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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.

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.

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

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.

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.

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

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.

A polymorphic CA repeat (locus name DXS1178) was isolated from a 1-megabase YAC (OTCC) containing the OTC gene, located at Xp21.1. However, amplification in human-rodent hybrid cells and segregation analysis in three CEPH families mapped the DXS1178 locus at Xq13. The mapping ambiguity is apparently caused by the chimeric nature of the OTCC YAC clone.

We have resumed the search for an autosomal linkage with affective disorder in the Old Order Amish and report the pairwise linkage results after screening 185 marked loci. No positive evidence of genetic linkage was found, and we estimate that roughly 23% of the autosomal genome has been excluded from linkage.

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.

Genetic differences have been offered as an hypothesis to explain the average IQ difference usually found between US black and white populations (Jensen, 1973; Shockley, 1972). While most behavioral scientists would choose to ignore the hypothesis as distasteful, there is little direct evidence against it (Scarr and Weinberg, 1976). Those who prefer an environmental hypothesis to account for the average difference between black and white groups on intellectual tests have not succeeded in accounting for the magnitude of the effect, nor have those who hold a genetic hypothesis been able to refute an environmental stance. No direct comparisons of black and white samples will settle the issue of possible genetic differences, because obvious environmental differences are confounded with any genetic differences between the populations that are socially classified as black and white (Scarr-Salapatek, 1971a, 1971b, 1972, 1973, 1974; Scarr and Weinberg, 1976). The fact that US blacks are a hybrid population 1 makes the study of admixture a potential method to evaluate the effects of racial genetic differences. Those environmental differences between the races that affect al l blacks equally, but no whites, will not contaminate the possible relationship between genetic racial differences and intellectual performance within the hybrid group. Thus, if genetic, racial differences do contribute to average intellectual differences between blacks and whites, then those blacks with higher degrees of white ancestry should perform better on intellectual tests than those with lesser degrees of admixture (Jensen, 1973; Shuey, 1966). Even within the hybrid group, the effects of environmental differences cannot be ignored. The amount of racial discrimination may be related to the degree of