Genetic similarities within and between human populations.

The proportion of human genetic variation due to differences between populations is modest, and individuals from different populations can be genetically more similar than individuals from the same population. Yet sufficient genetic data can permit accurate classification of individuals into populations. Both findings can be obtained from the same data set, using the same number of polymorphic loci. This article explains why. Our analysis focuses on the frequency, omega, with which a pair of random individuals from two different populations is genetically more similar than a pair of individuals randomly selected from any single population. We compare omega to the error rates of several classification methods, using data sets that vary in number of loci, average allele frequency, populations sampled, and polymorphism ascertainment strategy. We demonstrate that classification methods achieve higher discriminatory power than omega because of their use of aggregate properties of populations. The number of loci analyzed is the most critical variable: with 100 polymorphisms, accurate classification is possible, but omega remains sizable, even when using populations as distinct as sub-Saharan Africans and Europeans. Phenotypes controlled by a dozen or fewer loci can therefore be expected to show substantial overlap between human populations. This provides empirical justification for caution when using population labels in biomedical settings, with broad implications for personalized medicine, pharmacogenetics, and the meaning of race.

Human population genetic structure and diversity inferred from polymorphic L1(LINE-1) and Alu insertions.

BACKGROUND/AIMS: The L1 retrotransposable element family is the most successful self-replicating genomic parasite of the human genome. L1 elements drive replication of Alu elements, and both have had far-reaching impacts on the human genome. We use L1 and Alu insertion polymorphisms to analyze human population structure. METHODS: We genotyped 75 recent, polymorphic L1 insertions in 317 individuals from 21 populations in sub-Saharan Africa, East Asia, Europe and the Indian subcontinent. This is the first sample of L1 loci large enough to support detailed population genetic inference. We analyzed these data in parallel with a set of 100 polymorphic Alu insertion loci previously genotyped in the same individuals. RESULTS AND CONCLUSION: The data sets yield congruent results that support the recent African origin model of human ancestry. A genetic clustering algorithm detects clusters of individuals corresponding to continental regions. The number of loci sampled is critical: with fewer than 50 typical loci, structure cannot be reliably discerned in these populations. The inclusion of geographically intermediate populations (from India) reduces the distinctness of clustering. Our results indicate that human genetic variation is neither perfectly correlated with geographic distance (purely clinal) nor independent of distance (purely clustered), but a combination of both: stepped clinal.

Payback arising from research funding: evaluation of the Arthritis Research Campaign.

OBJECTIVES: Using a structured evaluation framework to systematically review and document the outputs and outcomes of research funded by the Arthritis Research Campaign in the early 1990s. To illustrate the strengths and weaknesses of different modes of research funding. METHODS: The payback framework was applied to 16 case studies of research grants funded in the early 1990s. Case study methodology included bibliometric analysis, literature and archival document review and key informant interviews. RESULTS: A range of research paybacks was identified from the 16 research grants. The payback included 302 peer-reviewed papers, postgraduate training and career development, including 28 PhD/MDs, research informing recommendations in clinical guidelines, improved quality of life for people with RA and the reduction of the likelihood of recurrent miscarriage for women with antiphospholipid syndrome. The payback arising from project grants appeared to be similar to that arising from other modes of funding that were better resourced. CONCLUSIONS: There is a wide diversity of research payback. Short focused project grants seem to provide value for money.

Evidence for natural selection in the HAVCR1 gene: high degree of amino-acid variability in the mucin domain of human HAVCR1 protein.

The family of genes encoding T-cell immunoglobulin and mucin-domain containing proteins (Tim), which are cell-surface molecules expressed in CD4(+) T helper cells, has important roles in the immune system. Here, we report three unusual patterns of genetic variation in the human hepatitis A virus cellular receptor 1 gene (HAVCR1) that are similar to patterns observed in major histocompatibility complex loci. First, levels of polymorphism in exon 4 of HAVCR1 were exceptionally high in humans (nucleotide diversity (pi)=45.45 x 10(-4)). Second, nonsynonymous substitutions and insertion/deletion variants were more frequent than synonymous substitutions in that exon (10 out of 12 variants). The rate of the mean number of nucleotide substitutions at nonsynonymous sites to synonymous sites at HAVCR1-exon 4 is >1 (P(A)/P(S)=1.92 and pi(A)/pi(S)=2.23). Third, levels of divergence among human, chimp, and gorilla sequences were unusually high in HAVCR1-exon 4 sequences. These features suggest that patterns of variation in HAVCR1 have been shaped by both positive and balancing natural selection in the course of primate evolution. Evidence that the effects of natural selection are largely restricted to the mucin domain of HAVCR1 suggests that this region may be of particular evolutionary and epidemiological interest.

Local adaptation and population differentiation at the interleukin 13 and interleukin 4 loci.

A 25.6 kb region at chromosome 5q31, covering the entire human interleukin 13 (IL-13) and interleukin 4 (IL-4) genes, has been reported to be associated with bronchial asthma. We have examined nucleotide variations at this locus in African, European American, and Japanese populations, using 120 diallelic variants. A block of strong linkage disequilibrium (LD) (mid R:D'mid R:>0.7) spans a 10 kb region containing IL-4 in European American and Japanese populations, and is present but less clear in African samples. Two major haplotypes at IL-4 account for >80% of haplotypes in European Americans and Japanese. These haplotypes are common and quite diverged from each other and the ancestral haplotype, resulting in highly significant deviations from neutrality. F(ST) statistics show that European American and Japanese populations are unusually distinct at the IL-4 locus. The most common haplotype in the European American population is much less common in the Japanese population, and vice versa. This implies that natural selection has acted on IL-4 haplotypes differently in different populations. This selected variation at IL-4 may account for some genetic variance underlying susceptibility to asthma and other allergic diseases. The strong LD observed in the IL-4 region may allow more efficient disease-association studies using this locus.

DNA sequence variation in a 3.7-kb noncoding sequence 5' of the CYP1A2 gene: implications for human population history and natural selection.

CYP1A2 is a cytochrome P450 gene that is involved in human physiological responses to a variety of drugs and toxins. To investigate the role of population history and natural selection in shaping genetic diversity in CYP1A2, we sequenced a 3.7-kb region 5' from CYP1A2 in a diverse collection of 113 individuals from three major continental regions of the Old World (Africa, Asia, and Europe). We also examined sequences in the 90-member National Institutes of Health DNA Polymorphism Discovery Resource (PDR). Eighteen single-nucleotide polymorphisms (SNPs) were found. Most of the high-frequency SNPs found in the Old World sample were also found in the PDR sample. However, six SNPs were detected in the Old World sample but not in the PDR sample, and two SNPs found in the PDR sample were not found in the Old World sample. Most pairs of SNPs were in complete linkage disequilibrium with one another, and there was no indication of a decline of disequilibrium with physical distance in this region. The average +/- SD nucleotide diversity in the Old World sample was 0.00043+/-0.00026. The African population had the highest level of nucleotide diversity and the lowest level of linkage disequilibrium. Two distinct haplotype clusters with broadly overlapping geographical distributions were present. Of the 17 haplotypes found in the Old World sample, 12 were found in the African sample, 8 were found in Indians, 5 were found in non-Indian Asians, and 5 were found in Europeans. Haplotypes found outside Africa were mostly a subset of those found within Africa. These patterns are all consistent with an African origin of modern humans. Seven SNPs were singletons, and the site-frequency spectrum showed a significant departure from neutral expectations, suggesting population expansion and/or natural selection. Comparison with outgroup species showed that four derived SNPs have achieved high (>0.90) frequencies in human populations, a trend consistent with the action of positive natural selection. These patterns have a number of implications for disease-association studies in CYP1A2 and other genes.

Do human and JC virus genes show evidence of host-parasite codemography?

Information about similarities and differences in the demographic history of host and parasite populations is potentially useful for making inferences about a variety of evolutionary processes. However, it is difficult to observe the historical demographic properties of natural populations directly. Here, the extent of demographic similarity in a host and its parasite was examined indirectly by inferring long-term population history from patterns of genetic variation. Nucleotide sequence diversity in human and JC virus (JCV) DNA is consistent with a long-term demographic connection between the two species: both show evidence of large-scale population expansion. However, genetic data also suggest that the two species have different patterns of population substructuring. These similarities and differences have implications for adaptive evolution in JCV that are not evident when the two species are considered separately.

Population structure and history in East Asia.

Archaeological, anatomical, linguistic, and genetic data have suggested that there is an old and significant boundary between the populations of north and south China. We use three human genetic marker systems and one human-carried virus to examine the north/south distinction. We find no support for a major north/south division in these markers; rather, the marker patterns suggest simple isolation by distance.

PRoMT: inferring demographic history from DNA sequences.

UNLABELLED: I describe a parallel implementation of Rogers' mismatch algorithm, a method for making inferences about demographic history from DNA sequence data. The program is distributed on clusters of workstations, providing a substantial speedup and low execution times on large numbers of nodes. AVAILABILITY: Source code and documentation are available at http://mombasa.anthro.utah.edu/wooding/ CONTACT: stephen.wooding@anthro.utah.edu

Child sexual abuse II: treatment.

OBJECTIVE: To evaluate the scientific literature concerning the treatment of child sexual abuse. METHOD: A critical review of the scientific literature. RESULTS: There are only nine published research studies in which subjects were randomly assigned to an index treatment or treatments and a comparison treatment or no-treatment control group. In seven of the studies, the index treatment exceeded the control or comparison group in regard to treatment outcome; in two studies it did not. The successful treatments involved group therapy, combined individual and group play therapy and cognitive behaviour therapy. CONCLUSIONS: Treatment should be based on an explicit conceptual model of the psychopathology of sexual abuse. The University of Queensland Sexual Abuse Treatment Project, which is based on a transactional model, is described.

The dynamics of golgi protein traffic visualized in living yeast cells.

We describe for the first time the visualization of Golgi membranes in living yeast cells, using green fluorescent protein (GFP) chimeras. Late and early Golgi markers are present in distinct sets of scattered, moving cisternae. The immediate effects of temperature-sensitive mutations on the distribution of these markers give clues to the transport processes occurring. We show that the late Golgi marker GFP-Sft2p and the glycosyltransferases, Anp1p and Mnn1p, disperse into vesicle-like structures within minutes of a temperature shift in sec18, sft1, and sed5 cells, but not in sec14 cells. This is consistent with retrograde vesicular traffic, mediated by the vesicle SNARE Sft1p, to early cisternae containing the target SNARE Sed5p. Strikingly, Sed5p itself moves rapidly to the endoplasmic reticulum (ER) in sec12 cells, implying that it cycles through the ER. Electron microscopy shows that Golgi membranes vesiculate in sec18 cells within 10 min of a temperature shift. These results emphasize the dynamic nature of Golgi cisternae and satisfy the kinetic requirements of a cisternal maturation model in which all resident proteins must undergo retrograde vesicular transport, either within the Golgi complex or from there to the ER, as anterograde cargo advances.

Phylogeography and pleistocene evolution in the North American black bear.

To determine the extent of phylogeographic structuring in North American black bear (Ursus americanus) populations, we examined mitochondrial DNA sequences (n = 118) and restriction fragment length polymorphism profiles (n = 258) in individuals from 16 localities. Among the bears examined, 19 lineages falling into two highly divergent clades were identified. The clades differ at 5.0% of nucleotide positions, a distance consistent with an origin 1.8 MYA, and have different but overlapping geographical distributions. Areas of clade cooccurrence show that eastern and western populations are currently mixing, but regional differences in lineage distribution suggest that mixing has begun only recently. The long-term population history of black bears appears to be characterized predominantly by long-term regional isolation followed by recent contact and hybridization. Congruence between the pattern of diversity observed in black bears and patterns of forest refuge formation during the Pleistocene supports earlier speculation that Pleistocene forest fragmentations underlie a common pattern in the phylogeography of North American forest taxa.

Nebivolol vasodilates human forearm vasculature: evidence for an L-arginine/NO-dependent mechanism.

Nebivolol, a beta 1 selective adrenergic receptor antagonist with additional properties, is a racemic mixture of (S,R,R,R)- and (R,S,S,S)-enantiomers. We investigated its effects on human forearm vasculature. Blood flow was measured using venous occlusion plethysmography during brachial artery infusion of drugs. Interaction between nebivolol and the L-arginine/nitric oxide pathway was investigated via comparison with carbachol (an endothelium-dependent agonist) and nitroprusside, and by coinfusion of a competitive inhibitor of nitric oxide synthase, NG-monomethyl L-arginine (LNMMA) +/- L-arginine. Nebivolol (354 micrograms/min) increased blood flow by 91 +/- 18% (mean +/- SEM, n = 8, P < .01) whereas an equimolar dose of atenolol had no significant effect. L-NMMA (1 mg/min) inhibited vasodilation to nebivolol (by 65 +/- 10%) and carbachol (by 49 +/- 8%) to a significantly greater extent than it reduced responses to nitroprusside. Inhibition of nebivolol response by L-NMMA was abolished by L-arginine (62 +/- 11% inhibition by L-NMMA, 15 +/- 17% inhibition by L-NMMA with L-arginine, 10 mg/min, n = 8). Vasodilation caused by the (S,R,R,R)- and (R,S,S,S)-enantiomers was similar. We conclude that nebivolol vasodilates human forearm vasculature via the L-arginine/nitric oxide pathway.

The value of routine microbial investigation in community-acquired pneumonia.

The way in which microbiological investigations are used in routine clinical practice and the value of such tests in directing antibiotic prescribing, was studied in adults admitted to hospital with a diagnosis of community-acquired pneumonia. One-hundred and twenty-two consecutive patients admitted to one teaching and one district general hospital were studied between April 1988 and March 1989. Blood cultures were performed in 81% of cases, sputum was examined in 45% and complete serological tests were performed in 28%. No causative pathogen was found in 74% of cases and results of microbial tests directed a change in antibiotic therapy in only 8% of cases. Routine microbial investigation of all adults admitted to hospital with community-acquired pneumonia is unhelpful and probably unnecessary. We suggest a strategy for microbial investigation linked to initial illness severity to replace the current haphazard approach.

Pattern ERG in amblyopia.

The authors have recorded pattern ERGs in 62 amblyopic children. In 12 who were occluded up until the morning of the test, the occluded eye response was reduced, and the ratio ([response amplitude of amblyopic eye]/[response amplitude of fellow eye]) was greater than unity. In the remainder, the ratio was considerably less than unity. Ratios of less than 1.0 were found for anisometropic, esotropic, exotropic, and microtropic amblyopes. The ratio was not related to visual acuity or to squint but was higher in those children whose vision was improved by orthoptic treatment. In a group of older children recalled to the clinic, the ratio was 1.0 in those who had maintained equal visual acuity and was less than unity in those children whose acuity had regressed after treatment, or had not improved during treatment. The reduction of the pattern ERG in amblyopes occurs without a corresponding reduction in the focal ERG. In adult amblyopes, the relationship between loss of acuity, loss of grating contrast sensitivity, and the reduction in the PERG is complex and may differ according to the type of amblyopia.