Mitochondrial genes and mammalian phylogenies: increasing the reliability of branch length estimation.

Since branch lengths provide important information about the timing and the extent of evolutionary divergence among taxa, accurate resolution of evolutionary history depends as much on branch length estimates as on recovery of the correct topology. However, the empirical relationship between the choice of genes to sequence and the quality of branch length estimation remains ill defined. To address this issue, we evaluated the accuracy of branch lengths estimated from subsets of the mitochondrial genome for a mammalian phylogeny with known subordinal relationships. Using maximum-likelihood methods, we estimated branch lengths from an 11-kb sequence of all 13 protein-coding genes and compared them with estimates from single genes (0.2-1.8 kb) and from 7 different combinations of genes (2-3.5 kb). For each sequence, we separated the component of the log-likelihood deviation due to branch length differences associated with alternative topologies from that due to those that are independent of the topology. Even among the sequences that recovered the same tree topology, some produced significantly better branch length estimates than others did. The combination of correct topology and significantly better branch length estimation suggests that these gene combinations may prove useful in estimating phylogenetic relationships for mammalian divergences below the ordinal level. Thus, the proper choice of genes to sequence is a critical factor for reliable estimation of evolutionary history from molecular data.

The intergenerational predisposition to operative delivery.

OBJECTIVE: To determine the risk of cesarean delivery for women who themselves were born via operative delivery. METHODS: A linked data base was constructed between the birth certificates of individuals born in Utah during 1947-1957 (parental cohort) and who subsequently became a parent of offspring born in Utah between 1970-1991 (offspring cohort). Parental cohort women (cases) who had been delivered operatively (cesarean delivery, mid- or high forceps) as well as women who had a sibling delivered by an operative procedure were matched (1:2) with parental-cohort women born by spontaneous vaginal delivery (controls). Both cases and controls were selected based on having a record of at least one delivery in Utah during 1970-1991. RESULTS: Women who were delivered by cesarean were at increased risk of subsequently delivering their children by cesarean (odds ratio [OR] 1.41, 95% confidence interval [CI] 1.18-1.70; P < .001). Progressive risk was associated with parental delivery by mid- or high forceps (OR 1.72, 95% CI 1.20-2.47; P = .004), parental cesarean because of cephalopelvic disproportion alone (OR 1.83, 95% CI 1.16-2.88; P = .01), or parental cesarean for dysfunctional labor (OR 5.97, 95% CI 1.5-23.6; P < .001). The attributable risk for cesarean delivery to the contemporary population is 3.5%. CONCLUSION: An intergenerational predisposition to cesarean delivery exists.

Angiotensin-converting enzyme gene polymorphism is associated with myocardial infarction but not with development of coronary stenosis.

BACKGROUND: Although both genetic and nongenetic factors contribute to the pathogenesis of coronary artery disease, the identification of specific genetic lesions has lagged behind the identification of critical environmental risk factors. A reported association between myocardial infarction (MI) and the insertion/deletion (I/D) polymorphism of the angiotensin-converting enzyme (ACE) gene in European men suggests a critical role for this genomic region. However, the generality of this association remains to be determined. It also is not clear at what stage in disease progression the association with the ACE I/D polymorphism becomes important. METHODS AND RESULTS: We evaluated the ACE I/D polymorphism in patients who had undergone coronary angiography (402 men and 295 women) and in 203 representative control subjects. After polymerase chain reaction amplification, genotypes were determined by agarose gel sizing and by hybridization with allele-specific oligonucleotides. After patients were categorized by the degree of coronary artery stenosis and the occurrence of an MI, the distribution of ACE I/D genotypes was evaluated by log linear analysis. Patients were genetically representative of the regional population, and patients with > 60% stenosis of their coronary arteries had the same distribution of ACE I/D genotypes as did patients with < 10% stenosis. However, among patients with stenosis, the occurrence of an MI was significantly associated with the D allele in all patients (odds ratio [OR], 1.59; P = .002) and in men alone (OR, 1.63; P = .006). The lack of significance in women (OR, 1.40; P = .263) is probably due to the fact that only 36 women in the present study had experienced an MI. Furthermore, the association between MI and the ACE I/D polymorphism was independent of blood pressure, smoking habits, and body mass index. CONCLUSIONS: Segregation of the ACE I/D polymorphism is a pervasive genetic risk factor for MI in whites but has no evident effect on the events leading to stenosis of the coronary arteries. This suggests that risk of MI is influenced by two independent processes--atherogenesis that leads to coronary stenosis followed by conversion to MI. The renin-angiotensin system appears to confer significant risk of infarction by influencing the conversion to MI but has no apparent effect on the development of atherostenosis.

Apolipoprotein polymorphisms fail to define risk of coronary artery disease. Results of a prospective, angiographically controlled study.

BACKGROUND: Because genetic factors are believed to contribute to the etiology of coronary artery disease (CAD), it has been suggested that DNA polymorphisms at candidate loci might identify individuals at high risk for developing disease. In this regard, apolipoprotein genes represent extremely promising loci because levels of apolipoproteins and their associated lipoproteins represent a major risk factor for CAD, and rare dysfunctional mutations in these genes result in a significant risk for CAD. To date, although some reports indicate that DNA polymorphisms at these loci are associated with increased risk of CAD, other reports have failed to find such associations. METHODS AND RESULTS: To resolve the question of whether genetic polymorphisms at apolipoprotein loci can be used to identify individuals at increased risk for CAD, we evaluated the distribution of apolipoprotein genetic polymorphisms in a large series of subjects (n = 848) undergoing coronary angiography. Blinded assessment of angiograms was used to discriminate between patients with CAD (> or = 60% stenosis of any major branch, n = 444) and control subjects without disease (< or = 10% stenosis, n = 404). A total of 12 polymorphisms were evaluated at the following loci: apolipoprotein (apo) A-I/C-III/A-IV (five restriction site polymorphisms--Msp I, Pst I, Sst I, Pvu IIa, Pvu IIb), apo B (three restriction site polymorphisms--Xba I, EcoRI, Msp I, plus an insertion/deletion polymorphism), apo A-II (Msp I polymorphism), apo C-II (Taq I polymorphism), and apo E (protein isoforms revealed by DNA analysis). All subjects were of Northern European (primarily Angloscandinavian) descent, and, within each sex, patients and control subjects were of comparable age. All 12 loci were in Hardy-Weinberg equilibrium, with no indication of population heterogeneity. As expected, patients were distinguished from control subjects by their lipid profiles and a higher frequency of known risk factors for CAD. However, analysis by log-linear models indicated that there were no significant associations between apolipoprotein polymorphisms and the risk of CAD (P = .10 to .90). The lack of association was maintained irrespective of whether the analysis was carried out for the entire sample or the contrast was made more stringent by comparing patients most likely to have a genetic component to their disease (ie, young patients with early-onset CAD) with the control subjects least likely to have genetic susceptibility (ie, older control subjects who had ample time to develop CAD). CONCLUSIONS: Despite the fundamental role of apolipoprotein genes in lipid metabolism, we find no evidence that common genetic polymorphisms of the major apolipoprotein loci have a significant influence on the risk of developing angiographically defined CAD in this representative population. Therefore, at this time we find no support for the hypothesis that mass screening for genetic polymorphisms at candidate loci can reduce the burden of CAD by identifying a substantial proportion of high-risk individuals. Instead, it appears more appropriate to direct attention toward modifying high-risk behaviors to alleviate the consequences of traditional environmental risk factors.