NATURAL SELECTION AND THE EVOLUTIONARY HISTORY OF MAJOR HISTOCOMPATIBILITY COMPLEX LOCI

Austin L. Hughes and Meredith Yeager

Department of Biology and Institute of Molecular Evolutionary Genetics, The Pennsylvania State University, University Park PA 16802 USA

Received 5/11/98 Accepted 5/22/98

2. INTRODUCTION

The major histocompatibility complex (MHC) of vertebrates has become an important paradigm for molecular evolutionary studies. First, certain polymorphic MHC loci represent probably the best documented examples of positive Darwinian selection at the molecular level. In particular, these loci are examples of balancing selection; that is, selection that acts to maintain polymorphism. Second, the genes of the MHC are members of a multi-gene family. Attempts to unravel the evolutionary history of these loci have revealed examples of evolutionary processes that are common to eukaryotic multi-gene families in general. These processes include gene duplication and the functional divergence of duplicated genes; the silencing of duplicate genes by mutation and deletion of certain duplicate genes, leading to the turnover of loci over evolutionary time; and inter-locus recombination.

The purpose of the present paper is to review some of the major findings regarding the evolution of MHC loci. We will emphasize in particular the evidence regarding the role of natural selection and the MHC as a paradigmatic case of a multi-gene family. It is by now widely accepted that most polymorphisms in natural populations are selectively neutral (1,2). Thus, the very fact that polymorphisms at certain MHC loci are selectively maintained makes these loci unusual. Most traits of MHC genes at the DNA sequence level that have puzzled investigators can be seen as consequences of the balancing selection acting at these loci (3). If the MHC is an atypical multi-gene family – and in certain respects it is – this is a consequence of the fact that it contains loci subject to an unusual type of natural selection.