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Equilibrium models of isolation by distance predict an increase in genetic differentiation with geographic distance. Here we find a linear relationship between genetic and geographic distance in a worldwide sample of human populations, with major deviations from the fitted line explicable by admixture or extreme isolation. A close relationship is shown to exist between the correlation of geographic distance and genetic differentiation (as measured by [F.sub.ST]) and the geographic pattern of heterozygosity across populations. Considering a worldwide set of geographic locations as possible sources of the human expansion, we find that heterozygosities in the globally distributed populations of the data set are best explained by an expansion originating in Africa and that no geographic origin outside of Africa accounts as well for the observed patterns of genetic diversity. Although the relationship between [F.sub.ST] and geographic distance has been interpreted in the past as the result of an equilibrium model of drift and dispersal, simulation shows that the geographic pattern of heterozygosities in this data set is consistent with a model of a serial founder effect starting at a single origin. Given this serial-founder scenario, the relationship between genetic and geographic distance allows us to derive bounds for the effects of drift and natural selection on human genetic variation. genetic distance | genetic drift | HGDP-CEPH | human origins | microsatellites

We study different physical, chemical, or biological processes involving replication, transformation, and disappearance processes, as well as transport processes, and assume that the time and space dependence of the species densities are known. We derive two types of Fisher equations. The first type relates the average value of the time derivative of the relative time-specific rates of growth of the different species to the variance of the relative, time-specific rates of growth. A second type relates the average value of the gradient or the divergence of the relative, space-specific rates of growth to the space correlation matrix of the relative, space-specific rates of growth. These Fisher equations are exact results, which are independent of the detailed kinetics of the process: they are valid whether the evolution equations are linear or nonlinear, local or nonlocal in space and/or time and can be applied for the study of a large class of physical, chemical, and biological systems described in terms of time- and/or space-dependent density fields. We examine the implications of our generalized Fisher relations in population genetics, biochemistry, and chemical kinetics (reaction-diffusion systems). We show that there is a connection between the enhanced (hydrodynamic) transport of mutations induced by population growth and space-specific rate vectors: the velocity of enhanced transport is proportional to the product of the diffusion coefficient of the species and the space rate vector; this relation is similar to a fluctuation-dissipation relation in statistical mechanics.

We consider a system made up of different physical, chemical, or biological species undergoing replication, transformation, and disappearance processes, as well as slow diffusive motion. We show that for systems with net growth the balance between kinetics and the diffusion process may lead to fast, enhanced hydrodynamic transport. Solitary waves in the system, if they exist, stabilize the enhanced transport, leading to constant transport speeds. We apply our theory to the problem of determining the original mutation position from the current geographic distribution of a given mutation. We show that our theory is in good agreement with a simulation study of the mutation problem presented in the literature. It is possible to evaluate migratory trajectories from measured data related to the current distribution of mutations in human populations.

Despite mounting genetic evidence implicating a recent origin of modern humans, the elucidation of early migratory gene-flow episodes remains incomplete. Geographic distribution of haplotypes may show traces of ancestral migrations. However, such evolutionary signatures can he erased easily by recombination and mutational perturbations. A 565-hp chromosome 21 region near the MX1 gene, which contains nine sites frequently polymorphic in human populations, has been found. It is unaffected by recombination and recurrent mutation and thus reflects only migratory history, genetic drift, and possibly selection. Geographic distribution of contemporary haplotypes implies distinctive prehistoric human migrations: one to Oceania, one to Asia and subsequently to America, and a third one predominantly to Europe. The findings with chromosome 21 are confirmed by independent evidence from a Y chromosome phylogeny. Loci of this type will help to decipher the evolutionary history of modern humans.

It is often taken for granted that the human species is divided in rather homogeneous groups or races, among which biological differences are large. Studies of allele frequencies do not support this view, but they have not been sufficient to rule it out either. We analyzed human molecular diversity at 109 DNA markers, namely 30 microsatellite loci and 79 polymorphic restriction sites (restriction fragment length polymorphism loci) in 16 populations of the world. By partitioning genetic variances at three hierarchical levels of population subdivision, we found that differences between members of the same population account for 84.4% of the total, which is in excellent agreement with estimates based on allele frequencies of classic, protein polymorphisms. Genetic variation remains high even within small population groups. On the average, microsatellite and restriction fragment length polymorphism loci yield identical estimates. Differences among continents represent roughly 1/10 of human molecular diversity, which does not suggest that the racial subdivision of our species reflects any major discontinuity in our genome.

A study was conducted on a polymorphic C - T transition found in the human Y chromosome. The mutation was theorized to have been introduced exclusively during the early stages of human colonization of the Americas. COmparative sequencing of the >4.2 kb of the nonrecombining part of the human Y chromosome showed detectable amounts of base substitution polymorphisms. The transition has potential on investigations of pre-Columbian colonization of the New World and the degree of admixture within indigenous populations.

Analysis of the Wilson disease CWND region, comprising 28 overlapping yeast artificial chromosome (YAC) clones, revealed a contig of approximately 4.5 mb. The contig extends from D13S25 to D13S59. Isolation of the WND gene requires a physical map, which acts as the structure around which the candidate genes are identified.

A study conducted by Chu et al focused on the genetic profiles of 28 sample populations in China participating in the Chinese Human Genome Diversity Project. Results supported the distinction between southern and northern populations. Substantial gene flow was evidenced by linguistic boundaries that often transgressed across language families. However, genetic evidence does not support an independent origin of Homo sapiens in China.

Some insight into human evolution has been gained from the sequencing of four Y chromosome genes. Primary genomic sequencing determined gene SMCY to be composed of 27 exons that comprise 4,620 bp of coding sequence. The unfinished sequencing of the 5' portion of gene UTY1 was completed by primer walking, and a total of 20 exons were found. By using denaturing HPLC, these two genes, as well as DBY and DFFRY, were screened for polymorphic sites in 53-72 representatives of the five continents. A total of 98 variants were found, yielding nucleotide diversity estimates of 2.45 x [10.sub.-5], 5.07 x [10.sub.-5], and 8.54 x [10.sub.-5] for the coding regions of SMCY, DFFRY, and UTY1, respectively, with no variant having been observed in DBY. In agreement with most autosomal genes, diversity estimates for the noncoding regions were about 2- to 3-fold higher and ranged from 9.16 x [10.sub.-5] to 14.2 x [10.sub.-5] for the four genes. Analysis of the frequencies of derived alleles for all four genes showed that they more closely fit the expectation of a Luria-Delbruck distribution than a distribution expected under a constant population size model, providing evidence for exponential population growth. Pairwise nucleotide mismatch distributions date the occurrence of population expansion to [approximately equals] 28,000 years ago. This estimate is in accord with the spread of Aurignacian technology and the disappearance of the Neanderthals.

Genetic and paleoanthropological evidence is in accord that today's human population is the result of a great demic (demographic and geographic) expansion that began approximately 45,000 to 60,000 y ago in Africa and rapidly resulted in human occupation of almost all of the Earth's habitable regions. Genomic data from contemporary humans suggest that this expansion was accompanied by a continuous loss of genetic diversity, a result of what is called the “serial founder effect.” In addition to genomic data, the serial founder effect model is now supported by the genetics of human parasites, morphology, and linguistics. This particular population history gave rise to the two defining features of genetic variation in humans: genomes from the substructured populations of Africa retain an exceptional number of unique variants, and there is a dramatic reduction in genetic diversity within populations living outside of Africa. These two patterns are relevant for medical genetic studies mapping genotypes to phenotypes and for inferring the power of natural selection in human history. It should be appreciated that the initial expansion and subsequent serial founder effect were determined by demographic and sociocultural factors associated with hunter-gatherer populations. How do we reconcile this major demic expansion with the population stability that followed for thousands years until the inventions of agriculture? We review advances in understanding the genetic diversity within Africa and the great human expansion out of Africa and offer hypotheses that can help to establish a more synthetic view of modern human evolution. [ABSTRACT FROM AUTHOR]

Examines a paper which focuses on genetics and origin of species. Procedure used for the examination of genetic history of a group of populations; Basis for suggestion that genetic differentiation of the population is mostly due to population fissions; Description of the absolute genetic dating method; Revelations following multivariate analyses.

The ability to infer the time and place of origin of a mutation can be very useful when reconstructing the evolutionary histories of populations and species. We use forward computer simulations of population growth, migration, and mutation in an analysis of an expanding population with a wave front that advances at a constant slow rate. A pronounced founder effect can be observed among mutations arising in this wave front where extreme population bottlenecks arise and are followed by major population growth. A fraction of mutations travel with the wave front and generate mutant populations that are on average much larger than those that remain stationary. Analysis of the diffusion of these mutants makes it possible to reconstruct migratory trajectories during population expansions, thus helping us better understand observed patterns in the evolution of species such as modern humans. Examination of some historical data supports our model.

Cultural inheritance can be considered as a mechanism of adaptation made possible by communication, which has reached its greatest development in humans and can allow long-term conservation or rapid change of culturally transmissible traits depending on circumstances and needs. Conservativeness/flexibility is largely modulated by mechanisms of sociocultural transmission. An analysis was carried out by testing the fit of three models to 47 cultural traits (classified in six groups) in 277 African societies. Model A (demic diffusion) is conservation over generations, as shown by correlations of cultural traits with language, used as a measure of historical connection. Model B (environmental adaptation) is measured by correlation to the natural environment. Model C (cultural diffusion) is the spread to neighbors by social contact in an epidemic-like fashion and was tested by measuring the tightness of geographic clustering of the traits. Most traits examined, in particular those affecting family structure and kinship, showed great conservation over generations, as shown by the fit of model A. They are most probably transmitted by family members. This is in agreement with the theoretical demonstration that cultural transmission in the family (vertical) is the most conservative one. Some traits show environmental effects, indicating the importance of adaptation to physical environment. Only a few of the 47 traits showed tight geographic clustering indicating that their spread to nearest neighbors follows model C, as is usually the case for transmission among unrelated people (called horizontal transmission).

We introduce a new genetic distance for microsatellite loci, incorporating features of the stepwise mutation model, and test its performance on microsatellite polymorphisms in humans, chimpanzees, and gorillas. We find that it performs well in determining the relations among the primates, but less well than other distance measures (not based on the stepwise mutation model) in determining the relations among closely related human populations. However, the deepest split in the human phylogeny seems to be accurately reconstructed by the new distance and separates African and non-African populations. The new distance is independent of population size and therefore allows direct estimation of divergence times if the mutation rate is known. Based on 30 microsatellite polymorphisms and a recently reported average mutation rate of 5.6 x 10(-4) at 15 dinucleotide microsatellites, we estimate that the deepest split in the human phylogeny occurred about 156,000 years ago. Unlike most previous estimates, ours requires no external calibration of the rate of molecular evolution. We can use such calibrations, however, to test our estimate.

A new set of European genetic data has been analyzed to dissect independent patterns of geographic variation. The most important cause of European genetic variation has been confirmed to correspond to the migration of Neolithic farmers from the area of origin of agriculture in the Middle East. The next most important component of genetic variation is apparently associated with a north-south gradient possibly due to adaptation to cold climates but also to the differentiation of the Uralic and the Indo-European language-speaking people; however, the relevant correlations are not significantly different from zero after elimination of the spatial autocorrelation. The third component is highly correlated with the infiltration of the Yamna ("Kurgan") people, nomadic pastoralists who domesticated the horse and who have been claimed to have spread Indo-European languages to Europe; this association, which is statistically significant even when taking spatial autocorrelations into account, does not completely exclude the hypothesis of Indo-European as the language of Neolithic farmers. It is possible that both expansions were responsible for the spread of different subfamilies of Indo-European languages, but our genetic data cannot resolve their relative importance.

Testing of nuclear DNA polymorphisms in human populations has been extended to closely related primates. For many polymorphisms, one allele is shared by two or more species: such shared alleles are likely to be ancestral and provide insight not only into the relationships among the primates but also into the evolutionary history of modern humans. Humans from among eight worldwide populations share an allele with chimpanzees for 62 out of 79 polymorphisms examined. Frequencies of these ancestral alleles strengthen the conclusion that the earliest major separation of modern humans was between Africans and non-Africans. The average time since mutation of the ancestral alleles producing the current set of polymorphisms is estimated to be 700,000 years. While differences among ancestral allele frequencies in human populations suggest that natural selection may have played a role in the evolution of a subset of these polymorphisms, simulations indicate that a European bias in the ascertainment of polymorphisms may be at least partially responsible for observed differences. Simulations also suggest that observed heterozygosity levels in African populations, for classical polymorphisms and restriction fragment length polymorphisms, are artificially low due to the same bias. Observed patterns of mean heterozygosity and mean ancestral allele frequency provide support for the hypothesis that Europeans and northeast Asians are closely related. This work suggests that polymorphisms should be selected by testing a random sample of extant humans.

In an earlier paper it was shown that linguistic families of languages spoken by a set of 38 populations associate rather strongly with an evolutionary tree of the same populations derived from genetic data. While the correlation was clearly high, there was no evaluation of statistical significance; no such test was available at the time. This gap has now been filled by adapting to this aim a procedure based on the consistency index, and the level of significance is found to be much stronger than 10(-3). Possible reasons for coevolution of strictly genetic characters and the strictly cultural linguistic system are discussed briefly. Results of this global analysis are compared with those obtained in independent local analysis.

Accuracy of evolutionary analysis of populations within a species requires the testing of a large number of genetic polymorphisms belonging to many loci. We report here a reconstruction of human differentiation based on 100 DNA polymorphisms tested in five populations from four continents. The results agree with earlier conclusions based on other classes of genetic markers but reveal that Europeans do not fit a simple model of independently evolving populations with equal evolutionary rates. Evolutionary models involving early admixture are compatible with the data. Taking one such model into account, we examined through simulation whether random genetic drift alone might explain the variation among gene frequencies across populations and genes. A measure of variation among populations was calculated for each polymorphism, and its distribution for the 100 polymorphisms was compared with that expected for a drift-only hypothesis. At least two-thirds of the polymorphisms appear to be selectively neutral, but there are significant deviations at the two ends of the observed distribution of the measure of variation: a slight excess of polymorphisms with low variation and a greater excess with high variation. This indicates that a few DNA polymorphisms are affected by natural selection, rarely heterotic, and more often disruptive, while most are selectively neutral.

The mtDNAs of 235 individuals from five ethnic groups were analyzed for restriction site variation by digestion with restriction endonuclease Hpa I, Southern transfer, and hybridization with 32P-labeled human mtDNA. Six different cleavage patterns (morphs) were found, all of which could be related to each other by single nucleotide substitutions. Differences were found in the frequency of these morphs among the populations. The largest difference observed was in the frequency of the morph most common in Caucasians and Orientals compared to the frequency of that found in Africans. This difference apparently originated by the sequence change G-T-C-A-A-C to G-T-T-A-A-C. This alteration permitted recognition by Hpa I but did not alter the amino acid sequence. Two other observed differences were due to separate substitutions occurring in the ribosomal RNA genes. Comparison with primate data shows that the morph with two fragments, found in 12.5% of Oriental and 4% of Bantu samples, might be the ancestral type common to all hominoids. These two conserved sites were localized in tRNA genes in the anticodon loop. Assuming that the two-fragment morph is ancestral, this finding is consistent with previous data suggesting that Asia is genetically central to the radiations that are thought to have given rise to the human ethnic groups.

Group-specific component (Gc) proteins are human plasma proteins for which a worldwide polymorphism exists. As yet no functional role has been assigned this protein. We show that the products of both Gc alleles, proteins Gc 1 and Gc 2 (distinguished electrophoretically), bind substantial quantities of vitamin D and 25-hydroxyvitamin D. Three lines of evidence are reported: (1) Polyacrylamide gel electrophoresis and autoradiography of serum labeled with (14-C)vitamin D3 revealed patterns of radioactive bands identical to those expected of the two Gc alleles. Population gene frequencies for these proteins binding vitamin D were in the range of those reported for Gc, and individuals of known Gc phenotype were found to have the corresponding vitamin-D-binding phenotype. (2) Immunoelectrophoresis and autoradiography of labeled serum reacted against antiserum to human Gc revealed labeling by (14-C)vitamin D3 of Gc-antibody precipitation ares. (3) (14-C)vitamin D3 or 25-hydroxy(3-H)vitamin D3 was found to coprecipitate specifically with Gc in serum incubated with Gc antiserum. Use of these techniques demonstrated further that plasma proteins that bind vitamin D and that are immunologically similar to human Gc are found in mouse, rat, cow, horse, dog, rhesus monkey, and chimpanzee. We propose that Gc and "vitamin-D-binding alpha-globulin" are in fact the same portein, and that the ability of Gc to bind vitamin D may be directly related to the action of selection on this locus. These techniques may also find application in the study of other plasms transport proteins.

In this study, restriction fragment length polymorphisms (RFLPs) were identified with an immunoglobulin variable heavy chain region (Ig VH) probe and the inheritance of the polymorphisms was analyzed in families. Linkage within the VHII gene cluster and between the VHII and Ig CH genes was investigated by lod (logarithm of odds) score analysis. In addition, the position of the VHII genes was determined in relation to another polymorphic locus--D14S1, which is tightly linked and centromeric to the CH genes. Genetic associations between genes in the CH and VH clusters were analyzed. These RFLPs represent genetically characterized VH region polymorphisms and it is hoped that they will facilitate the study of disease correlations as well as further the understanding of the genetics of the immunoglobulin heavy chain genes in humans.

Five restriction fragment length polymorphisms in the human alpha/beta interferon (IFN-alpha/beta) gene region were identified, three with an IFN-alpha probe and two with an IFN-beta probe. Heterozygosities are 74% for IFN-alpha, 57% for IFN-beta, and 87% jointly, making IFN-alpha/beta genes excellent markers for the short arm of chromosome 9. The pedigrees of about 25 families of Caucasian background were studied. Segregation analysis disclosed the occurrence of 12 of 32 possible haplotypes. No recombinant was found between IFN-alpha and -beta genetic markers; linkage disequilibrium within the IFN-alpha markers is of a similar order of magnitude as that between the IFN-alpha and -beta markers. The IFN-alpha and -beta genes might cluster within several hundred kilobases. In two parents, the IFN-beta gene is duplicated; the duplications segregate regularly. They are of independent, probably recent, origin. Therefore, some degree of multiplicity might even be found for IFN-beta, at least in some individuals.

The genetic information for this work came from a very large collection of gene frequencies for "classical" (non-DNA) polymorphisms of the world aborigines. The data were grouped in 42 populations studied for 120 alleles. The reconstruction of human evolutionary history thus generated was checked with statistical techniques such as "boot-strapping". It changes some earlier conclusions and is in agreement with more recent ones, including published and unpublished DNA-marker results. The first split in the phylogenetic tree separates Africans from non-Africans, and the second separates two major clusters, one corresponding to Caucasoids, East Asians, Arctic populations, and American natives, and the other to Southeast Asians (mainland and insular), Pacific islanders, and New Guineans and Australians. Average genetic distances between the most important clusters are proportional to archaeological separation times. Linguistic families correspond to groups of populations with very few, easily understood overlaps, and their origin can be given a time frame. Linguistic superfamilies show remarkable correspondence with the two major clusters, indicating considerable parallelism between genetic and linguistic evolution. The latest step in language development may have been an important factor determining the rapid expansion that followed the appearance of modern humans and the demise of Neanderthals.

Communication between individuals of a species is likely to increase the capacity to acquire skills useful for survival and propagation and thus may confer important selective advantages. Since interaction occurs between two or more individuals, the selective process is frequency dependent, and the analysis shows that communication cannot initially increase at a reasonable rate when it is limited to random unrelated individuals, so that it is likely to abort for stochastic reasons. However, this bottleneck is removed if the communication process takes place in the nuclear family or among close relatives or if aggregation of communicators occurs because of assortative mating or meeting. Use of the individual conditional fitnesses we have introduced earlier permits an exact analysis. We show that, in general, the initial rate of increase can be geometric if and only if, in the class of selective models considered, the conditional probability of a communicator interacting with another contains a positive constant term. In our discussion of communication, cost factors for the act of communication have been omitted. However, the model has been generalized to include cooperativeness, and also altruism, or competition, by introducing costs. There is a close relationship among these situations, and the same considerations about the initial bottleneck and its resolution also extend to them. The models given here are for haploids but they extend to diploids and the conclusions are similar.

The dynamics of the interaction between genetic and cultural transmission are studied by using a simple two-phenotype diallelic haploid genetic system. The value of an individual's phenotype is determined by cultural transmission from its parent or by a randomly chosen member of the parental population. In the absence of phenotypic selection, polymorphic equilibria of the gene and trait frequencies are obtained. The correlation between genotype and phenotype within or between populations depends on a quantity formally similar to linkage disequilibrium and is determined by a relationship among transmission coefficients analogous to a coefficient of epistasis. With natural selection on the phenotype and no mutation, only degenerate transmission rules allow polymorphic equilibria to be attained, and, in general, the genotype allowing the strongest transmission of the favored phenotype is successful.

The world distribution of 39 independent gene frequencies in human populations is analyzed by multivariate techniques and synthetic geographic maps. Most genetic variation is associated with longitude, with South Asia showing a tendency to be central. Also latitude and, more particularly, distance from the equator play a significant role in a way that suggests that climatic factors exercise selective pressures, especially for certain genes.

The highly polymorphic system of serologically defined genetic markers on human IgG heavy chains (Gm allotypes) is second only to the HLA complex in terms of the large number of determinants, alleles, and haplotypes that can be used for analyses of disease associations and other genetic studies. However, present typing methods are based on the use of anti-Gm antisera that are derived mainly from fortuitously immunized human donors, often requiring processing before use, and must be used in a hemagglutination-inhibition assay that cannot be used in typing for isoallotypic determinants (currently termed "non-markers"). In studies presented here, we describe an allotyping system that utilizes monoclonal antibodies in a "sandwich" modification of the solid-phase radioimmunoassay, which is capable of reliable quantitative typing of allotypic, isoallotypic, and isotypic immunoglobulin determinants. We show that these highly reproducible, easily disseminated, and essentially inexhaustible reagents can be used for rapid, sensitive, and quantitative Gm typing. Using this system we define two previously unrecognized Gm determinants, one of which, found to date only in Caucasians, is different from all known Gm markers and thus defines previously unrecognized alleles and haplotypes. The other determinant co-segregates with the conventional G3m(b1) marker but is distinct from that marker on serological grounds. The successful preparation of mouse monoclonal antibodies that detect human Gm allotypic differences and the development of an assay system capable of typing isoallotypic as well as allotypic determinants opens the way to further dissection and application of this rich genetic system.

Models of sexual haploids under kin selection are constructed. The trait of altruism is transmitted vertically from parent to child, but not in a strictly genetic manner. Two systems of altruism are considered: parent-to-offspring and sib-to-sib. In the former case it is shown that even when Hamilton's conditions for the success of genetically determined altruism are met, genes that increase the transmission of altruism may not invade the population. With sib-to-sib altruism, such genes will always increase initially.

The method of evolutionary stable strategies (ESS), in its current form, is confronted with a difficulty when it tries to explain how some social behaviors initiate their evolution. We show that this difficulty may be removed by changing the assumption made tacitly in game theory (and in ESS) of randomness of meetings or encounters. In reality, such randomness seems to be rare in nature. Family, population and social structure, customs, and habits impose various types of deviation from randomness. Introducing nonrandomness of meeting in a way formally similar to assortative mating, we show that the bar to initial increase of inherited cooperative or altruistic behaviors can be removed, provided there is sufficient assortment of meetings. Family structure may cause contacts predominantly between certain types of relatives, and one can reconstruct some results of classical kin selection in terms of evolutionary stable strategy with assortative meetings. Neighbor effects and group selection might be similarly treated. Assortment need not be a passive consequence of population and social structure, but it can also be actively pursued. Behaviors favoring the choice of cooperative companions will have the effect of favoring the evolution of cooperativeness. It can be shown that discrimination in the choice of companions, especially if combined with assortment, can favor the development of cooperativeness, making initial increase of cooperative behavior possible even at levels of assortment passively imposed which would not be adequate, per se, to guarantee the increase of cooperativeness. It is possible that, in some cases, cooperativeness and behavior favoring some type of assortment are coselected.

The evolutionary dynamics of the joint distribution of genotypes and phenotypes is studied. The model, originally devised to study the joint effects of Mendelian and other types of transmissions, provides results of interest also to the theory of direct Mendelian transmission with natural selection. Assuming bivariate normal distributions, it is shown that in the latter case genotypic and phenotypic means and variances, and genotype-phenotype correlation can be expressed recursively as functions of the parameters for the selection, environmental, and mutation variance. Equilibria and rates of approach for these moments are calculated. It is also proved that in the presence of selection the heritability,defined as the ratio of expected genotypic to expected phenotypic variance after selection, is greater than that before selection by a predictable amount and that it can be greater than unity.

We analyze the problem of the competition between genetic and cultural adaptation, testing various types of cultural transmission models versus a genetic (haploid) transmission model. With a vertical (parent-to-child) plus an infectious (oblique) cultural transmission, genetic adaptation always prevails, although its relative increase may be slow and polymorphism may persist for some time. Only under very special conditions of cultural transmission may a permanent polymorphism in which the two types of adaptation are represented be reached. There may, however, be an overall evolutionary advantage to a flexible mechanism of cultural transmission that allows adaptation to new situations for which no genetic mutants are available.

DNA probes containing the switch region (S) associated with the human immunoglobulin heavy chain mu gene were used to investigate polymorphisms in the germ-line human DNA. Six polymorphisms, detected by a single restriction enzyme (Sst I) are described. Linkage studies in 29 families show that five of the six polymorphisms, although relatively unassociated in random individuals, segregate in complete linkage one to the other and to Gm allotypes (markers on the heavy chain of IgG), while the sixth segregates independently. Altogether, when one considers the DNA markers at the five closely linked loci and the IgG1 and IgG3 heavy chain allotypes, 33 different haplotypes have been described; of these, 28 are detected by the DNA polymorphism alone. Study of 158-187 random haplotypes showed strong linkage disequilibrium only between one DNA polymorphism (Sst A) and Gm. Of the polymorphic Sst I loci, one, Sst E [associated with 2.2- to 2.7-kilobase (kb) fragments], is included in the mu chain S region (S mu); another, Sst A (6.8-7.4 kb), must be very close to the gamma 1-gamma 3 chain gene cluster. Based on studies of an IgE human myeloma, a third polymorphism, Sst C (4.8-5.5 kb), should map 3' of the active epsilon chain gene. An Sst I restriction enzyme map of phage clones carrying the two alpha chain genes indicates that Sst A and Sst C loci probably overlap with the alpha 1 and alpha 2 S regions, respectively. Both deletion/duplications and point mutations were detected.

Two models involving non-Mendelian transmission of a discrete valued trait through within- and across-generation contagion are proposed in an investigation of the joint evolution of phenotype and genotype. A single locus with two alleles determines susceptibility to contagion. The incorporation of within-generation contagious transmission extends the parameter ranges allowing phenotypic polymorphism and introduces a new phenotypic equilibrium configuration. The latter is characterized by a threshold in the initial value of the trait which determines whether the trait can increase. Phenotypic evolution is accelerated by within-generation contagion, but the rate of genetic evolution is retarded relative to that under uniparental transmission across generations. The second model studied allows the trait to be acquired, at genotype-dependent rates, even if the transmitting parent does not have the trait. Both the pattern of phenotypic transmission and the selection on the trait influence the course of evolution. Some important aspects of the structure of the one locus-two allele model are shown to be preserved with more alleles. At equilibrium, the leading eigenvalue of the transmission-selection matrix assumes the role of genotypic fitness.

Two basement membrane collagen genes coding for the pro alpha 1 chain and pro alpha 2 chain of type IV collagen map to 13q34 and are linked with a maximum likelihood estimate of recombination of 0.028 at a logarithm of odds (lod) score of 19.98. The single-copy sequence that identifies the locus D13S3 is also closely linked to both collagen genes. Four enzymes reveal polymorphisms with COL4A1, and 10 haplotypes have been observed in Caucasoids. Within COL4A1 a nonrandom association of alleles exists only between alleles defined by Hae III and those defined by the other three enzymes. A random association of alleles of COL4A1 and COL4A2 is observed. Between the two collagen genes were detected three meiotic recombination events that contributed to the estimate of 2.8% recombination. This is higher than expected for two genes that lie within 650 kilobases of each other. The lack of linkage disequilibrium between COL4A1 and COL4A2 is in agreement with the relatively high recombination that is observed.

Polymorphic markers in genes encoding that alpha chain of the human T-cell receptor (TcR) have been detected by Southern blot analysis in Pss I digests. Polymorphic bands were observed at 6.3 and 2.0 kilobases (kb) with frequencies of 0.30 and 0.44, respectively, in the general population. Using the polymerase chain reaction (PCR) method, we amplified selected sequences derived from the full-length TcR alpha cDNA probe. These PCR products were used as specific probes to demonstrate that the 6.3-kb polymorphic fragment hybridizes to the variable (V)-region probe and the 2.0-kb fragment hybridizes to the constant (C)-region probe. Segregation of the polymorphic bands was analyzed in family studies. To look for associations between these markers and autoimmune diseases, we have studied the restriction fragment length polymorphism distribution of the Pss I markers in patients with multiple sclerosis, myasthenia gravis, and Graves disease. Significant differences in the frequency of the polymorphic V alpha and C alpha markers were identified between patients and healthy individuals.