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Biomedical subjects

M D Shriver

Publications and source records attributed to M D Shriver.

At least 19 recordsLinked to original sources
PubMed2004

Design and analysis of admixture mapping studies.

Admixture between populations originating on different continents can be exploited to detect disease susceptibility loci at which risk alleles are distributed differentially between these populations. We first examine the statistical power and mapping resolution of this approach in the limiting situation in which gamete admixture and locus ancestry are measured without uncertainty. We show that, for a rare disease, the most efficient design is to study affected individuals only. In a typical African American population (two-way admixture proportions 0.8/0.2, ancestry crossover rate 2 per 100 cM), a study of 800 affected individuals has 90% power to detect at P values <10(-5) a locus that generates a risk ratio of 2 between populations, with an expected mapping resolution (size of 95% confidence region for the position of the locus) of 4 cM. In practice, to infer locus ancestry from marker data requires Bayesian computationally intensive methods, as implemented in the program ADMIXMAP. Affected-only study designs require strong prior information on the frequencies of each allele given locus ancestry. We show how data from unadmixed and admixed populations can be combined to estimate these ancestry-specific allele frequencies within the admixed population under study, allowing for variation between allele frequencies in unadmixed and admixed populations. Using simulated data based on the genetic structure of the African American population, we show that 60% of information can be extracted in a test for linkage using markers with an ancestry information content of 36% at 3-cM spacing. As in classic linkage studies, the most efficient strategy is to use markers at a moderate density for an initial genome search and then to saturate regions of putative linkage with additional markers, to extract nearly all information about locus ancestry.

Black People↗
PubMed2004

Implications of correlations between skin color and genetic ancestry for biomedical research.

Skin pigmentation is a central element of most discussions on 'race' and genetics. Research on the genetic basis of population variation in this phenotype, which is important in mediating both social experiences and environmental exposures, is sparse. We studied the relationship between pigmentation and ancestry in five populations of mixed ancestry with a wide range of pigmentation and ancestral proportions (African Americans from Washington, DC; African Caribbeans living in England; Puerto Ricans from New York; Mexicans from Guerrero; and Hispanics from San Luis Valley). The strength of the relationship between skin color and ancestry was quite variable, with the correlations ranging in intensity from moderately strong (Puerto Rico, rho = 0.633) to weak (Mexico, rho = 0.212). These results demonstrate the utility of ancestry-informative genetic markers and admixture methods and emphasize the need to be cautious when using pigmentation as a proxy of ancestry or when extrapolating the results from one admixed population to another.

Biomedical Research↗
PubMed2004

Admixture in the Hispanics of the San Luis Valley, Colorado, and its implications for complex trait gene mapping.

Hispanic populations are a valuable resource that can and should facilitate the identification of complex trait genes by means of admixture mapping (AM). In this paper we focus on a particular Hispanic population living in the San Luis Valley (SLV) in Southern Colorado. We used a set of 22 Ancestry Informative Markers (AIMs) to describe the admixture process and dynamics in this population. AIMs are defined as genetic markers that exhibit allele frequency differences between parental populations >or=30%, and are more informative for studying admixed populations than random markers. The ancestral proportions of the SLV Hispanic population are estimated as 62.7 +/- 2.1% European, 34.1 +/- 1.9% Native American and 3.2 +/- 1.5% West African. We also estimated the ancestral proportions of individuals using these AIMs. Population structure was demonstrated by the excess association of unlinked markers, the correlation between estimates of admixture based on unlinked marker sets, and by a highly significant correlation between individual Native American ancestry and skin pigmentation (R2= 0.082, p < 0.001). We discuss the implications of these findings in disease gene mapping efforts.

Adult↗
PubMed2001

A role for the Agouti-Related Protein promoter in obesity and type 2 diabetes.

The murine Agouti-Related Protein (mAGRP) is upregulated in obese and diabetic mice and can stimulate hyperphagia when overexpressed in transgenic models. Here we report upstream nucleotide sequences of the human hAGRP gene with putative recognition sites for transcription factors including a site for the STAT transactivators. A polymorphism (-38C-->T) was identified in the promoter region and the C/C genotype had significantly higher promoter activity and affinity for transcription factors as tested in periphery- and hypothalamus-derived cell lines. The polymorphic site could affect the expression levels of hAGRP and the high expressing C/C genotype was significantly associated with high BMI and type 2 diabetes in Africans.

Agouti-Related Protein↗
PubMed2001

Ancestral proportions and admixture dynamics in geographically defined African Americans living in South Carolina.

We analyzed admixture in samples of six different African-American populations from South Carolina: Gullah-speaking Sea Islanders in coastal South Carolina, residents of four counties in the "Low Country" (Berkeley, Charleston, Colleton, and Dorchester), and persons living in the city of Columbia, located in central South Carolina. We used a battery of highly informative autosomal, mtDNA, and Y-chromosome markers. Two of the autosomal markers (FY and AT3) are linked and lie 22 cM apart on chromosome 1. The results of this study indicate, in accordance with previous historical, cultural, and anthropological evidence, a very low level of European admixture in the Gullah Sea Islanders (m = 3.5 +/- 0.9%). The proportion of European admixture is higher in the Low Country (m ranging between 9. 9 +/- 1.8% and 14.0 +/- 1.9%), and is highest in Columbia (m = 17.7 +/- 3.1%). A sex-biased European gene flow and a small Native American contribution to the African-American gene pool are also evident in these data. We studied the pattern of pairwise allelic associations between the FY locus and the nine other autosomal markers in our samples. In the combined sample from the Low Country (N = 548), a high level of linkage disequilibrium was observed between the linked markers, FY and AT3. Additionally, significant associations were also detected between FY and 4 of the 8 unlinked markers, suggesting the existence of significant genetic structure in this population. A continuous gene flow model of admixture could explain the observed pattern of genetic structure. A test conditioning on the overall admixture of each individual showed association of ancestry between the two linked markers (FY and AT3), but not between any of the unlinked markers, as theory predicts. Thus, even in the presence of genetic structure due to continuous gene flow or some other factor, it is possible to differentiate associations due to linkage from spurious associations due to genetic structure.

Africa↗
PubMed2001

Interaction between the melanocortin-1 receptor and P genes contributes to inter-individual variation in skin pigmentation phenotypes in a Tibetan population.

The melanocortin-1 receptor (MC1R) and P gene product are two important components of the human pigmentary system that have been shown to be associated with red hair/fair skin and cause type II oculocutaneous albinism, respectively. However, their contribution to inter-individual variation at the population level is not well defined. To this end, we genotyped 3 single nucleotide polymorphisms (SNPs) in the MC1R gene (Arg67Gln, Gln163Arg, Val92Met) and 2 SNPs in the P gene (IVS 13-15 and Gly780Gly) in 184 randomly ascertained Tibetan subjects, whose skin color was measured as a quantitative trait by reflective spectroscopy. Single locus analyses failed to demonstrate an association between any of the 5 SNPs and skin pigmentation. However, when an epistatic model was applied to the data, a significant gene-gene interaction was identified between Val92Met in MCIR and IVS13-15 in the P gene (F=2.43; P=0.0105). We also discuss the possible mechanisms of how gene interactions arise in signal transduction pathways.

Adolescent↗
PubMed2001

Melting curve analysis of SNPs (McSNP): a gel-free and inexpensive approach for SNP genotyping.

High-throughput methods for assaying DNA variation require two important steps: (i) discriminating the variation and (ii) detecting the signal. In this report, we describe a novel SNP genotyping method that we refer to as melting curve analysis of SNPs (McSNP). McSNP combines a classic approach for discriminating alleles, restriction enzyme digestion, with a more recent method for detecting DNA fragments, melting curve analysis. Melting curve analysis is performed by slowly heating DNA fragments in the presence of the dsDNA-specific fluorescent dye SYBR Green I. As the sample is heated, fluorescence rapidly decreases when the melting temperature of a particular fragment is reached. We show that it is possible to determine the composition of simple mixtures of DNA fragments, such as those that result from restriction enzyme digestions of short PCR products. McSNP is well suited for high-throughput genotyping because 96 samples can be analyzed and automatically scored in 20 min. Our results clearly demonstrate that McSNP is a simple, inexpensive, and accurate means of genotyping SNP variation.

Genotype↗
PubMed2000

Population structure in admixed populations: effect of admixture dynamics on the pattern of linkage disequilibrium.

Gene flow between genetically distinct populations creates linkage disequilibrium (admixture linkage disequilibrium [ALD]) among all loci (linked and unlinked) that have different allele frequencies in the founding populations. We have explored the distribution of ALD by using computer simulation of two extreme models of admixture: the hybrid-isolation (HI) model, in which admixture occurs in a single generation, and the continuous-gene-flow (CGF) model, in which admixture occurs at a steady rate in every generation. Linkage disequilibrium patterns in African American population samples from Jackson, MS, and from coastal South Carolina resemble patterns observed in the simulated CGF populations, in two respects. First, significant association between two loci (FY and AT3) separated by 22 cM was detected in both samples. The retention of ALD over relatively large (>10 cM) chromosomal segments is characteristic of a CGF pattern of admixture but not of an HI pattern. Second, significant associations were also detected between many pairs of unlinked loci, as observed in the CGF simulation results but not in the simulated HI populations. Such a high rate of association between unlinked markers in these populations could result in false-positive linkage signals in an admixture-mapping study. However, we demonstrate that by conditioning on parental admixture, we can distinguish between true linkage and association resulting from shared ancestry. Therefore, populations with a CGF history of admixture not only are appropriate for admixture mapping but also have greater power for detection of linkage disequilibrium over large chromosomal regions than do populations that have experienced a pattern of admixture more similar to the HI model, if methods are employed that detect and adjust for disequilibrium caused by continuous admixture.

Africa↗
PubMed2000

Polynesian origins: insights from the Y chromosome.

The question surrounding the colonization of Polynesia has remained controversial. Two hypotheses, one postulating Taiwan as the putative homeland and the other asserting a Melanesian origin of the Polynesian people, have received considerable attention. In this work, we present haplotype data based on the distribution of 19 biallelic polymorphisms on the Y chromosome in a sample of 551 male individuals from 36 populations living in Southeast Asia, Taiwan, Micronesia, Melanesia, and Polynesia. Surprisingly, nearly none of the Taiwanese Y haplotypes were found in Micronesia and Polynesia. Likewise, a Melanesian-specific haplotype was not found among the Polynesians. However, all of the Polynesian, Micronesian, and Taiwanese haplotypes are present in the extant Southeast Asian populations. Evidently, the Y-chromosome data do not lend support to either of the prevailing hypotheses. Rather, we postulate that Southeast Asia provided a genetic source for two independent migrations, one toward Taiwan and the other toward Polynesia through island Southeast Asia.

Biological Evolution↗
PubMed2000

Comparison of narrow-band reflectance spectroscopy and tristimulus colorimetry for measurements of skin and hair color in persons of different biological ancestry.

We have used two modern computerized handheld reflectometers, the Photovolt ColorWalk colorimeter (a tristimulus colorimeter; Photovolt, UMM Electronics, Indianapolis, IN) and the DermaSpectrometer (a specialized narrow-band reflectometer; Cortex Technology, Hadsund, Denmark), to compare two methods for the objective determination of skin and hair color. These instruments both determine color by measuring the intensity of reflected light of particular wavelengths. The Photovolt ColorWalk instrument does so by shining a white light and sensing the intensity of the reflected light with a linear photodiode array. The ColorWalk results can then be expressed in terms of several standard color systems, most importantly, the Commission International d'Eclairage (CIE) Lab system, in which any color can be described by three values: L*, the lightness; a*, the amount of green or red; and b*, the amount of yellow or blue. Instead of a white light and photodiodes, the DermaSpectrometer uses two light-emitting diodes (LEDs), one green and one red, to illuminate a surface, and then it records the intensity of the reflected light. The results of these readings are expressed in terms of erythema (E) and melanin (M) indices. We measured the unexposed skin of the inner upper arm, the exposed skin of the forehead, and the hair, of 80 persons using these two instruments. Since it is important for the application of these measures in anthropology that we understand their relationship across a number of different pigmentation levels, we sampled persons from several different groups, namely, European Americans (n = 55), African Americans (n = 9), South Asians (n = 7), and East Asians (n = 9). In these subjects, there is a very high correlation between L* and the M index for the inner arm (R(2) = 0.928, P < 0.001), the forehead (R(2) = 0.822, P < 0.001), and the hair (R(2) = 0.827, P < 0.001). The relationship between a* and the E index is complex and dependent on the pigmentation level. We conclude that while both types of instruments provide accurate estimates of pigment level in skin and hair, measurements using narrow-band instruments may be less affected by the greater redness of certain body sites due to increased vascularization.

Adult↗
PubMed2000

Estimation of admixture and detection of linkage in admixed populations by a Bayesian approach: application to African-American populations.

We describe a novel method for analysis of marker genotype data from admixed populations, based on a hybrid of Bayesian and frequentist approaches in which the posterior distribution is generated by Markov chain simulation and score tests are obtained from the missing-data likelihood. We analysed data on unrelated individuals from eight African-American populations, genotyped at ten marker loci of which two (FY and AT3) are linked (22 cM apart). Linkage between these two loci was detected by testing for association of ancestry conditional on parental admixture. The strength of this association was consistent with European gene flow into the African-American population between five and nine generations ago. To mimic the mapping of an unknown gene in an 'affecteds- only' analysis, a binary trait was constructed from the genotype at the AT3 locus and a score test was shown to detect linkage of this 'trait' with the FY locus. Mis-specification of the ancestry-specific allele frequencies - the probabilities of each allelic state given the ancestry of the allele - was detected at three of the ten marker loci. The methods described here have wide application to the analysis of data from admixed populations, allowing the effects of linkage and population structure (variation of admixture between individuals) to be distinguished. With more markers and a more complex statistical model, genes underlying ethnic differences in disease risk could be mapped by this approach.

Bayes Theorem↗
PubMed2000

Structural interventions to encourage primary HIV prevention among people living with HIV.

This analysis focuses on primary prevention for people living with HIV and the importance of actively involving HIV-infected people in developing prevention strategies. Structural-level or policy interventions--as opposed to behavioral or psychological interventions--help shape the world in which HIV-infected people live. Thus, we assess potential policy-level interventions that may serve either as a barrier to or a facilitator of primary HIV prevention from the perspective of the people living with HIV. Among potential barriers, we discuss criminalization of nondisclosure in specific sexual situations, laws limiting travel and immigration, name-based HIV reporting and mandatory partner notification. Under potential facilitators, we discuss confidentiality laws, antidiscrimination protections, expansion of HIV primary care, and primary prevention programs designed to actively involve infected people. Ultimately, whether any given policy is a 'barrier' or 'facilitator' of primary HIV prevention is an empirical question, dependent on the acceptability of an intervention to those already infected and those at risk, thus policy research evaluating the impact of structural factors on people living with HIV is encouraged.

Communicable Disease Control↗
PubMed1999

Analysis of five Y-specific microsatellite loci in Asian and Pacific populations.

We have analyzed five Y-specific microsatellite loci (DYS388, DYS390, DYS391, DYS394, DYS395) in 17 Asian and Pacific populations representing a broad geographical area and different linguistic families, with an emphasis on populations from mainland and insular Southeast Asia. Analysis of gene diversity indicates that several of the studied populations have experienced substantial genetic isolation, and a reduction in male effective sizes (viz. the Northeast Indian populations Nishi, Adi and the Taiwanese aboriginals). The average values of the F(ST) and ((ST) statistics indicate a high degree of genetic differentiation among these populations at the five Y-specific markers (F(ST) =0.21 and ((ST) = 0.33, based on individual loci; F(ST) = 0.09 and ((ST) = 0.36, based on haplotypes), which conform to the expectation of a fourfold smaller effective size of the Y-linked loci compared with the autosomal loci. Dendrogram and principal coordinates analysis, with few exceptions, show a major separation between mainland and insular populations. Among the mainland populations, the Tibeto-Burman speakers from Northeast India cluster in a well-defined group, supported by high bootstrap values. The Southern Chinese, Northern Thai, So, and Cambodian also are integral to this cluster. The other major cluster is rather heterogeneous and includes, among others, the Austronesian-speaking populations. The Samoans of the Pacific, with a distinctive pattern of allelic distributions, stand as an outlier in the tree and PC representations. Although trends of genetic affinities among ethnically and geographically related populations are evident from the Y-specific microsatellite data, microsatellites are not optimal for deciphering complex migratory patterns of human populations, which could possibly be clarified by using additional and more stable genetic markers.

Asia, Southeastern↗
PubMed1999

Genetic variation at 9 autosomal microsatellite loci in Asian and Pacific populations.

Genetic variation at 9 autosomal microsatellite loci (CFS1R, TH01, PLA2A, F13A1, CYP19, LPL, D20S481, D20S473, and D20S604) has been characterized in 16 Asian and Oceanic populations, mostly from mainland and insular Southeast Asia. The neighbor-joining tree and the principal coordinates analysis of the genetic relationships of these populations show a clear separation of Papua New Guinea Highlanders and, to a lesser extent, Malayan aborigines (Orang Asli or Semai) from the rest of the populations. Although the number of markers used in this study appears to be inadequate for clarifying the patterns of genetic relationships among the studied populations, in the principal coordinates analysis a geographic trend is observed in the mainland and insular Southeast Asian populations. Furthermore, in an attempt to contrast the extent of variation between autosomal and Y-chromosome-specific microsatellite loci and to reveal potential differences in the patterns of male and female migrations, we have also compared genetic variation at these 9 autosomal loci with variation observed at 5 Y-chromosome-specific microsatellites in a common set of 14 Asian populations.

Asia↗
PubMed1998

Trinucleotide repeat length variation in the human ribosomal protein L14 gene (RPL14): localization to 3p21.3 and loss of heterozygosity in lung and oral cancers.

Chromosome 3p is consistently deleted in lung cancer, oral squamous cell carcinoma, and renal cell carcinoma, and is believed to contain several tumor suppressor genes. We have shown a role for chromosome 3 in tumor suppression by microcell-mediated chromosome transfer experiments. We have isolated a gene that is located at 3p21.3 within the smallest region of deletion overlap in lung tumors and is the human homolog of the ribosomal protein L14 gene (RPL14). The RPL14 sequence contains a highly polymorphic trinucleotide repeat array which encodes a variable-length polyalanine tract. Genotype analysis of RPL14 shows that this locus is 68% heterozygous in the normal population, compared with 25% in non-small cell lung cancer (NSCLC) cell lines (p = 0.008). Cell cultures derived from normal bronchial epithelium show a 65% level of heterozygosity, reflecting that of the normal population. Squamous cell carcinoma of the head and neck (SCCHN), which has the same risk factors as lung cancer and is hypothesized to have a similar etiology, demonstrates 54% loss of heterozygosity at the RNA level, suggesting that transcriptional loss may be a primary mechanism of RPL14 alteration in SCCHN. In addition, RPL14 shows significant differences in allele frequency distribution in ethnically-defined populations, making this sequence a useful marker for the study of ethnicity-adjusted lung cancer risk.

Biopsy↗
PubMed1998

Estimating African American admixture proportions by use of population-specific alleles.

We analyzed the European genetic contribution to 10 populations of African descent in the United States (Maywood, Illinois; Detroit; New York; Philadelphia; Pittsburgh; Baltimore; Charleston, South Carolina; New Orleans; and Houston) and in Jamaica, using nine autosomal DNA markers. These markers either are population-specific or show frequency differences >45% between the parental populations and are thus especially informative for admixture. European genetic ancestry ranged from 6.8% (Jamaica) to 22.5% (New Orleans). The unique utility of these markers is reflected in the low variance associated with these admixture estimates (SEM 1.3%-2.7%). We also estimated the male and female European contribution to African Americans, on the basis of informative mtDNA (haplogroups H and L) and Y Alu polymorphic markers. Results indicate a sex-biased gene flow from Europeans, the male contribution being substantially greater than the female contribution. mtDNA haplogroups analysis shows no evidence of a significant maternal Amerindian contribution to any of the 10 populations. We detected significant nonrandom association between two markers located 22 cM apart (FY-null and AT3), most likely due to admixture linkage disequilibrium created in the interbreeding of the two parental populations. The strength of this association and the substantial genetic distance between FY and AT3 emphasize the importance of admixed populations as a useful resource for mapping traits with different prevalence in two parental populations.

Africa↗