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Abstract High-altitude environments (>2,500 m) provide scientists with a natural laboratory to study the physiological and genetic effects of low ambient oxygen tension on human populations. One approach to understanding how life at high altitude has affected human metabolism is to survey genome-wide datasets for signatures of natural selection. In this work, we report on a study to identify selection-nominated candidate genes involved in adaptation to hypoxia in one highland group, Andeans from the South American Altiplano. We analysed dense microarray genotype data using four test statistics that detect departures from neutrality. Using a candidate gene, single nucleotide polymorphism-based approach, we identified genes exhibiting preliminary evidence of recent genetic adaptation in this population. These included genes that are part of the hypoxia-inducible transcription factor (HIF) pathway, a biochemical pathway involved in oxygen homeostasis, as well as three other genomic regions previously not known to be associated with high-altitude phenotypes. In addition to identifying selection-nominated candidate genes, we also tested whether the HIF pathway shows evidence of natural selection. Our results indicate that the genes of this biochemical pathway as a group show no evidence of having evolved in response to hypoxia in Andeans. Results from particular HIF-targeted genes, however, suggest that genes in this pathway could play a role in Andean adaptation to high altitude, even if the pathway as a whole does not show higher relative rates of evolution. These data suggest a genetic role in high-altitude adaptation and provide a basis for genotype/phenotype association studies that are necessary to confirm the role of putative natural selection candidate genes and gene regions in adaptation to altitude.

This study examined compliance parameters for 18 children (ages 2-10) who had been referred to a clinic for behavior problems and for 35 non-referred children. Although there were significant differences for percentage compliance, there were no significant differences between the referred and nonreferred in terms of initiation or completion latencies. (Author/CR)

Abstract Understanding the distribution of human genetic variation is an important foundation for research into the genetics of common diseases. Some of the alleles that modify common disease risk are themselves likely to be common and, thus, amenable to identification using gene-association methods. A problem with this approach is that the large sample sizes required for sufficient statistical power to detect alleles with moderate effect make gene-association studies susceptible to false-positive findings as the result of population stratification 12. Such type I errors can be eliminated by using either family-based association tests or methods that sufficiently adjust for population stratification 345. These methods require the availability of genetic markers that can detect and, thus, control for sources of genetic stratification among populations. In an effort to investigate population stratification and identify appropriate marker panels, we have analysed 11,555 single nucleotide polymorphisms in 203 individuals from 12 diverse human populations. Individuals in each population cluster to the exclusion of individuals from other populations using two clustering methods. Higher-order branching and clustering of the populations are consistent with the geographic origins of populations and with previously published genetic analyses. These data provide a valuable resource for the definition of marker panels to detect and control for population stratification in population-based gene identification studies. Using three US resident populations (European-American, African-American and Puerto Rican), we demonstrate how such studies can proceed, quantifying proportional ancestry levels and detecting significant admixture structure in each of these populations.

Abstract Understanding the nature of evolutionary relationships among persons and populations is important for the efficient application of genome science to biomedical research. We have analysed 8,525 autosomal single nucleotide polymorphisms (SNPs) in 84 individuals from four populations: African-American, European-American, Chinese and Japanese. Individual relationships were reconstructed using the allele sharing distance and the neighbour-joining tree making method. Trees show clear clustering according to population, with the root branching from the African-American clade. The African-American cluster is much less star-like than European-American and East Asian clusters, primarily because of admixture. Furthermore, on the East Asian branch, all ten Chinese individuals cluster together and all ten Japanese individuals cluster together. Using positional information, we demonstrate strong correlations between inter-marker distance and both locus-specific FST (the proportion of total variation due to differentiation) levels and branch lengths. Chromosomal maps of the distribution of locus-specific branch lengths were constructed by combining these data with other published SNP markers (total of 33,704 SNPs). These maps clearly illustrate a non-uniform distribution of human genetic substructure, an instructional and useful paradigm for education and research.

This article reviews current research on the long-term outcomes of children exposed to alcohol, cocaine, heroin, marijuana, and multiple drugs in utero. Differential intervention efforts based primarily on knowledge of a child's intrauterine exposure to drugs were unsupported by available evidence. The use of an ecological model for assessment and intervention is urged. (Author/DB)

Abstract Admixture is an important evolutionary force that can and should be used in efforts to apply genomic data and technology to the study of complex disease genetics. Admixture linkage disequilibrium (ALD) is created by the process of admixture and, in recently admixed populations, extends for substantial distances (of the order of 10 to 20 cM). The amount of ALD generated depends on the level of admixture, ancestry information content of markers and the admixture dynamics of the population, and thus influences admixture mapping (AM). The authors discuss different models of admixture and how these can have an impact on the success of AM studies. Selection of markers is important, since markers informative for parental population ancestry are required and these are uncommon. Rarely does the process of admixture result in a population that is uniform for individual admixture levels, but instead there is substantial population stratification. This stratification can be understood as variation in individual admixtures and can be both a source of statistical power for ancestry-phenotype correlation studies as well as a confounder in causing false-positives in gene association studies. Methods to detect and control for stratification in case/control and AM studies are reviewed, along with recent studies showing individual ancestry-phenotype correlations. Using skin pigmentation as a model phenotype, implications of AM in complex disease gene mapping studies are discussed. Finally, the article discusses some limitations of this approach that should be considered when designing an effective AM study.

The effect of high altitude on reducing birth weight is markedly less in populations of high- (e.g., Andeans) relative to low-altitude origin (e.g., Europeans). Uterine artery (UA) blood flow is greater during pregnancy in Andeans than Europeans at high altitude; however, it is not clear whether such blood flow differences play a causal role in ancestry-associated variations in fetal growth. We tested the hypothesis that greater UA blood flow contributes to the protection of fetal growth afforded by Andean ancestry by comparing UA blood flow and fetal growth throughout pregnancy in 137 Andean or European residents of low (400 m; European n = 28, Andean n = 23) or high (3,100-4,100 m; European n = 51, Andean n = 35) altitude in Bolivia. Blood flow and fetal biometry were assessed by Doppler ultrasound, and maternal ancestry was confirmed, using a panel of 100 ancestry-informative genetic markers (AIMs). At low altitude, there were no ancestry-related differences in the pregnancy-associated rise in UA blood flow, fetal biometry, or birth weight. At high altitude, Andean infants weighed 253 g more than European infants after controlling for gestational age and other known influences. UA blood flow and [O.sub.2] delivery were twofold greater at 20 wk in Andean than European women at high altitude, and were paralleled by greater fetal size. Moreover, variation in the proportion of Indigenous American ancestry among individual women was positively associated with UA diameter, blood flow, [O.sub.2] delivery, and fetal head circumference. We concluded that greater UA blood flow protects against hypoxia-associated reductions in fetal growth, consistent with the hypothesis that genetic factors enabled Andeans to achieve a greater pregnancyassociated rise in UA blood flow and [O.sub.2] delivery than European women at high altitude. genetic adaptation; hypoxia; intrauterine growth restriction; uteroplacental blood flow

The relationship between ethnicity and biology is of interest to anthropologists, biomedical scientists, and historians in understanding how human groups are constructed. Ethnic self-identification in recently admixed groups such as Hispanics, African Americans, and Native Americans (NA) is likely to be complex due to the heterogeneity in individual admixture proportions and social environments within these groups. This study examines the relationships between self-identified ethnicity, self-estimated admixture proportions, skin pigmentation, and genetic marker estimated admixture proportions. These measures were assessed using questionnaires, skin color measurements, and genotyping of a panel of 76 ancestry informative markers, among 170 Hispanics and NAs from New Mexico, a state known for its complex history of interactions between people of NA and European (EU) ancestry. Results reveal that NAs underestimate their degree of EU admixture, and that Hispanics underestimate their degree of NA admixture. Within Hispanics, genetic-marker estimated admixture is better predicted by forehead skin pigmentation than by self-estimated admixture. We also find that Hispanic individuals self-identified as 'half-White, half Hispanic' and 'Spanish' have lower levels of NA admixture than those self-identified as 'Mexican' and 'Mexican American.' Such results highlight the interplay between culture and biology in how individuals identify and view themselves, and have implications for how ethnicity and disease risk are assessed in a medical setting. KEY WORDS ethnic identity; New Mexico; genetic ancestry

To link to full-text access for this article, visit this link: http://dx.doi.org/10.1016/j.cell.2007.10.055 Byline: Craig T. Miller (1), Sandra Beleza (2), Alex A. Pollen (1), Dolph Schluter (3), Rick A. Kittles (4), Mark D. Shriver (5), David M. Kingsley (1) Keywords: DEVBIO; EVO_ECOL Abstract: Dramatic pigmentation changes have evolved within most vertebrate groups, including fish and humans. Here we use genetic crosses in sticklebacks to investigate the parallel origin of pigmentation changes in natural populations. High-resolution mapping and expression experiments show that light gills and light ventrums map to a divergent regulatory allele of the Kit ligand (Kitlg) gene. The divergent allele reduces expression in gill and skin tissue and is shared by multiple derived freshwater populations with reduced pigmentation. In humans, Europeans and East Asians also share derived alleles at the KITLG locus. Strong signatures of selection map to regulatory regions surrounding the gene, and admixture mapping shows that the KITLG genomic region has a significant effect on human skin color. These experiments suggest that regulatory changes in Kitlg contribute to natural variation in vertebrate pigmentation, and that similar genetic mechanisms may underlie rapid evolutionary change in fish and humans. Author Affiliation: (1) HHMI and Department of Developmental Biology, Stanford University School of Medicine, Stanford, CA 94305, USA (2) Institute of Molecular Pathology and Immunology of the University of Porto (IPATIMUP), 4250-400 Porto, Portugal (3) Department of Zoology and Biodiversity Research Centre, University of British Columbia, Vancouver, BC, V6T 1Z4, Canada (4) Department of Medicine, Section of Genetic Medicine, The University of Chicago, Chicago, IL 60637, USA (5) Department of Anthropology, The Pennsylvania State University, University Park, PA 16802, USA Article History: Received 15 August 2007; Revised 10 October 2007; Accepted 19 October 2007 Article Note: (miscellaneous) Published: December 13, 2007

A genomewide admixture mapping (AM) panel for Hispanic/Latino populations is described. The AM panel has 2,120 ancestry markers and the main criteria for marker selection were both high information content for Native American/European ancestry and small frequency differences between the Mesoamerican and South American samples.

The population structure in Europeans of known and unknown ancestry is explored using a report on genomewide typing of approximately 10,000 single-nucleotide polymorphisms in 297 individuals. The results show the presence of several significant axes of stratification, particularly in a northern-southeastern trend and also along an east-west axis.

Skin and hair pigmentation are two of the most easily visible examples of human phenotypic variation. Selection-based explanations for pigmentation variation in humans have focused on the relationship between melanin and ultraviolet radiation, which is largely dependent on latitude. In this study, skin and hair pigmentation were measured as the melanin (M) index, using narrow-band reflectance spectroscopy for 1,135 individuals from Island Melanesia. Overall, the results show remarkable pigmentation variation, given the small geographic region surveyed. This variation is discussed in terms of differences between males and females, among islands, and among neighborhoods within those islands. The relationship of pigmentation to age, latitude, and longitude is also examined. We found that male skin pigmentation was significantly darker than females in 5 of 6 islands examined. Hair pigmentation showed a negative, but weak, correlation with age, while skin pigmentation showed a positive, but also weak, correlation with age. Skin and hair pigmentation varied significantly between islands as well as between neighborhoods within those islands. Bougainvilleans showed significantly darker skin than individuals from any other island considered, and are darker than a previously described African-American population. These findings are discussed in relation to prevailing hypotheses about the role of natural selection in shaping pigmentation variation in the human species, as well as the role of demographic processes such as admixture and drift in Island Melanesia. KEY WORDS skin pigmentation; M index; Island Melanesia; natural selection

We studied 156 individuals of Native American descent from the city of Tlapa in the state of Guerrero in western Mexico. Most individuals' ethnicity was either Nahua, Mixtec, or Tlapanec, but self-identified Mestizos and individuals of mixed ethnicities were also included in the sample. We typed 24 autosomal, one Y-chromosome, and four mitochondrial ancestry-informative markers (AIMs) to estimate group and individual admixture proportions, and determine whether the admixture process involved directional gene flow between parental groups. When genetically defined (GD) Mestizos were excluded from the analysis, Native American ancestry represented ~98% of the population's gene pool, while European and West African ancestry represented ~1% each. Maternally inherited markers also showed an exceptionally high Native American contribution (98.5%), as did the paternally inherited marker, DYS199 (90.7%). We did not detect genetic structure in this population using these AIMs, which appears consistent with the homogeneity of the sample in terms of admixture proportions. The addition of GD Mestizos to the sample did not produce a considerable change in admixture estimates, but it had a major effect on population structure. These results show that the population of Tlapa in Guerrero, Mexico, has experienced little admixture with Europeans and/or West Africans. They also show that the impact of a small number of admixed individuals on an otherwise homogeneous population might have profound implications on subsequent ancestry/phenotype analysis and mapping strategies. We suggest that heterogeneity is a major characteristic of Mexican populations and, as a consequence, should not be disregarded when designing epidemiological studies of Mexican and Mexican American populations. KEY WORDS population admixture; Mexicans; ancestry informative markers

To better understand the population substructure of African Americans living in coastal South Carolina, we used restriction site polymorphisms and an insertion/deletion in mitochondrial DNA (mtDNA) to construct seven-position haplotypes across 1,395 individuals from Sierra Leone, Africa, from U.S. European Americans, and from the New World African-derived populations of Jamaica, Gullah-speaking African Americans of the South Carolina Sea Islands (Gullahs), African Americans living in Charleston, South Carolina, and West Coast African Americans. Analyses showed a high degree of similarity within the New World African-derived populations, where haplotype frequencies and diversities were similar. [PHI]-statistics indicated that very little genetic differentiation has occurred within New World African-derived populations, but that there has been significant differentiation of these populations from Sierra Leoneans. Genetic distance estimates indicated a close relationship of Gullahs and Jamaicans with Sierra Leoneans, while African Americans living in Charleston and the West Coast were progressively more distantly related to the Sierra Leoneans. We observed low maternal European American admixture in the Jamaican and Gullah samples (m = 0.020 and 0.064, respectively) that increased sharply in a clinal pattern from Charleston African Americans to West Coast African Americans (m = 0.099 and 0.205, respectively). The appreciably reduced maternal European American admixture noted in the Gullah indicates that the Gullah may be uniquely situated to allow genetic epidemiology studies of complex diseases in African Americans with low European American admixture. Am J Phys Anthropol 127:427-438, 2005. KEY WORDS admixture; population genetic substructure; [PHI]-statistics

Andean high-altitude (HA) natives have a low (blunted) hypoxic ventilatory response (HVR), lower effective alveolar ventilation, and lower ventilation (VE) at rest and during exercise compared with acclimatized newcomers to HA. Despite blunted chemosensitivity and hypoventilation, Andeans maintain comparable arterial [O.sub.2] saturation ([Sa.sub.O.sub.2]. This study was designed to evaluate the influence of ancestry on these trait differences. At sea level, we measured the HVR in both acute (HVR-A) and sustained (HVR-S) hypoxia in a sample of 32 male Peruvians of mainly Quechua and Spanish origins who were born and raised at sea level. We also measured resting and exercise VE after 10-12 h of exposure to altitude at 4,338 m. Native American ancestry proportion (NAAP) was assessed for each individual using a panel of 80 ancestry-informative molecular markers (AIMs). NAAP was inversely related to HVR-S after 10 rain of isocapnic hypoxia (r = -0.36, P = 0.04) but was not associated with HVR-A. In addition, NAAP was inversely related to exercise VE (r = -0.50, P = 0.005) and ventilatory equivalent (VE/[V.sub.O.sub.2], r = -0.51, P = 0.004) measured at 4,338 m. Thus Quechua ancestry may partly explain the well-known blunted HVR (10, 35, 36, 57, 62) at least to sustained hypoxia, and the relative exercise hypoventilation at altitude of Andeans compared with European controls. Lower HVR-S and exercise VE could reflect improved gas exchange and/or attenuated chemoreflex sensitivity with increasing NAAP. On the basis of these ancestry associations and on the fact that developmental effects were completely controlled by study design, we suggest both a genetic basis and an evolutionary origin for these traits in Quechua. genetic markers; admixture; arterial saturation; Andes

An 11-year-old boy presented in an outpatient clinic with a vocal habit that occurred during reading and conversation. A brief reading assessment was conducted to determine an effective intervention to decrease the habit. A modified version of the word error-correction procedure resulted in positive changes and was implemented by his mother during home reading practices. Significant decreases in the rate of vocal habit were observed during home reading probes, generalization probes, and follow-up. DESCRIPTORS: habit reversal, habit disorders, reading, experimental assessment, generalization