Population Genetic Substructure Research Articles

Integrating Linguistics, Social Structure, and Geography to Model Genetic Diversity within India.

India represents an intricate tapestry of population substructure shaped by geography, language, culture, and social stratification. Although geography closely correlates with genetic structure in other parts of the world, the strict endogamy imposed by the Indian caste system and the large number of spoken languages add further levels of complexity to understand Indian population structure. To date, no study has attempted to model and evaluate how these factors have interacted to shape the patterns of genetic diversity within India. We merged all publicly available data from the Indian subcontinent into a data set of 891 individuals from 90 well-defined groups. Bringing together geography, genetics, and demographic factors, we developed Correlation Optimization of Genetics and Geodemographics to build a model that explains the observed population genetic substructure. We show that shared language along with social structure have been the most powerful forces in creating paths of gene flow in the subcontinent. Furthermore, we discover the ethnic groups that best capture the diverse genetic substructure using a ridge leverage score statistic. Integrating data from India with a data set of additional 1,323 individuals from 50 Eurasian populations, we find that Indo-European and Dravidian speakers of India show shared genetic drift with Europeans, whereas the Tibeto-Burman speaking tribal groups have maximum shared genetic drift with East Asians.

Climatic oscillations during the Mio/Pliocene epochs induced cladogenesis in the terrestrial snail genus Gittenedouardia (Mollusca: Gastropoda: Cerastidae) from South Africa

In South Africa, the terrestrial snail genus Gittenedouardia is the most species-rich member of the Cerastidae, where it is primarily distributed in the highly fragmented Afrotemperate and Indian Ocean coastal belt (IOCB) forest biomes. Phylogenetic relationships and cladogenetic events within the genus remain unstudied. In this respect, we reconstructed a dated phylogeny for eight Gittenedouardia species, and two populations identified to genus level using a combined mitochondrial (16S rRNA and COI) DNA sequencing dataset analysed using Bayesian inference and Maximum Likelihood framework. Furthermore, we investigated the population genetic substructure of the three widely distributed species (Gittenedouardia spadicea, G. natalensis and G. arenicola) for the COI locus, while also subsampling these species using the nuclear DNA ITS-2 locus. Phylogenetic results based on the combined mtDNA dataset supported the monophyly of Gittenedouardia and revealed three major clades and deep genetic structure among the three widely distributed species. Divergence-time estimates suggest that diversification within Gittenedouardia occurred during the middle Miocene/late Pliocene, a period characterised by a decrease in precipitation and the contraction of the Afrotemperate and IOCB forest biomes. We used two species delimitation methods, (PTP and STACEY) to infer putative species in G. spadicea, G. natalensis and G. arenicola. The two methods recovered a large number of evolutionary distinct units, with minimal consensus in the exact number of lineages. Our findings suggest the presence of undescribed diversity, necessitating the need for taxonomic revisionary work on Gittenedouardia. We discuss the climatic factors which may have contributed to the observed cladogenesis and compare our results with other studies of forest dwelling faunal taxa.

Accounting for cryptic population substructure enhances detection of inbreeding depression with genomic inbreeding coefficients: an example from a critically endangered marsupial.

Characterizing inbreeding depression in wildlife populations can be critical to their conservation. Coefficients of individual inbreeding can be estimated from genome-wide marker data. The degree to which sensitivity of inbreeding coefficients to population genetic substructure alters estimates of inbreeding depression in wild populations is not well understood. Using generalized linear models, we tested the power of two frequently used inbreeding coefficients that are calculated from genome-wide SNP markers, FH and F^III , to predict four fitness traits estimated over two decades in an isolated population of the critically endangered Leadbeater's possum. FH estimates inbreeding as excess observed homozygotes relative to equilibrium expectations, whereas F^III quantifies allelic similarity between the gametes that formed an individual, and upweights rare homozygotes. We estimated FH and F^III from 1,575 genome-wide SNP loci in individuals with fitness trait data (N=179-237 per trait), and computed revised coefficients, FHby group and F^IIIby group , adjusted for population genetic substructure by calculating them separately within two different genetic groups of individuals identified in the population. Using FH or F^III in the models, inbreeding depression was detected for survival to sexual maturity, longevity and whether individuals bred during their lifetime. F^IIIby group (but not FHby group ) additionally revealed significant inbreeding depression for lifetime reproductive output (total offspring assigned to each individual). Estimates of numbers of lethal equivalents indicated substantial inbreeding load, but differing between inbreeding estimators. Inbreeding depression, declining population size, and low and declining genetic diversity suggest that genetic rescue may assist in preventing extinction of this unique Leadbeater's possum population.

Multidecade Mortality and a Homolog of Hepatitis C Virus in Bald Eagles (Haliaeetus leucocephalus), the National Bird of the USA

The bald eagle (Haliaeetus leucocephalus) once experienced near-extinction but has since rebounded. For decades, bald eagles near the Wisconsin River, USA, have experienced a lethal syndrome with characteristic clinical and pathological features but unknown etiology. Here, we describe a novel hepacivirus-like virus (Flaviviridae: Hepacivirus) identified during an investigation of Wisconsin River eagle syndrome (WRES). Bald eagle hepacivirus (BeHV) belongs to a divergent clade of avian viruses that share features with members of the genera Hepacivirus and Pegivirus. BeHV infected 31.9% of eagles spanning 4,254 km of the coterminous USA, with negative strand viral RNA demonstrating active replication in liver tissues. Eagles from Wisconsin were approximately 10-fold more likely to be infected than eagles from elsewhere. Eagle mitochondrial DNA sequences were homogeneous and geographically unstructured, likely reflecting a recent population bottleneck, whereas BeHV envelope gene sequences showed strong population genetic substructure and isolation by distance, suggesting localized transmission. Cophylogenetic analyses showed no congruity between eagles and their viruses, supporting horizontal rather than vertical transmission. These results expand our knowledge of the Flaviviridae, reveal a striking pattern of decoupled host/virus coevolution on a continental scale, and highlight knowledge gaps about health and conservation in even the most iconic of wildlife species.

Lack of spatial and temporal genetic structure of Japanese eel (Anguilla japonica) populations

Japanese eel (Anguilla japonica) is an important food source in East Asia whose population has dramatically declined since the 1970s. Despite past analysis with DNA sequencing, microsatellite and isozyme methods, management decisions remain hampered by contradictory findings. For example, it remains unresolved whether Japanese eels are a single panmictic population or whether they harbor significant substructure. Accurate assessment of population genetic substructure, both spatial and temporal, is essential for determining the relevant number of distinct management units appropriate for this species. In the present study, we assayed genetic variation genome-wide using Restriction Site Associated DNA Sequencing (RAD-seq) technology to analyze the population genetic structure of Japanese eels. For analysis of temporal isolation, five “cohort” samples were collected yearly from 2005 to 2009 in the Yangtze River Estuary. For analysis of spatial structure, five “arrival wave” samples were collected in China in 2009, and two arrival wave samples were collected in Japan in 2001. In each cohort of each arrival wave, five individuals were collected for a total of 55 eels sampled. In total, 214,210 loci were identified from these individuals, 106,652 of which satisfied quality checks and were retained for further analysis. There was relatively little population differentiation between arrival waves and cohorts collected either at different locations during the same year (Fst = 0.077) or at the same location collected over subsequent years (Fst = 0.082), and locations displayed no consistent isolation-by-distance.

Weak population structure in the ant Formica fusca.

Dispersal is a fundamental trait of a species’ biology. High dispersal results in weakly structured or even panmictic populations over large areas, whereas weak dispersal enables population differentiation and strong spatial structuring. We report on the genetic population structure in the polygyne ant Formica fusca and the relative contribution of the dispersing males and females to this. We sampled 12 localities across a ∼35 km2 study area in Finland and generated mitochondrial DNA (mtDNA) haplotype data and microsatellite data. First, we assessed queen dispersal by estimating population differentiation from mtDNA haplotype data. Second, we analysed nuclear DNA microsatellite data to determine overall population genetic substructure in the study area with principal components analysis, Bayesian clustering, hierarchical F statistics and testing for evidence of isolation-by-distance. Third, we directly compared genetic differentiation estimates from maternally inherited mtDNA and bi-parentally inherited DNA microsatellites to test for sex-bias in dispersal. Our results showed no significant spatial structure or isolation by distance in neither mtDNA nor DNA microsatellite data, suggesting high dispersal of both sexes across the study area. However, mitochondrial differentiation was weaker (Fst-mt = 0.0047) than nuclear differentiation (Fst-nuc = 0.027), which translates into a sixfold larger female migration rate compared to that of males. We conclude that the weak population substructure reflects high dispersal in both sexes, and it is consistent with F. fusca as a pioneer species exploiting unstable habitats in successional boreal forests.

Genetic ancestry in normal breast tissue donors from the Susan G. Komen tissue bank at the IU Simon Cancer Center (KTB).

e13065 Background: When studying complex diseases with a heritable component, such as breast cancer, chances of finding disease susceptibility genes can be increased by accounting for genetic ancestry within the population investigated. The limitation in using self-reported race to reveal population genetic substructure has been extensively reported. Therefore, we employed a panel of genetic polymorphisms, or Ancestry Informative Markers (AIMs), to genetically determine the racial and ethnic background of the tissue donors in the KTB, the only existing biobank of breast tissue cores taken from healthy women. Methods: 4112 women donated breast tissue between 2006 and 2016, and also provided race and ethnicity information. We used a panel of 41 AIMs to estimate genetic ancestry and to maximize the difference between European/ Middle East (Caucasian, C), East Asia and Central/South Asia (Asian), African, and Hispanic populations. We employed the Bayesian Markov chain Monte Carlo (MCMC) method implemented in the program STRUCTURE 2.2. A reference set was obtained from the Human Genome Diversity Project. Results: In women self-identified as Black/African American (AA),White and Asian, the assigned genetic ancestry proportions were 93.8% African, 95% C and 96.6% Asian respectively, while the racial composition among the 318 self-identified Hispanics (of which only 178 were confirmed by the genetic ancestry) was 45.3% C, 5.3% African, and 14.7% Asian. Interestingly, 46.9% of the Asian population failed to report the racial background. This percentage was lower for C (1.3% ) and AA (0.5%). Women with African ancestry were younger (≤35 yrs) at the time of donation (24%), as compared to the C (32%) and Asian (33.7%) donors. The obesity rate (BMI > 30) is higher in the AA (60.6%) and C (36.6%), as compared to the Asian population (26.6%). Conclusions: A well-characterized genetic background of the normal breast tissue donors in the KTB will allow a more accurate examination of the association of the genetic ancestry with breast cancer events or risk factors with the ultimate goal of more fully understanding breast cancer racial disparities and their possible role in the risks for and outcomes of breast cancer.

Genetic characterization of an X-STR decaplex system in the State of Mato Grosso, Brazil: distribution, forensic efficiency and population structure

Studies with X-STR loci show population genetic substructure, which makes necessary the characterization of such markers in the different geographical and/or ethnic populations. Therefore, this study assessed the distribution and forensic efficiency of an X-STR decaplex system in the population of the State of Mato Grosso, as well as analysed the population structure of this State based on the aforementioned system. All X-STR markers were in Hardy-Weinberg equilibrium and linkage equilibrium, and the DXS6809 was the most informative marker. The power of discrimination value in females and males was 0.99999999995 and 0.9999994, respectively. Analysis of molecular variance indicated 1.10% (p<0.00001) of heterogeneity among Europeans, Africans, Brazilians and other Latin Americans, and in relation to such groups, the population of the State of Mato Grosso showed lower genetic variation when compared with the Brazilian group (-0.10%, p=0.67327). The genetic distance analysis showed lower values of F ST (0.0004≤F ST≤0.00331), with non-significant p value (p>0.00024), between the populations of Mato Grosso and Mato Grosso do Sul, Paraná and the Southeast region of Brazil (except for one sample of Rio de Janeiro). F ST values with significant p values (p≤0.00024) were obtained between the population of Mato Grosso and Iberian, African and some Latin American populations. The X-STR decaplex system proved to be extremely useful in the population of the State of Mato Grosso, and the data obtained does not show the need for a specific forensic database for this State in relation to the Brazilian populations compared in this study, except for population of Rio de Janeiro.

Genetic structure of Tibetan populations in Gansu revealed by forensic STR loci

The origin and diversification of Sino-Tibetan speaking populations have been long-standing hot debates. However, the limited genetic information of Tibetan populations keeps this topic far from clear. In the present study, we genotyped 15 forensic autosomal short tandem repeats (STRs) from 803 unrelated Tibetan individuals from Gansu Province (635 from Gannan and 168 from Tianzhu) in northwest China. We combined these data with published dataset to infer a detailed population affinities and genetic substructure of Sino-Tibetan populations. Our results revealed Tibetan populations in Gannan and Tianzhu are genetically very similar with Tibetans from other regions. The Tibetans in Tianzhu have received more genetic influence from surrounding lowland populations. The genetic structure of Sino-Tibetan populations was strongly correlated with linguistic affiliations. Although the among-population variances are relatively small, the genetic components for Tibetan, Lolo-Burmese, and Han Chinese were quite distinctive, especially for the Deng, Nu, and Derung of Lolo-Burmese. Han Chinese but not Tibetans are suggested to share substantial genetic component with southern natives, such as Tai-Kadai and Hmong-Mien speaking populations, and with other lowland East Asian populations, which implies there might be extensive gene flow between those lowland groups and Han Chinese after Han Chinese were separated from Tibetans. The dataset generated in present study is also valuable for forensic identification and paternity tests in China.

High population genetic substructure in Hypochaeris leontodontoides (Asteraceae), an endemic rupicolous species of the Atlas Mountains in NW Africa

Hypochaeris leontodontoides is a rupicolous species endemic to the Atlas Mountains (Morocco), where it occurs in scattered populations. This study aims to understand the biogeographic structure of a high mountain species in a rather small area of NW Africa. We used Amplified Fragment Length Polymorphism (AFLP) to investigate the population structure and phylogeography of H. leontodontoides in 19 populations sampled from the entire species distribution range. Multivariate analyses including PCoA, UPGMA analysis, and Bayesian clustering were applied to infer the influence of past biogeographic events. The AFLP differentiation among the populations was high (FST = 0.508). A significant geographical pattern by mountain region was found. The different phylogeographical analyses revealed four main groups corresponding to four well-defined geographic regions: Middle Atlas, Eastern High Atlas, Central High Atlas, and Western High Atlas, and highlighted the Western High Atlas as the most divergent group. Our data also indicate two regions as refuges during the Pleistocene ice ages: the Middle Atlas and the northernmost area of the Western High Atlas.

Uniparental ancestry markers in Chilean populations.

The presence of Native Americans, Europeans, and Africans has led to the development of a multi-ethnic, admixed population in Chile. This study aimed to contribute to the characterization of the uniparental genetic structure of three Chilean regions. Newborns from seven hospitals in Independencia, Providencia, Santiago, Curicó, Cauquenes, Valdívia, and Puerto Montt communes, belonging to the Chilean regions of Santiago, Maule, and Los Lagos, were studied. The presence of Native American mitochondrial DNA (mtDNA) haplogroups and two markers present in the non-recombinant region of the Y chromosome, DYS199 and DYS287, indicative of Native American and African ancestry, respectively, was determined. A high Native American matrilineal contribution and a low Native American and African patrilineal contributions were found in all three studied regions. As previously found in Chilean admixed populations, the Native American matrilineal contribution was lower in Santiago than in the other studied regions. However, there was an unexpectedly higher contribution of Native American ancestry in one of the studied communes in Santiago, probably due to the high rate of immigration from other regions of the country. The population genetic sub-structure we detected in Santiago using few uniparental markers requires further confirmation, owing to possible stratification for autosomal and X-chromosome markers.

Serotonin transporter gene 5-HTTLPR VNTR allele frequency distribution in Africa and Eurasia

Background. VNTR-polymorphism at 5 HTTLPR regulatory region of human serotonin transporter gene SLC6A4, which is associated with some psychiatric diseases and personality traits, is presented by two alleles, S and L, affecting the gene transcription level. A correlation between the S allele frequency in populations of European and Asian origin and a Hofstede’s individualism-collectivism index was revealed and a hypothesis of culture-gene coevolution was suggested (Chiao, Blizinsky, 2010). Methods. As another reason for the correlation we examined underlying population genetic substructure, which may affect genetic association level. Results. We have experimentally established the 5 HTTLPR genotypes for 2144 individuals to calculate S and L allele frequencies in 21 populations of Eurasia and Africa. In contrast to Eurasia populations, we have found low S allele frequencies in all four African populations studied, although the collectivism index in the populations was high. The total set of Eurasian and African populations analysis does not confirm the correlation (R= 0.263, p=0.146). We have applied principal component (PC) analysis to check a correlation between S allele frequency distribution and a frequency distribution for alleles which are supposed to be neutral. PC analysis for 68 alleles of five CODIS STR loci revealed correlation between PC2 and S allele frequency (R= 0.820, p0.0001). The correlation means that S allele frequency distribution corresponds to general genetic variability distribution in the human populations studied. The correlation between the Hofestede’s index and frequency of four out of 68 STR alleles is even higher than the correlation with S allele frequency in the same populations. Conclusion. Our findings do not support the hypothesis on culture-gene coevolution of “individualism-collectivism” and the S allele frequency of serotonin transporter gene.

Evaluating sample allocation and effort in detecting population differentiation for discrete and continuously distributed individuals

One of the most pressing issues in spatial genetics concerns sampling. Traditionally, substructure and gene flow are estimated for individuals sampled within discrete populations. Because many species may be con- tinuously distributed across a landscape without discrete boundaries, understanding sampling issues becomes para- mount. Given large-scale, geographically broad conserva- tion efforts, researchers are looking for guidance as to the trade-offs between sampling more individuals within a population versus few individuals scattered across more populations. Here, we conducted simulations that address these issues. We first established two archetypical patterns of dispersion: (1) individuals within discrete populations, and (2) continuously distributed individuals with limited dispersal. We used genotypes generated from a spatially- explicit, individual-based program and simulated genetic structure in individuals from nine different population sizes across a landscape that either had barriers to movement (defining discrete populations) or isolation-by-distance patterns (defining continuously distributed individuals). Then, given each pattern of dispersion, we allocated sam- ples across four different sampling strategies for each of the nine population sizes in various configurations for sampling more individuals within a population versus fewer individuals scattered across more populations. We assessed the population genetic substructure with both the population-based metric, FST, and an individual-based metric, DPS regardless of the true pattern of dispersion to allow us to better understand the effect of incorrectly matching the metric and the distribution (e.g., FST with continuously distributed individuals, and vice versa). We show that sampling many subpopulations (or sampling areas), thus sampling fewer individuals per subpopulation, overestimates measures of population subdivision with the population-based metric for both patterns of dispersion. In contrast, using the individual-based metric gives the opposite results: sampling too few subpopulations, and many individuals per subpopulation, produces an under- estimate of the strength of isolation-by-distance. By com- paring all results, we were able to suggest a strong predictive model of a chosen genetic structure metric for elucidating the sampling design trade-offs given each pat- tern of dispersion and configuration on the landscape.

Racial/Ethnic Disparities in Breast Cancer Risk: Genomics Meets Metabolomics

Although breast cancer is by far the most common cancer among all women worldwide, its incidence rates vary substantially in different populations. In the United States, rates are highest among white women, followed by African American (AA) and Hispanic American (HA) women. Among HA women, breast cancer incidence rates are higher among those born in the United States than among first-generation immigrants, who, in turn, have higher rates than their counterparts in their countries of origin. Among foreign-born HA women, breast cancer risk has been shown to increase with the duration of U.S. residency, degree of acculturation, and younger age at migration, underscoring the importance of environmental influence on breast cancer risk. On the other hand, overall breast cancer risk among HA women has been shown to increase with the degree of European contribution to their genetic admixture. Among AA women, a higher proportion of European ancestry has been associated with a less aggressive form of breast cancer (estrogen receptor [ER] positive/progesterone receptor [PR] positive and localized). These observations highlight the need for understanding the population genetic substructure in the evaluation of racial/ ethnic disparities in breast cancer incidence and prognosis. Although breast cancer is more likely to occur in white women, AA and HA breast cancer patients are more likely to die of their disease. The age at onset tends to be earlier in AA and HA women, and these cases tend to have more aggressive histologic characteristics, including the triplenegative breast cancer (TNBC) that lacks expression of ER, PR, and human epidermal growth factor receptor 2 (HER2). Interestingly, limited evidence suggests that TNBC is also overrepresented among Hispanic and African women in their countries of origin. The predisposition to more aggressive tumors likely has contributed to the higher mortality rates among young minority women. However, the poor prognosis of breast cancer among AA and HA women has also been attributed, in part, to inadequate health insurance, limited access to mammography, advanced disease stage at diagnosis, delayed and inadequate treatment, and a high prevalence of comorbidity.

Abstract MP065: Genetic Loci Associated With Plasma Phospholipid Fatty Acids in the De Novo Lipogenesis Pathway: A Meta-analysis of Genome-wide Association Studies From the Charge Consortium

Background Palmitic acid (16:0), stearic acid (18:0), palmitoleic acid (16:1n-7), and oleic acid (18:1n-9) are major saturated and mono-unsaturated fatty acids that are synthesized via de novo lipogenesis (DNL) or obtained from the diet. Circulating levels of these fatty acids are linked to several diseases including diabetes and heart disease. Prior family and twin studies suggest high heritability of circulating levels, but potential genes involved are unknown. Objective To carry out a Genome-Wide Association Study (GWAS) to investigate genetic determinants of circulating levels of these fatty acids. Methods GWAS in 5 population-based cohorts (n=8,961) of European ancestry. Each study conducted linear regression analysis using an additive genetic model. All analyses were adjusted for age, sex, site of recruitment, and principal components to account for possible population genetic substructure where appropriate. Study-specific results were combined using inverse-variance weighted meta-analysis. Results We found SNPs at 7 novel loci linked at GWA significance to levels of one or more of these fatty acids ( Figure ). Directionality is reported for minor alleles. SNPs in ALG14 were associated with higher levels of 16:0 ( P =2.7x10 -11 ) and lower levels of 18:0 ( P =2.7x10 -11 ). SNPs in FADS1 /2 were associated with higher 18:1n-9 ( P =2.2x10 -32 ) and 16:1n-7 ( P =6.6x10 -13 ), and lower 18:0 ( P =1.3x10 -20 ). SNPs in LPGAT1 were associated with lower 18:0 ( P =2.8x10 -9 ). SNPs in GCKR ( P =9.8x10 -10 ) and HIF1AN ( P =5.7x10 -9 ) were associated with higher 16:1n-7, whereas those in PKD2L1 ( P =5.7x10 -15 ) and another locus on chromosome 2 (not near known genes) were associated with lower 16:1n-7. Conclusion Our findings provide novel evidence that common variations in genes with diverse functions, including protein glycosylation, polyunsaturated fatty acid metabolism, phospholipid modeling, and glucose- and oxygen-sensing pathways, are associated with circulating levels of fatty acids in the DNL pathway.

Association of Systemic Lupus Erythematosus Clinical Features with European Population Genetic Substructure

Systemic Lupus Erythematosus (SLE) is an autoimmune disease with a very varied spectrum of clinical manifestations that could be partly determined by genetic factors. We aimed to determine the relationship between prevalence of 11 clinical features and age of disease onset with European population genetic substructure. Data from 1413 patients of European ancestry recruited in nine countries was tested for association with genotypes of top ancestry informative markers. This analysis was done with logistic regression between phenotypes and genotypes or principal components extracted from them. We used a genetic additive model and adjusted for gender and disease duration. Three clinical features showed association with ancestry informative markers: autoantibody production defined as immunologic disorder (P = 6.8×10−4), oral ulcers (P = 6.9×10−4) and photosensitivity (P = 0.002). Immunologic disorder was associated with genotypes more common in Southern European ancestries, whereas the opposite trend was observed for photosensitivity. Oral ulcers were specifically more common in patients of Spanish and Portuguese self-reported ancestry. These results should be taken into account in future research and suggest new hypotheses and possible underlying mechanisms to be investigated. A first hypothesis linking photosensitivity with variation in skin pigmentation is suggested.

Complex pattern of genetic structuring in the Atlantic salmon (Salmo salar L.) of the River Foyle system in northwest Ireland: disentangling the evolutionary signal from population stochasticity.

Little is known about the microevolutionary processes shaping within river population genetic structure of aquatic organisms characterized by high levels of homing and spawning site fidelity. Using a microsatellite panel, we observed complex and highly significant levels of intrariver population genetic substructure and Isolation-by-Distance, in the Atlantic salmon stock of a large river system. Two evolutionary models have been considered explaining mechanisms promoting genetic substructuring in Atlantic salmon, the member-vagrant and metapopulation models. We show that both models can be simultaneously used to explain patterns and levels of population structuring within the Foyle system. We show that anthropogenic factors have had a large influence on contemporary population structure observed. In an analytical development, we found that the frequently used estimator of genetic differentiation, FST, routinely underestimated genetic differentiation by a factor three to four compared to the equivalent statistic Jost's Dest (Jost 2008). These statistics also showed a near-perfect correlation. Despite ongoing discussions regarding the usefulness of “adjusted”FST statistics, we argue that these could be useful to identify and quantify qualitative differences between populations, which are important from management and conservation perspectives as an indicator of existence of biologically significant variation among tributary populations or a warning of critical environmental damage.

Impact of population genetic substructure on association studies and risk assessment for melanoma.

8521 Background: Genetic substructure due to varying allele frequencies between populations can confound association studies. Ancestry informative genetic marker (AIMs) data combined with statistical adjustment can reveal spurious associations and identify population specific risk markers. In melanoma, AIMs may also be risk markers, e.g. pigment genes contribute to melanoma susceptibility and segregate with ancestry. We have thus developed a strategy to adjust for population genetic substructure (PGS) using AIMs, while identifying potentially novel genes associated with melanoma. Methods: 326 melanoma patients and 400 controls of European ancestry from the New York area were studied. Tag SNPs spanning 14 candidate genes and 75 AIMs were genotyped and odds ratios (OR), unadjusted and adjusted for PGS, computed. Results: A PGS model based on all AIMs separated cases and controls, suggesting that some AIMs were associated with melanoma. An algorithm was developed to select AIMs least capable of separating cases and controls to infer PGS and validated using simulations. The resulting model, which was reproduced using 49 additional AIMs, separated Northern (NE) and Southern Europeans (SE) and was used to adjust ORs. Three classes of SNPs were identified 1. Associated before and after PGS correction in both groups (10 SNPs localized to MATP, TYR and ERCC5). 2. Not associated in unadjusted analysis, but significantly associated with melanoma in NEs (6 SNPs localized to XPC, ERCC4, OCA2, ASIP and TYR). 3. Associated with melanoma before but not after adjustment. To determine if AIMs that separate cases and controls can identify novel melanoma genes, we genotyped 16 SNPs localized to 4 genes that house candidate AIMs. Four SNPs at 2 different loci were associated with melanoma (e.g. AIM1: OR=0.35, p=0.01; AIM2: OR=1.77, p=0.03). Conclusions: Our approach demonstrated that ancestry is a significant confounding factor in identifying melanoma susceptibility genes. Melanoma risk markers vary significantly between groups and a DNA based risk assessment model will require adjustment for ancestry. We have also identified potentially novel susceptibility melanoma genes for futher study.

Classification and Regression Tree and Spatial Analyses Reveal Geographic Heterogeneity in Genome Wide Linkage Study of Indian Visceral Leishmaniasis

BackgroundGenome wide linkage studies (GWLS) have provided evidence for loci controlling visceral leishmaniasis on Chromosomes 1p22, 6q27, 22q12 in Sudan and 6q27, 9p21, 17q11-q21 in Brazil. Genome wide studies from the major focus of disease in India have not previously been reported.Methods and FindingsWe undertook a GWLS in India in which a primary ∼10 cM (515 microsatellites) scan was carried out in 58 multicase pedigrees (74 nuclear families; 176 affected, 353 total individuals) and replication sought in 79 pedigrees (102 nuclear families; 218 affected, 473 total individuals). The primary scan provided evidence (≥2 adjacent markers allele-sharing LOD≥0.59; nominal P≤0.05) for linkage on Chromosomes 2, 5, 6, 7, 8, 10, 11, 20 and X, with peaks at 6p25.3-p24.3 and 8p23.1-p21.3 contributed to largely by 31 Hindu families and at Xq21.1-q26.1 by 27 Muslim families. Refined mapping confirmed linkage across all primary scan families at 2q12.2-q14.1 and 11q13.2-q23.3, but only 11q13.2-q23.3 replicated (combined LOD = 1.59; P = 0.0034). Linkage at 6p25.3-p24.3 and 8p23.1-p21.3, and at Xq21.1-q26.1, was confirmed by refined mapping for primary Hindu and Muslim families, respectively, but only Xq21.1-q26.1 replicated across all Muslim families (combined LOD 1.49; P = 0.0045). STRUCTURE and SMARTPCA did not identify population genetic substructure related to religious group. Classification and regression tree, and spatial interpolation, analyses confirm geographical heterogeneity for linkages at 6p25.3-p24.3, 8p23.1-p21.3 and Xq21.1-q26.1, with specific clusters of families contributing LOD scores of 2.13 (P = 0.0009), 1.75 (P = 0.002) and 1.84 (P = 0.001), respectively.ConclusionsGWLS has identified novel loci that show geographical heterogeneity in their influence on susceptibility to VL in India.

European Population Genetic Substructure: Further Definition of Ancestry Informative Markers for Distinguishing among Diverse European Ethnic Groups

The definition of European population genetic substructure and its application to understanding complex phenotypes is becoming increasingly important. In the current study using over 4,000 subjects genotyped for 300,000 single-nucleotide polymorphisms (SNPs), we provide further insight into relationships among European population groups and identify sets of SNP ancestry informative markers (AIMs) for application in genetic studies. In general, the graphical description of these principal components analyses (PCA) of diverse European subjects showed a strong correspondence to the geographical relationships of specific countries or regions of origin. Clearer separation of different ethnic and regional populations was observed when northern and southern European groups were considered separately and the PCA results were influenced by the inclusion or exclusion of different self-identified population groups including Ashkenazi Jewish, Sardinian, and Orcadian ethnic groups. SNP AIM sets were identified that could distinguish the regional and ethnic population groups. Moreover, the studies demonstrated that most allele frequency differences between different European groups could be controlled effectively in analyses using these AIM sets. The European substructure AIMs should be widely applicable to ongoing studies to confirm and delineate specific disease susceptibility candidate regions without the necessity of performing additional genome-wide SNP studies in additional subject sets.