EMERGENCE OF A BRAIN-EXPRESSED VARIANT MELANIN-CONCENTRATING HORMONE GENE DURING HIGHER PRIMATE EVOLUTION - A GENE IN SEARCH OF A FUNCTION

Two related but distinct melanin-concentrating hormone (MCH) gene syst ems, i.e., the authentic and variant genes, have been characterized in the human, while only a single MCH gene has been found in the rat. We previously established that the variant gene corresponds to exon-I-de leted copies of the authentic gene mapped on chromosomes 5 and 12, res pectively. In this report, we examined the expression of the authentic and variant MCH genes in the human brain. Mature mRNAs of the authent ic MCH gene appeared to be predominantly expressed in the hypothalamus , whereas putative unprocessed transcripts of the variant MCH gene wer e found in other brain areas but not in the hypothalamus. Several prod ucts of the variant MCH gene were identified by RACE-PCR in the fetal human brain. One of these transcripts encoded a putative protein of 72 amino acids, while another transcript may potentially generate a prot ein of 35 amino acids. Thereafter, we explored the question of MCH gen e transposition during Primate evolution. Southern blotting, PCR analy ses using several genomic DNAs of Primates, and in situ hybridization on metaphase chromosomes led us to define at least three types of gene tic events associated with the emergence of the variant MCH gene: (1) translocation of an exon II-exon III copy of the authentic MCH gene on to the equivalent of the human chromosome 5p arm of Anthropoidea ances tors (between 25 and 55 MYA); (2) exon LI truncation and mutations bef ore divergence of the Hylobatidae (about 15 MYA); and (3) duplication of the variant gene on the equivalent of the human chromosome 5p and 5 q arms in the Hominidae, i.e., 5-10 MYA. Taken together, these results support the hypothesis that transposition/gene rearrangement processe s could underlie the evolutionary emergence of new MCH-related genes e xpressed differentially in the brains of higher Primates, illustrating the concept of genes ''in search of a function'' instead of true ''ps eudogenes.''