Biomedical subjects

Andrew J Pakstis

Publications and source records attributed to Andrew J Pakstis.

17 recordsLinked to original sources

PubMed2007

Significant variation in haplotype block structure but conservation in tagSNP patterns among global populations.

The initial belief that haplotype block boundaries and haplotypes were largely shared across populations was a foundation for constructing a haplotype map of the human genome using common SNP markers. The HapMap data document the generality of a block-like pattern of linkage disequilibrium (LD) with regions of low and high haplotype diversity but differences among the populations. Studies of many additional populations demonstrate that LD patterns can be highly variable among populations both across and within geographic regions. Because of this variation, emphasis has shifted to the generalizability of tagSNPs, those SNPs that capture the bulk of variation in a region. We have examined the LD and tagSNP patterns based upon over 2000 individual samples in 38 populations and 134 SNPs in 10 genetically independent loci for a total of 517 kb with an average density of 1 SNP/5 kb. Four different 'block' definitions and the pairwise LD tagSNP selection algorithm have been applied. Our results not only confirm large variation in block partition among populations from different regions (agreeing with previous studies including the HapMap) but also show that significant variation can occur among populations within geographic regions. None of the block-defining algorithms produces a consistent pattern within or across all geographic groups. In contrast, tagSNP transferability is much greater than the similarity of LD patterns and, although not perfect, some generalizations of transferability are possible. The analyses show an asymmetric pattern of tagSNP transferability coinciding with the subsetting of variation attributed to the spread of modern humans around the world.

Genetic Variation↗

PubMed2006

Intra- and interpopulation genotype reconstruction from tagging SNPs.

The optimal method to be used for tSNP selection, the applicability of a reference LD map to unassayed populations, and the scalability of these methods to genome-wide analysis, all remain subjects of debate. We propose novel, scalable matrix algorithms that address these issues and we evaluate them on genotypic data from 38 populations and four genomic regions (248 SNPs typed for approximately 2000 individuals). We also evaluate these algorithms on a second data set consisting of genotypes available from the HapMap database (1336 SNPs for four populations) over the same genomic regions. Furthermore, we test these methods in the setting of a real association study using a publicly available family data set. The algorithms we use for tSNP selection and unassayed SNP reconstruction do not require haplotype inference and they are, in principle, scalable even to genome-wide analysis. Moreover, they are greedy variants of recently developed matrix algorithms with provable performance guarantees. Using a small set of carefully selected tSNPs, we achieve very good reconstruction accuracy of "untyped" genotypes for most of the populations studied. Additionally, we demonstrate in a quantitative manner that the chosen tSNPs exhibit substantial transferability, both within and across different geographic regions. Finally, we show that reconstruction can be applied to retrieve significant SNP associations with disease, with important genotyping savings.

Algorithms↗

PubMed2006

Conservative evolution in duplicated genes of the primate Class I ADH cluster.

Humans have seven alcohol dehydrogenase genes (ADH) falling into five classes. Three out of the seven genes (ADH1A, ADH1B and ADH1C) belonging to Class I are expressed primarily in liver and code the main enzymes catalyzing ethanol oxidization. The three genes are tandemly arrayed within the ADH cluster on chromosome 4 and have very high nucleotide similarity to each other (exons: >90%; introns: >70%), suggesting the genes have been generated by duplication event(s). One explanation for maintaining similarity of such clustered genes is homogenization via gene conversion(s). Alternatively, recency of the duplications or some other functional constraints might explain the high similarities among the genes. To test for gene conversion, we sequenced introns 2, 3, and 8 of all three Class I genes (total>15.0 kb) for five non-human primates--four great apes and one Old World Monkey (OWM)--and compared them with those of humans. The phylogenetic analysis shows each intron sequence clusters strongly within each gene, giving no evidence for gene conversion(s). Several lines of evidence indicate that the first split was between ADH1C and the gene that gave rise to ADH1A and ADH1B. We also analyzed cDNA sequences of the three genes that have been previously reported in mouse and Catarrhines (OWMs, chimpanzee, and humans) and found that the synonymous and non-synonymous substitution (dN/dS) ratios in all pairs are less than 1 representing purifying selection. This suggests that purifying selection is more important than gene conversion(s) in maintaining the overall sequence similarity among the Class I genes. We speculate that the highly conserved sequences on the three duplicated genes in primates have been achieved essentially by maintaining stability of the hetero-dimer formation that might have been related to dietary adaptation in primate evolution.

Alcohol Dehydrogenase↗

PubMed2005

Developing a SNP panel for forensic identification of individuals.

Single nucleotide polymorphisms (SNPs) are likely in the near future to have a fundamental role in forensics in both human identification and description. However, considerable research is necessary to establish adequate scientific foundations for these applications. In the case of identification, because allele frequencies can vary greatly among populations, the population genetics of match probabilities is a critical issue. Some SNPs, however, show little allele frequency variation among populations while remaining highly informative. We describe here both an efficient strategy for identifying and characterizing such SNPs, and test that strategy on a broad representation of world populations. Markers with high heterozygosity and little frequency variation among African American, European American, and East Asian populations are selected for additional screening on seven populations that provide a sampling of genetic variation from the world's major geographical regions. Those with little allele frequency variation on the seven populations are then screened on a total of 40 populations ( approximately 2100 individuals) and the most promising retained. The preliminary panel of 19 SNPs, from an initial selection of 195 SNPs, gives an average match probability of <10(-7) in most of 40 populations studied and no greater than 10(-6) in the most isolated, inbred populations. Expansion of this panel to approximately 50 comparable SNPs should give match probabilities of about 10(-15) with a small global range.

DNA Fingerprinting↗

PubMed2005

HAPLOT: a graphical comparison of haplotype blocks, tagSNP sets and SNP variation for multiple populations.

UNLABELLED: Understanding of human variation relevant to association studies can benefit from population comparison, especially comparing populations in the same geographical region. Variations in linkage disequilibrium patterns, in tagSNP sets, and in SNP heterozygosities among populations can be used to infer the evolutionary pattern. We present here a win32 system based Perl/Tk application for visual comparisons of these variations in different populations. AVAILABILITY: The application package is available at http://info.med.yale.edu/genetics/kkidd/programs.html CONTACT: sheng.gu@yale.edu.

Chromosome Mapping↗

PubMed2005

Use of autosomal loci for clustering individuals and populations of East Asian origin.

We studied the genetic relationships among East Asian populations based on allele frequency differences to clarify the relative similarities of East Asian populations with a specific focus on the relationships among the Koreans, the Japanese, and the Chinese populations known to be genetically similar. The goal is to find markers appropriate for differentiating among the specific populations. In this study, no prior data existed for Koreans and the markers were selected to differentiate Chinese and Japanese. We typed, using AB TaqMan assays, single-nucleotide polymorphisms (SNPs) at 43 highly selected mostly independent diallelic sites, on 386 individuals from eight East Asian populations (Han Chinese from San Francisco, Han Chinese from Taiwan, Hakka, Koreans, Japanese, Ami, Atayal, and Cambodians) and one Siberian population (Yakut). We inferred group membership of individuals using a model-based clustering method implemented by the STRUCTURE program and population clustering by using computer programs DISTANCE, NEIGHBOR, LSSEARCH, and DRAWTREE, respectively, calculating genetic distances among populations, calculating neighbor-joining and least-squares trees, and drawing the calculated trees. On average 52% of individuals in the three Chinese groups were assigned into one cluster, and, respectively, 78 and 69% of Koreans and Japanese into a different cluster. Koreans differentiated from the Chinese groups and clustered with the Japanese in the principal component analysis (PCA) and in the best least-squares tree. The majority of Koreans were difficult to distinguish from the Japanese. This study shows that a relatively few highly selected markers can, within limits, differentiate between closely related populations.

Asian People↗

PubMed2005

Linkage disequilibrium patterns vary substantially among populations.

A major initiative to create a global human haplotype map has recently been launched as a tool to improve the efficiency of disease gene mapping. The 'HapMap' project will study common variants in depth in four (and to a lesser degree in up to 12) populations to catalogue haplotypes that are expected to be common to all populations. A hope of the 'HapMap' project is that much of the genome occurs in regions of limited diversity such that only a few of the SNPs in each region will capture the diversity and be relevant around the world. In order to explore the implications of studying only a limited number of populations, we have analyzed linkage disequilibrium (LD) patterns of three 175-320 kb genomic regions in 16 diverse populations with an emphasis on African and European populations. Analyses of these three genomic regions provide empiric demonstration of marked differences in frequencies of the same few haplotypes, resulting in differences in the amount of LD and very different sets of haplotype frequencies. These results highlight the distinction between the statistical concept of LD and the biological reality of haplotypes and their frequencies. The significant quantitative and qualitative variation in LD among populations, even for populations within a geographic region, emphasizes the importance of studying diverse populations in the HapMap project to assure broad applicability of the results.

Asian People↗

PubMed2005

Considerable haplotype diversity within the 23kb encompassing the ADH7 gene.

BACKGROUND: Of the seven known human alcohol dehydrogenase (ADH) genes, the non-liver expressed ADH7 gene codes for the enzyme with the highest maximal activity for ethanol. Previous study from our laboratory has suggested that ADH7 has an epistatic role for protection against alcoholism based on a single ADH7 SNP. METHODS: We have now studied seven SNPs, additional populations for the SNP previously examined, and six more new SNPs, across 23 kb of ADH7 in 38 population samples originating from different geographical regions of the world. RESULTS: The overall linkage disequilibrium is moderate to strong across this region even though considerable 7-SNP haplotype diversity is observed. This uncommonly high haplotype diversity is explained by high LD within each "half," the three upstream SNPs and the four downstream SNPs, but near randomization between the "halves." This division significantly simplified the haplotype pattern: only four major haplotypes account for almost all chromosomes in all populations in each "half." CONCLUSIONS: The low linkage disequilibrium between these two "halves" suggests multiple recombination(s) have occurred in this region, specifically, within intron 7. The absence of strong LD between the functional variation in ADH1B that is strongly associated with alcoholism and any of the variation in ADH7 supports the genetic independence of ADH7 in association studies. Thus, the previously observed epistatic effect of ADH7 cannot be explained by its linkage disequilibrium with a causative factor in ADH1B.

Alcohol Dehydrogenase↗

PubMed2004

Haplotype block structures show significant variation among populations.

Recent studies suggest that haplotypes tend to have block-like structures throughout the human genome. Several methods were proposed for haplotype block partitioning and for tagging single-nucleotide polymorphism (SNP) identification. In population genetics studies, several research groups compared block structures across human populations. However, the measures used to quantify population similarity are either less than satisfactory or nonexistent. In this article, we propose several similarity measures to facilitate the comparisons of haplotype structures, namely block boundaries and tagging SNPs, across populations. With these measures, we can more objectively compare haplotype block structures and tagging SNP sets between different populations. In addition, these measures allow us to compare the results of different methods for block partition and tagging SNP identification. When we applied these measures to a real data set on chromosome 10 in 16 worldwide populations, we found that in this genome region: 1) haplotype block boundaries vary among populations, with European and some African populations showing similar boundaries but other populations showing other patterns; 2) tagging SNP sets are generally similar for populations with similar haplotype block structures but differ if the block structures differ; and 3) all but one of the block finding methods we tested yield consistent results, although variations exist regarding consistency. Our tentative results show that at least in the genome region studied, it is unlikely that a common haplotype pattern exists for all human populations: many populations, even in the same geographical region, may have different haplotype patterns.

Chromosome Mapping↗

PubMed2004

The evolution and population genetics of the ALDH2 locus: random genetic drift, selection, and low levels of recombination.

The catalytic deficiency of human aldehyde dehydrogenase 2 (ALDH2) is caused by a nucleotide substitution (G1510A; Glu487Lys) in exon 12 of the ALDH2 locus. This SNP, and four non-coding SNPs, including one in the promoter, span 40 kb of ALDH2; these and one downstream STRP have been tested in 37 worldwide populations. Only four major SNP-defined haplotypes account for almost all chromosomes in all populations. A fifth haplotype harbours the functional variant and is only found in East Asians. Though the SNPs showed virtually no historic recombination, LD values are quite variable because of varying haplotype frequencies, demonstrating that LD is a statistical abstraction and not a fundamental aspect of the genome, and is not a function solely of recombination. Among populations, different sets of tagging SNPs, sometimes not overlapping, can be required to identify the common haplotypes. Thus, solely because haplotype frequencies vary, there is no common minimum set of tagging SNPs globally applicable. The Fst values of the promoter region SNP and the functional SNP were about two S.D. above the mean for a reference distribution of 117 autosomal biallelic markers. These high Fst values may indicate selection has operated at these or very tightly linked sites.

Aldehyde Dehydrogenase↗

PubMed2004

Bitter receptor gene (TAS2R38), 6-n-propylthiouracil (PROP) bitterness and alcohol intake.

BACKGROUND: Phenylthiocarbamide (PTC) and 6-n-propylthiouracil (PROP), chemically related compounds, are probes for genetic variation in bitter taste, although PROP is safer with less sulfurous odor. Threshold for PROP distinguishes nontasters (increased threshold) from tasters (lower threshold); perceived intensity subdivides tasters into medium tasters (PROP is bitter) and supertasters (PROP is very bitter). Compared with supertasters, nontasters have fewer taste papillae on the anterior tongue (fungiform papillae) and experience less negative (e.g., bitterness) and more positive (eg, sweetness) sensations from alcohol. We determined whether the TAS2R38 gene at 7q36 predicted PROP bitterness, alcohol sensation and use. METHODS: Healthy adults (53 women, 31 men; mean age 36 years)--primarily light and moderate drinkers--reported the bitterness of five PROP concentrations (0.032-3.2 mM) and intensity of 50% ethanol on the general Labeled Magnitude Scale. PROP threshold and density of fungiform papillae were also measured. Subjects had common TAS2R38 gene haplotypes [alanine-valine-isoleucine (AVI) and proline-alanine-valine (PAV)]. RESULTS: PROP bitterness varied significantly across genotypes with repeated measures ANOVA: 26 AVI/AVI homozygotes tasted less bitterness than either 37 PAV/AVI heterozygotes or 21 PAV/PAV homozygotes. The PAV/PAV group exceeded the PAV/AVI group for bitterness only for the top PROP concentrations. The elevated bitterness was musch less than if we defined the groups using psychophysical criteria. With multiple regression analyses, greater bitterness from 3.2 mM PROP was a significant predictor of greater ethanol intensity and less alcohol intake--effects separate from age and sex. Genotype was a significant predictor of alcohol intake, but not ethanol intensity. With ANOVA, AVI/AVI homozygotes reported higher alcohol use than either PAV/AVI heterozygotes or PAV/PAV homozygotes. When age effects were minimized, PROP bitterness explained more variance in alcohol intake than did the TAS2R38 genotype. CONCLUSIONS: These results support taste genetic effects on alcohol intake. PROP bitterness serves as a marker of these effects.

Adult↗

PubMed2003

Obsessive-compulsive symptom dimensions in affected sibling pairs diagnosed with Gilles de la Tourette syndrome.

Obsessive-compulsive disorder (OCD) is an etiologically heterogeneous disorder. Recent factor analyses have consistently identified several symptom dimensions, two of which are associated with increased familial risk for OCD; aggressive, sexual, and religious obsessions and checking compulsions (FACTOR 1) and symmetry and ordering obsessions and compulsions (FACTOR 2). Both of these symptom dimensions are also frequently seen in association with Gilles de la Tourette syndrome (GTS). The purpose of this study was to determine whether these obsessive-compulsive (OC) symptom dimensions are correlated within families (between sibs and between parent-child pairs). Using data collected by the Tourette Syndrome Association International Consortium for Genetics Affected Sibling Pair Study, the authors selected all available GTS sib pairs and their parents for which these OC symptom dimensions (factor scores) could be generated. This group included 128 full sibs and their mothers (54) and fathers (54). Four OC symptom dimension scores were computed for each family member using an algorithm derived from item endorsements from the Yale-Brown Obsessive-Compulsive Scale (Y-BOCS) symptom checklist. In addition to a series of univariate analyses, complex segregation analyses were also completed using these quantitative OC symptom dimension scores. FACTOR 1 and FACTOR 2 scores were significantly correlated in sib pairs concordant for GTS. The mother-child correlations, but not father-child correlations, were also significant for these two factors. Segregation analyses were consistent with dominant major gene effects for both FACTOR 1 and FACTOR 2. We conclude that familial factors contribute significantly to OC symptom dimension phenotypes in GTS families. This familial contribution could be genetic or environmental.

Adolescent↗

PubMed2003

Global survey of haplotype frequencies and linkage disequilibrium at the RET locus.

We have constructed haplotypes based on normal variation at six polymorphic sites-five single nucleotide polymorphisms (SNPs) and one short tandem repeat polymorphism (STRP)-at the RET locus for samples of normal individuals from 32 populations distributed across the major continental regions of the world. The haplotyped system spans 41.6 kilobases and encompasses most of the coding region of the gene. All of the markers are polymorphic in all regions of the world and in most individual populations. Expected heterozygosities for the six-site haplotypes range from 82 to 94% for all populations studied except for two Amerindian groups from the Amazon basin at 61 and 76%. Individual populations had from four to eight haplotypes with frequencies exceeding 5%. In general, African, southwest Asian and European groups have the highest numbers of total and of commonly occurring haplotypes; the lowest numbers are observed in Amerindian populations. Overall linkage disequilibrium (LD) for the five SNP sites was very significant (P</=0.001) for all the non-African populations, but significant at that level for only one of the seven African populations. In general, the permutation-based xi coefficient that quantifies overall LD tends to increase the farther the population is from Africa, but variability of this measure of LD is often large within geographic regions. Pairwise LD measures among the SNPs also show considerable variation among populations. Association of STRP alleles with the SNP-defined background haplotypes is generally higher outside of Africa than in Africa, but is highly variable.

Alleles↗

PubMed2002

Population variation in linkage disequilibrium across the COMT gene considering promoter region and coding region variation.

Catechol-O-methyl transferase (COMT) catalyzes the first step in one of the major pathways in the degradation of catecholamines. The COMT gene on chromosome 22 has been considered a candidate gene for many neuropsychiatric disorders, in part because an exon 4 single nucleotide polymorphism (SNP) in COMT causes an amino acid substitution associated with significantly altered enzyme activity. This functional variant, detected as an NlaIII restriction site polymorphism (RSP), is polymorphic in populations from around the world. A four-site haplotype spanning 28 kb effectively encompasses COMT. This haplotype is comprised of two novel polymorphisms [a tetranucleotide short tandem repeat polymorphism (STRP) in intron 1 and a HindIII RSP at the 5' end of COMT], the NlaIII site, and another previously published site - a BglI RSP at the 3' end of the gene. Overall linkage disequilibrium (LD) for this haplotype is strong and significant in 32 population samples from around the world. Conditional probabilities indicate that, in spite of moderate to strong disequilibrium in most non-African populations, the NlaIII site, although often used for prediction, would not always be a reliable predictor of allelic variation at the other sites. Because other functional variation might exist, especially regulatory variation, these findings indicate that haplotypes would be more effective indicators of possible involvement of COMT in disease etiology.

Base Sequence↗

PubMed2002

A global perspective on genetic variation at the ADH genes reveals unusual patterns of linkage disequilibrium and diversity.

Variants of different Class I alcohol dehydrogenase (ADH) genes have been shown to be associated with an effect that is protective against alcoholism. Previous work from our laboratory has shown that the two sites showing the association are in linkage disequilibrium and has identified the ADH1B Arg47His site as causative, with the ADH1C Ile349Val site showing association only because of the disequilibrium. Here, we describe an initial study of the nature of linkage disequilibrium and genetic variation, in population samples from different regions of the world, in a larger segment of the ADH cluster (including the three Class I ADH genes and ADH7). Linkage disequilibrium across approximately 40 kb of the Class I ADH cluster is moderate to strong in all population samples that we studied. We observed nominally significant pairwise linkage disequilibrium, in some populations, between the ADH7 site and some Class I ADH sites, at moderate values and at a molecular distance as great as 100 kb. Our data indicate (1) that most ADH-alcoholism association studies have failed to consider many sites in the ADH cluster that may harbor etiologically significant alleles and (2) that the relevance of the various ADH sites will be population dependent. Some individual sites in the Class I ADH cluster show Fst values that are among the highest seen among several dozen unlinked sites that were studied in the same subset of populations. The high Fst values can be attributed to the discrepant frequencies of specific alleles in eastern Asia relative to those in other regions of the world. These alleles are part of a single haplotype that exists at high (>65%) frequency only in the eastern-Asian samples. It seems unlikely that this haplotype, which is rare or unobserved in other populations, reached such high frequency because of random genetic drift alone.

Alcohol Dehydrogenase↗

PubMed2002

ALFRED: An allele frequency database for anthropology.

The deluge of data from the human genome project (HGP) presents new opportunities for molecular anthropologists to study human variation through the promise of vast numbers of new polymorphisms (e.g., single nucleotide polymorphisms or SNPs). Collecting the resulting data into a single, easily accessible resource will be important to facilitate this research. We created a prototype Web-accessible database named ALFRED (ALelle FREquency Database, http://alfred.med.yale.edu/alfred/) to store and make publicly available allele frequency data on diverse polymorphic sites for many populations. In constructing this database, we considered many different concerns relating to the types of information needed for anthropology, population genetics, molecular genetics, and statistics, as well as issues of data integrity and ease of access to data. We also developed links to other Web-based databases as well as procedures for others to make links to the data in ALFRED. Here we present an overview of the issues considered and provisional solutions, as well as an example of data already available. It is our hope that this database will be useful for research and teaching in a wide range of fields, and that colleagues from various fields will contribute to making ALFRED an important resource for many studies as yet unforeseen.

Anthropology, Physical↗

PubMed2002

A proline-threonine substitution in codon 351 of ADH1C is common in Native Americans.

BACKGROUND: The alcohol dehydrogenase (ADH) genes have been repeatedly associated with protection against alcoholism. Until now, only four protein coding variants have been identified (ADH1C Arg271Gln, Ile349Val, ADH1B Arg47His, and Arg369Cys), and only two of these (ADH1CIle349Val and ADH1B Arg47His) have been routinely tested in association studies with alcoholism. METHODS: The new ADH1C*351Thr allele was identified by direct sequencing of DNA samples that gave different typing results for the ADH1C Ile349Val polymorphism with different typing protocols. RESULTS: A new coding variant has been identified at codon 351 of ADH1C. This allele is found in most Native American populations that we have studied with allele frequencies of the new ADH1C*351Thr allele as high as 26%. Only two instances of this allele have been seen in a large survey of African and Eurasian populations. CONCLUSIONS: The changes in charge, size, and rotational mobility caused by this amino acid substitution should be significant. Because this new variant codes for a new enzyme form in Native Americans, the kinetics of this enzyme should be studied and considered in studies of the role of in the protection against alcoholism in Native Americans.

Alcohol Dehydrogenase↗