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Physiol. Genomics 5: 113-118, 2001;
1094-8341/01 $5.00
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Received 27 July 2000; accepted in final form 5 February 2001.
Physiological Genomics 5:113-118 (2001)
1094-8341/01 $5.00 © 2001 American Physiological Society

Genetic variation in mRNA coding sequences of highly conserved genes

ANNELOOR L. M. A. TEN ASBROEK1, JEFFREY OLSEN2, DAVID HOUSMAN3, FRANK BAAS1 and VINCE STANTON, JR.2

1 Neurozintuigen Laboratory, Academic Medical Center, 1105 AZ, Amsterdam, The Netherlands
2 Variagenics, Cambridge 02139-1562
3 Center for Cancer Research, Massachusetts Institute of Technology, Cambridge, Massachusetts 02140

The frequency and distribution of genetic polymorphism in the human genome is a question of major importance. We have studied this in highly conserved genes, which encode crucial functions such as DNA replication, mRNA transcription, and translation. Evolutionary comparisons suggest that these genes are under particularly strong selective pressure, and their frequency of nucleotide sequence polymorphism would be expected to represent a minimum estimate for sequence variation throughout the genome. We have analyzed the complete coding sequence and the 3'-untranslated region (3'-UTR) of 22 human genes, most of which have homologs in all cellular organisms and all of which are at least 25% amino acid identical to homologs in yeast. Comparisons with similar studies of less conserved human disease genes indicate that 1) evolutionarily conserved genes are, on average, less polymorphic than disease related genes; 2) the difference in polymorphism levels is attributable almost entirely to reduced levels of variation in protein coding sequences, whereas noncoding sequences have similar levels of polymorphism; and 3) the character of polymorphism, in terms of the spectrum and frequency of mutational changes, is similar.

polymorphism; diversity; single nucleotide polymorphisms; human




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