AMERICAN JOURNAL OF HUMAN BIOLOGY 1 :505-507 (1 989)

Introduction: Uses of Molecular Biology: Understanding the Basis of Genetic Disease, Determining Evolutionary Pathways, and

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Other Applications JEFFREY C . LONG Department of Anthropology, University of New Mexico, Albuquerque, New Mexico 87131

Recent developments in the methods of molecular biology have been manifold and, as a consequence, new directions in human biological research are being forged. In light of these recent developments, a sympo- sium-"Uses of Molecular Biology: Under- standing the Basis of Genetic Disease, Determining Evolutionary Pathways, and Other Applications"-was organized by Dr. W.S. Pollitizer (University of North Caro- lina) for the 12th annual meeting of the Human Biology Council (1988). Before turn- ing to five papers that were originally pre- sented at the symposium, I will provide a very brief overview of the ways in which new molecular methods have changed our per- spectives of genomic organization and the processes that structure genomic organiza- tion and expression. The relevance of these new perspectives to the research and goals of human biologists will be clear.

Analysis of variability within and among human populations is central to understand- ing issues of interest to human biologists: Health and disease, social biology, adapta- tion, and evolution (Johnston, 1989). The success of such analyses largely depends on our ability to characterize the genetic states of populations and to apply the laws of trans- formation of genetic states in time and space. Ultimately, the genetic state of a population is described in terms of the frequencies of variations in information encoded in nucleic acid sequences. As discussed by Lewontin (1974), the laws of transformation are di- verse. They must include: 1) Epigenetic pro- cesses that give the distribution of pheno- types that result from the development of various genotypes in various environments, 2) the rules of mating, migration, and natu- ral selection, 3) laws of inference for geno- types from the distribution of phenotypes, and 4) the genetic rules of heredity that allow us to predict the array of genotypes in the next generation from the array of parental

genotypes. Since the rules of transformation are closely tied to the chemical basis of life, advances in molecular biology have contrib- uted to all aspects of our understanding of human biology.

Our ability to characterize the human ge- nome has always been incomplete; until re- cently variations in DNA structure were best inferred from variations in polypeptide se- quences. The picture is now improving with direct measures of genomic content, restric- tion enzyme assays, and nucleic acid se- quencing. We have discovered that the human (eukaryotic) genome is far more com- plex than the cistrons coding for proteins (Watson et al., 1987). There is an abundance of highly repetitive DNA sequences dis- persed along chromosomes and concentrated at telomeres and centromeres (satellite DNA). Structural loci are split into ex- pressed sequences (exons) and intervening sequences (introns). Additionally, genes can often be grouped into families with a com- mon evolutionary origin. Genomic constancy in development must be reconsidered in light of transposable elements and ontogenetic DNA rearrangements.

Two decades ago it seemed that, given an array of parental genotypes, the prediction of genotypes in the next generation simply re- sulted from application of the rules of Men- del and Morgan (Lewontin, 1974), and the infrequent deviations from these rules caused by new mutations. The newly discov- ered features of genetic organization dis- cussed above have led to discoveries of new processes. Gene conversion, the meiotic pro- cess whereby one parental allele is substi- tuted for another to produce 3:l or 1:3 gamete ratios at a given heterozygous site, in opposition to the normal 2:2 ratio, is now known to be ubiquitous in eukaryotes. The potential for amplification of loci to meet environmental stresses is now apparent (Schimke, 1984), and the role of unequal

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506 J.C. LONG

crossing over in the origin of new genes and in the evolutionary dynamics of multigene families is established. It is now clear that each of these processes has an impact on evolutionary change and the distribution of phenotypes.

Establishment of the processes leading from genotypes to phenotypes remains one of the most important areas of inquiry in the study of human biology. The results of these inquiries will reveal the cumulative and in- teractive effects of genes and environments on phenotypes. Heretofore efforts in this area have been difficult because our knowl- edge of genotypes has been acquired very indirectly. One of the most illuminating ex- amples of how advances in molecular biology are changing our knowledge along these lines comes from the study of variations in color vision (Nathans et al., 1986a,b). These authors have demonstrated that gene dupli- cation and unequal crossing-over in inter- genic regions of X-chromosome loci are the molecular basis of quantitative variations in visual sensitivity. Much of the variability in color vision stems from the fact that people may be variable in the number of loci that they possess. Ironically, we have always as- sumed that people are variable for the alleles that they possess, but not for the loci. Clearly, the Fisherian model of polygenic variation will require modifications in light of findings such as these. Studies of the low-density lipoprotein receptor (LDLR) have also been revealing how genotypes af- fect phenotypes (Brown and Goldstein, 1986). LDLR deficiency results immediately in (familial) hypercholesterolemia and ulti- mately in ischaemic heart disease (IHD). While LDLR deficiency is only a minor con- tributor to population variability in IHD, the effects of factors such as allelic heterogeneity in LDLR deficiency and gene dosage on IHD are increasing our general knowledge about the contribution of genes to disease.

The refinements of our knowledge of ge- nomic structure and processes and our abil- ity to characterize genetic variability by directly probing DNA sequences are contrib- uting immensely to studies of evolutionary relationships among individuals and popula- tions (Jeffreys et al., 1985; Nei, 1987) and to studies of natural selection and adaptation (FIint et al., 1986; Nei, 1987). We can now estimate the evolutionary relationships among individual genes (Yokoyama and Yokoyama, 1989) or the relationships among the mitochondrial genomes of different indi-

viduals. This information can be used to assess relationships among human popula- tions (Cann et al., 1987; Johnson et al., 1983; Long et al., 1989; Nei, 1987; Wainscoat et al., 1986).

All of the symposium papers address one, or more, of the issues raised above. The contributions of Marks, Spuhler, and Weiss pertain to new issues in molecular evolution. The approach of both Marks and Weiss is novel because they analyze genomic ele- ments that are outside polypeptide coding regions. Spuhler (the Raymond Pearl Memo- rial Lecturer) provides a broad and interpre- tative review of evolutionary studies of mitochondrial DNA variability. The papers by Garruto and Ferrell deal with the molec- ular underpinnings of disease phenotypes; accordingly, they fall under the general ru- bric of genetic epidemiology (Motulsky. 1984). These papers provide a new direction for the Human Biology Council; within a few years, however, the research directions es- tablished here should be well established in the publications of this journal.

ACKNOWLEDGMENTS Funding for the symposium “Uses of Mo-

lecular Biology: Understanding the Basis of Genetic Disease, Determining Evolutionary Pathways, and Other Applications” was gen- erously provided by a grant to W.S. Pollitizer and J.C. Long from the Wenner-Gren Foun- dation for Anthropological Research, and by the Human Biology Council.

LITERATURE CITED Brown MS, and Goldstein JL (1986) Areceptor-mediated

pathway for cholesterol homeostasis. Science 232334-47.

Cann RL, Stoneking M, and Wilson AC (1987) Mitochon- drial DNA and human evolution. Nature 325:31-36.

Flint J, Hill AVS, Bowden DK, Openheimer SJ, Sill PR, Serjeantson SW, Bana-koiri J , Bhatsu K, Alpers MP, Boyce AJ, Weatherall DJ, and Clegg JB (1986) High frequencies of alpha thalassemia are the result of natural selection by malaria. Nature 321:744-750.

Jeffreys AJ, Wilson V, and Thein SL (1985) Hypervari- able ’minisatellite’ regions in human DNA. Nature

Johnson MJ, Wallace DC, Rattazi MC, and Cavalli- Sforza LL (1983) Radiation of human mitochondrial DNA types analysed by restriction endonuclease cleavage patterns. J. Mol. Evol. 19:255-271.

314r67-73.

Johnston FE (1989) Editorial. Am. J . Hum. Biol. 1:l. Lewontin RC (1974) The Genetic Basis of Evolutionary

Change. New York: Columbia University Press. Long JC, Chakravarti A, Boehm CD, Antonarakis S, and

JSazazian HH (1989) A phylogeny of human P-globin haplotypes and its implications for recent human evo- lution. Am. J . Phys. Anthropol. (in press).

INTRODUCTION: USES OF MOLECULAR BIOLOGY 507

Motulsky AG (1984) Genetic epidemiology. Genet. Epi- demiol. 1:143-144.

Nathans J , Thomas D, and Hogness DS (1986a) Molecu- lar genetics of human color vision: The genes encoding blue, green, and red pigments. Science 232:193-202.

Nathans J , Piantanida TP, Eddy RL, Shows TB, and Hogness DS (1986b) Molecular genetics of inherited variation in human color vision. Science 232~203-210.

Nei M (1987) Molecular Evolutionary Genetics. New York Columbia University Press.

Schimke RT (1984) Gene amplification in cultured cells. Cell 3 7:705-7 13.

Wainscoat JS, Hill AVS, Boyce AL, Flint J, Hernandez

M, Thein SL, Old JM, Lynch JFt, Falusi AG, Weather- all DJ, and Clegg JB (1986) Evolutionary relationships of human populations from an analysis of nuclear DNA polymorphisms. Nature 319:491-493.

Watson JD, Hopkins NH, Roberts JW, Steitz JA, and Weiner AM (1987) Molecular Biology of the Gene, Vol. I, 4th ed. Menlo Park Ca.: BenjamidCummings Pub- lishing Co.

Weiss ML (1989) DNA fingerprints in physical anthro- pology. Am. J. Hum. Biol. (this issue).

Yokoyama S, and Yokoyama R (1989) Molecular evolu- tion of human visual pigment genes. Mol. Biol. Evol. 6r18G197.