Admixture studies and the detection of selection.

Three methods can be used to search for evidence of natural selection from admixture studies. These include classification of the admixture estimates into two groups; calculation of the rank correlation between estimates from more than one population; and the testing of admixture estimates for homogeneity. The use of these methods is discussed with special reference to black-white admixture in the United States. Using revised estimates of African gene frequencies, derived from a consideration of the geographical origin of the slaves, we calculated admixture estimates and their variances for five U.S. black populations; Claxton (Georgia); Sapelo Island (Georgia); James Island (South Carolina); Charleston (South Carolina); Oakland (California). Two out of the five populations yielded heterogeneous admixture estimates but all other tests were non-significant. The data provide little evidence for the action of selection. The few, inconsistent significant results are more indicative of the action of random drift or biased gene frequency estimates than natural selection, and in general these effects cannot be differentiated. It seems doubtful that admixture studies can ever provide unequivocal evidence for the action of natural selection in human populations. In the search for natural selection, perhaps admixture studies should only be used as a preliminary screening device.

Immune response factors in rheumatic heart disease: meta-analysis of HLA-DR associations and evaluation of additional class II alleles.

OBJECTIVES: This study used a meta-analysis to examine HLA-DR frequencies in rheumatic heart disease and prospectively examined other class II allelic disease associations. BACKGROUND: Studies of rheumatic heart disease have reported HLA class II allelic associations, but these are inconsistent. METHODS: A meta-analysis combined all known (n = 10) studies to determine disease risk associated with HLA-DR antigen expression. Meta-analysis of studies grouped by ethnic derivation of subjects was also performed. The present study also examined DQA, DQB and DPB allele frequencies by DNA-based strategies. RESULTS: Meta-analysis showed a significant negative disease association with DR5 (odds ratio [OR] 0.67, p < 0.00003) for all combined studies. Among black patients, DR1 was increased (OR 2.80, p < 0.004); DR6 was increased (OR, 2.03, p < 0.003); and DR 8 was decreased (OR 0.32, p < 0.02). Among Eastern Indian patients, DR3 was increased (OR 2.44, p < 0.00003), with decreased expression for DR2 (OR 0.31, p < 0.00001) and DR5 (OR 0.52, p < 0.05). DR4 was increased among American whites (OR 1.74, p < 0.03), although there was significant heterogeneity among studies of whites. DQA, DQB and DPB allele frequencies were similar for control subjects and patients. CONCLUSIONS: Our findings support an association between major histocompatibility complex class II alleles and risk for rheumatic heart disease. However, heterogeneity in associations was observed among different ethnic and racial groups; regional and temporal differences in streptococcal outbreaks may compound this heterogeneity. Further studies are necessary to elucidate the respective contributions of these variables.

Angiotensin-converting enzyme genotypes and risk for myocardial infarction in women.

OBJECTIVES: We tested for an association between the angiotensin-converting enzyme (ACE) DD polymorphic genotype and myocardial infarction (MI) in a sample group composed exclusively of women. BACKGROUND: The human ACE gene occurs with either an insertion (I allele) or a deletion (D allele) of a 287-base pair (bp) Alu element. Part of the variance in serum ACE levels may be accounted for by this polymorphism. Also, the DD genotype has been associated with an increased risk of MI in predominantly male populations. However, the risk in women is poorly defined. METHODS: Genomic DNA was extracted from buffy coat blood using a phenol/chloroform method. Angiotensin-converting enzyme alleles were identified using primers to bracket the insertion region in intron 16. Amplification using polymerase chain reaction allowed identification of a 490-bp (I allele) or a 190-bp (D allele) product, or both. RESULTS: Allelic and genotypic frequencies in control subjects were similar to those reported in mostly male populations, and frequencies of genotypes were in the Hardy-Weinberg equilibrium. In contrast, the distribution of genotypes in patients with MI diverged from the equilibrium. Specifically, DD genotypic frequency was increased in women with (n = 141) versus without (n = 338) a previous MI (39% vs. 29%, odds ratio [OR] 1.54, 95% confidence interval 1.02 to 2.32, p < 0.04). Risk was particularly increased in women <60 years old (OR 2.04, p < 0.05). In contrast, the DD genotype did not predict angiographic coronary artery disease. CONCLUSIONS: Consistent with findings in male-dominated populations, a modest association of the ACE DD genotype with MI was found in women. The basis for this association requires further study.

The genetic structure of a tribal population, the Yanomama Indians. XIV. Clines and their interpretation.

The Yanomama Indians are a South American tribe distributed over an irregular area approximately 200 X 300 miles. The gene frequencies observed at 12 loci in 47 villages within this area have been analyzed for the occurrence of clines. Apparently significant clines are observed for alleles of the Rh, MNSs, Kidd, Gm, Inv and serum albumin system. Available data concerning recent tribal expansion and admixture permit a tentative analysis of the causes of these clines. Although the action of selection cannot be rigorously excluded, it seems unlikely to be the major couse. Admixture with surrounding tribes plays a role which can be quantified because of the fortuitous cicumstance of two genetic markers for admixture. It is suggested that an important factor in the origin of these clines is the manner in which the tribe has recently expanded through successive village fissionings and a predominantly centrifugal pattern of village migration.

The genetic structure of a tribal population, the Yanomama Indians. VI. Analysis by F-statistics (including a comparison with the Makiritare and Xavante).

The infra-structure of three relatively undisturbed tribes of American Indians (Yanomama, Makiritare, Xavante) has been investigated by means of the F-statistics of Wright, using 8, 9 and 6 codominant systems respectively. The data for the first two mentioned tribes are much more extensive (37 and 7 villages) than for the third (3 villages), and much of the argument is based on the first two. An additive model partitioning F(IS) into an average effect (F(A)) and deviations due to deme size, systems effects, village effects, and random error has been employed. The Cannings-Edwards formulation suggests that the small size of the demes alone would result in an F(IS) of -0.008 for the Yanomama and -0.007 for the Makiritare. There is no evidence for significant village or systems effects. Despite considerable scatter, F(A) values are not significantly heterogeneous and tend to be negative (-0.012 to -0.023). On the basis of a computer simulation model, it appears that there is an excess of consanguineous marriage over random expectation, i.e. the negative F(A) values are probably not due to avoidance of close inbreeding in a subdivided population in which demes are small. Aspects of population structure which could contribute to negative F(A) values are identified. These include unequal gene frequencies in the sexes and occasional marked differential fertility. It is at this point unnecessary to introduce overdominance as a cause of the negative F(A) values, since a computer simulation program which does not incorporate selection satisfactorily reproduces the observed F(IS) values. If population breeding structure alone can result in negative F(IS) values, then this may constitute a mechanism for retarding random fixation.-Mean F(ST) values are 0.063 for the Yanomama and 0.036 for the Makiritare. While truly comparable data are lacking, it seems likely these will be found to be relatively high values for human populations. F(IT) values have been calculated by both direct and indirect approaches. The direct approach yields a value of 0.045 for the Yanomama and -0.009 for the Makiritare; the respective indirect values are 0.085 and 0.017. The primary identifiable reason for this difference between tribes is the greater genetic heterogeneity among Yanomama villages. The assumptions underlying the indirect approach to the calculation of F(IT) do not appear to be met in these populations.

A comparison of the genetic infrastructure of the Ye'cuana and the Yanomama: a likelihood analysis of genotypic variation among populations.

A general procedure is described for measuring and testing population differences in gametic frequencies. The total dispersion among populations is subdivided in hierachical fashion. The multiple-locus treatment is simply the sum of the single-locus analyses, provided gametic equilibrium obtains among the loci. In the event that gametic equilibrium does not obtain, correlations among loci need to be dealt with.--The analysis is then used to examine the genetic infrastructure of two Indian tribes from South America, the Ye'cuana (Makiritare) and the Yanomama. From historical evidence, we may identify several "clusters" of villages within each tribe. The demographic and cultural practices affecting village formation and the maintenance of peer integrity are rather different in these tribes, however, and lead us to postulate rather different patterns of genetic variation among villages. Analyses of five codominant two-allele loci, four dominant two-allele loci and two complex loci (with four codominant haplotypes each) demonstrate that Yanomama clusters are more disparate than Ye'cuana clusters, as would have been predicted on sociocultural grounds.

Reduced mtDNA diversity in the Ngöbé Amerinds of Panamá.

Mitochondrial DNA (mtDNA) haplotype diversity was determined for 46 Ngöbé Amerinds sampled widely across their geographic range in western Panamá. The Ngöbé data were compared with mtDNA control region I sequences from two additional Amerind groups located at the northern and southern extremes of Amerind distribution, the Nuu-Chah-Nulth of the Pacific Northwest and the Chilean Mapuche and from one Na-Dene group, the Haida of the Pacific Northwest. The Ngöbé exhibit the lowest mtDNA control region sequence diversity yet reported for an Amerind group. Moreover, they carry only two of the four Amerind founding lineages first described by Wallace and coworkers. We posit that the Ngöbé passed through a population bottleneck caused by ethnogenesis from a small founding population and/or European conquest and colonization. Dating of the Ngöbé population expansion using the Harpending et al. approach to the analysis of pairwise genetic differences indicates a Ngöbé expansion at roughly 6800 years before present (range: 1850-14,000 years before present), a date more consistent with a bottleneck at Chibcha ethnogenesis than a conquest-based event.

Major histocompatibility complex class II gene frequencies by serologic and deoxyribonucleic acid genomic typing in idiopathic dilated cardiomyopathy.

Certain immunologic features associated with idiopathic dilated cardiomyopathy (IDC) suggest an infectious and/or autoimmune etiology. In this regard, an association between the major histocompatibility complex class II allele, DR4, and increased risk for IDC was previously identified. In the present report, 43 additional patients with IDC and 236 control subjects were studied for major histocompatibility class II allele associations. DR alleles were identified by microcytotoxicity. No significant differences between control subjects and patients with IDC were seen, although the frequency of DR4 was increased among patients. DR4 subtyping (n = 9) was performed by "dot blot" hybridization of allele-specific oligonucleotide probes to PCR-amplified genomic deoxyribonucleic acid. The DRB1*0401 and DRB1*0404 alleles were each found in 44% (n = 4) of patients with IDC, and DRB1*0407 was identified in 1 patient (11%). DQ and DP alleles were identified by restriction endonuclease codigestion of polymerase chain reaction-amplified deoxyribonucleic acid. The digested fragments were separated and identified by polyacrylamide gel electrophoresis. Differences between patients and control subjects were observed for DQA1*0501 (11% of patients vs 28% of control subjects, p < 0.05) and DQB1*0201 (13% patients vs 25% control subjects, p < 0.05). A modest difference was noted for DQA1*0301 (35% patients vs 23% control subjects, p = 0.08). These findings suggest a complex immune-related etiology for IDC that cannot be explained solely by the presence or absence of a single class II allele. However, this and other studies continue to implicate genes within the class II region in determining the risk for IDC.

HTLV type I/II in British Columbia Amerindians: a seroprevalence study and sequence characterization of an HTLV type IIa isolate.

It has been established that the human T cell lymphotropic viruses type I and II (HTLV-I and HTLV-II) are both present in some indigenous peoples of the Americas. While HTLV-I has been identified in coastal British Columbia Indians (BCIs), HTLV-II has not been previously reported in the BCIs or other Canadian Amerindians. The prevalence of HTLV-I and HTLV-II in these populations has not been extensively studied. In this article, we examine a group of BCIs from Vancouver Island who belong to the Nuu-Chah-Nulth and are known to have an increased incidence of rheumatic disease. In 494 serum samples from this tribe, the levels of prevalence of HTLV-I and HTLV-II were 2.8 and 1.6%, respectively. No association could be made between arthropathy and HTLV-I infection. In addition, we characterized an HTLV-II isolate of a BCI from the coastal mainland of British Columbia and with a history of intravenous drug abuse. This case represents the first molecular characterization of a Canadian Amerindian HTLV-II isolate: a subtype IIa virus with phylogenetic affinity for intravenous drug user isolates and containing an extended form of the Tax protein. These results are consistent either with this strain having been sampled from a polymorphic ancestral pool of HTLV-II that gave rise to the current epidemic spread of this virus by intravenous drug use and sexual transmission, or with its being "back-transmitted" into the BC Amerindian population in association with intravenous drug use.

Age structure and the distribution of rare genetic diseases.

Equilibrium frequencies of rare deleterious genes in an age-structured population have been studied by using mathematical models. In the models, variable age-of-onset and variable penetrance of a trait have been incorporated. Numerical analyses show that the equilibrium gene frequencies can be approximated extremely well to those in nonoverlapping generations, as Haldane [1927] claimed. This property of rare deleterious genes in an age-structured population is important because population dynamics of such genes in a finite population can be studied easily.

Multiple sclerosis: updated risks for relatives.

Two important characteristics of multiple sclerosis (MS) are familial clustering and a variable age of onset. There is increasing evidence for a genetically influenced susceptibility in MS. Because of this, patients and their relatives are increasingly asking about the risk for relatives of developing MS. In the MS Clinic in Vancouver, genetic histories are taken routinely for all patients and are updated annually. Patients do not attend the clinic specifically to participate in genetic studies, which could result in over-representation of familial cases. Data were available for 815 MS index cases and 11,345 of their relatives. Age-specific MS risks were calculated for first-, second-, and third-degree relatives of probands and are presented in an easy-reference format. In general, first-degree relatives of probands have a risk that is 30-50 times greater than the 0.1% risk for the general population.

Aqueous-venous shunt for glaucoma. A further report.

The aqueous-venous shunt procedure is a new microsurgical procedure for the relief of glaucoma. The procedure is therapeutically effective in control of glaucoma, is relatively simple to perform, is associated with low risk, and is well tolerated. As measured by tonography and clinical observations, intraocular pressure reduction following the procedure is due mainly to an improvement in aqueous outflow facility. It can be considered clinically as a useful alternative in the management of selected cases of open angle glaucoma.

The risk of preterm birth across generations.

OBJECTIVE: To examine the risk of preterm birth for mothers who themselves were born before term. METHODS: Data were taken from a linked data base of birth certificates composed of two cohorts: 1) a parental cohort of women born between 1947 and 1957 and 2) their offspring born between 1970 and 1992. "Preterm mothers" were women in the parental cohort who were born at less than 37 weeks' gestation. "Term mothers" were women in the parental cohort born at or after 38 weeks' gestation. Preterm mothers and term mothers were matched for birth year, county of birth, marital status, parity, and age. Odds ratios (ORs) and 95% confidence intervals (CIs) were calculated for the risk of preterm delivery in preterm mothers. Multiple logistic regression was used to assess the interaction of concomitant variables with the risk of premature delivery. RESULTS: The risk of preterm birth was significantly higher in preterm mothers than in term mothers (OR 1.18; 95% CI 1.02, 1.37). The risk increased as the gestational age at the mothers' birth decreased (less than 30 weeks'; OR 2.38; 95% CI 1.37, 4.16). The interaction between maternal age and parity increased the risk of preterm delivery at less than 34 weeks in some age and parity strata. CONCLUSION: An increased risk of preterm delivery exists for women who themselves were born before 37 weeks' gestation. The risk is inversely correlated with the maternal gestational age at birth and is influenced by maternal age and parity.

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.

Biological variability in a migrating isolate, the Tokelau Islands: Child growth in different environments.

The magnitude and rates of growth have been compared among two cross-sectional samples of Tokelau children on the basis of 26 anthropometric dimensions. One of the samples consisted of children living on the Tokelau Islands. The migrant sample consisted of children of Tokelau descent who were living in New Zealand. The comparison between samples suggest significant differences in the rate of linear growth at the younger ages. However, most differences were not significant among 17 year olds. The results support the hypothesis that even when the original environment is favorable, qualitative changes in the environment may affect the general pattern of growth. The effects of an accelerated growth pattern cannot be determined at this time.

Mitochondrial DNA polymorphism in three Brazilian Indian tribes.

The first 360 base pairs of the mitochondrial DNA (mtDNA) major noncoding region from 82 individuals affiliated with the Brazilian Xavante, Zoró and Gavião tribes were sequenced. A total of 14 different lineages were observed, the largest number (8) being found among the Zoró. The latter share five lineages with the Gavião (who are their neighbors and are culturally similar to them), but only one with the Xavante. The lineages can be grouped into four clusters, previously identified by other authors. The 9 base pair deletion characteristic of Asian and Pacific populations occurs in 32% of the individuals, whose mtDNA was classified in five lineages, all grouped in one of the four clusters. Nucleotide diversity, as evaluated by three indices, are not much different from those observed in Indians from Central and North America, despite the fact that the Xavante consistently show lower numbers. These results do not confirm previous generalizations about the genetic diversity of Amerindians, and the need for additional studies in this system is stressed. © 1996 Wiley-Liss, Inc.

Diagnostic fetal blood sampling for the haemoglobinopathies--10-year experience.

The development of methods for fetal blood sampling in the second trimester of pregnancy offers the possibility of fetal diagnosis for couples at risk for having children with a haemoglobinopathy. We review the evolution of 10 years' experience of fetal blood sampling for 681 patients. The obstetric risk associated with the procedure has fallen from an initial 15% (in the first 87 pregnancies) to about 3%, in parallel with increased experience, improved ultrasound control, identification of the causes of complications and implementation of simple steps to avert them.

Changes in circulating alphafetoprotein and human chorionic gonadotrophin following chorionic villus sampling.

Chorionic villus sampling (CVS) is rapidly becoming established as a routine procedure for first-trimester fetal diagnosis. The technique can result in fetomaternal haemorrhage and this might sensitize Rhesus-negative mothers and on occasion lead to spontaneous abortion. Serial sampling indicates that there is a rapid rise in alphafetoprotein (AFP) levels following CVS; however, this is not reflected by raised levels at 16-18 weeks and does not influence the subsequent pregnancy outcome. Unlike AFP, alterations in hCG levels are small and variable. Anti-D prophylaxis for non-sensitized Rhesus negative mothers should be given after CVS and the procedure may be contra-indicated in patients who are already sensitized.

Modeling the evolution of the human mitochondrial genome.

Mitochondrial DNA data have been used extensively to study evolution and early human origins. These applications require estimates of the rate at which nucleotide substitutions occur in the DNA sequence. We consider the problem of estimating substitution rates in the presence of site-to-site rate variation. A coalescent model is presented that allows for different substitution rates for purines and pyrimidines, as well as more detailed models that allow fast and slow rates within each of the purine and pyrimidine classes. A method for estimating such rates is presented. Even for these simple models of site heterogeneity, there are, typically, insufficient data to obtain reliable estimates of site-specific substitution rates. However, estimates of the average rate across all sites appear to be relatively stable even in the presence of site heterogeneity. Simulations of models with site-to-site variation in mutation rate show that hypervariable sites can produce peaks in the pairwise difference curves that have previously been attributed to population dynamics.

Ectopic pancreas. A cause of false-positive peritoneal cytology.

A patient with a history of ovarian adenocarcinoma underwent further surgery because malignant cells were reported in peritoneal washings on two separate occasions. Subsequent laparotomy revealed an ectopic pancreas on the jejunum. Review of the peritoneal cytologies confirmed that the cells previously thought to be malignant were in fact consistent with cells detached from the ectopic pancreas.