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

Background Childhood obesity increases the risk of obesity in adulthood, but how parental obesity affects the chances of a child's becoming an obese adult is unknown. We investigated the risk of obesity in young adulthood associated with both obesity in childhood and obesity in one or both parents. Methods Height and weight measurements were abstracted from the records of 854 subjects born at a health maintenance organization in Washington State between 1965 and 1971. Their parents' medical records were also reviewed. Childhood obesity was defined as a body-mass index at or above the 85th percentile for age and sex, and obesity in adulthood as a mean body-mass index at or above 27.8 for men and 27.3 for women. Results In young adulthood (defined as 21 to 29 years of age), 135 subjects (16 percent) were obese. Among those who were obese during childhood, the chance of obesity in adulthood ranged from 8 percent for 1- or 2-year-olds without obese parents to 79 percent for 10-to-14-year-olds with at least on...

https://www.nejm.org/doi/pdf/10.1056/NEJM199709253371301

Predicting Obesity in Young Adulthood from Childhood and Parental Obesity

The Multi-Ethnic Study of Atherosclerosis was initiated in July 2000 to investigate the prevalence, correlates, and progression of subclinical cardiovascular disease (CVD) in a population-based sample of 6,500 men and women aged 45-84 years. The cohort will be selected from six US field centers. Approximately 38% of the cohort will be White, 28% African-American, 23% Hispanic, and 11% Asian (of Chinese descent). Baseline measurements will include measurement of coronary calcium using computed tomography; measurement of ventricular mass and function using cardiac magnetic resonance imaging; measurement of flow-mediated brachial artery endothelial vasodilation, carotid intimal-medial wall thickness, and distensibility of the carotid arteries using ultrasonography; measurement of peripheral vascular disease using ankle and brachial blood pressures; electrocardiography; and assessments of microalbuminuria, standard CVD risk factors, sociodemographic factors, life habits, and psychosocial factors. Blood samples will be assayed for putative biochemical risk factors and stored for use in nested case-control studies. DNA will be extracted and lymphocytes will be immortalized for genetic studies. Measurement of selected subclinical disease indicators and risk factors will be repeated for the study of progression over 7 years. Participants will be followed through 2008 for identification and characterization of CVD events, including acute myocardial infarction and other coronary heart disease, stroke, peripheral vascular disease, and congestive heart failure; therapeutic interventions for CVD; and mortality.

/pdf/multi-ethnic-study-of-atherosclerosis-objectives-and-design-2ly8fyhifg.pdf

Multi-Ethnic Study of Atherosclerosis: Objectives and Design

Medical genetics was revolutionized during the 1980s by the application of genetic mapping to locate the genes responsible for simple Mendelian diseases. Most diseases and traits, however, do not follow simple inheritance patterns. Genetics have thus begun taking up the even greater challenge of the genetic dissection of complex traits. Four major approaches have been developed: linkage analysis, allele-sharing methods, association studies, and polygenic analysis of experimental crosses. This article synthesizes the current state of the genetic dissection of complex traits--describing the methods, limitations, and recent applications to biological problems.

https://focus.psychiatryonline.org/doi/pdf/10.1176/foc.4.3.442

Genetic dissection of complex traits

This statement examines the cardiovascular complications of diabetes mellitus and considers opportunities for their prevention. These complications include coronary heart disease (CHD), stroke, peripheral arterial disease, nephropathy, retinopathy, and possibly neuropathy and cardiomyopathy. Because of the aging of the population and an increasing prevalence of obesity and sedentary life habits in the United States, the prevalence of diabetes is increasing. Thus, diabetes must take its place alongside the other major risk factors as important causes of cardiovascular disease (CVD). In fact, from the point of view of cardiovascular medicine, it may be appropriate to say, “diabetes is a cardiovascular disease.”

The most prevalent form of diabetes mellitus is type 2 diabetes. This disorder typically makes its appearance later in life. The underlying metabolic causes of type 2 diabetes are the combination of impairment in insulin-mediated glucose disposal (insulin resistance) and defective secretion of insulin by pancreatic β-cells. Insulin resistance develops from obesity and physical inactivity, acting on a substrate of genetic susceptibility.1 2 Insulin secretion declines with advancing age,3 4 and this decline may be accelerated by genetic factors.5 6 Insulin resistance typically precedes the onset of type 2 diabetes and is commonly accompanied by other cardiovascular risk factors: dyslipidemia, hypertension, and prothrombotic factors.7 8 The common clustering of these risk factors in a single individual has been called the metabolic syndrome. Many patients with the metabolic syndrome manifest impaired fasting glucose (IFG)9 even when they do not have overt diabetes mellitus.10 The metabolic syndrome commonly precedes the development of type 2 diabetes by many years11 ; of great importance, the risk factors that constitute this syndrome contribute independently to CVD risk.

Recently, new criteria have been accepted for the diagnosis of diabetes.9 The upper threshold of fasting plasma glucose for the …

https://cdr.lib.unc.edu/downloads/m900nw482

Diabetes and cardiovascular disease : A statement for healthcare professionals from the American heart association

The incidence of end-stage renal disease in patients with diabetes mellitus is reportedly higher among blacks than among whites. This finding may be explained by the greater prevalence of diabetes among blacks. The relation of the type of diabetes to the risk of diabetic end-stage renal disease is largely unstudied. We addressed these issues in a study of all the black and white diabetic patients with end-stage renal disease (470 blacks and 861 whites) reported to the Michigan Kidney Registry who began treatment during 1974 through 1983. We also reviewed the medical records of a subpopulation of such patients (284 blacks and 310 whites) who were less than 65 years of age at the start of treatment for end-stage renal disease to determine what type of diabetes they had. In this study, we made use of national data on the prevalence of diabetes. We found that the incidence of diabetic end-stage renal disease was 2.6-fold higher (P less than or equal to 0.0001) among blacks after we adjusted for the higher prevalence of diabetes among blacks, with the excess risk occurring predominantly among blacks with non-insulin-dependent diabetes mellitus (NIDDM). Most black patients with diabetic end-stage renal disease had NIDDM (77 percent), whereas most white patients with diabetic end-stage renal disease had insulin-dependent diabetes mellitus (IDDM) (58 percent) (P less than or equal to 0.0005 for the difference between the races). For both races combined, the risk of diabetic end-stage renal disease during the 10-year period we studied was markedly greater for patients with IDDM (5.8 percent) than for those with NIDDM (0.5 percent). Our results indicate an increased risk of diabetic end-stage renal disease among blacks as compared with whites, particularly blacks with NIDDM. Although the risk of diabetic end-stage renal disease is higher in patients with IDDM, the majority of patients with diabetic end-stage renal disease in the population we studied had NIDDM.

Disparities in Incidence of Diabetic End-Stage Renal Disease According to Race and Type of Diabetes

To assess the relationship of coronary artery calcification to angiographically detectable disease, the authors evaluated 100 patients less than 60 years of age who underwent clinically indicated coronary angiography and ultrafast computed tomography (CT). The ultrafast CT technique consisted of 3-mm-thick contiguous sections and a 100-msec acquisition time. All patients with clinically significant disease at angiography (defined as at least one stenosis with a diameter narrowing of at least 50%) had some coronary artery calcification present at ultrafast CT (100% sensitivity in this population). The absence of calcification at ultrafast CT had a 100% negative predictive value for clinically significant coronary artery disease. Specificity and positive predictive value were 47% and 62%, respectively. Sensitivity and specificity of ultrafast CT in the detection of patients with angiographically detectable disease were 94% and 72%, respectively. Ultrafast CT of the heart is an anatomically based, noninvasive test with high sensitivity for the detection of coronary artery calcification. Ultrafast CT may be beneficial in the screening of selected populations for the presence of atherosclerotic coronary disease.

Coronary artery calcification detected with ultrafast CT as an indication of coronary artery disease

The role of genetic and environmental factors in determining the variability in body mass index (BMI; kg/m2) was investigated in 1,302 relatives identified through 284 schoolchildren from Muscatine, IA. BMI levels were first adjusted for variability in age, by gender and by relative type. There was significant familial aggregation of adjusted BMI in the pedigrees, as indicated by inter- and intraclass correlation coefficients significantly different from zero. A mixture of two normal distributions fit the adjusted BMI data better than did a single normal distribution. Genetic and environmental models that could explain both the familial aggregation and the mixture of normal distributions were investigated using complex segregation analysis. There was strong support for a single recessive locus with a major effect that accounted for almost 35% of the adjusted variation in BMI. Polygenic loci accounted for an additional 42% of the variation. Approximately 23% of the adjusted variation was not explained by genetic factors. For spouses living in the same household, their shared environment accounted for 12% of their variation. For siblings living in the same household, their shared environment accounted for 10% of their variation. While shared environments contributed to variation in adjusted BMI, more than 75% of the variation was explained by genetic factors that include a single recessive locus. Approximately 6% of the individuals in the population from which these pedigrees were sampled are predicted to have two copies of the recessive gene, while 37% of the individuals are predicted to have one copy of the gene.

The genetic and environmental sources of body mass index variability : the muscatine ponderosity family study

PURPOSE: To identify a minimum definition of coronary artery calcification (CAC) at electron beam computed tomography (CT) that would give repeatable results and be accurate as a marker for coronary artery disease. MATERIALS AND METHODS: Hyperattenuating (> 130 HU) foci 0.69-3.09 mm2 in area were evaluated for 256 subjects who underwent two sequential electron beam CT examinations to determine the percentage of hyperattenuating foci seen on a first examination that were seen again on a second examination. Accuracies of varying minimum definitions of CAC were determined in 160 subjects who underwent electron beam CT and coronary arteriography. RESULTS: Hyperattenuating foci more than 2 mm2 in area were seen again at a second examination in more than 50% of cases (P < .0001). At this minimum definition of CAC, the sensitivity and specificity for identifying any angiographically defined coronary artery disease were 82% and 85%, respectively. CONCLUSION: The 2-mm2-area definition of CAC was reliable and provi...

Small lesions in the heart identified at electron beam CT: calcification or noise?

Environmental and genetic sources of variation in blood pressure have been assessed for an 82% sample of the Tecumseh, Michigan, population during the period 1962-1965. Correlations of systolic blood pressure and diastolic blood pressure were calculated for sets of related and unrelated individuals living together and related individuals living apart. These correlations were analyzed using a biologic model which partitions the total phenotypic variance into components associated with shared genes and components associated with shared household environments both within and across generations. Heritabilities were estimated to be 0.42 and 0.30 for systolic blood pressure and diastolic blood pressure, respectively. The model confirms the hypothesis that the determinants of blood pressure consist of both significant genetic (p less than 0.005) and environmental (p less than 0.005) components. However, only the shared household environments within generations were found to be significant for systolic blood pressure (p less than 0.005) and diastolic blood pressure (p less than 0.05). Although not significant, the across generation shared environment between mothers and offspring tended to have some importance, while that between fathers and offspring was negligible. The implication that there may be some maternal influence in addition to the genetic influence on the determination of blood pressure in offspring warrants further investigation.

Patricia P. Moll

Papers

Disparities in Incidence of Diabetic End-Stage Renal Disease According to Race and Type of Diabetes

Coronary artery calcification detected with ultrafast CT as an indication of coronary artery disease

The genetic and environmental sources of body mass index variability : the muscatine ponderosity family study

Small lesions in the heart identified at electron beam CT: calcification or noise?

Environmental and genetic sources of familial aggregation of blood pressure in tecumseh, michigan