Search

DNA polymorphic markers and self-defined ethnicity groupings are used to group individuals with shared ancient geographic ancestry. Here we studied whether ancestral relationships between individuals could be identified from metabolic screening data reported by the California newborn screening (NBS) program. NBS data includes 41 blood metabolites measured by tandem mass spectrometry from singleton babies in 17 parent-reported ethnicity groupings. Ethnicity-associated differences identified for 71% of NBS metabolites (29 of 41, Cohen's dgt; 0.5) showed larger differences in blood levels of acylcarnitines than of amino acids (Plt; 1e-4). A metabolic distance measure, developed to compare ethnic groupings based on metabolic differences, showed low positive correlation with genetic and ancient geographic distances between the groups' ancestral world populations. Several outlier group pairs were identified with larger genetic and smaller metabolic distances (Black versus White) or with smaller genetic and larger metabolic distances (Chinese versus Japanese) indicating the influence of genetic and of environmental factors on metabolism. Using machine learning, comparison of metabolic profiles between all pairs of ethnic groupings distinguished individuals with larger genetic distance (Black versus Chinese, AUC = 0.96), while genetically more similar individuals could not be separated metabolically (Hispanic versus Native American, AUC = 0.51). Additionally, we identified metabolites informative for inferring metabolic ancestry in individuals from genetically similar populations, which included biomarkers for inborn metabolic disorders (C10:1, C12:1, C3, C5OH, Leucine-Isoleucine). This work sheds new light on metabolic differences in healthy newborns in diverse populations, which could have implications for improving genetic disease screening.

Single-nucleotide polymorphisms (SNPs) and small genomic regions with multiple SNPs (microhaplotypes, MHs) are rapidly emerging as novel forensic investigative tools to assist in individual identification, kinship analyses, ancestry inference, and deconvolution of DNA mixtures. Here, we analyzed information for 90 microhaplotype loci in 4009 individuals from 79 world populations in 6 major biogeographic regions. The study included multiplex microhaplotype sequencing (mMHseq) data analyzed for 524 individuals from 16 populations and genotype data for 3485 individuals from 63 populations curated from public repositories. Analyses of the 79 populations revealed excellent characteristics for this 90-plex MH panel for various forensic applications achieving an overall average effective number of allele values (Ae) of 4.55 (range 1.04–19.27) for individualization and mixture deconvolution. Population-specific random match probabilities ranged from a low of 10–115 to a maximum of 10–66. Mean informativeness (In) for ancestry inference was 0.355 (range 0.117–0.883). 65 novel SNPs were detected in 39 of the MHs using mMHseq. Of the 3018 different microhaplotype alleles identified, 1337 occurred at frequencies > 5% in at least one of the populations studied. The 90-plex MH panel enables effective differentiation of population groupings for major biogeographic regions as well as delineation of distinct subgroupings within regions. Open-source, web-based software is available to support validation of this technology for forensic case work analysis and to tailor MH analysis for specific geographical regions.

In recent years, the number of publications on microhaplotypes has averaged more than a dozen papers annually. Many have contributed to a significant increase in the number of highly polymorphic microhaplotype loci. This increase allows microhaplotypes to be very informative in four main areas of forensic uses of DNA: individualization, ancestry inference, kinship analysis, and mixture deconvolution. The random match Probability (RMP) can be as small as 10−100 for a large panel of microhaplotypes. It is possible to measure the heterozygosity of an MH as the effective number of alleles (Ae). Ae > 7.5 exists for African populations and >4.5 exists for Native American populations for a smaller panel of two dozen selected microhaplotypes. Using STRUCTURE, at least 10 different ancestral clusters can be defined by microhaplotypes. The Ae for a locus is also identical to the Paternity Index (PI), the measure of how informative a locus will be in parentage testing. High Ae loci can also be useful in missing persons cases. Finally, high Ae microhaplotypes allow the near certainty of seeing multiple additional alleles in a mixture of two or more individuals in a DNA sample. In summary, a panel of higher Ae microhaplotypes can outperform the standard CODIS markers.

The single nucleotide polymorphisms (SNPs) of the dopamine D3 receptor (DRD3), the CUB and sushi multiple domains 1 (CSMD1) and the neuregulin 1 (NRG1) genes were used to study the genetic diversity and affinity among North African populations and to examine their genetic relationships in worldwide populations.The rs3773678, rs3732783 and rs6280 SNPs of the DRD3 gene located on chromosome 3, the rs10108270 SNP of the CSMD1 gene and the rs383632, rs385396 and rs1462906 SNPs of the NRG1 gene located on chromosome 8 were analysed in 366 individuals from seven North African populations (Libya, Kairouan, Mehdia, Sousse, Kesra, Smar and Kerkennah).The low values of FThe Kairouan population exhibited a relatively low rate of genetic variability. The North African population has undergone significant gene flow but also evolutionary forces that have made it genetically distinct from other populations.

A small panel of highly informative loci that can be genotyped on the same equipment as the standard CODIS short tandem repeat (STR) markers has strong potential for application in forensic casework. Single nucleotide polymorphisms (SNPs) can be typed by a couple of methods on capillary electrophoresis (CE) machines and on sequencers, but the amount of information relative to the laboratory effort has hindered use of SNPs in actual casework. Insertion-deletion markers (InDels) suffer from similar problems. Microhaplotypes (MHs) are much more informative per locus but have similar technical difficulties unless they are typed by massively parallel sequencing (MPS). As forensic labs are acquiring sequencing machines, MHs become more likely to be used in casework, especially if multiplexed with STRs. Here we present the details of a multipurpose panel of 24 MHs with the highest effective number of alleles (A

Population genetic studies of North Asian ethnic groups have focused on genetic variation of sex chromosomes and mitochondria. Studies of the extensive variation available from autosomal variation have appeared infrequently. We focus on relationships among population samples using new North Asia microhaplotype data. We combined genotypes from our laboratory on 58 microhaplotypes, distributed across 18 autosomes, on 3945 individuals from 75 populations with corresponding data extracted for 26 populations from the Thousand Genomes consortium and for 22 populations from the GenomeAsia 100 K project. A total of 7107 individuals in 122 total populations are analyzed using STRUCTURE, Principal Component Analysis, and phylogenetic tree analyses. North Asia populations sampled in Mongolia include: Buryats, Mongolians, Altai Kazakhs, and Tsaatans. Available Siberians include samples of Yakut, Khanty, and Komi Zyriane. Analyses of all 122 populations confirm many known relationships and show that most populations from North Asia form a cluster distinct from all other groups. Refinement of analyses on smaller subsets of populations reinforces the distinctiveness of North Asia and shows that the North Asia cluster identifies a region that is ancestral to Native Americans.

Background Only a few studies have investigated the association of single nucleotide polymorphisms in STAT3 gene with the susceptibility to cancer and response to chemotherapy. Our aim was to determine the allele frequencies of rs3869550, rs957971, and rs7211777 at the STAT3 gene in North African populations and compare them to 1000 genomes populations, and to investigate their relation with cancer. Methods The targeted SNPs have been analyzed in six Tunisian populations and a sample of Libyans using TaqMan® Assay. The results were compared to 1000 Genomes Project population samples. Targeting of the regions encompassing the three SNPs by micro‐ARN was assessed using miR databases. Results The analysis of the 3 SNPs showed that North African populations were close to South Asians. As expected, African populations presented a significant frequency of the ancestral CCG haplotype in contrast to other populations where the fully derived TGA haplotype was more frequent. The presence and diversity of rare haplotypes at STAT3 in North African populations could have been generated by recombination between the two major haplotypes. A screening of the micro‐RNA databases showed that the STAT3 region with the mutated allele of rs7211777 (G>A) could be targeted by miR hsa‐miR‐3606‐5p, which also targets genes involved in breast cancer., There are very few studies that have studied the STAT3 gene in North Africa. Determine the distribution of allelic, genotypic and haplotypic frequencies of rs3869550, rs957971, and rs7211777 at the STAT3 gene in North African populations and make comparison to other populations. The STAT3 region with the mutated allele of rs7211777 (G>A) could be targeted by miR hsa‐miR‐3606‐5p, which also target genes involved in breast cancer.

The COMT gene encodes for catechol-O-methyl-transferase, an enzyme playing a major role in regulation of synaptic catecholamine neurotransmitters. Investigating 4 markers of the COMT gene (rs2020917, rs4818, rs4680, rs9332377) in 6 Tunisian populations and a pool of Libyans. Our objective was to determine the distribution of allelic, genotypic and haplotypic frequencies by comparison to other populations of the 1000 genomes project and 59 populations from the Kidd Lab dataset. The allelic frequencies established for these SNPs in the North African populations are similar to those of Europeans and South Asians. Linkage disequilibrium between these SNPs and haplotypes frequencies are different between populations whose clustering in principal components analysis (PCA) according to their geographic origin was more significant using haplotypic frequencies. COMT activity prediction by haplotypes genotyping could be limited to rs4818-rs4680 micro-haplotypes. The Low activity haplotype (CG) displays the highest frequency in African populations (55%), in the 59 Kidd Lab populations we found also that Sub-Saharan Africans, Native Americans, and some East Asian and Pacific Island populations all have frequencies in the 50-81% range for (CG) where as its lowest frequency was found in Europeans (10%), this results have been also confirmed for Southwest Asians. North Africans and South Asians with intermediate frequencies have approximately similar values (20% and 25%). Europeans show the highest frequencies of haplotypes with predicted High and Medium activity in contrast to Africans. North Africans and South Asians present similar results for all the category of the COMT activity prediction by haplotypes genotyping. The high level of genetic diversity of COMT haplotypes, not only allows distinction between populations according to their history settlement, origin and ethnicity, it constitutes a basis for studies of association of the COMT gene polymorphism with pathologies, drugs response and for forensic investigation in North African populations. This work was partially supported by the Tunisian Ministry of Higher Education and Scientific Research as well as by the University of Tunis El Manar . Special thanks go to the thousands of individuals around the world who volunteered to give blood and saliva samples to made this study possible. Scopus

WOS:000577218500005 PubMed ID: 32963319 Oculocutaneous Albinism type 2 (OCA2) is a gene of great interest because of genetic variation affecting normal pigmentation variation in humans. The diverse geographic patterns for variant frequencies at OCA2 have been evident but have not been systematically investigated, especially outside of Europe. Here we examine population genetic variation in and near the OCA2 gene from a worldwide perspective. The very different patterns of genetic variation found across world regions suggest strong selection effects may have been at work over time. For example, analyses involving the variants that affect pigmentation of the iris argue that the derived allele of the rs1800407 single nucleotide polymorphism, which produces a hypomorphic protein, may have contributed to the previously demonstrated positive selection in Europe for the enhancer variant responsible for light eye color. More study is needed on the relationships of the genetic variation at OCA2 to variation in pigmentation in areas beyond Europe. NIJ Grants - National Institute of Justice, Office of Justice Programs, U.S. Department of Justice [2018-75-CX-0041, 2015-DN-BX-K023, 2016-DN-BX-0162, 2014-DN-BX-K030] The assembly and data analyses were funded primarily by NIJ Grants 2018-75-CX-0041, 2015-DN-BX-K023, 2016-DN-BX-0162, and 2014-DN-BX-K030 to KKK awarded by the National Institute of Justice, Office of Justice Programs, U.S. Department of Justice. Points of view in this presentation are those of the authors and do not necessarily represent the official position or policies of the U.S. Department of Justice. The authors thank Dr. Francoise R. Friedlaender for her expert help in creating Figs. 1, 2, 3 and 4. We would like to acknowledge all of our collaborators who helped collect the samples used in this research as well as the National Laboratory for the Genetics of Israeli Populations at Tel Aviv University and the Coriell Cell Repositories. Special thanks are due to the many hundreds of individuals who volunteered to give blood or saliva samples for studies of gene frequency variation.

The benefits of ancestry informative SNP (AISNP) panels can best accrue and be properly evaluated only as sufficient reference population data become readily accessible. Ideally the set of reference populations should approximate the genetic diversity of human populations worldwide. The Kidd and Seldin AISNP sets are two panels that have separately accumulated thus far the largest and most diverse collections of data on human reference populations from the major continental regions. A recent tally in the ALFRED allele frequency database finds 164 reference populations available for all the 55 Kidd AISNPs and 132 reference populations for all the 128 Seldin AISNPs. Although much more of the genetic diversity in human populations around the world still needs to be documented, 81 populations have genotype data available for all 170 AISNPs in the union of the Kidd and Seldin panels. In this report we examine admixture and principal component analyses on these 81 worldwide populations and some regional subsets of these reference populations to determine how well the combined panel illuminates population relationships. Analyses of this dataset that focused on Native American populations revealed very strong cluster patterns associated with many of the individual populations studied.

Massively parallel sequencing is transforming forensic work by allowing various useful forensic markers, such as STRPs and SNPs, to be multiplexed providing information on ancestry, individual and familial identification, phenotypes for eye/hair/skin pigmentation, and the deconvolution of mixtures. Microhaplotypes also become feasible with massively parallel sequencing, these are DNA segments (smaller than 300 nucleotides) that are selected to contain multiple SNPs unambiguously defining three or more haplotype alleles occurring at common frequencies. The physical extent of a microhaplotype can thus be covered by a single sequence read making these loci phase-known codominant genetic systems. Such microhaplotypes supply significantly more information than a single SNP can. Our efforts to develop useful sets of microhaplotypes have already identified 182 such loci that we have studied on a large number of human populations from around the world. We present various analyses on 83 populations in our ongoing study for a subset of the best microhaplotypes currently available illustrating their characteristics and potential utility for ancestry, identification, and mixture deconvolution.

The Kidd Lab panel of 55 AISNPs can provide up to 10 statistically relevant biogeographic groupings of a global set of populations. A second-tier panel would be useful for increasing the accuracy for further differentiation of populations within a specific global grouping. Because recent advances in massively parallel sequencing (MPS) methods allow the genotyping of many more SNPs, we are now identifying additional SNPs to provide refined discrimination among regional subsets of populations; Southwest Asia and the nearby Mediterranean region (SWA) is our current target for such a “second tier” panel. We selected the potentially best SNPs from various sources: our own laboratory database (>4600 SNPs), AISNP panels (Kidd 55 and Seldin 128 SNP panels), and published papers reporting European and SW Asian populations. Rosenberg’s Informativeness, Fst, and allele frequency heatmap matrices are used to determine the best SNPs for the region. A total of 2568 individuals, from 39 different populations ranging from North-East Africa through the SW Asia and Europe to the Ural Mountains, were included in the refinement processes and analyses. Heatmap, PCA, Structure (K = 4), and ancestry inference for selected individuals with an in-lab version of FROG-kb analyses indicate that these 86 AISNPs provide the basis for building an improved, optimized panel of AISNPs that collectively provide additional information on differences among populations in that part of the world. Testing this panel with additional populations from the area and with new SNPs and/or microhaplotypes is expected to improve the panel.

Microhaplotypes have become a new type of forensic marker with a great ability to identify and deconvolute mixtures because massively parallel sequencing (MPS) allows the alleles (haplotypes) of the multi-SNP loci to be determined directly for an individual. As originally defined, a microhaplotype locus is a short segment of DNA with two or more SNPs defining three or more haplotypes. The length is short enough, less than about 300 bp, that the read length of current MPS technology can produce a phase-known sequence of each chromosome of an individual. As part of the discovery phase of our studies, data on 130 microhaplotype loci with estimates of haplotype frequency data on 83 populations have been published. To provide a better picture of global allele frequency variation, we have now tested 13 more populations for 65 of the microhaplotype loci from among those with higher levels of inter-population gene frequency variation, including 8 loci not previously published. These loci provide clear distinctions among 6 biogeographic regions and provide some information distinguishing up to 10 clusters of populations. Electronic supplementary material The online version of this article (10.1007/s00414-017-1748-6) contains supplementary material, which is available to authorized users.

Today the primary DNA markers used in forensics are short tandem repeat (STR) polymorphisms (STRPs), initially selected because they are highly polymorphic. However, the increasingly common need to deal with samples with a mixture of DNA from two or more individuals sometimes is complicated by the inherent stutter involved with PCR amplification, especially in strongly unbalanced mixtures when the minor component coincides with the stutter range of the major component. Also, the STRPs in use provide little evidence of ancestry of a single source sample beyond broad "continental" resolution. Methodologies for analyzing DNA have become much more powerful in recent years. Massively parallel sequencing (MPS) is a new method being considered for routine use in forensics. Primarily to aid in mixture deconvolution and avoid the issue of stutter, we have begun to investigate a new type of forensic marker, microhaplotype loci, that will provide useful information on mixtures of DNA and on ancestry when typed using massively parallel sequencing (MPS). We have identified 130 loci and estimated their haplotype (allele) frequencies in 83 different population samples. Many of these loci are shown to be highly informative for individual identification and for mixture identification and deconvolution.

The set of 55 ancestry informative SNPs (AISNPs) originally developed by the Kidd Lab has been studied on a large numberof populations and continues to be applied to new population samples. The existing reference database of population samplesallows the relationships of new population samples to be inferred on a global level. Analyses show that these autosomalmarkers constitute one of the better panels of AISNPs. Continuing to build this reference database enhances its value.Because more than half of the 25 ethnic groups recently studied with these AISNPs are from Southwest Asia and theMediterranean region, we present here various analyses focused on populations from these regions along with selectedreference populations from nearby regions where genotype data are available. Many of these ethnic groups have not beenpreviously studied for forensic markers. Data on populations from other world regions have also been added to the databasebut are not included in these focused analyses. The new population samples added to ALFRED and FROG-kb increase thetotal to 164 population samples that have been studied for all 55 AISNPs.

The dopamine - related genes, like dopamine D2 receptor (DRD2) gene and ankyrin repeat and kinase domain containing 1 (ANKK1) gene are implicated in neurological functions. Some polymorphisms of the DRD2/ANKK1 locus (TaqIA, TaqIB, TaqID) have been used to study genetic diversity and the evolution of human populations. The present investigation aims to assess the genetic diversity in seven North African populations in order to explore their genetic structure and to compare them to others worldwide populations studied for the same locus. Nine single nucleotide polymorphisms (SNPs) from the DRD2/ANKK1 locus (rs1800497 TaqIA, rs2242592, rs1124492, rs6277, rs6275, rs1079727, rs2002453, rs2234690 and rs1079597 TaqIB) were typed in 366 individuals from seven North African populations: six from Tunisia (Sousse, Smar, Kesra, Kairouan, Mehdia and Kerkennah) and one from Libya. The allelic frequencies of rs2002453 and rs2234690 were higher in the Smar population than in the other North African populations. More, the Smar population showed the lowest average heterozygosity (0.313). The principal component analysis (PCA) showed that the Smar population was clearly separated from others. Furthermore, linkage disequilibrium analysis shown a high linkage disequilibrium in the North African population and essentially in Smar population. Comparison with other world populations has shown that the heterozygosity of North African population was very close to that of the African and European populations. The PCA and the haplotypic analysis suggested the presence of an important Eurasian genetic component for the North African population. These results suggested that the Smar population was isolated from the others North Africans ones by its peculiar genetic structure because of isolation, endogamy and genetic drift. On the other hand, the North African population is characterized by a multi ancestral gene pool from Eurasia and sub-Saharan Africa due to human migration since prehistoric times.

Objectives North Africa has a complex demographic history of migrations from within Africa, Europe, and the Middle East. However, population genetic studies, especially for autosomal genetic markers, are few relative to other world regions. We examined autosomal markers for eight Tunisian and Libyan populations in order to place them in a global context. Materials and Methods Data were collected by TaqMan on 399 autosomal single nucleotide polymorphisms on 331 individuals from Tunisia and Libya. These data were combined with data on the same SNPs previously typed on 2585 individuals from 57 populations from around the world. Where meaningful, close by SNPs were combined into multiallelic haplotypes. Data were evaluated by clustering, principal components, and population tree analyses. For a subset of 102 SNPs, data from the literature on seven additional North African populations were included in analyses. Results Average heterozygosity of the North African populations is high relative to our global samples, consistent with a complex demographic history. The Tunisian and Libyan samples form a discrete cluster in the global and regional views and can be separated from sub-Sahara, Middle East, and Europe. Within Tunisia the Nebeur and Smar are outlier groups. Across North Africa, pervasive East-West geographical patterns were not found. Discussion Known historical migrations and invasions did not displace or homogenize the genetic variation in the region but rather enriched it. Even a small region like Tunisia contains considerable genetic diversity. Future studies across North Africa have the potential to increase our understanding of the historical demographic factors influencing the region. Am J Phys Anthropol, 2016. © 2016 The Authors American Journal of Physical Anthropology Published by Wiley Periodicals, Inc.

Patients with autosomal dominant vibratory urticaria have localized hives and systemic manifestations in response to dermal vibration, with coincident degranulation of mast cells and increased histamine levels in serum. We identified a previously unknown missense substitution in ADGRE2 (also known as EMR2), which was predicted to result in the replacement of cysteine with tyrosine at amino acid position 492 (p.C492Y), as the only nonsynonymous variant cosegregating with vibratory urticaria in two large kindreds. The ADGRE2 receptor undergoes autocatalytic cleavage, producing an extracellular subunit that noncovalently binds a transmembrane subunit. We showed that the variant probably destabilizes an autoinhibitory subunit interaction, sensitizing mast cells to IgE-independent vibration-induced degranulation. (Funded by the National Institutes of Health.)

The web-based application, FROG-kb (the Forensic Resource/Reference on Genetics-knowledge base, https://frog.med.yale.edu ) supports the use of Single Nucleotide Polymorphisms (SNPs) for individual identification and ancestry inference in a forensic setting. The primary functionality provided by FROG-kb on the web is computation of relative likelihoods of populations being the origin of an individual, utilizing the underlying reference population allele frequency data curated and organized in ALFRED, the ALlele FREquency Database ( https://alfred.med.yale.edu/ ). Here we present a downloadable stand-alone tool, FrogAncestryCalc that can simultaneously compute population likelihoods for multiple individuals for a selected panel of SNPs. The program calculates for a given Ancestry Inference (AI) panel the probability of each individual’s genotype profile arising in each of the reference populations. Five of the AI panels catalogued in FROG-kb are implemented in this version of FrogAncestryCalc.

The derived human alcohol dehydrogenase (ADH)1B*48His allele of the ADH1B Arg48His polymorphism (rs1229984) has been identified as one component of an East Asian specific core haplotype that underwent recent positive selection. Our study has been extended to Southwest Asia and additional markers in East Asia. Fst values (Sewall Wright’s fixation index) and long-range haplotype analyses identify a strong signature of selection not only in East Asian but also in Southwest Asian populations. However, except for the ADH2B*48His allele, different core haplotypes occur in Southwest Asia compared to East Asia and the extended haplotypes also differ. Thus, the ADH1B*48His allele, as part of a core haplotype of 10 kb, has undergone recent rapid increases in frequency independently in the two regions after divergence of the respective populations. Emergence of agriculture may be the common factor underlying the evident selection.

Massively parallel sequencing (MPS, aka NGS) is revolutionizing the field of forensics. Existing forensic short tandem repeat polymorphisms (STRPs) are more informative when typed by MPS. MPS also allows STRPs and forensic SNP panels to be multiplexed to add information, on ancestry and phenotype, to the identification information from STRPs. MPS also makes possible microhaplotypes: small segments of DNA (

The Forensic Resource/Reference on Genetics-knowledge base (FROG-kb) web sitehttps://frog.med.yale.edu/FrogKB/was introduced in 2011 and in the five years since the previous publication ongoing research into how the database can better serve forensics has resulted in extensive redesign of the database interface and functionality. Originally designed as a prototype to support forensic use of single nucleotide polymorphisms (SNPs), FROG-kb provides a freely accessible web interface that facilitates forensic practice and can be useful for teaching and research. Based on knowledge gained through its use, the web interface has been redesigned for easier navigation through the multiple components. The site also has functional enhancements, extensive new documentation, and new reference panels of SNPs with new curated data. FROG-kb focuses on single nucleotide polymorphisms (SNPs) and provides reference population data for several published panels of individual identification SNPs (IISNPs) and several published panels of ancestry inference SNPs (AISNPs). For each of the various marker panels with reference population data, FROG-kb calculates random match probabilities (RMP) and relative likelihoods of ancestry for a user-entered genotype profile (either completely or partially specified). Example genotype profiles are available and the User's Manual presents interpretation guidelines for the calculations. The extensive documentation along with ongoing updates makes FROG-kb a comprehensive tool in facilitating use of SNPs in forensic practice and education. An overview of the new FROG-kb with examples and material explaining the results of its use are presented here.

SNPs that are molecularly very close (

Background Variation at the serotonin transporter gene, SLC6A4 , has been associated with a variety of neuropsychiatric disorders and could be involved in other health-related phenotypes. Methods To determine the extent of variation at SLC6A4 , we genotyped 23 markers on approximately 2500 individuals from 47 global populations, including the promoter variable number tandem repeat (VNTR) and 2 single nucleotide polymorphisms (SNPs) immediately flanking its variable region (rs25531 and rs25532), the intron 2 VNTR, and 19 additional SNPs. Results We observed several rare alleles at the promoter VNTR (some novel) and population-specific distributions of the reported functional SNPs rs25531, rs25532, and rs6355, as well as two alleles at the intron 2 VNTR. Alleles of interest at the VNTRs occurred on specific haplotype backgrounds. The repeat-number variants at the promoter VNTR and the intron 2 VNTR, as well as the putative functional SNPs, showed ethnic variation in frequencies. The more common alleles at the VNTR polymorphisms show wide geographic distributions, whereas rare alleles at both show more restricted distributions. The derived alleles at the two functional SNPs in the promoter VNTR show restricted distributions and occur primarily on different repeat number alleles. Conclusions Our findings illustrate significant variation worldwide at SLC6A4 and that the functionally implicated alleles at the SNPs rs25531, rs25532, and rs6355 occur on limited haplotypes and vary significantly in global distribution. Association studies at SLC6A4 cannot a priori extrapolate across populations and should account for the multiple polymorphisms with possible functional variation across this locus, rather than focusing solely on one or two polymorphisms as commonly seen.

Background Endometriosis is a common disease that causes pain and infertility. The heritable predisposition toward endometriosis motivates an interest to identify the genes and genomic variants involved in the pathogenesis of endometriosis. Both genetic and environmental factors contribute to this disease. Here we investigated in Pakistani women the association of endometriosis and single nucleotide polymorphisms (SNP) in genes previously identified in the development of this disease. Methods DNA samples from 52 genetically unrelated endometriosis subjects with endometriosis and 52 randomly selected controls were analyzed by direct sequencing to determine polymorphisms in four genes. These included estrogen receptor alpha (ESR1) (rs2234693 C/T, rs9340799 G/A SNP), estrogen receptor beta (ESR2) (rs4986938 G/A SNP), progesterone receptor (PGR) (rs1042838 G/T, rs10895068 G/A SNPs) and interleukin 10 (IL10) (rs1800871 C/T, rs1800872 C/A and rs1800896 G/A SNPs). Results The allele A at −592, T at −819 and G at −1080 of IL10 and all of the SNPs studied at ESR2 and PGR show strong, statistically significant associations with the disease. However, the genetic variation at ESR1 was distributed similarly among cases and control groups. Conclusion These findings suggest that the functional promoter polymorphism of the IL10 gene, identified by the “ATG” genotype, may contribute to the risk of endometriosis. Genetic variants of ESR2 and PGR gene may also be a risk factor as well as influence the fertility status of patients with endometriosis.

Toll-like receptor 1, when dimerized with Toll-like receptor 2, is a cell surface receptor that, upon recognition of bacterial lipoproteins, activates the innate immune system. Variants in TLR1 associate with the risk of a variety of medical conditions and diseases, including sepsis, leprosy, tuberculosis, and others. The foremost of these is rs5743618 c.2079T>G(p.(Ile602Ser)), the derived allele of which is associated with reduced risk of sepsis, leprosy, and other diseases. Interestingly, 602Ser, which shows signatures of selection, inhibits TLR1 surface trafficking and subsequent activation of NFκB upon recognition of a ligand. This suggests that reduced TLR1 activity may be beneficial for human health. To better understand TLR1 variation and its link to human health, we have typed all 7 high-frequency missense variants (>5% in at least one population) along with 17 other variants in and around TLR1 in 2548 individuals from 56 populations from around the globe. We have also found additional signatures of selection on missense variants not associated with rs5743618, suggesting that there may be multiple functional alleles under positive selection in this gene.

Genetic data on North and Central Asian populations are underrepresented in the literature, especially for autosomal markers. In the present study we used 812 single nucleotide polymorphisms (SNPs) distributed across all the human autosomes and extensively studied at Yale to examine the affinities of two recently collected samples of populations: rural and cosmopolitan Mongolians from Ulaanbaatar and nomadic, Turkic-speaking Tsaatan from Mongolia near the Siberian border. We compare these two populations with each other and with a global set of populations and discuss their relationships to New World populations. Specifically, we analyze data on 521 autosomal loci (single SNPs and multi-SNP haplotypes) studied in 57 populations representing all the major geographical regions of the world. We conclude that these North and Central Asian populations are genetically distinct from all other populations in our study and may be close to the ancestral lineage leading to the New World populations.

Mutations in the gene OCA2 are responsible for oculocutaneous albinism type 2, but polymorphisms in and around OCA2 have also been associated with normal pigment variation. In Europeans, three haplotypes in the region have been shown to be associated with eye pigmentation and a missense SNP (rs1800407) has been associated with green/hazel eyes (Branicki et al. in Ann Hum Genet 73:160–170, 2009). In addition, a missense mutation (rs1800414) is a candidate for light skin pigmentation in East Asia (Yuasa et al. in Biochem Genet 45:535–542, 2007; Anno et al. in Int J Biol Sci 4, 2008). We have genotyped 3,432 individuals from 72 populations for 21 SNPs in the OCA2-HERC2 region including those previously associated with eye or skin pigmentation. We report that the blue-eye associated alleles at all three haplotypes were found at high frequencies in Europe; however, one is restricted to Europe and surrounding regions, while the other two are found at moderate to high frequencies throughout the world. We also observed that the derived allele of rs1800414 is essentially limited to East Asia where it is found at high frequencies. Long-range haplotype tests provide evidence of selection for the blue-eye allele at the three haplotyped systems but not for the green/hazel eye SNP allele. We also saw evidence of selection at the derived allele of rs1800414 in East Asia. Our data suggest that the haplotype restricted to Europe is the strongest marker for blue eyes globally and add further inferential evidence that the derived allele of rs1800414 is an East Asian skin pigmentation allele. Electronic supplementary material The online version of this article (doi:10.1007/s00439-011-1110-x) contains supplementary material, which is available to authorized users.

ALFRED (http://alfred.med.yale.edu) is a free, web accessible, curated compilation of allele frequency data on DNA sequence polymorphisms in anthropologically defined human populations. Currently, ALFRED has allele frequency tables on over 663 400 polymorphic sites; 170 of them have frequency tables for more than 100 different population samples. In ALFRED, a population may have multiple samples with each ‘sample’ consisting of many individuals on which an allele frequency is based. There are 3566 population samples from 710 different populations with allele frequency tables on at least one polymorphism. Fifty of those population samples have allele frequency data for over 650 000 polymorphisms. Records also have active links to relevant resources (dbSNP, PharmGKB, OMIM, Ethnologue, etc.). The flexible search options and data display and download capabilities available through the web interface allow easy access to the large quantity of high-quality data in ALFRED.

Autosomal DNA polymorphisms can pro- vide new information and understanding of both the ori- gins of and relationships among modern Native American populations. At the same time that autosomal markers can be highly informative, they are also susceptible to ascer- tainment biases in the selection of the markers to use. Identifying markers that can be used for ancestry inference among Native American populations can be considered sep- arate from identifying markers to further the quest for his- tory. In the current study, we are using data on nine Native American populations to compare the results based on a large haplotype-based dataset with relatively small inde- pendent sets of single nucleotide polymorphisms. We are interested in what types of limited datasets an individual laboratory might be able to collect are best for addressing two different questions of interest. First, how well can we differentiate the Native American populations and/or infer ancestry by assigning an individual to her population(s) of origin? Second, how well can we infer the historical/ evolutionary relationships among Native American popula- tions and their Eurasian origins? We conclude that only a large comprehensive dataset involving multiple autosomal markers on multiple populations will be able to answer both questions; different small sets of markers are able to answer only one or the other of these questions. Using our largest dataset, we see a general increasing distance from Old World populations from North to South in the New World except for an unexplained close relationship between our Maya and Quechua samples. Am J Phys Anthropol 146:495-502, 2011. V

A variant allele, ADH1B*48His, also known as ADH1B*2, at the human Alcohol Dehydrogenase 1B gene (ADH1B) is strongly associated with alcoholism in some populations and has an unusual geographic distribution. Strong evidence implies selection has increased the frequency of this allele in some East Asian populations but does not fully explain its geographic pattern. We have studied haplotypes of ten single nucleotide polymorphisms (SNPs) and two short tandem repeat polymorphisms (STRPs) in the ADH1B region in 2,206 individuals from a worldwide set of populations. These SNPs and STRPs define nine common haplogroups most of which have distinct geographic patterns. The haplogroups H5 and H6, both with the derived ADH1B*48His allele, appear restricted to the Middle East and East Asia, respectively. The positively selected H7 is derived from H6 by a new regulatory region variant defining SNP rs3811801 restricted to East Asia. Age estimates of the haplogroups based on the STRPs also agree with the time of the migration events estimated by other studies. H7 is estimated to have expanded recently, around 2,800 years ago, and ancient DNA samples from North China confirm its presence about that time. The dating of the H7 expansion may help understand the selective force on the ADH1B gene.

Objective Variation in the catechol-O-methyltransferase gene (COMT) has been associated with antisocial behavior in populations with attention deficit/hyperactivity disorder (ADHD). This study examined whether COMTwould predict antisocial behavior in a sample with high levels of behavior problems, not necessarily ADHD. In addition, because previous research suggests that COMT may be associated with ADHD in males, association between COMT and ADHD symptoms was examined. Method This study tested whether variation in three polymorphisms of the COMT gene was predictive of symptoms of conduct disorder and ADHD, in a sample of 174 incarcerated Russian adolescent male delinquents. Results The Val allele of the Val 158 Met polymorphism was significantly associated with conduct disorder diagnosis and symptoms, whereas the Met allele was associated with ADHD symptoms. Conclusion The Val 158 Met polymorphism of the COMT gene shows a complex relation to behavior problems, influencing conduct disorder and ADHD symptoms in opposite directions in a high-risk population. Psychiatr Genet 20:20–24 � c 2010 Wolters Kluwer Health | Lippincott Williams & Wilkins. Psychiatric Genetics 2010, 20:20–24

An efficient method to uniquely identify every individual would have value in quality control and sample tracking of large collections of cell lines or DNA as is now often the case with whole genome association studies. Such a method would also be useful in forensics. SNPs represent the best markers for such purposes. We have developed a globally applicable resource of 92 SNPs for individual identification (IISNPs) with extremely low probabilities of any two unrelated individuals from anywhere in the world having identical genotypes. The SNPs were identified by screening over 500 likely/candidate SNPs on samples of 44 populations representing the major regions of the world. All 92 IISNPs have an average heterozygosity >0.4 and the F st values are all

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 ( d N / d S ) 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.

The alcohol dehydrogenase (ADH) family of enzymes catalyzes the reversible oxidation of alcohol to acetaldehyde. Seven ADH genes exist in a segment of ~370 kb on 4q21. Products of the three class I ADH genes that share 95% sequence identity are believed to play the major role in the first step of ethanol metabolism. Because the common belief that selection has operated at the ADH1B*47His allele in East Asian populations lacks direct biological or statistical evidence, we used genomic data to test the hypothesis. Data consisted of 54 single-nucleotide polymorphisms (SNPs) across the ADH clusters in a global sampling of 42 populations. Both the F(st) statistic and the long-range haplotype (LRH) test provided positive evidence of selection in several East Asian populations. The ADH1B Arg47His functional polymorphism has the highest F(st) of the 54 SNPs in the ADH cluster, and it is significantly above the mean F(st) of 382 presumably neutral sites tested on the same 42 population samples. The LRH test that uses cores including that site and extending on both sides also gives significant evidence of positive selection in some East Asian populations for a specific haplotype carrying the ADH1B*47His allele. Interestingly, this haplotype is present at a high frequency in only some East Asian populations, whereas the specific allele also exists in other East Asian populations and in the Near East and Europe but does not show evidence of selection with use of the LRH test. Although the ADH1B*47His allele conveys a well-confirmed protection against alcoholism, that modern phenotypic manifestation does not easily translate into a positive selective force, and the nature of that selective force, in the past and/or currently, remains speculative.

Single nucleotide polymorphisms (SNPs) are likely in the near future to have a fundamental role both in human identification and description. However, because allele frequencies can vary greatly among populations, a critical issue is the population genetics underlying calculation of the probabilities of unrelated individuals having identical multi-locus genotypes. Here we report on progress in identifying SNPs that show little allele frequency variation among a worldwide sample of 40 populations, i.e., have a low F(st), while remaining highly informative. Such markers have match probabilities that are nearly uniform irrespective of population and become candidates for a universally applicable individual identification panel applicable in forensics and paternity testing. They are also immediately useful for efficient sample identification/tagging in large biomedical, association, and epidemiologic studies. Using our previously described strategy for both identifying and characterizing such SNPs (Kidd et al. in Forensic Sci Int 164:20-32, 2006), we have now screened a total of 432 SNPs likely a priori to have high heterozygosity and low allele frequency variation and from these have selected the markers with the lowest F(st) in our set of 40 populations to produce a panel of 40 low F(st), high heterozygosity SNPs. Collectively these SNPs give average match probabilities of less than 10(-16) in most of the 40 populations and less than 10(-14) in all but one small isolated population; the range is 2.02 x 10(-17) to 1.29 x 10(-13). These 40 SNPs constitute excellent candidates for the global forensic community to consider for a universally applicable SNP panel for human identification. The relative ease with which these markers could be identified also provides a cautionary lesson for investigations of possible balancing selection.

Many ancestry informative SNP (AISNP) panels have been published. Ancestry resolution in them varies from three to eight continental clusters of populations depending on the panel used. However, none of these panels differentiates well among East Asian populations. To meet this need, we have developed a 74 AISNP panel after analyzing a much larger number of SNPs for Fst and allele frequency differences between two geographically close population groups within East Asia. The 74 AISNP panel can now distinguish at least 10 biogeographic groups of populations globally: Sub-Saharan Africa, North Africa, Europe, Southwest Asia, South Asia, North Asia, East Asia, Southeast Asia, Pacific and Americas. Compared with our previous 55-AISNP panel, Southeast Asia and North Asia are two newly assignable clusters. For individual ancestry assignment, the likelihood ratio and ancestry components were analyzed on a different set of 500 test individuals from 11 populations. All individuals from five of the test populations - Yoruba (YRI), European (CEU), Han Chinese in Henan (CHNH), Rondonian Surui (SUR) and Ticuna (TIC) - were assigned to their appropriate geographical regions unambiguously. For the other test populations, most of the individuals were assigned to their self-identified geographical regions with a certain degree of overlap with adjacent populations. These alternative ancestry components for each individual thus help give a clearer picture of the possible group origins of the individual. We have demonstrated that the new AISNP panel can achieve a deeper resolution of global ancestry.

Objective: Obsessive-compulsive disorder (OCD) and Tourette's syndrome are highly heritable neurodevelopmental disorders that are thought to share genetic risk factors. However, the identification of definitive susceptibility genes for these etiologically complex disorders remains elusive. The authors report a combined genome-wide association study (GWAS) of Tourette's syndrome and OCD.Method: The authors conducted a GWAS in 2,723 cases (1,310 with OCD, 834 with Tourette's syndrome, 579 with OCD plus Tourette's syndrome/chronic tics), 5,667 ancestry-matched controls, and 290 OCD parent-child trios. GWAS summary statistics were examined for enrichment of functional variants associated with gene expression levels in brain regions. Polygenic score analyses were conducted to investigate the genetic architecture within and across the two disorders.Results: Although no individual single-nucleotide polymorphisms (SNPs) achieved genome-wide significance, the GWAS signals were enriched for SNPs strongly associated with variations in brain gene expression levels (expression quantitative loci, or eQTLs), suggesting the presence of true functional variants that contribute to risk of these disorders Polygenic score analyses identified a significant polygenic component for OCD (p=2x10(-4)), predicting 3.2% of the phenotypic variance in an independent data set. In contrast, Tourette's syndrome had a smaller, nonsignificant polygenic component, predicting only 0.6% of the phenotypic variance (p=0.06). No significant polygenic signal was detected across the two disorders, although the sample is likely underpowered to detect a modest shared signal. Furthermore, the OCD polygenic signal was significantly attenuated when cases with both OCD and co-occurring Tourette's syndrome/chronic tics were included in the analysis (p=0.01).Conclusions: Previous work has shown that Tourette's syndrome and OCD have some degree of shared genetic variation. However, the data from this study suggest that there are also distinct components to the genetic architectures of these two disorders. Furthermore, OCD with co-occurring burette's syndrome/chronic tics may have different underlying genetic susceptibility compared with OCD alone.

Summary 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.

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. Genet. Epidemiol. & 2004 Wiley-Liss, Inc.

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

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.

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 (ADH1C Ile349Val 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 ADH1C in the protection against alcoholism in Native Americans.