Coltman et al.’s genetic study tracked 1867 sheep over a 10-year interval, providing a valiant attempt to quantify multifactorial genetic and nongenetic regulation of species survival. It is the first study to implicate a fatal parasite outbreak as a selective agent against increased genomic homozygosity, although there have been other examples of recessive genetic influence for specific genes on infectious disease outcomes6xAIDS: A role for host genes. O’Brien, S.J. Hosp. Pract. 1998; 33: 53–79CrossrefSee all References6. We are used to thinking that genetic drift on islands leads to increased genetic loss and homozygosity; but in these sheep the parasite load actually reverses the process.There are two remarkable aspects of this study. First Coltman et al.1xParasite-mediated selection against inbred Soay sheep in a free-living, island population. Coltman, D.W. et al. Evolution. 1999; 53: 1259–1267CrossrefSee all References1 provide a comprehensive epidemiological analysis of the interaction of genome-wide zygosity with nongenetic parameters that regulate the likelihood of survival in different ways (Fig. 1Fig. 1, Table 1Table 1). Second, they demonstrate that the association of survival with genetic heterozygosity vanishes when the parasite selective pressures are eliminated by antihelminthic treatment. It is not often we catch such a glimpse of the consequence of both factor-dependent mortality and acute selective pressures exerted by infectious diseases in an isolated free-ranging natural population.A puzzle that comes from this study is which of the specific sheep genes are responsible for the heterozygosity relationship? The studies by Paterson et al.7xEvidence for balancing selection at the major histocompatibility complex in a free-living ruminant. Paterson, S. J. Hered. 1998; 89: 289–294Crossref | PubMed | Scopus (47)See all References, 8xMajor histocompatibility complex variation associated with juvenile survival and parasite resistance in a large unmanaged ungulate population (Ovis aries, L.). Paterson, S. et al. Proc. Natl. Acad. Sci. U. S. A. 1998; 95: 3714–3719Crossref | PubMed | Scopus (312)See all References reveal that the sheep MHC shows signals of historic and recent heterozygote advantage (historic evidence is an excess of nonsynonymous variants among compared MHC class II alleles; recent evidence is the ‘even’ allele distribution of MHC linked microsatellite loci). Nevertheless, specific MHC loci (e.g. class I, class II, TNF, Tap, or any of a hundred genes in the MHC) were not genotyped and analysed epidemiologically. Somewhat perplexing is the simultaneous association for MHC region and for whole-genome heterozygosity with survival in the same population. Is it possible that the genome-wide homozygosity is a marker for MHC effect? Alternatively, could MHC effects be surrogates for genome-wide homozygosity? MHC diversity is frequently used to screen for historic inbreeding in natural populations. Yet, in at least one case, MHC gene homozygosity influence on infectious disease progression (AIDS) was uncoupled with MHC linked and with overall genome-wide microsatellite zygosity4xHLA and HIV-1: Heterozygote advantage and B*35-Cw*04 disadvantage. Carrington, M. et al. Science. 1999; 283: 1748–1752Crossref | PubMed | Scopus (853)See all References4.The identification of gene variants that drive these critical population events should soon be possible. With a full-length sequence of both the human and mouse genomes only a few years away, the power of comparative genomics will allow genome scans to pinpoint responsible genes11xThe promise of comparative genomics in mammals. O’Brien, S.J. Science. 1999; 286: 458–481Crossref | PubMed | Scopus (356)See all References11. A sheep genetic map including integrated coding (Type I) and microsatellite loci is rapidly developing. The Soay sheep population might be one of the first in which interacting population genetic methods, gene-map driven analyses and ecological insight are employed to describe what until recently have been called stochastic variables. Is it possible that these fluctuations can become deterministic as field ecologists harness the power of comparative molecular genetics? It will not be long.