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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 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

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.

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 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.

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.

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.

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

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.

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.

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

Haplotype analysis has become increasingly important for the study of human disease as well as for reconstruction of human population histories. Computer programs have been developed to estimate haplotype frequencies statistically from marker phenotypes in unrelated individuals. However, there currently are few empirical reports on the accuracy of statistical estimates that must infer linkage phase. We have analyzed haplotypes at the CD4 locus on chromosome 12 that consist of a short tandem-repeat polymorphism and an Alu insertion/deletion polymorphism located 9.8 kb apart, in 398 individuals from 10 geographically diverse sub-Saharan African populations. Haplotype frequency estimates obtained using gene counting based on molecularly haplotyped (phase-known) data were compared with haplotype frequency estimates obtained using the expectation-maximization algorithm. We show that the estimated frequencies of common haplotypes do not differ significantly with the use of phase-known versus phase-unknown data. However, rare haplotypes are occasionally miscalled when their presence/absence must be inferred. Thus, for those research questions for which the common haplotypes are most important, frequency estimates based on the phase-unknown marker-typing results from unrelated individuals will be sufficient. However, in cases where knowledge of rare haplotypes is critical, molecular haplotyping will be necessary to determine linkage phase unambiguously.

A four-site haplotype system at the dopamine D2 receptor locus (DRD2) has been studied in a global sample of 28 distinct populations. The haplotype system spans about 25 kb, encompassing the coding region of the gene. The four individual markers include three TaqI restriction site polymorphisms (RSPs) -- TaqI "A", "B", and "D" sites -- and one dinucleotide short tandem repeat polymorphism (STRP). All four of the marker systems are polymorphic in all regions of the world and in most individual populations. The haplotype system shows the highest average heterozygosity in Africa, a slightly lower average heterozygosity in Europe, and the lowest average heterozygosities in East Asia and the Americas. Across all populations, 20 of the 48 possible haplotypes reached a frequency of at least 5% in at least one population sample. However, no single population had more than six haplotypes reaching that frequency. In general, African populations had more haplotypes present in each population and more haplotypes occurring at a frequency of at least 5% in that population. Permutation tests for significance of overall disequilibrium (all sites considered simultaneously) were highly significant (P

Human population genetics is a completely different science today compared to two decades ago, at least at the empiric level. Our paper [Chang (Hum Genet 98:91–101, 1996a)] demonstrated that three different alleles were common when one considered many populations although other low frequency alleles occurred. Because previous work had been largely done on European subjects, our findings involved 36 distinct populations and showed that East Asian populations had nearly lost the 7-repeat allele, and that Native American populations had the highest frequencies of that allele globally, was a significant early empiric demonstration of the potential magnitude of population variation at important genes. There are thousands of loci tested on many of the same populations and the gene frequency pattern seen for the DRD4 7-repeat allele is seen at other loci, arguing that this pattern commonly reflects the pattern of divergence of populations and accumulated random genetic drift.

The direct estimation of heritability from genome-wide common variant data as implemented in the program Genome-wide Complex Trait Analysis (GCTA) has provided a means to quantify heritability attributable to all interrogated variants. We have quantified the variance in liability to disease explained by all SNPs for two phenotypically-related neurobehavioral disorders, obsessive-compulsive disorder (OCD) and Tourette Syndrome (TS), using GCTA. Our analysis yielded a heritability point estimate of 0.58 (se = 0.09, p = 5.64e-12) for TS, and 0.37 (se = 0.07, p = 1.5e-07) for OCD. In addition, we conducted multiple genomic partitioning analyses to identify genomic elements that concentrate this heritability. We examined genomic architectures of TS and OCD by chromosome, MAF bin, and functional annotations. In addition, we assessed heritability for early onset and adult onset OCD. Among other notable results, we found that SNPs with a minor allele frequency of less than 5% accounted for 21% of the TS heritability and 0% of the OCD heritability. Additionally, we identified a significant contribution to TS and OCD heritability by variants significantly associated with gene expression in two regions of the brain (parietal cortex and cerebellum) for which we had available expression quantitative trait loci (eQTLs). Finally we analyzed the genetic correlation between TS and OCD, revealing a genetic correlation of 0.41 (se = 0.15, p = 0.002). These results are very close to previous heritability estimates for TS and OCD based on twin and family studies, suggesting that very little, if any, heritability is truly missing (i.e., unassayed) from TS and OCD GWAS studies of common variation. The results also indicate that there is some genetic overlap between these two phenotypically-related neuropsychiatric disorders, but suggest that the two disorders have distinct genetic architectures., Author Summary Family and twin studies have shown that genetic risk factors are important in the development of Tourette Syndrome (TS) and obsessive compulsive disorder (OCD). However, efforts to identify the individual genetic risk factors involved in these two neuropsychiatric disorders have been largely unsuccessful. One possible explanation for this is that many genetic variations scattered throughout the genome each contribute a small amount to the overall risk. For TS and OCD, the genetic architecture (characterized by the number, frequency, and distribution of genetic risk factors) is presently unknown. This study examined the genetic architecture of TS and OCD in a variety of ways. We found that rare genetic changes account for more genetic risk in TS than in OCD; certain chromosomes contribute to OCD risk more than others; and variants that influence the level of genes expressed in two regions of the brain can account for a significant amount of risk for both TS and OCD. Results from this study might help in determining where, and what kind of variants are individual risk factors for TS and OCD and where they might be located in the human genome.

In this paper we describe PhenoDB, an Internet-accessible client/server database application for population and linkage genetics. PhenoDB stores genetic marker data on pedigrees and populations. A database for population and linkage genetics requires two core functions: data management tasks, such as interactive validation during data entry and editing, and data analysis tasks, such as generating summary population statistics and performing linkage analyses. In PhenoDB we attempt to make these tasks as easy as possible. The client/server architecture allows efficient management and manipulation of large datasets via an easy-to-use graphical interface. PhenoDB data (73 populations, 34 pedigrees, approximately 4200 individuals, and close to 80,000 typings) are stored in a generic format that can be readily exported to (or imported from) the file formats required by various existing analysis programs such as LIPED and Lathrop and Lalouel's Multipoint Linkage. PhenoDB allows performance of complex ad-hoc queries and can generate reports for use in project management. Finally, PhenoDB can produce statistical summaries such as allele frequencies, phenotype frequencies, and Chi-square tests of Hardy-Weinberg ratios of population/pedigree data.

In recent years, a possible role of the dopamine D2 receptor (DRD2) locus in the etiology of alcoholism has been the focus of considerable attention. The literature now contains a mix of association studies with positive and negative conclusions. Various methodological flaws undermine the claims in many of the studies that conclude a positive association exists between alcoholism and the DRD2*A1 allele at the Taql "A" site. Although the studies with negative findings have more often come from studies using better analytic methodology, satisfactory resolution of whether or not genetic variation at the DRD2 locus plays some role in the etiology of alcoholism is unlikely to come from additional studies of the kind conducted thus far; an approach enlightened by a more thorough understanding of the population genetics of DRD2 and the phylogenetic origins of the DRD2 alleles is one alternative. If genetic variation at the DRD2 locus affects susceptibility to alcoholism, then such variation has a mutational and evolutionary history that can be traced with the aid of the various genetic polymorphisms that have been identified at the DRD2 locus. In this study, a third Taql restriction fragment-length polymorphism at DRD2, the Taql "D" site, has been converted to polymerase chain reaction-based typing and its frequencies determined in 22 populations from around the world. Haplotypes defined by the polymorphisms at the Taql "B" and "A" sites, and the short tandem repeat polymorphism in intron 2 have been constructed and the diversity of haplotypes containing the DRD2*A1 allele examined for all 22 populations. The ancestral origins of the three Taql polymorphisms have also been determined by sequencing the homologous regions in other higher primates. Because A1-containing haplotypes in populations of European, Middle Eastern, and African origin show considerable diversity within and among populations, properly designed association studies in populations descended from those areas of the world need to use haplotypes, not a single allelic system, and need to use appropriate methods to compensate for the near impossibility of genetically matching unrelated control samples.

Recently, the single nucleotide polymorphism (SNP) identified as rs1260326, in the glucokinase regulatory protein (GCKR), was associated with hypertriglyceridemia in adults. Because accumulation of triglycerides in hepatocytes represents the hallmark of steatosis, we aimed to investigate whether this variant might be associated with fatty liver (hepatic fat content, HFF%). Moreover, because recently rs738409 in the PNPLA3 and rs2854116 in the APOC3 were associated with fatty liver, we explored how the GCKR SNP and these two variants jointly influence hepatosteatosis. We studied 455 obese children and adolescents (181 Caucasians, 139 African Americans, and 135 Hispanics). All underwent an oral glucose tolerance test and fasting lipoprotein subclasses measurement by proton nuclear magnetic resonance. A subset of 142 children underwent a fast gradient magnetic resonance imaging to measure the HFF%. The rs1260326 was associated with elevated triglycerides (Caucasians P = 0.00014; African Americans P = 0.00417), large very low-density lipoprotein (VLDL) (Caucasians P = 0.001; African Americans, P = 0.03), and with fatty liver (Caucasians P = 0.034; African Americans P = 0.00002; and Hispanics P = 0.016). The PNPLA3, but not the APOC3 rs2854116 SNP, was associated with fatty liver but not with triglyceride levels. There was a joint effect between the PNPLA3 and GCKR SNPs, explaining 32% of HFF% variance in Caucasians (P = 0.00161), 39.0% in African Americans (P = 0.00000496), and 15% in Hispanics (P = 0.00342). Conclusion: The rs1260326 in GCKR is associated with hepatic fat accumulation along with large VLDL and triglyceride levels. GCKR and PNPLA3 act together to convey susceptibility to fatty liver in obese youths. (Hepatology 2012)

ALFRED (the ALelle FREquency Database) is designed to store and disseminate frequencies of alleles at human polymorphic sites for multiple populations, primarily for the population genetics and molecular anthropology communities. Currently ALFRED has information on over 180 polymorphic sites for more than 70 populations. Since our initial release of the database we have focussed on increasing the quantity and quality of data, making reciprocal links between ALFRED and other related databases, and providing useful tools to make the data more comprehensible to the end user. ALFRED is accessible from the Kidd Lab home page (http://info.med.yale.edu/genetics/kkidd/) or from ALFRED directly (http://alfred.med.yale.edu/alfred/index.asp).

The potential value of SNPs for individual identification has been recognized by many researchers and different panels have been proposed. Here we present a new interface in the ALFRED database to access compendia of allele frequencies for several published panels of markers for forensic uses. One of those is our panel of individual identification SNPs (IISNPs) based on samples of 44 populations originating from many parts of the world. Here we also present additional data and additional statistical analyses that continue to support the value of our panel of IISNPs as a universal panel. We also describe initial developments of multiplex methods and various robustness analyses for our 45 marker IISNP panel.

:::::::::::::::: :::::::::::: A number of dopamine-related genes have been implicated in the etiology of violent behavior and conduct problems. Of these genes, the ones that code for the enzymes that influence the turnover of dopamine (DA) have received the most attention. In this study, we investigated 12 genetic polymorphisms in four genes involved with DA functioning (COMT, MAOA and MAOB, and DbH) in 179 incarcerated male Russian adolescents and two groups of matched controls: boys without criminal records referred to by their teachers as (a) ‘‘troubled-behavior-free’’ boys, n 5 182; and (b) ‘‘troubled-behavior’’ boys, n 5 60. The participants were classified as (1) being incarcerated or not, (2) having the DSM-IV diagnosis of conduct disorder (CD) or not, and (3) having committed violent or nonviolent crimes (for the incarcerated individuals only). The findings indicate that, although no single genetic variant in any of the four genes differentiated individuals in the investigated groups, various linear combinations (i.e., haplotypes) and nonlinear combinations (i.e., interactions between variants within and across genes) of genetic variants resulted in informative and robust classifications for two of the three groupings. These combinations of genetic variants differentiated individuals in incarceration vs. nonincarcerated and CD vs. no-CD groups; no informative combinations were established consistently for the grouping by crime within the incarcerated individuals. This study underscores the importance of considering multiple rather than single markers within candidate genes and their additive and interactive combinations, both with themselves and with nongenetic indicators, while attempting to understand the genetic background of such complex behaviors as serious conduct problems. Aggr. Behav. 36:158–176, 2010. r 2010 Wiley-Liss, Inc.

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.

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 of10(-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.

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.

Over the past century researchers have identified normal genetic variation and studied that variation in diverse human populations to determine the amounts and distributions of that variation. That information is being used to develop an understanding of the demographic histories of the different populations and the species as a whole, among other studies. With the advent of DNA-based markers in the last quarter century, these studies have accelerated. One of the challenges for the next century is to understand that variation. One component of that understanding will be population genetics. We present here examples of many of the ways these new data can be analyzed from a population perspective using results from our laboratory on multiple individual DNA-based polymorphisms, many clustered in haplotypes, studied in multiple populations representing all major geographic regions of the world. These data support an "out of Africa" hypothesis for human dispersal around the world and begin to refine the understanding of population structures and genetic relationships. We are also developing baseline information against which we can compare findings at different loci to aid in the identification of loci subject, now and in the past, to selection (directional or balancing). We do not yet have a comprehensive understanding of the extensive variation in the human genome, but some of that understanding is coming from population genetics.

Elaboration of ALFRED (http://alfred.med.yale.edu) is being continued in two directions. One of which is developing tools for efficiently annotating the entries and checking the integrity of the data already in the database while the other is to increase the quantity and accessibility of data. Information contained in ALFRED such as, polymorphic sites, number of populations and frequency tables (one sample typed for one site) has significantly increased.

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.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.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.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.

The deluge of data from the human ge- nome project (HGP) presents new opportunities for molec- ular 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 fre- quency data on diverse polymorphic sites for many popu- lations. In constructing this database, we considered many different concerns relating to the types of informa- tion needed for anthropology, population genetics, molec- ular 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 provi- sional 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 mak- ing ALFRED an important resource for many studies as yet unforeseen. Am J Phys Anthropol 119:77- 83, 2002. © 2002 Wiley-Liss, Inc.

We have developed a publicly accessible database (ALFRED, the ALlele FREquency Database) that catalogues allele frequency data for a wide range of population samples and DNA polymorphisms. This database is web-accessible through our laboratory (Kidd Lab) Web site: http://info.med.yale.edu/ genetics/kkidd . ALFRED currently contains data on 60 populations and 156 genetic systems including single nucleotide polymorphisms (SNPs), short tandem repeat polymorphisms (STRPs), variable number of tandem repeats (VNTRs) and insertion‐ deletion polymorphisms. While data are not available for all population‐DNA polymorphism combinations, over 2000 allele frequency tables have been entered. Our database is designed (i) to address our specific research requirements as well as broader scientific objectives; (ii) to allow researchers and interested educators to easily navigate and retrieve data of interest to them; and (iii) to integrate links to other related public databases such as dbSNP, GenBank and PubMed.

The dopamine D4 receptor gene (DRD4) has an expressed polymorphism in the third exon that may have functional relevance. The polymorphism exists at two levels. At the higher level there is an imperfect tandem repeat of 48 base pairs (bp) coding for 16 amino acids; alleles have been identified with 2 (32 amino acids) to 10 (160 amino acids) repeats. The imperfect nature of the repeats is responsible for a more subtle level of variation since alleles with the same number of repeats can differ in the exact sequences or in the order of the variants of the 48-bp unit. We have undertaken a global survey of this expressed polymorphism as one approach to understanding the evolutionary significance and origins of the polymorphism as well as understanding what selective forces, if any, may be operating at this locus. As the first step, we have determined the repeat number genotype of the DRD4 repeat polymorphism in 1,327 individuals from 36 different populations. The allele frequencies differ considerably among the different populations. The 4-repeat allele was the most prevalent (global mean allele frequency = 64.3%) and appeared in every population with a frequency ranging from 0.16 to 0.96. The 7-repeat allele was the second most common (global mean = 20.6%), appearing quite frequently in the Americas (mean frequency = 48.3%) but only occasionally in East and South Asia (mean frequency = 1.9%). The 2-repeat allele was the third most common (global mean frequency = 8.2%) and was quite frequent in East and South Asia (mean frequency = 18.1%) while uncommon in the Americas (mean frequency = 2.9%) and Africa (mean frequency = 1.7%). The universality of the polymorphism with only three common repeat-number alleles (4, 7, and 2) indicates that the polymorphism is ancient and arose before the global dispersion of modern humans. The diversity of actual allele frequencies for this expressed polymorphism among different populations emphasizes the importance of population considerations in the design and interpretation of any association studies carried out with this polymorphism.

Several lines of evidence suggest that the sex chromosomes have a role in the expression of schizophrenia. Gender differences in response to treatment, age at onset of illness, and prognosis indicate an influence of sex in differential expression of schizophrenia. On the basis of a higher-than-expected concordance for sex among siblings with schizophrenia, as well as the findings of cytogenetic abnormalities of the sex chromosomes in some schizophrenia patients, a pseudoautosomal location for a schizophrenia susceptibility locus has been proposed. To test this hypothesis, we investigated genetic linkage of the pseudoautosomal region to schizophrenia in a large Swedish kindred. Using pairwise analyses we tested eight markers spanning the most telomeric region to the boundary of the sex-specific region. In addition, we used multi-point analysis with five markers spanning the region to test for the presence of a schizophrenia susceptibility locus in the pseudoautosomal region. No evidence was found for linkage to schizophrenia under the given genetic model: "autosomal" dominant, f (penetrance) = 0.72, q (gene frequency) = 0.02, phenocopies = 0.001.

A cDNA clone of the β subunit of human fibronectin receptor (FNRB) detects two different polymorphic loci: (a) a codominant system previously mapped to the pericentromeric region of chromosome 10, the site of the functional FNRB gene; and (b) a dominant system not linked to the first one or to any chromosome 10 marker tested. This second polymorphism is characterized by the presence or absence of a band (or a set of bands). We have used linkage analysis and biotin-labeled in situ hybridization to map this dominant polymorphism to the short arm of chromosome 19; we hypothesize that it may be due to the insertion of part of the cDNA from the chromosome 10 gene into chromosome 19. This “insertion” is polymorphic in all populations studied.

Maximum likelihood estimates of gene frequencies and their standard errors are presented for 21 blood group and serum protein polymorphisms. The observed frequencies for certain high and low frequency antigens also are reported. The data come from a sample of 399 same-sex twin pairs and two sets of triplets from the Greater Philadelphia urban region encompassing roughly five counties in southeastern Pennsylvania and three counties of southern New Jersey. Analyses are carried out separately for the four subgroups created by subdividing the sample by race and co-twin. Total sample estimates are also calculated within the two socially defined racial groups. The gene frequency estimates generally appear to be consistent with previously reported data for U.S. urban populations. The frequency of the Fy allele in the Duffy system, however, seems to be the highest value thus far published for a white population. The white sample Fy allele very well may be a heterogeneous class in which only a very small fraction is comparable to the Fy allele common in the black sample.

Because defects in the phenylalanine hydroxylase gene (PAH) cause phenylketonuria (PKU), PAH was studied for normal polymorphisms and linkage disequilibrium soon after the gene was cloned. Studies in the 1980s concentrated on European populations in which PKU was common and showed that haplotype-frequency variation exists between some regions of the world. In European populations, linkage disequilibrium generally was found not to exist between RFLPs at opposite ends of the gene but was found to exist among the RFLPs clustered at each end. We have now undertaken the first global survey of normal variation and disequilibrium across the PAH gene. Four well-mapped single-nucleotide polymorphisms (SNPs) spanning approximately 75 kb, two near each end of the gene, were selected to allow linkage disequilibrium across most of the gene to be examined. These SNPs were studied as PCR-RFLP markers in samples of, on average, 50 individuals for each of 29 populations, including, for the first time, multiple populations from Africa and from the Americas. All four sites are polymorphic in all 29 populations. Although all but 5 of the 16 possible haplotypes reach frequencies >5% somewhere in the world, no haplotype was seen in all populations. Overall linkage disequilibrium is highly significant in all populations, but disequilibrium between the opposite ends is significant only in Native American populations and in one African population. This study demonstrates that the physical extent of linkage disequilibrium can differ substantially among populations from different regions of the world, because of both ancient genetic drift in the ancestor common to a large regional group of modern populations and recent genetic drift affecting individual populations.

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.

Mutations at the cystic fibrosis transmembrane conductance regulator gene (CFTR) cause cystic fibrosis, the most prevalent severe genetic disorder in individuals of European descent. We have analyzed normal allele and haplotype variation at four short tandem repeat polymorphisms (STRPs) and two single-nucleotide polymorphisms (SNPs) in CFTR in 18 worldwide population samples, comprising a total of 1,944 chromosomes. The rooted phylogeny of the SNP haplotypes was established by typing ape samples. STRP variation within SNP haplotype backgrounds was highest in most ancestral haplotypes—although, when STRP allele sizes were taken into account, differences among haplotypes became smaller. Haplotype background determines STRP diversity to a greater extent than populations do, which indicates that haplotype backgrounds are older than populations. Heterogeneity among STRPs can be understood as the outcome of differences in mutation rate and pattern. STRP sites had higher heterozygosities in Africans, although, when whole haplotypes were considered, no significant differences remained. Linkage disequilibrium (LD) shows a complex pattern not easily related to physical distance. The analysis of the fraction of possible different haplotypes not found may circumvent some of the methodological difficulties of LD measure. LD analysis showed a positive correlation with locus polymorphism, which could partly explain the unusual pattern of similar LD between Africans and non-Africans. The low values found in non-Africans may imply that the size of the modern human population that emerged “Out of Africa” may be larger than what previous LD studies suggested.

Ancestry inference for an individual can only be as good as the reference populations with allele frequency data on the SNPs being used. If the most relevant ancestral population(s) does not have data available for the SNPs studied, then analyses based on DNA evidence may indicate a quite distantly related population, albeit one among the more closely related of the existing reference populations. We have added reference population allele frequencies for 14 additional population samples (with >1100 individuals studied) to the 125 population samples previously published for the Kidd Lab 55 AISNP panel. Allele frequencies are now publicly available for all 55 SNPs in ALFRED and FROG-kb for a total of 139 population samples. This Kidd Lab panel of 55 ancestry informative SNPs has been incorporated in commercial kits by both ThermoFisher Scientific and Illumina for massively parallel sequencing. Researchers employing those kits will find the enhanced set of reference populations useful. Electronic supplementary material The online version of this article (doi:10.1007/s00414-016-1524-z) contains supplementary material, which is available to authorized users.