J. psychiat. Res., Vol. 21, No. 4, pp. 597-608, 1987. 0022-3956/87 $3.00+ .00 Printed in Great Britain. © 1987 Pergamon Journals Ltd. PROTEIN POLYMORPHISMS DETECTED BY TWO-DIMENSIONAL ELECTROPHORESIS: AN ANALYSIS OF OVERALL INFORMATIVENESS OF A PANEL OF LINKAGE MARKERS DAvm GOLDMAN* and CARL R. MERRIL'~ *Laboratory on Clinical Studies, National Institute on Alcohol Abuse and Alcoholism, Bldg I0, 3C-215, 9000 RockvillePike; tBiologicalPsychiatryBranch, National Institute of Mental Health, Bethesda, MD 20892, U.S.A. (Received 18, October 1986; revised 4 December 1986) Summary--Forty-two independent polymorphic loci are detectable by two-dimensional electrophoresis (2DE) of four peripherally accessible human tissues. Fifteen have been chromosomally mapped and, taken together, these constitute a useful panel of markers for genetic linkage studies in humans. An analysisof the overallinformativeness for linkageof tiffspanel of markersis presented, taking into account the effect of varying the number of families or matings studies. Use of 2DE polymorpiffcmarkers for linkage of genetically determined behaviour traits in humans and mice is reviewed. INTRODUCTION THE DISCOVERY of large numbers of DNA restriction fragment length polymorphisms has raised the possibility that most human genetic traits transmitted in Mendelian fashion can be mapped by familial linkage analysis. Furthermore, polygenic, multifactorial traits should be approachable through the use of sib-pair analysis. Several recent technical developments may enhance the efficiency of RFLP typing and thereby facilitate the use of this method. These include a DNA amplification strategy to reduce the amount of genomic DNA which must be initially purified (SAIKI et al., 1985), single probes which recognize multiple polymorphic DNA segments on a single gel (JEFFREYS et al., 1985), specific oligonucleotides (ORKIN et al., 1983), and new procedures for labelling probes without radioisotopes to make the process safer and less cumbersome (LEARY et al., 1983). However, because RFLP typing remains labor-intensive, other linkage markers are also valuable if they can be efficiently scored. The two-stage electrophoresis method (2DE) of O'FARRELL (1975) is a 2-3 day procedure which simultaneously detects hundreds of gene products and effectively resolves all of their protein charge mobility variants (STEIt,raERG et aL, 1977). Thus, most protein polymorphic variants detectable by one-dimensional electrophoresis are resolved (WA~t,rER et aL, 1983), but numerous variants can be detected and scored on a single gel through the use of general protein stains or autoradiography. The first large panel of polymorphic human proteins detected by 2DE consisted of 19 independant polymorphic systems detected among 186 human lymphocyte proteins visualized by autoradiography. Each consisted of 2-3 charge variants showing codominant expression :~Addresscorrespondenceto" David Goldman, LCS, NIAAA, Bldg 10, 3C-215, 9000 RockvillePike, Bethesda, MD 20892, U.S.A. 597