. (2) I will study how the expression of different members of the haptoglobin gene cluster has changed during evolution. (3) I will broaden my studies to include the molecular and chromosomal dynamics of another type of multigene family, using as a model the small dispersed family of retrovirus-like (RTVL-I) sequences, three members of which I have shown were inserted into the haptoglobin gene cluster at about the time it was triplicated. (4) I will start experiments aimed at testing in vitro, in a tissue culture based system, the recombinational properties of sequences, mainly from the haptoglobin gene cluster, that appear from evolutionary considerations to have been particularly active in recombination.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Project (R01)
Project #
5R01GM037567-09
Application #
2178832
Study Section
Genome Study Section (GNM)
Project Start
1988-07-01
Project End
1995-11-30
Budget Start
1993-12-01
Budget End
1994-11-30
Support Year
9
Fiscal Year
1994
Total Cost
Indirect Cost
Name
University of North Carolina Chapel Hill
Department
Pathology
Type
Schools of Medicine
DUNS #
078861598
City
Chapel Hill
State
NC
Country
United States
Zip Code
27599
Hatada, Seigo; Grant, Delores J; Maeda, Nobuyo (2003) An intronic endogenous retrovirus-like sequence attenuates human haptoglobin-related gene expression in an orientation-dependent manner. Gene 319:55-63
Hatada, Seigo; Seed, John R; Barker, Chad et al. (2002) No trypanosome lytic activity in the sera of mice producing human haptoglobin-related protein. Mol Biochem Parasitol 119:291-4
Hatada, S; Kuziel, W; Smithies, O et al. (1999) The influence of chromosomal location on the expression of two transgenes in mice. J Biol Chem 274:948-55
Kuziel, W A; Morgan, S J; Dawson, T C et al. (1997) Severe reduction in leukocyte adhesion and monocyte extravasation in mice deficient in CC chemokine receptor 2. Proc Natl Acad Sci U S A 94:12053-8
Erickson, L M; Maeda, N (1995) A new family of retroviral long terminal repeat elements in the human genome identified by their homologies to an element 5' to the spider monkey haptoglobin gene. Genomics 27:531-4
Erickson, L M; Maeda, N (1994) Parallel evolutionary events in the haptoglobin gene clusters of rhesus monkey and human. Genomics 22:579-89
Grant, D J; Maeda, N (1993) A base substitution in the promoter associated with the human haptoglobin 2-1 modified phenotype decreases transcriptional activity and responsiveness to interleukin-6 in human hepatoma cells. Am J Hum Genet 52:974-80
Kim, H S; Lyons, K M; Saitoh, E et al. (1993) The structure and evolution of the human salivary proline-rich protein gene family. Mamm Genome 4:3-14
Maeda, N (1991) DNA polymorphisms in the controlling region of the human haptoglobin genes: a molecular explanation for the haptoglobin 2-1 modified phenotype. Am J Hum Genet 49:158-66
Maeda, N; Kim, H S (1990) Three independent insertions of retrovirus-like sequences in the haptoglobin gene cluster of primates. Genomics 8:671-83

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