E D I T O R I A L

Polygenic, multffactorial, quantitative, complex - there are several terms to describe the mode of inheritance that is the theme of this special issue of Trends in Genetics. They all refer to the characteristics or traits of organ- isms that are determined by multiple genes, usually with a significant envi- ronmental component as well. Until a few years ago, the task of identifying the genes involved in multffactorial traits seemed too huge to contem- plate. However, the progress of gen- ome projects in many species and, in particular, the wealth of polymor- phisms that have been characterized and mapped has brought the task of identifying polygenic trait loci into the realms of practicality. The benefits to human health and the economic rewards have also provided massive incentives. This issue of Trends in Genetics draws together many differ- ent aspects of research into multifac- torial inheritance, examines the state of play in significant projects in dif- ferent organisms and looks at some of the problems that will need to be tackled in the future.

The greatest research effort is sharply focused on the analysis of complex human diseases. Two of the success stories are type I diabetes (reviewed by Corder and Todd) and Alzheimer disease (reviewed by Pericak-Vance and Haines). In type 1 diabetes, there is evidence for strong interactions or epistasis between multiple loci. However, both in Alzheimer disease and in type 1 dia- betes accumulating evidence sug- gests that there are also independent genetic causes of disease. This could ultimately provide a basis for sub- dividing groups of patients to receive different therapeutic interventions. Furthermore, such a subdivision into genetically homogeneous groups might help to determine the environ- mental component of complex dis- ease as discussed by Sim, Stanley, Risch and Thygesen. The identifica- tion of genes for complex traits and diseases also raises ethical questions (reviewed by Parker).

Because any genetic study of human populations is limited by the family structures available, a great deal of effort has gone into the de- velopment of sophisticated statistical methods. Some of this methodology

A complex issue was developed and first applied in the analysis of the major histocom- patibility complex, and a historical view of these developments is pro- vided by Tomlinson and Bodmer. Weeks and Lathrop discuss the power of the currently most widely used statistical approaches for the analysis of complex disease.

Of course, humans are not the best experimental system, and the analysis of multifactorial inheritance in the mouse has been an area of intense activity for many years. Frankel describes some of the power- ful genetic methods that can be used in the mouse, and the value of this approach for human studies of diabetes is amply demonstrated by Cordell and Todd.

However, as in so many areas of genetic research, the model organism that leads the way in the genetic analysis of quantitative variation is Drosophila. The pioneers of the work include Mather and Thoday who studied bristle number in the fmitfly. Mackay shows, in this issue, how bristle number can be studied using the modem tools of molecular biol- ogy and genetics. One of her most intriguing observations is the evi- dence for epistasis in this system. Genes do not act independently and additively to produce a phenotype as expected from the classical analy- sis. The ro~'ent data suggest that com- plex phenotypes are determined by overlapping and interacting biochem- ical pathways.

Plant and domestic animal breed- ers are keen to exploit knowledge of the genes controlling economically important traits to breed better and more vigorous crops and animals. Haley describes the progress in pigs and cattle, and also discusses the pros- pects and possible pitfalls for using mapped loci in breeding programmes. The analysis of plants is covered by Stuber (maize) and McCouch and Doerge (rice). Loci involved in a vari- ety of traits have been mapped, and particularly in plants, daere is evi- dence for the conservation of the loci across species. This is likely to accel- erate the identification of loci in the future. The prospects for the use of the loci are less certain. There has already been some success in marker- assisted selection where loci are

TIG DECEMBER 1995 VOL. 11 No. 12

moved into different genetic environ- ments, but there are also some poten- tial problems awaiting the breeders. Transgenesis may be a distant goal, but here again there are many obstacles, not least progressing from the mapping of loci to the identifi- cation of the genes involved.

Having !dentified a polygenic trait locus, how do you fred the gene? The first step is to map the locus as pre- cisely as possible. Various methods are discussed for achieving this, a powerful example being linkage dis- equilibrium mapping. But even when that is achieved, there will still be a lot of DNA to look at. This is where the genome projects come in again. To highlight the human example, once the positions of all the expressed sequences have been mapped, it will be possible to call up a list of the candidates in a particular region. The proof of identity depends on the limitations of the experiment~ ,rgan- ism. For the mouse, as pointed out by Frankel, the ultimate test will be to modify that gene directly by targeted mutagenesis. Such studies will also help human projects where such di- rect tests are not possible, but knowl- edge of the function of a gene from different experimental approaches and from the identification of variants of the gene associated with the trait or disease will establish the significance of any candidate.

There can be no doubt that multi- factorial inheritance is a complex topic. From the statistical tools that are used to tease out the genetic components of a polygenic trait, to the ethical issues raised by the use of the new-found knowledge, there is a great deal to think about. We hope that some of this complexity is rationalized in this issue of Trends in Genetics.

Mark Patterson John A. Todd Editor Guest Editor

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