The difficulty of identifying susceptibility genes for common diseases has polarized geneticists' views on what disease models are appropriate and how best to proceed once high-density genome maps become available. Different disease models have different implications for using linkage or linkage-disequilibrium-based approaches for mapping complex disease genes. We argue that the choice of study population is a critical factor when designing a study, and that genetically simplified isolates are more useful than diverse continental populations under most assumptions.

Population choice in mapping genes for complex diseases.

Much of the theory of population genetics is based on the assumption that populations are panmictic. While this may be nearly true in some instances, most populations of interest (particularly in man) exhibit some form of subdivision. Most often, spatial subdivision is observable, and population geneticists have studied subdivisions ranging in magnitude from villages to continents. Other types of subdivisions exist as well. Linguistic differences often define barriers to random mating, as do differences in social class, clan or caste membership, and religious affiliation. In addition, various cultural regulations, such as taboos or prescribed mating systems, result in subdivision.

The Genetic Structure of Subdivided Human Populations

Questions concerning the relative effects of various evolutionary forces in molding the genetic variability exhibited by groups of human populations have typically been investigated by comparing a variety of genetic and cultural/historical "distance" matrices. A major methodological difficulty has been the lack of formal testing procedures with which to assess the degree of confirmation or disconfirmation of an estimated measure of relationship between such matrices. In this paper, we examine a very flexible matrix combinatorial procedure which generates statistical significance levels for correlational measures of pattern similarity between distance matrices. A recent generalization of the basic procedure to the three-matrix case allows questions concerning which of two matrices best fits a third matrix to be formally tested. Applications of these hypothesis testing and inference procedures to two separate sets of genetic, geographic, and cultural distance matrices illustrates their potential for finally solving a long-standing problem in anthropological genetics.

Comparison of distance matrices in studies of population structure and genetic microdifferentiation: Quadratic assignment

This is an exciting time for research into genetic and environmental influences on obesity. Advances in molecular biology, pharmacology, and other fields are allowing rapid advances to be made in this arena. Knowledge that there is a genetic component to variations in body wt and composition is not new. Indeed, animal breeders and ranchers have known for centuries that animals could be selectively bred for traits related to body wt and composition (1). For example, the average pig used for pork production in the United States today has substantially more lean body mass and substantially less fat mass than its ancestors, thus demonstrating the influence of selective breeding (2). Many argue that the ability to induce species-wide changes in the average value of a trait by selective breeding provides the strongest evidence for a genetic effect on that trait (3), a phenomenon that has been demonstrated in livestock (4) and laboratory animals (5).

Genetic and Environmental Influences on Obesity

A major challenge in the post-genomic era is to identify the physiological functions of genes and elucidate the molecular basis for human disease. Genetic polymorphisms offer a convenient avenue for these efforts by providing evidence for the involvement of a given gene in human pathophysiology. Here we review the current evidence linking the low-molecular-weight protein tyrosine phosphatase (LMPTP) to several common diseases, including allergy, asthma, obesity, myocardial hypertrophy, and Alzheimer's disease. Based on the known effects of the genetic polymorphisms on the alternative mRNA splicing and enzyme levels of LMPTP, we discuss the possible molecular mechanisms of LMPTP involvement in these diseases.

https://www.iitd.pan.wroc.pl/files/AITEFullText/50z202.pdf

Low-molecular-weight protein tyrosine phosphatase and human disease: in search of biochemical mechanisms.

The present study reports an analysis of genetic differentiation among 14 Sardinian villages located mainly in the center of the island. Chi-square tests show significant genetic heterogeneity among villages, and analyses by F- and R- statistics indicate an essentially random pattern of differentiation for all alleles. Using the kinship methods of Morton, a matrix, R, with elements rij describing the correlations between the gene frequencies of villages i and j is obtained. Use of Malecot's formula relating the rij to the geographic distances between villages shows a rapid decline of kinship with increasing distance but reveals essentially no relationship for distances over 40 km. Rotation of a two-dimensional reduction of the kinship matrix to maximum congruence with the geographic distances indicates that about 25% of the genetic distances can be accounted for by the geographic location of the villages. Isolation due in part to cultural factors, genetic drift, and special local or regional patterns of villages associations appear to be involved in the pattern of genetic variation.

Genetic differentiation among Sardinian villages.

The frequency of PC allele for acid phosphatase in fourteen Sardinian villages correlates positively with the altitude and negatively with past malarial morbidity and GdMed prevalence.



The susceptibility towards hemolytic favism in Sardinian males with G6PD deficiency is dependent on the erythrocyte acid phosphatase and thalassemia phenotypes. Thalassemia trait exerts a protective action only in subjects carrying PA allele for acid phosphatase.



The data suggest that the gradient for malaria morbidity directly or indirectly, through interactions with thalassemia and G6PD polymorphisms, mediated by the habit of eating Vecia faba, may have had a significant role in determining the heterogeneous distribution of acid phosphatase polymorphism in Sardinia. Besides malaria, other environmental factors related with altitude seem to have been very important in shaping the present pattern of distribution of both acid phosphatase and G6PD polymorphisms in Sardinia.

Red cell acid phosphatase: another polymorphism correlated with Malaria?

Red blood cell adenosine deaminase and G-6-PD polymorphisms have been studied in the populations of 17 Sardinian villages located at various altitudes. A total of 1615 individuals of both sexes, with age between 7 and 14 years were examined.

Adenosine deaminase polymorphism in Sardinia.

NADH diaphorase is considered the most important enzyme which controls the level of methaemoglobin in the erythrocyte, thereby maintaining the pigment in the reduced functional state. Electrophorctic variants of this enzyme have been shown in subjects with methaemoglobinaemia (Kaplan and Beutler, 1967; West et al., 1967; Bloom and Zarkowsky, 1969). Studies on the frequency of such variants in healthy individuals were reported by Kaplan and Beutler (1967), Brewer et al. (1967), Defter et al. (1970) and tIopkinson et al. (1970). The last group carried out an extensive investigation on thousands of individuals : the overall frequency of variant phenotypes was about 1 °/o in European, Indian and Negro populations. In addition to the common phenotype Dia 1, Hopkinson et al. described 6 variant phenotypes: Dia 2 1 , 3--1, 4--1, 5--1, 6--1 and Dia 2. Family data support the hypothesis that the first 5 represent heterozygotes of one of a series of rare alleles (Dia 2, Dia ~, Dia 4, Dia 5 and Dia 6) with a common allele Oia 1 at an autosomal locus. The phenotype Dia 2 corresponds to the homozygote for Dia 2 allele. The present paper reports a study of red blood cell (RBC) NADH diaphorase in the Roman and Sardinian populations.

R. Agostino

Papers

Genetic differentiation among Sardinian villages.

Red cell acid phosphatase: another polymorphism correlated with Malaria?

Adenosine deaminase polymorphism in Sardinia.

Red Blood Cell NADH Diaphorase in Italian Populations