Yoruba Population Research Articles

A Comparative Analysis of Genetic Ancestry and Admixture in the Colombian Populations of Chocó and Medellín.

At least 20% of Colombians identify as having African ancestry, yielding the second largest population of Afro-descendants in Latin America. To date, there have been relatively few studies focused on the genetic ancestry of Afro-Latino populations. We report a comparative analysis of the genetic ancestry of Chocó, a state located on Colombia’s Pacific coast with a population that is >80% Afro-Colombian. We compared genome-wide patterns of genetic ancestry and admixture for Chocó to six other admixed American populations, with an emphasis on a Mestizo population from the nearby Colombian city of Medellín. One hundred sample donors from Chocó were genotyped across 610,545 genomic sites and compared with 94 publicly available whole genome sequences from Medellín. At the continental level, Chocó shows mostly African genetic ancestry (76%) with a nearly even split between European (13%) and Native American (11%) fractions, whereas Medellín has primarily European ancestry (75%), followed by Native American (18%) and African (7%). Sample donors from Chocó self-identify as having more African ancestry, and conversely less European and Native American ancestry, than can be genetically inferred, as opposed to what we previously found for Medellín, where individuals tend to overestimate levels of European ancestry. We developed a novel approach for subcontinental ancestry assignment, which allowed us to characterize subcontinental source populations for each of the three distinct continental ancestry fractions separately. Despite the clear differences between Chocó and Medellín at the level of continental ancestry, the two populations show overall patterns of subcontinental ancestry that are highly similar. Their African subcontinental ancestries are only slightly different, with Chocó showing more exclusive shared ancestry with the modern Yoruba (Nigerian) population, and Medellín having relatively more shared ancestry with West African populations in Sierra Leone and Gambia. Both populations show very similar Spanish ancestry within Europe and virtually identical patterns of Native American ancestry, with main contributions from the Embera and Waunana tribes. When the three subcontinental ancestry components are considered jointly, the populations of Chocó and Medellín are shown to be most closely related, to the exclusion of the other admixed American populations that we analyzed. We consider the implications of the existence of shared subcontinental ancestries for Colombian populations that appear, at first glance, to be clearly distinct with respect to competing notions of national identity that emphasize ethnic mixing (mestizaje) vs. group-specific identities (multiculturalism).

New-onset diabetes after transplant: Incidence, risk factors and outcome.

The outcome of renal transplantation depends on achieving effective immunosuppression while minimising the consequences of such treatment. The occurrence of new-onset diabetes in the post-transplant period has been associated with several risk factors including some immunosuppressive medication. Better understanding of the clinical and genetic risk factors associated with new-onset diabetes after transplant (NODAT) could enable risk stratification of patients in the pre-transplant period, with the goal of applying measures that will reduce the incidence. To ascertain the incidence of and clinical and genetic risk factors that predispose to NODAT, and to examine its effect on the outcome of renal transplantation. We performed a retrospective cohort review of all renal transplants at Groote Schuur Hospital, Cape Town, South Africa, between 2004 and 2008. Patients who were lost to follow-up or had pre-transplant diabetes or primary non-function were excluded. A subset of the cohort who gave informed consent was enlisted for genetic tests. We identified 111 patients who met the inclusion criteria. The incidence of NODAT was 18.0% (n=20 patients). Risk factors for NODAT included age at transplant (p=0.03), body weight (p=0.04), treatment for acute cellular rejection (p=0.02) and polycystic kidney disease as the cause of renal failure (p=0.005). None of the genes investigated (TCF7L2 rs11196205, rs12255372 and rs7903146 and HNF1β rs1800575, rs121918671 and rs121918672) was found to be significantly associated with the risk of NODAT. The genotype frequencies for the single-nucleotide polymorphisms studied were closer (although not identical) to those reported for Caucasians than to those reported for the Yoruba (black) population in West Africa. Overall patient survival was 78% at five years, while graft survival was 72%. There was no significant difference in patient or graft survival between the group with NODAT and the group without. NODAT was common in renal transplant recipients. Some risk factors predate transplant and could be used to risk-stratify patients to determine appropriate risk-reduction strategies. The genetic determinants for NODAT in this population may differ from those reported elsewhere. NODAT had no impact on patient or graft survival in this cohort.

Accuracy of Demographic Inferences from the Site Frequency Spectrum: The Case of the Yoruba Population

Some methods for demographic inference based on the observed genetic diversity of current populations rely on the use of summary statistics such as the Site Frequency Spectrum (SFS). Demographic models can be either model-constrained with numerous parameters, such as growth rates, timing of demographic events, and migration rates, or model-flexible, with an unbounded collection of piecewise constant sizes. It is still debated whether demographic histories can be accurately inferred based on the SFS. Here, we illustrate this theoretical issue on an example of demographic inference for an African population. The SFS of the Yoruba population (data from the 1000 Genomes Project) is fit to a simple model of population growth described with a single parameter (e.g., founding time). We infer a time to the most recent common ancestor of 1.7million years (MY) for this population. However, we show that the Yoruba SFS is not informative enough to discriminate between several different models of growth. We also show that for such simple demographies, the fit of one-parameter models outperforms the stairway plot, a recently developed model-flexible method. The use of this method on simulated data suggests that it is biased by the noise intrinsically present in the data.

Abstract B2-14: Ancestrally derived SNPs influence on gene expression in breast cancer data sets

Abstract There is a critical need to identify factors driving aggressive breast cancer (BCa) that is more likely to develop in African American (AA) women who have a lower incidence BCa, but have a higher mortality from all invasive BCa subtypes compared to Caucasian (CA) women. The etiology driving these disparities has remained confounding though experimental evidence has shown a statistically significant biological difference stemming from an immunobiological gene signature in prostate, breast or colorectal tumor tissues. It is currently unknown if this signature can influence tumor initiation, progression and/or therapeutic intervention. Furthermore, there is a significant lack of a mechanistic understanding in the measured gene expression network signature between AA and CA BCa tumors. Using existing data from the NIH's Cancer Genome Atlas (TCGA), we correlated gene expression between AA and CA tumors with 63 genes containing ancestry informative missense mutations. The genes were selected from single nucleotide polymorphisms (SNPs) using the Affymetrix SNP 6 array. Briefly, SNPs with a minor allele frequency (MAF) greater than 0.3 in the HapMap's Yoruba population from Ibadan, Nigeria (YRI) as well as a MAF less than 0.05 in the Caucasian (CEU), Chinese (CHB) and Japanese (JPT) populations resulted in a list of 17,995 SNP candidates. Those SNPs in non-coding regions were removed resulting in 7,782 gene annotated SNPS. Finally, only those SNPs in exonic regions with protein coding mutations (non-synonymous SNPs) lead to the 63 gene list. To compare these genes with existing gene expression, admixture analysis was performed on the TCGA genotypes from the Affymetrix Genome-Wide Human SNP Array 6.0 using normal tissues. An initial independent list of 4,323 cross-platform comparable SNPs were chosen for admixture analysis. Each SNP for each individual was filtered for a birdseed confidence score <0.1. Using PLINK v1.07, an additional 828 SNPs were excluded from further analysis if they had a minor allele frequency (MAF) <0.05 or displayed deviation from the Hardy-Weinberg equilibrium (p < 0.00001). A total of 641 SNPs were used in admixture analysis from the Bayesian Markov Chain Monte Carlo method from the program Structure 2.3.4. Gene expression analysis was performed on tumors by stage (I to III) or subtype (Luminal A, Luminal B, HER2 positive or Triple Negative) between AA with CA patients. Though additional genes related to an immunobiological signature were in the list of 63 candidate genes (e.g. CD86 molecule and chemokine C-X-C motif receptor 6) only a statistically significant correlation between only one gene with the filtered SNP mutation list was found. This gene was the interleukin 6 signal transducer (IL6ST) with a SNP mutation in rs2228046 resulting in a switch from isoleucine to threonine. The functional consequence of this switch in breast cancer is unknown. The use of this approach may uncover additional tumor gene expression that is a result of ancestral variation in coding sequences. The functional consequences of these variations in normal and tumor cells may potentiate tumor initiation, progression and response to therapy. Future investigation of sequence specific variant analysis between CA and AA tumors and impact on additional gene as well as protein expression using the TCGA data is currently under investigation. Citation Format: John Tyson McDonald, Luisel Ricks-Santi. Ancestrally derived SNPs influence on gene expression in breast cancer data sets. [abstract]. In: Proceedings of the AACR Special Conference on Computational and Systems Biology of Cancer; Feb 8-11 2015; San Francisco, CA. Philadelphia (PA): AACR; Cancer Res 2015;75(22 Suppl 2):Abstract nr B2-14.

Translation, cross-cultural adaptation and psychometric evaluation of yoruba version of the short-form 36 health survey.

Background and objectiveThe Short-Form Health Survey (SF-36) is a valid quality of life tool often employed to determine the impact of medical intervention and the outcome of health care services. However, the SF-36 is culturally sensitive which necessitates its adaptation and translation into different languages. This study was conducted to cross-culturally adapt the SF-36 into Yoruba language and determine its reliability and validity.MethodsBased on the International Quality of Life Assessment project guidelines, a sequence of translation, test of item-scale correlation, and validation was implemented for the translation of the Yoruba version of the SF-36. Following pilot testing, the English and the Yoruba versions of the SF-36 were administered to a random sample of 1087 apparently healthy individuals to test validity and 249 respondents completed the Yoruba SF-36 again after two weeks to test reliability. Data was analyzed using Pearson’s product moment correlation analysis, independent t-test, one-way analysis of variance, multi trait scaling analysis and Intra-Class Correlation (ICC) at p < 0.05.ResultsThe concurrent validity scores for scales and domains ranges between 0.749 and 0.902 with the highest and lowest scores in the General Health (0.902) and Bodily Pain (0.749) scale. Scale-level descriptive result showed that all scale and domain scores had negative skewness ranging from −2.08 to −0.98. The mean scores for each scales ranges between 83.2 and 88.8. The domain scores for Physical Health Component and Mental Health Component were 85.6 ± 13.7 and 85.9 ± 15.4 respectively. The convergent validity was satisfactory, ranging from 0.421 to 0.907. Discriminant validity was also satisfactory except for item ‘1’. The ICC for the test-retest reliability of the Yoruba SF-36 ranges between 0.636 and 0.843 for scales; and 0.783 and 0.851 for domains.ConclusionThe data quality, concurrent and discriminant validity, reliability and internal consistency of the Yoruba version of the SF-36 are adequate and it is recommended for measuring health-related quality of life among Yoruba population.

OR9 Multiethnic rna sequencing analysis of HLA reveals HLA-allele specific eQTLs

Aim The HLA is major regulator for immune responses and several auto-immune or inflammatory diseases show a strong association with specific HLA alleles. However, it remains unclear what is the effect of individual HLA alleles on variation in cell phenotype and gene expression that potentially contribute to disease predisposition. Our aim was to characterize the role of individual HLA-alleles on gene expression over two ethnic groups and multiple populations. Methods We used RNA sequencing from lymphoblastoid cell lines, including HLA region, combined with HLA typing data from the 1000 genomes and Geuvadis projects in 462 individuals from European (CEPH, Finnish, British, Toscani) and African (Yoruba) populations. The analysis was normalized using PANAMA and analyzed with linear mixed model in R v3.2.0. Results The effect of HLA-alleles on gene expression revealed several genome-wide significant cis-eQTLs for other genes at the HLA region. Importantly, we also characterized several robust trans-eQTL signals for HLA class I and class II alleles ( P −8 ) that were enriched in genes mediating immune responses and shared among different populations. Conclusion HLA-alleles have a robust effect on gene expression and cellular phenotype that is shared across multiple populations.

Genotypic and allelic variability in CYP19A1 among populations of African and European ancestry.

CYP19A1 facilitates the bioconversion of estrogens from androgens. CYP19A1 intron single nucleotide polymorphisms (SNPs) may alter mRNA splicing, resulting in altered CYP19A1 activity, and potentially influencing disease susceptibility. Genetic studies of CYP19A1 SNPs have been well documented in populations of European ancestry; however, studies in populations of African ancestry are limited. In the present study, ten ‘candidate’ intronic SNPs in CYP19A1 from 125 African Americans (AA) and 277 European Americans (EA) were genotyped and their frequencies compared. Allele frequencies were also compared with HapMap and ASW 1000 Genomes populations. We observed significant differences in the minor allele frequencies between AA and EA in six of the ten SNPs including rs10459592 (p<0.0001), rs12908960 (p<0.0001), rs1902584 (p = 0.016), rs2470144 (p<0.0001), rs1961177 (p<0.0001), and rs6493497 (p = 0.003). While there were no significant differences in allele frequencies between EA and CEU in the HapMap population, a 1.2- to 19-fold difference in allele frequency for rs10459592 (p = 0.004), rs12908960 (p = 0.0006), rs1902584 (p<0.0001), rs2470144 (p = 0.0006), rs1961177 (p<0.0001), and rs6493497 (p = 0.0092) was observed between AA and the Yoruba (YRI) population. Linkage disequilibrium (LD) blocks and haplotype clusters that is unique to the EA population but not AA was also observed. In summary, we demonstrate that differences in the allele frequencies of CYP19A1 intron SNPs are not consistent between populations of African and European ancestry. Thus, investigations into whether CYP19A1 intron SNPs contribute to variations in cancer incidence, outcomes and pharmacological response seen in populations of different ancestry may prove beneficial.

Robust demographic inference from genomic and SNP data.

We introduce a flexible and robust simulation-based framework to infer demographic parameters from the site frequency spectrum (SFS) computed on large genomic datasets. We show that our composite-likelihood approach allows one to study evolutionary models of arbitrary complexity, which cannot be tackled by other current likelihood-based methods. For simple scenarios, our approach compares favorably in terms of accuracy and speed with , the current reference in the field, while showing better convergence properties for complex models. We first apply our methodology to non-coding genomic SNP data from four human populations. To infer their demographic history, we compare neutral evolutionary models of increasing complexity, including unsampled populations. We further show the versatility of our framework by extending it to the inference of demographic parameters from SNP chips with known ascertainment, such as that recently released by Affymetrix to study human origins. Whereas previous ways of handling ascertained SNPs were either restricted to a single population or only allowed the inference of divergence time between a pair of populations, our framework can correctly infer parameters of more complex models including the divergence of several populations, bottlenecks and migration. We apply this approach to the reconstruction of African demography using two distinct ascertained human SNP panels studied under two evolutionary models. The two SNP panels lead to globally very similar estimates and confidence intervals, and suggest an ancient divergence (>110 Ky) between Yoruba and San populations. Our methodology appears well suited to the study of complex scenarios from large genomic data sets.

KGVDB: a population-based genomic map of CNVs tagged by SNPs in Koreans

Despite a growing interest in a correlation between copy number variations (CNVs) and flanking single nucleotide polymorphisms, few databases provide such information. In particular, most information on CNV available so far was obtained in Caucasian and Yoruba populations, and little is known about CNV in Asian populations. This article presents a database that provides CNV regions tagged by single nucleotide polymorphisms in about 4700 Koreans, which were detected under strict quality control, manually curated and experimentally validated. KGVDB is freely available for non-commercial use at http://biomi.cdc.go.kr/KGVDB. Supplementary data are available at Bioinformatics online.

FOXP2 Targets Show Evidence of Positive Selection in European Populations

Forkhead box P2 (FOXP2) is a highly conserved transcription factor that has been implicated in human speech and language disorders and plays important roles in the plasticity of the developing brain. The pattern of nucleotide polymorphisms in FOXP2 in modern populations suggests that it has been the target of positive (Darwinian) selection during recent human evolution. In our study, we searched for evidence of selection that might have followed FOXP2 adaptations in modern humans. We examined whether or not putative FOXP2 targets identified by chromatin-immunoprecipitation genomic screening show evidence of positive selection. We developed an algorithm that, for any given gene list, systematically generates matched lists of control genes from the Ensembl database, collates summary statistics for three frequency-spectrum-based neutrality tests from the low-coverage resequencing data of the 1000 Genomes Project, and determines whether these statistics are significantly different between the given gene targets and the set of controls. Overall, there was strong evidence of selection of FOXP2 targets in Europeans, but not in the Han Chinese, Japanese, or Yoruba populations. Significant outliers included several genes linked to cellular movement, reproduction, development, and immune cell trafficking, and 13 of these constituted a significant network associated with cardiac arteriopathy. Strong signals of selection were observed for CNTNAP2 and RBFOX1, key neurally expressed genes that have been consistently identified as direct FOXP2 targets in multiple studies and that have themselves been associated with neurodevelopmental disorders involving language dysfunction.

PXR and CAR single nucleotide polymorphisms influence plasma efavirenz levels in South African HIV/AIDS patients

BackgroundThis study investigated variation in NR1I2 and NR1I3 and its effect on plasma efavirenz levels in HIV/AIDS patients. Variability in plasma drug levels has largely led research on identifying causative variants in drug metabolising enzyme (DME) genes, with little focus on the nuclear receptor genes NR1I2 and NR1I3, coding for PXR and CAR, respectively, that are involved in regulating DMEs.Methods464 Bantu-speaking South Africans comprising of HIV/AIDS patients on efavirenz-based treatment (n=301) and 163 healthy subjects were genotyped for 6 SNPs in NR1I2 and NR1I3. 32 of the 301 patients had their DNA binding domains (DBDs) in NR1I2 and NR1I3 sequenced.ResultsSignificantly decreased efavirenz plasma concentrations were observed in patients carrying the NR1I3 rs3003596C/C and T/C genotypes (P=0.015 and P=0.010, respectively). Sequencing resulted in the discovery of a further 13 SNPs, 3 of which are novel variants in the DBD of NR1I2. There were significant differences in the distribution of NR1I2 and NR1I3 SNPs between South Africans when compared to Caucasian, Asian and Yoruba population groups.ConclusionFor the realisation of personalised medicine, PXR and CAR genetic variation should be taken into consideration because of their involvement in the regulation of DMEs.

Abstract 1880: Incorporating protein levels with genetic variation and gene expression in sensitivity to chemotherapy

Abstract Genome-wide studies of genes important in chemotherapeutic sensitivity or disease susceptibility and progression have primarily relied on mRNA expression levels; however, mRNA expression levels do not always accurately reflect downstream protein abundances. We have applied a novel technology, microwestern arrays, along with reverse phase lysate arrays, to evaluate the role that over 400 transcription factor and signaling proteins play in mediating cellular sensitivity to ten chemotherapeutic agents. Utilizing unrelated International HapMap lymphoblastoid cell lines derived from the Yoruba population, we evaluated the relationship between protein abundances, genetic variation, microRNA and mRNA expression, and chemotherapeutic-induced cytotoxicity and apoptosis. Using ∼12 million single nucleotide polymorphism (SNPs) imputed from the 1000 Genomes Project, we identified SNPs associated with protein abundance (protein quantitative trait loci, pQTLs) and SNPs associated with chemotherapeutic sensitivity (drug quantitative trait loci, dQTLs). Chemotherapeutic agents included platinating agents, antimetabolites and microtubule inhibitors. For cytarabine there was a significant (p&amp;lt;0.0001) enrichment of pQTLs in the SNPs associated with cytotoxicity and apoptosis. We also identified 71 protein levels associated with cytarabine-induced cytotoxicity and apoptosis at p&amp;lt;0.05. One protein, ATF2, was associated (p&amp;lt;0.006) with both high (40 µM) and low (5 µM) dose cytarabine-induced apoptosis and there were six SNPs associated with apoptosis phenotypes (p&amp;lt;0.00007) that also associated with the protein level (p&amp;lt;0.00009). Knockdown of ATF2 protein with siRNA resulted in 40-51% of endogenous levels concomitant with a significant increase in apoptosis induced by cytarabine at both doses (p=0.001). This relationship was not identified in analyses correlating mRNA with phenotypes thus demonstrating the importance of incorporating protein levels into studies that aim to identify potential biomarkers. By incorporating genetic variation, mRNA, protein, and microRNA levels with chemotherapeutic sensitivity, the complex role of the genetic architecture in cellular chemotherapy response through its effects on expression and protein can be better understood. This study has broad potential for application to other chemotherapeutic drugs and complex traits. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 1880. doi:1538-7445.AM2012-1880

Discriminant Function Analysis as a Proof for Sexual Dimorphism among the Yoruba Ethnic Group of Nigeria: A Cephalometry Study

Background: Forensic scientists study human skeleton in legal setting. Discriminant function analysis has become important in forensic anthropology. The aim of this study was to determine the sex of adolescent Yoruba ethnic group of Nigeria using iscriminant function analysis. Methodology: One thousand (500 males and 500 females) were used. Eight cephalometric parameters were measured, namely head length, head width, bizygomatic distance, skull height, upper facial height, lower facial height, total facial height and nose width. Discriminant function analysis was done Results: Discriminant function score equation was determined for both direct and stepwise approach for the determination of the adolescent Yoruba population of Nigeria with between 89.70 %( direct) and 91.10% (stepwise) Conclusion: This study shows that these cephalometric parameters are sexually dimorphic and therefore could be used in sex determination especially in crime scenes where the body is mutilated but the head is left intact.Key Words discriminant function analysis, sex determination, Yoruba, Nigeria

Glutathione-S-transferase (M1 and T1) polymorphisms in Nigerian populations

The Mu ( �) and Theta ( Θ) classes of glutathione transferase gene, GSTM1 and GSTT1 are polymorphic in humans. GSTM1 and GSTT1 enzyme deficiencies have been suggested to predispose people to lung, bladder and colorectal cancer. This study was carried out to investigate the distribution of Glutathione transferases (GSTs) genotype frequency in the three major Nigerian ethnic groups with a view to understanding the implication of the GST polymorphisms on disease susceptibility. Three hundred unrelated volunteers from the three major Nigerian ethnic groups of Hausa, Ibo and Yoruba who consented to the study were genotyped for GSTM1*1, GSTM1*0, GSTT1*1 and GSTT1*0 by polymerase chain reaction (PCR) technique. The homozygous null GSTM1*0 genotype frequency was found to be 37% in Hausa, 23% in Ibo and 31% in Yoruba with significant difference (p<0.05) especially, in the Ibo ethnic group while GSTT1*0 genotype was found at a comparably high frequencies of 42, 36, and 35% in the Hausa, Ibo and Yoruba populations of Nigeria, respectively. The genotype frequencies of the null GSTM1 and GSTT1 were found to be relatively high in the Nigerian population with a possible implication on increase susceptibility to some cancers.

Abstract 5452: Functional genome-wide approach identifies genes associated with chemotherapeutic susceptibility in individuals of African descent

Abstract Chemotherapeutic agents are used in the treatment of many cancers, yet variable resistance and toxicities among individuals limit successful outcomes. Several studies have indicated outcome differences associated with ancestry among patients with various cancer types. We performed genome-wide association studies (GWAS) in lymphoblastoid cell lines derived from Yoruba (YRI; n = 176) and African American (ASW; n = 83) populations and identified SNP predictors of cellular susceptibility to cisplatin, carboplatin, capecitabine and ara-C. To account for population structure in African American population, we incorporated local ancestry information into our association model. We found that chemotherapeutic susceptibility SNPs in the YRI are enriched for expression quantitative trait loci (eQTLs, p&amp;lt;10-3). Most of these are trans eQTLs and thus simply examining the region directly surrounding a SNP that associates with a phenotype of interest for possible functional genes is inadequate. Traditional GWAS that test single markers are powered to detect SNP associations with relatively strong effects, but are unable to detect multiple smaller effects working together. Using a novel functional gene-based genome-wide association approach, we identified 10, 13, and 1 suggestive candidate genes for association with cytarabine-, carboplatin-, and cisplatin-induced cytotoxicity, respectively (p≤10-4) in ASW. Functional GWAS in the YRI resulted in the genome-wide significant association of 234 genes with cisplatin IC50, 81 genes with 5’-deoxyfluorouridine AUC, 64 genes with carboplatin IC50 and 13 genes with cytarabine AUC (p&amp;lt;10-6). Our genome-wide SNP- and gene-based approaches that incorporate local ancestry information can be used to elucidate genes functionally contributing to a wide range of phenotypes in African American populations. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 5452. doi:10.1158/1538-7445.AM2011-5452

CNVnator: An approach to discover, genotype, and characterize typical and atypical CNVs from family and population genome sequencing

Copy number variation (CNV) in the genome is a complex phenomenon, and not completely understood. We have developed a method, CNVnator, for CNV discovery and genotyping from read-depth (RD) analysis of personal genome sequencing. Our method is based on combining the established mean-shift approach with additional refinements (multiple-bandwidth partitioning and GC correction) to broaden the range of discovered CNVs. We calibrated CNVnator using the extensive validation performed by the 1000 Genomes Project. Because of this, we could use CNVnator for CNV discovery and genotyping in a population and characterization of atypical CNVs, such as de novo and multi-allelic events. Overall, for CNVs accessible by RD, CNVnator has high sensitivity (86%-96%), low false-discovery rate (3%-20%), high genotyping accuracy (93%-95%), and high resolution in breakpoint discovery (<200 bp in 90% of cases with high sequencing coverage). Furthermore, CNVnator is complementary in a straightforward way to split-read and read-pair approaches: It misses CNVs created by retrotransposable elements, but more than half of the validated CNVs that it identifies are not detected by split-read or read-pair. By genotyping CNVs in the CEPH, Yoruba, and Chinese-Japanese populations, we estimated that at least 11% of all CNV loci involve complex, multi-allelic events, a considerably higher estimate than reported earlier. Moreover, among these events, we observed cases with allele distribution strongly deviating from Hardy-Weinberg equilibrium, possibly implying selection on certain complex loci. Finally, by combining discovery and genotyping, we identified six potential de novo CNVs in two family trios.

Polycystic ovary syndrome: an ancient disorder?

Polycystic ovary syndrome (PCOS) appears to be an ancient disorder, which has persisted in human evolution despite reduced fecundity because of the benefits to affected women such as greater sturdiness and improved energy utilization, a rearing advantage for their children and kin, and a reduction in the risk of perinatal mortality. This raises the possibility that gene variants that are eventually found to be associated with PCOS will be similar across ethnic groups and races.

Worldwide distribution of the MYH9 kidney disease susceptibility alleles and haplotypes: evidence of historical selection in Africa.

MYH9 was recently identified as renal susceptibility gene (OR 3–8, p<10−8) for major forms of kidney disease disproportionately affecting individuals of African descent. The risk haplotype (E-1) occurs at much higher frequencies in African Americans (≥60%) than in European Americans (<4%), revealing a genetic basis for a major health disparity. The population distributions of MYH9 risk alleles and the E-1 risk haplotype and the demographic and selective forces acting on the MYH9 region are not well explored. We reconstructed MYH9 haplotypes from 4 tagging single nucleotide polymorphisms (SNPs) spanning introns 12–23 using available data from HapMap Phase II, and by genotyping 938 DNAs from the Human Genome Diversity Panel (HGDP). The E-1 risk haplotype followed a cline, being most frequent within sub-Saharan African populations (range 50–80%), less frequent in populations from the Middle East (9–27%) and Europe (0–9%), and rare or absent in Asia, the Americas, and Oceania. The fixation indexes (FST) for pairwise comparisons between the risk haplotypes for continental populations were calculated for MYH9 haplotypes; FST ranged from 0.27–0.40 for Africa compared to other continental populations, possibly due to selection. Uniquely in Africa, the Yoruba population showed high frequency extended haplotype length around the core risk allele (C) compared to the alternative allele (T) at the same locus (rs4821481, iHs = 2.67), as well as high population differentiation (FST(CEU vs. YRI) = 0.51) in HapMap Phase II data, also observable only in the Yoruba population from HGDP (FST = 0.49), pointing to an instance of recent selection in the genomic region. The population-specific divergence in MYH9 risk allele frequencies among the world's populations may prove important in risk assessment and public health policies to mitigate the burden of kidney disease in vulnerable populations.

Promoter Variant ofPIK3C3Is Associated with Autoimmunity against Ro and Sm Epitopes in African-American Lupus Patients

The PIK3C3 locus was implicated in case-case genome-wide association study of systemic lupus erythematosus (SLE) which we had performed to detect genes associated with autoantibodies and serum interferon-alpha (IFN-α). Herein, we examine a PIK3C3 promoter variant (rs3813065/-442 C/T) in an independent multiancestral cohort of 478 SLE cases and 522 controls. rs3813065 C was strongly associated with the simultaneous presence of both anti-Ro and anti-Sm antibodies in African-American patients [OR = 2.24 (1.34–3.73), P = 2.0 × 10−3]. This autoantibody profile was associated with higher serum IFN-α (P = 7.6 × 10−6). In the HapMap Yoruba population, rs3813065 was associated with differential expression of ERAP2 (P = 2.0 × 10−5), which encodes an enzyme involved in MHC class I peptide processing. Thus, rs3813065 C is associated with a particular autoantibody profile and altered expression of an MHC peptide processing enzyme, suggesting that this variant modulates serologic autoimmunity in African-American SLE patients.

Retraction: An African Ancestry-Specific Allele of CTLA4 Confers Protection against Rheumatoid Arthritis in African Americans

Cytotoxic T-lymphocyte associated protein 4 (CTLA4) is a negative regulator of T-cell proliferation. Polymorphisms in CTLA4 have been inconsistently associated with susceptibility to rheumatoid arthritis (RA) in populations of European ancestry but have not been examined in African Americans. The prevalence of RA in most populations of European and Asian ancestry is ∼1.0%; RA is purportedly less common in black Africans, with little known about its prevalence in African Americans. We sought to determine if CTLA4 polymorphisms are associated with RA in African Americans. We performed a 2-stage analysis of 12 haplotype tagging single nucleotide polymorphisms (SNPs) across CTLA4 in a total of 505 African American RA patients and 712 African American controls using Illumina and TaqMan platforms. The minor allele (G) of the rs231778 SNP was 0.054 in RA patients, compared to 0.209 in controls (4.462×10−26, Fisher's exact). The presence of the G allele was associated with a substantially reduced odds ratio (OR) of having RA (AG+GG genotypes vs. AA genotype, OR 0.19, 95% CI: 0.13–0.26, p = 2.4×10−28, Fisher's exact), suggesting a protective effect. This SNP is polymorphic in the African population (minor allele frequency [MAF] 0.09 in the Yoruba population), but is very rare in other groups (MAF = 0.002 in 530 Caucasians genotyped for this study). Markers associated with RA in populations of European ancestry (rs3087243 [+60C/T] and rs231775 [+49A/G]) were not replicated in African Americans. We found no confounding of association for rs231778 after stratifying for the HLA-DRB1 shared epitope, presence of anti-cyclic citrullinated peptide antibody, or degree of admixture from the European population. An African ancestry-specific genetic variant of CTLA4 appears to be associated with protection from RA in African Americans. This finding may explain, in part, the relatively low prevalence of RA in black African populations.