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.
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