Toward a system of microbial forensics: from sample collection to interpretation of evidence.
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Bioterrorism↗
Biomedical subjects
Ranajit Chakraborty
Publications and source records attributed to Ranajit Chakraborty.
Examining population stratification via individual ancestry estimates versus self-reported race.
Population stratification has the potential to affect the results of genetic marker studies. Estimating individual ancestry provides a continuous measure to assess population structure in case-control studies of complex disease, instead of using self-reported racial groups. We estimate individual ancestry using the Federal Bureau of Investigation CODIS Core short tandem repeat set of 13 loci using two different analysis methods in a case-control study of early-onset lung cancer. Individual ancestry proportions were estimated for "European" and "West African" groups using published allele frequencies. The majority of Caucasian, non-Hispanics had >50% European ancestry, whereas the majority of African Americans had <20% European ancestry, regardless of ancestry estimation method, although significant overlap by self-reported race and ancestry also existed. When we further investigated the effect of ancestry and self-reported race on the frequency of a lung cancer risk genotype, we found that the frequency of the GSTM1 null genotype varies by individual European ancestry and case-control status within self-reported race (particularly for African Americans). Genetic risk models showed that adjusting for individual European ancestry provided a better fit to the data compared with the model with no group adjustment or adjustment for self-reported race. This study suggests that significant population substructure differences exist that self-reported race alone does not capture and that individual ancestry may be confounded with disease status and/or a candidate gene risk genotype.
Black People↗
Informativeness of the CODIS STR loci for admixture analysis.
Population admixture (or ancestry) is used as an approach to gene discovery in complex diseases, particularly when the disease prevalence varies widely across geographic populations. Admixture analysis could be useful for forensics because an indication of a perpetrator's ancestry would narrow the pool of suspects for a particular crime. The purpose of this study was to use Fisher's information to identify informative sets of markers for admixture analysis. Using published founding population allele frequencies we test three marker sets for efficacy for estimating admixture: the FBI CODIS Core STR loci, the HGDP-CEPH Human Genome Diversity Cell Line Panel and the set of 39 ancestry informative SNPS from the Shriver lab at Pennsylvania State University. We conclude that the FBI CODIS Core STR set is valid for admixture analysis, but not the most precise. We recommend using a combination of the most informative markers from the HGDP-CEPH and Shriver loci sets.
Databases as Topic↗
Genetic variation at nine short tandem repeat loci among islanders of the eastern Adriatic coast of Croatia.
We have analyzed the extent of genetic variation at nine autosomal short tandem repeat loci (D3S1358, VWA, FGA, TH01, TPOX, CSF1PO, D5S818, D13S317, D7S820) among six populations from Croatia: five distributed in the islands of the eastern Adriatic coast and one from the mainland. The purpose is to investigate the usefulness of these loci in detecting regional genetic differentiation in the studied populations. Significant heterogeneity among the island and mainland populations is revealed in the distributions of allele frequencies; however, the absolute magnitude of the coefficient of gene differentiation is small but significant. The summary measures of genetic variation, namely, heterozygosity, number of alleles, and allele size variance, do not indicate reduced genetic variation in the island populations compared to the mainland population. In contrast to the two measures of genetic variation, allele size variance and within-locus heterozygosity, the imbalance index (beta) indicates evidence of recent expansion of population sizes in all islands and in the mainland. High mutation rates of the studied loci together with local drift effects are likely explanations for interisland genetic variation and the observed lack of reduced genetic diversity among the island populations.
Alleles↗
Genetic structure of Hmong-Mien speaking populations in East Asia as revealed by mtDNA lineages.
Hmong-Mien (H-M) is a major language family in East Asia, and its speakers distribute primarily in southern China and Southeast Asia. To date, genetic studies on H-M speaking populations are virtually absent in the literature. In this report, we present the results of an analysis of genetic variations in the mitochondrial DNA (mtDNA) hypervariable segment 1 (HVS1) region and diagnostic variants in the coding regions in 537 individuals sampled from 17 H-M populations across East Asia. The analysis showed that the haplogroups that are predominant in southern East Asia, including B, R9, N9a, and M7, account for 63% (ranging from 45% to 90%) of mtDNAs in H-M populations. Furthermore, analysis of molecular variance (AMOVA), phylogenetic tree analysis, and principal component (PC) analysis demonstrate closer relatedness between H-M and other southern East Asians, suggesting a general southern origin of maternal lineages in the H-M populations. The estimated ages of the mtDNA lineages that are specific to H-M coincide with those based on archeological cultures that have been associated with H-M. Analysis of genetic distance and phylogenetic tree indicated some extent of difference between the Hmong and the Mien populations. Together with the higher frequency of north-dominating lineages observed in the Hmong people, our results indicate that the Hmong populations had experienced more contact with the northern East Asians, a finding consistent with historical evidence. Moreover, our data defined some new (sub-)haplogroups (A6, B4e, B4f, C5, F1a1, F1a1a, and R9c), which will direct further efforts to improve the phylogeny of East Asian mtDNAs.
Asia, Southeastern↗
Genetic evidence supports demic diffusion of Han culture.
The spread of culture and language in human populations is explained by two alternative models: the demic diffusion model, which involves mass movement of people; and the cultural diffusion model, which refers to cultural impact between populations and involves limited genetic exchange between them. The mechanism of the peopling of Europe has long been debated, a key issue being whether the diffusion of agriculture and language from the Near East was concomitant with a large movement of farmers. Here we show, by systematically analysing Y-chromosome and mitochondrial DNA variation in Han populations, that the pattern of the southward expansion of Han culture is consistent with the demic diffusion model, and that males played a larger role than females in this expansion. The Han people, who all share the same culture and language, exceed 1.16 billion (2000 census), and are by far the largest ethnic group in the world. The expansion process of Han culture is thus of great interest to researchers in many fields.
Agriculture↗
Assessment of optimal size and composition of the U.S. National Registry of hematopoietic stem cell donors.
BACKGROUND: The National Marrow Donor Program (NMDP) receives federal funding to operate a registry of over 4 million volunteer donors for patients in need of a hematopoietic stem cell transplant. Because minority patients are less likely to find a suitably matched donor than whites, special efforts have been aimed toward recruitment of minorities. Significant financial resources are required to recruit and tissue type additional volunteer donors. METHODS: Population genetics models have been constructed to project likelihoods of finding a human leukocyte antigen (HLA)-matched donor for patients of various racial/ethnic groups. These projections have been made under a variety of strategies for expansion of the NMDP Registry. Cost-effectiveness calculations incorporated donor unavailability and other barriers to transplantation. RESULTS: At current recruitment rates, the probability of an available HLA-A,B,DRB1 matched donor is projected to increase from 27% to 34%; 45% to 54%; 75% to 79%; and 48% to 55%, for blacks, Asians/Pacific Islanders, whites and Hispanics, respectively, by the year 2007. Substantial increases in minority recruitment would have only modest impacts on these projections. These projections are heavily affected by donor availability rates, which are less than 50% for minority volunteers. CONCLUSIONS: Continued recruitment of additional volunteers can improve the likelihood of finding an HLA-matched donor, but will still leave significant numbers of patients of all racial/ethnic groups without a match. Efforts to improve donor availability (especially among minorities) and to increase the number of patients with access to the NMDP Registry may prove to be more cost-effective means of increasing transplants.
Genetics, Population↗
Genomewide scan for gout in taiwanese aborigines reveals linkage to chromosome 4q25.
Gout is a disorder of uric-acid metabolism. The Pacific Austronesian population, including Taiwanese aborigines, has a remarkably high prevalence of hyperuricemia and gout, which suggests a founder effect across the Pacific region. We report here a genomewide linkage study of 21 multiplex pedigrees with gout from an aboriginal tribe in Taiwan. From observations of familial clustering, early onset of gout, and clinically severe manifestations, we hypothesized that a major gene plays a role in this trait. Using 382 random polymorphic markers spread across 22 autosomes, we demonstrated a highly significant linkage for gout at marker D4S2623 on chromosome 4q25 (P=.0002 by nonparametric linkage [the NPL(all) statistic]; empirical P=.0006; LOD=4.3, P=4.4x10-6 by logistic regression). When alcohol consumption was included as a covariate in the model, the LOD score increased to 5.66 (P=1.3x10-6). Quantitative traits, including serum uric acid and creatinine, also showed a moderate linkage to this region. To our knowledge, this is the first genome-scan report to identify a genetic locus harboring a gout-susceptibility gene.
Adult↗
A Ser49Cys variant in the ataxia telangiectasia, mutated, gene that is more common in patients with breast carcinoma compared with population controls.
BACKGROUND: Mothers of children who have ataxia telangiectasia have been reported to be at increased risk for development of breast carcinoma. To test whether sequence variants in the ataxia telangiectasia, mutated, gene (ATM) are associated with breast carcinoma, the authors compared the frequency of ATM cDNA sequence changes in patients with breast carcinoma with the corresponding frequency in control patients. METHODS: The authors sequenced ATM cDNA from 91 patients with breast carcinoma and compared the frequencies of sequence changes in these patients with the corresponding frequencies in a control sample of 940 individuals with no history of malignant disease. RESULTS: Thirty-five patients with breast carcinoma had one or more single-base changes in ATM. Three genetic variants were found in at least two patients. These variants resulted in Asp1853Asn, Pro1054Arg, or Ser49Cys amino acid substitutions in the ATM protein. The Ser49Cys variant was more common in patients with breast carcinoma than in the control patients, with respective frequencies of 6.7% (5 of 75 patients) and 1.3% (12 of 940 patients; P=0.006; Fisher two-sided exact test). The subgroup of patients with bilateral breast carcinoma had a Ser49Cys frequency of 11.8% (2 of 17 patients), which again was significantly different from what was observed in the control group (P=0.024; Fisher two-sided exact test). The allele frequencies of the other two variants were not different between case patients and control patients. CONCLUSIONS: Patients with breast carcinoma, particularly those with bilateral disease, were more likely to have a variant in the ATM gene that resulted in a Ser49Cys substitution in the gene product. Additional studies are needed to evaluate the potential functional consequences of the Ser49Cys substitution and confirm the relevance of this variant in the development of breast carcinoma.
Adult↗
Analyses of genetic structure of Tibeto-Burman populations reveals sex-biased admixture in southern Tibeto-Burmans.
An unequal contribution of male and female lineages from parental populations to admixed ones is not uncommon in the American continents, as a consequence of directional gene flow from European men into African and Hispanic Americans in the past several centuries. However, little is known about sex-biased admixture in East Asia, where substantial migrations are recorded. Tibeto-Burman (TB) populations were historically derived from ancient tribes of northwestern China and subsequently moved to the south, where they admixed with the southern natives during the past 2600 years. They are currently extensively distributed in China and Southeast Asia. In this study, we analyze the variations of 965 Y chromosomes and 754 mtDNAs in >20 TB populations from China. By examining the haplotype group distributions of Y-chromosome and mtDNA markers and their principal components, we show that the genetic structure of the extant southern Tibeto-Burman (STB) populations were primarily formed by two parental groups: northern immigrants and native southerners. Furthermore, the admixture has a bias between male and female lineages, with a stronger influence of northern immigrants on the male lineages (approximately 62%) and with the southern natives contributing more extensively to the female lineages (approximately 56%) in the extant STBs. This is the first genetic evidence revealing sex-biased admixture in STB populations, which has genetic, historical, and anthropological implications.
Chromosomes, Human, Y↗
Genetic signatures of pre-expansion bottleneck in the Choctaw population of Oklahoma.
Previous research showed that the Choctaw Indians of Oklahoma exhibit considerable linkage disequilibria (LD) in a number of regions of the genome that has allowed genetic fine mapping for potential susceptibility genes for the autoimmune connective tissue disease scleroderma, or systemic sclerosis (SSc). In principle, such enhanced background LD in the Choctaws could be caused by population bottleneck event(s) followed by recent population expansion. This investigation utilizes genome-scan data on 175 dinucleotide loci from 76 Choctaw individuals to seek genetic evidence of the demographic history of the Choctaw Nation. Of the 175 loci examined, 105 are in Hardy-Weinberg equilibrium. The average unbiased homozygosity over the 105 loci for the Choctaws (29.3%) is significantly higher than that in the European descent group (20.9%); and when adjusted for sample-size differences, the Choctaw also exhibit a significantly smaller number of segregating alleles (6.65 vs. 8.14) at these loci. Both of these observations are consistent with the trend expected in an isolated population. Comparison of the allele size variance and gene diversity yields an imbalance index (lnbeta) of 0.811 in the Choctaw. Of the 105 loci examined, 93 exhibit excess expected homozygosity in comparison to the expectations of a stepwise mutation model in a population of constant size. Taken together, these observations are consistent with a signature of the recent population size expansion of the Choctaws, preceded by bottleneck event(s).
Female↗
HLA class II haplotypes in Mexican systemic lupus erythematosus patients.
Systemic lupus erythematosus (SLE) is an autoimmune disease in which polymorphisms within the human leukocyte antigen (HLA) region have been associated to its etiology. For this study, HLA-DQB1, DQA1, and DRB1 genes were typed by polymerase chain reaction-sequence-specific primer in 237 individuals, taken from 74 families, who had a member with SLE, and who had their residence in the western region of Mexico; as well as in 159 ethnically matched healthy volunteers taken from 32 families. Genotype and allele frequency analysis was performed in 74 SLE patients and 54 unrelated controls. Precise three-loci identification of independent haplotypes was performed in 48 patients and 54 controls by familial segregation. Genotype distribution at each loci was concordant with Hardy-Weinberg's equilibrium in the control group. In general, no genotype effect was observed in SLE patients. Allele distribution comparison showed in the SLE group a significant increase of HLA-DQA1*0102, DQB1*0402, and DRB1*15; whereas alleles HLA-DQB1*0303 and *0501 were significantly decreased. SLE patients showed haplotype DQB1*0602-DQA1-*0102-DRB1*15 increased. As expected, patients with SLE have a reduced haplotype genetic diversity. The associations found in this study are related to an ancestral haplotype that has been observed in SLE populations of different origins.
Adolescent↗
Evidence for a major gene influence on persistent developmental stuttering.
Stuttering is a complex developmental speech disorder of unknown etiology. There is a substantial aggregation of stuttering in families, suggesting a genetic component to the disorder. However, the exact mode of transmission is still unknown. An earlier study of 56 multigenerational pedigrees ascertained through single adult probands (38 males and 18 females) found that biological relatives of persistent developmental stutterers have an approximately 10-fold higher risk than in the general population; risk is higher for male relatives, and proband's sex does not affect recurrence and relative risks. In the present paper we conduct a complex segregation analysis of the same data, using the logistic regression model of the SAGE software. Based on the comparisons of model likelihoods, the Mendelian model was selected over all other nongenetic models and the general transmission model. This model was further refined into the most parsimonious model, which shows an autosomal dominant major gene effect influenced by two covariates: sex and affection status of parents. With this model applied to 47 informative multiplex pedigrees, a power calculation based on linkage simulation produced an average lod score of 6.8 for 10-cM density genome scan markers. These results give impetus for a genomewide linkage analysis of susceptibility to persistent developmental stuttering.
Adult↗
Utility of the Y-STR typing systems Y-PLEX 6 and Y-PLEX 5 in forensic casework and 11 Y-STR haplotype database for three major population groups in the United States.
The Y-PLEX 6 and Y-PLEX 5 systems enable analysis for 11 Y-STR loci. We present here the utility of these systems in forensic casework. A total of 188 samples, including 127 evidence samples, were analyzed using either or both of the systems. The evidence sample types included fingernail scrapings, sperm or seminal fluid, epithelial cells, blood and other tissues. The Y-STR typing systems provided useful probative results in difficult cases. A reference database for Caucasian (n = 517), African American (n = 535), and Hispanic (n = 245) population groups within the United States was generated for estimating the haplotype frequency in forensic casework. Among the individuals profiled, 311 Caucasians, 412 African Americans, and 194 Hispanics provided unique profiles in their respective population datasets. This is the first report describing the haplotype database for the set of 11 Y-STR loci recommended by the Scientific Working Group on DNA Analysis Methods (SWGDAM). Linkage analysis reveals that the frequencies from forensically important autosomal loci can be multiplied with the Y-STR haplotype frequency. The results from Y-PLEX systems have been accepted in courts in the United States.
Chromosomes, Human, Y↗
Addressing the use of phylogenetics for identification of sequences in error in the SWGDAM mitochondrial DNA database.
The SWGDAM mtDNA database is a publicly available reference source that is used for estimating the rarity of an evidence mtDNA profile. Because of the current processes for generating population data, it is unlikely that population databases are error free. The majority of the errors are due to human error and are transcriptional in nature. Phylogenetic analysis of data sets can identify some potential errors, and coupled with a review of the sequence data or alignment sheets can be a very useful tool. Seven sequences with errors have been identified by phylogenetic analysis. In addition, two samples were inadvertently modified when placed in the SWGDAM database. The corrected sequences are provided so that users can modify appropriately the current iteration of the SWGDAM database. From a practical perspective, upper bound estimates of the percentage of matching profiles obtained from a database search containing an incorrect sequence and those of a database containing the corrected sequence are not substantially different. Community wide access and review has enabled identification of errors in the SWGDAM data set and will continue to do so. The result of public accessibility is that the quality of the SWGDAM forensic dataset is always improving.
Base Sequence↗
Randomly distributed crossovers may generate block-like patterns of linkage disequilibrium: an act of genetic drift.
There is considerable interest in identifying and characterizing block-like patterns of linkage disequilibrium (LD; haplotype blocks) in the human genome as these may facilitate the identification of complex disease genes via genome-wide association studies. Although recombination hot-spots have been suggested as the primary mechanism to explain the block-like pattern of LD, other forces, such as genetic drift, may also be important. To this end, we have studied the effect of various recombination models on patterns of LD by using extensive simulations. As expected, haplotype blocks were observed under a model allowing recombination hot-spots. However, we also observed similar block-like patterns in the models where recombination crossovers are randomly and uniformly distributed, and we demonstrate that these blocks are generated by genetic drift. We caution that genetic drift may be an alternative mechanism (in addition to recombination hot-spots) that can lead to block-like patterns of LD. Our findings highlight the necessity of characterizing haplotype blocks in world-wide populations.
Computer Simulation↗
Genome-wide association study for regions of systemic sclerosis susceptibility in a Choctaw Indian population with high disease prevalence.
OBJECTIVE: Systemic sclerosis (SSc) is a complex, multisystem connective tissue disease in which genetic factors contribute to disease susceptibility. The aim of this study was to localize chromosome regions associated with susceptibility to SSc in a relatively isolated and homogeneous population of Choctaw Indians with a high prevalence of SSc. METHODS: A genome-wide microsatellite screen at 10 cM resolution (400 markers) was performed in 20 Choctaw patients with SSc and 76 ethically matched controls. Based on the results of the initial screen, fine-scale microsatellite mapping at < or =1 cM resolution was performed in 10 selected chromosome regions. Allele and marker haplotype frequencies were compared between SSc patients and controls. RESULTS: From the genome-wide screen, 12 markers showed evidence of highly significant associations with SSc in this population (P < 0.01), while 5 other markers showed significant associations (0.01 < P < 0.05). Among these markers, loci D5S410, D6S422, D15S978, and D20S107 are near the SPARC, MHC, FBN1, and TOPOI genes, respectively, confirming the results of our previous studies, which used different markers. D1S2800 and D14S63 have been reported to show linkage to systemic lupus erythematosus (SLE) in family-based studies, and D1S206, D6S422, and D6S264 are loci on 1p21.2, 6p22.3, and 6q23-27, respectively, which are in regions reported as showing linkage to SLE and other autoimmune diseases. Other markers showing unique associations with SSc were D7S510 (7p12-11), D7S661 (7q35), D8S514 (8q24.12), D19S221 (19p13.2), D19S220 (19q13.2), D22S423 (22q13.1), DXS1068 (Xp11.4), and DXS8055 (Xq21-23). Further analysis with fine-scale microsatellite mapping revealed at least 14 potential haplotypes associated with SSc. CONCLUSION: Our findings indicate that a number of genetic loci may contribute to the high prevalence of SSc in the Choctaw and are consistent with the paradigm that some autoimmune rheumatic diseases are likely to share genetic determinants.
Chromosomes, Human↗
Examination of the possible role of biologically relevant genes around FBN1 in systemic sclerosis in the Choctaw population.
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Chromosomes, Human, Pair 15↗