The mechanisms that balance food intake and energy expenditure determine who will be obese and who will be lean. One of the molecules that regulates energy balance in the mouse is the obese (ob) gene. Mutation of ob results in profound obesity and type II diabetes as part of a syndrome that resembles morbid obesity in humans. The ob gene product may function as part of a signalling pathway from adipose tissue that acts to regulate the size of the body fat depot.

Positional cloning of the mouse obese gene and its human homologue

Background Type 2 diabetes mellitus is increasingly common, primarily because of increases in the prevalence of a sedentary lifestyle and obesity. Whether type 2 diabetes can be prevented by interventions that affect the lifestyles of subjects at high risk for the disease is not known. Methods We randomly assigned 522 middle-aged, overweight subjects (172 men and 350 women; mean age, 55 years; mean body-mass index [weight in kilograms divided by the square of the height in meters], 31) with impaired glucose tolerance to either the intervention group or the control group. Each subject in the intervention group received individualized counseling aimed at reducing weight, total intake of fat, and intake of saturated fat and increasing intake of fiber and physical activity. An oral glucose-tolerance test was performed annually; the diagnosis of diabetes was confirmed by a second test. The mean duration of follow-up was 3.2 years. Results The mean (±SD) amount of weight lost between base line and the end of ye...

Prevention of type 2 diabetes mellitus by changes in lifestyle among subjects with impaired glucose tolerance.

So far in this course we have dealt entirely with the evolution of characters that are controlled by simple Mendelian inheritance at a single locus. There are notes on the course website about gametic disequilibrium and how allele frequencies change at two loci simultaneously, but we didn’t discuss them. In every example we’ve considered we’ve imagined that we could understand something about evolution by examining the evolution of a single gene. That’s the domain of classical population genetics. For the next few weeks we’re going to be exploring a field that’s actually older than classical population genetics, although the approach we’ll be taking to it involves the use of population genetic machinery. If you know a little about the history of evolutionary biology, you may know that after the rediscovery of Mendel’s work in 1900 there was a heated debate between the “biometricians” (e.g., Galton and Pearson) and the “Mendelians” (e.g., de Vries, Correns, Bateson, and Morgan). Biometricians asserted that the really important variation in evolution didn’t follow Mendelian rules. Height, weight, skin color, and similar traits seemed to

Human biochemical genetics

There is increasing evidence that genome-wide association ( GWA) studies represent a powerful approach to the identification of genes involved in common human diseases. We describe a joint GWA study ( using the Affymetrix GeneChip 500K Mapping Array Set) undertaken in the British population, which has examined similar to 2,000 individuals for each of 7 major diseases and a shared set of similar to 3,000 controls. Case-control comparisons identified 24 independent association signals at P < 5 X 10(-7): 1 in bipolar disorder, 1 in coronary artery disease, 9 in Crohn's disease, 3 in rheumatoid arthritis, 7 in type 1 diabetes and 3 in type 2 diabetes. On the basis of prior findings and replication studies thus-far completed, almost all of these signals reflect genuine susceptibility effects. We observed association at many previously identified loci, and found compelling evidence that some loci confer risk for more than one of the diseases studied. Across all diseases, we identified a large number of further signals ( including 58 loci with single-point P values between 10(-5) and 5 X 10(-7)) likely to yield additional susceptibility loci. The importance of appropriately large samples was confirmed by the modest effect sizes observed at most loci identified. This study thus represents a thorough validation of the GWA approach. It has also demonstrated that careful use of a shared control group represents a safe and effective approach to GWA analyses of multiple disease phenotypes; has generated a genome-wide genotype database for future studies of common diseases in the British population; and shown that, provided individuals with non-European ancestry are excluded, the extent of population stratification in the British population is generally modest. Our findings offer new avenues for exploring the pathophysiology of these important disorders. We anticipate that our data, results and software, which will be widely available to other investigators, will provide a powerful resource for human genetics research.

/pdf/genome-wide-association-study-of-14-000-cases-of-seven-5ay7q0q3vy.pdf

Genome-wide association study of 14,000 cases of seven common diseases and 3,000 shared controls

Based upon observations on 48 cases of retinoblastoma and published reports, the hypothesis is developed that retinoblastoma is a cancer caused by two mutational events. In the dominantly inherited form, one mutation is inherited via the germinal cells and the second occurs in somatic cells. In the nonhereditary form, both mutations occur in somatic cells. The second mutation produces an average of three retinoblastomas per individual inheriting the first mutation. Using Poisson statistics, one can calculate that this number (three) can explain the occasional gene carrier who gets no tumor, those who develop only unilateral tumors, and those who develop bilateral tumors, as well as explaining instances of multiple tumors in one eye. This value for the mean number of tumors occurring in genetic carriers may be used to estimate the mutation rate for each mutation. The germinal and somatic rates for the first, and the somatic rate for the second, mutation, are approximately equal. The germinal mutation may arise in some instances from a delayed mutation.

/pdf/mutation-and-cancer-statistical-study-of-retinoblastoma-3lfgdufscj.pdf

Mutation and Cancer: Statistical Study of Retinoblastoma

FOR THE POPULATION GENETICIST, diabetes mellitus has long presented an enigma. Here is a relatively frequent disease, often interfering with reproduction by virtue of an onset during the reproductive or even pre-reproductive years, with a well-defined genetic basis, perhaps as simple in many families as a single recessive or incompletely recessive gene (cf. Allan, 1933; Pincus and White, 1933, 1934; Harris, 1950; Steinberg and Wilder, 1952; Lamy, Frezal and de Grouchy, 1957; Steinberg, 1959; Post, 1962a). If the considerable frequency of the disease is of relatively long duration in the history of our species, how can this be accounted for in the face of the obvious and strong genetic selection against the condition? If, on the other hand, this frequency is a relatively recent phenomenon, what changes in the environment are responsible for the increase? Current developments in the study of this disease suggest an explanation with important biological ramifications.

Diabetes mellitus: a "thrifty" genotype rendered detrimental by "progress"?

A clinical, biochemical and genetic study has been made of a rare hereditary disease, acatalasemia, characterized by the absence of activity of the enzyme catalase from the blood and other tissues. Clinically, about half of the acatalasemics suffer from a peculiar type of oral gangrene (Takahara's disease) in childhood. This disease, sporadically distributed throughout Japan, is as yet unreported elsewhere in the world. To date 38 acatalasemics in 17 sibships are known. The high incidence of consanguineous marriages between the parents of the affected persons, the normality of the parents, and the ratio of affected to normal in segregting sibships indicate that the acatalasemia phenotype is recessively inherited. Heterozygotes for this disease have now been identified using a biochemical assay for red blood cell catalase activity; the mean activity (K/sub cat/ in this report) of a normal control group is 5.38 units while that of the heterozygotes is 2.17, and no overlap in values between the two groups has been found. The identification of this carrier state would thus place the gene responsible for acatelasemia in the category of an incompletely recessive (or incompletely dominant). In one of the six families studied, no carrier state could be demonstrated. There aremore » apparently no clinical manifestations in the heterozygotes. 46 references, 4 figures, 3 tables.« less

/pdf/hypocatalasemia-a-new-genetic-carrier-state-4tpd5v8gvl.pdf

Hypocatalasemia: a new genetic carrier state

A clinical, pathological, and genetic study of multiple neurofibromatosis

The Yanomamo Indians are an unacculturated tribe inhabiting the tropical equatorial rain forest of northern Brazil and southern Venezuela who do not use salt in their diet. The group therefore presented an unusual opportunity to study the hormonal regulation of sodium metabolism in a culture with life-long extreme restriction of dietary sodium, with parallel observations on blood pressure. Blood pressures increased from the first to second decade but, in constrast to civilized populations, do not systematically increase during subsequent years of life. In twenty-four hour urine collections on adult male Indians, excretion of sodium averaged only 1 plus or minus 1.5 (SD) mEq. Simultaneous plasma renin activities were elevated and comparable to those of civilized subjects placed for brief periods on 10 mEq sodium diets. Similarly, excretion rates of aldosterone equaled those of acculturated subjects on low sodium diets. The findings suggest that the hormonal adjustments to life-long low sodium intakes are similar to those achieved in acute sodium restriction of civilized man. Parenthetically, these elevated levels of aldosterone and renin were probably the norm for man during much of human evolution and suggest that the values observed in civilized controls are depressed by an excessive salt intake in contemporary diets.

Blood pressure, sodium intake, and sodium related hormones in the Yanomamo Indians, a "no-salt" culture.

eases and their pathophysiology, and review the arguments for regarding the genetic predisposition to all three of these conditions as formerly adaptive genotypes, the functioning of which is now compromised by the changing lifestyles of the technologically advanced nations. Finally, we will discuss the probable relative effectiveness in the future of a genetically based in contrast to an environmentally based program of prevention and therapy for these diseases.

/pdf/the-thrifty-genotype-in-1998-1lmgcqmwaf.pdf

James V. Neel

Papers

Diabetes mellitus: a "thrifty" genotype rendered detrimental by "progress"?

Hypocatalasemia: a new genetic carrier state

A clinical, pathological, and genetic study of multiple neurofibromatosis

Blood pressure, sodium intake, and sodium related hormones in the Yanomamo Indians, a "no-salt" culture.

The "thrifty genotype" in 1998.