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The timing of parturition is crucial for neonatal survival and infant health. Yet, its genetic basis remains largely unresolved. We present a maternal genome-wide meta-analysis of gestational duration (n= 195,555), identifying 22 associated loci (24 independent variants) and an enrichment in genes differentially expressed during labor. A meta-analysis of preterm delivery (18,797 cases, 260,246 controls) revealed seven associated loci and large genetic similarities with gestational duration. Analysis of the parental transmitted and nontransmitted alleles (n= 136,833) shows that 15 of the gestational duration genetic variants act through the maternal genome, whereas 7 act both through the maternal and fetal genomes and 2 act only via the fetal genome. Finally, the maternal effects on gestational duration show signs of antagonistic pleiotropy with the fetal effects on birth weight: maternal alleles that increase gestational duration have negative fetal effects on birth weight. The present study provides insights into the genetic effects on the timing of parturition and the complex maternal–fetal relationship between gestational duration and birth weight.

Genetic variations in the tumor necrosis factor-[alpha], TNF receptors, interleukin-6 (IL-6) and IL-6 receptor genes predict high-risk status for spontaneous preterm birth in European-American women. Spontaneous preterm birth (sPTB) and low birth weight caused by preterm birth are primary risk factors for infant morbidity and mortality in the US and multiple extrinsic factors like infection, stress, socioeconomic status, nutrition, and behavioral factors are associated with the risk of sPTB.

Background:Plasmodium vivaxmalaria is endemic in Madagascar, where populations have genetic inheritance from Southeast Asia and East Africa. Primaquine, a drug of choice for vivax malaria, is metabolized principally via CYP2D6. CYP2D6variation was characterized by locus-specific gene sequencing and was compared with TaqMan™ genotype data. Materials & methods:Long-range PCR amplicons were generated from 96 Malagasy samples and subjected to next-generation sequencing. Results:The authors observed high concordance between TaqMan™-based CYP2D6genotype calls and the base calls from sequencing. In addition, there are new variants and haplotypes present in the Malagasy. Conclusion:Sequencing unique admixed populations provides more detailed and accurate insights regarding CYP2D6variability, which may help optimize primaquine treatment across human genetic diversity.

Diabetes and obesity have long been known to be related. The recently characterized adipocyte hormone resistin (also called FIZZ3/ADSF) has been implicated as a molecular link between impaired glucose tolerance [...]

Infection with Helicobacter pylori (H. pylori)is necessary but not sufficient for the development of gastric cancer, the third leading cause of cancer death globally. H. pyloriinfection affects over half of people globally; however, it does not affect populations uniformly. H. pyloriinfection rates are declining in western industrialized countries but are plateauing in developing and newly industrialized countries where gastric cancer is most prevalent. Despite H. pyloriinfection being the primary causative agent for gastric cancer, H. pyloriinfection can also cause other effects, detrimental or beneficial, throughout an individual’s life, with the beneficial effects often being seen in childhood and the deleterious effects in adulthood. H. pyloriis an ancient bacterium and its likelihood of affecting disease or health is dependent on both human and bacterial genetics that have co-evolved over millennia. In this review, we focus on the impact of infection and its genetic bases in different populations and diseases throughout an individual’s lifespan, highlighting the benefits of individualized treatment and argue that universal eradication of H. pyloriin its host may cause more harm than good for those infected with H. pylori.

The primary cause of gastric cancer is chronic infection with Helicobacter pylori (H. pylori), particularly the high-risk genotype cagA, and risk modification by human genetic variants. We studied 94 variants in 54 genes for association with gastric cancer, including rs2302615 in ornithine decarboxylase (ODC1), which may affect response to chemoprevention with the ODC inhibitor, eflornithine (difluoromethylornithine; DFMO). Our population-based, case-control study included 1366 individuals (664 gastric cancer cases and 702 controls) from Western Honduras, a high incidence region of Latin America. CagA seropositivity was strongly associated with cancer (OR = 3.6; 95% CI: 2.6, 5.1). The ODC1variant rs2302615 was associated with gastric cancer (OR = 1.36; p= 0.018) in a model adjusted for age, sex, and CagA serostatus. Two additional single nucleotide polymorphisms (SNPs) in CASP1(rs530537) and TLR4(rs1927914) genes were also associated with gastric cancer in univariate models as well as models adjusted for age, sex, and CagA serostatus. The ODC1SNP association with gastric cancer was stronger in individuals who carried the TT genotype at the associating TLR4polymorphism, rs1927914 (OR = 1.77; p= 1.85 × 10−3). In conclusion, the ODC1variant, rs2302615, is associated with gastric cancer and supports chemoprevention trials with DFMO, particularly in individuals homozygous for the T allele at rs1927914.

To link to full-text access for this article, visit this link: http://dx.doi.org/10.1016/j.ajog.2008.08.051 Byline: Digna R. Velez (a)(b), Stephen Fortunato (c)(d), Poul Thorsen (e), Salvatore J. Lombardi (c), Scott M. Williams (b), Ramkumar Menon (c)(e) Keywords: complex disease; genetic epidemiology; infection/inflammation; reproductive genetics Abstract: The objective of the study was to study the genetic risk factors of spontaneous preterm birth (PTB) in African Americans. Author Affiliation: (a) Dr John T. Macdonald Foundation Department of Human Genetics and Miami Institute of Human Genomics, University of Miami, Miami, FL (b) Center for Human Genetics Research, Vanderbilt University, Nashville, TN (c) Perinatal Research Center, Nashville, TN (d) Department of Obstetrics and Gynecology and Reproductive Science, Yale University Medical School, New Haven, CT (e) Northern Atlantic Epidemiologic Alliance, University of Aarhus, Aarhus, Denmark Article History: Received 15 April 2008; Revised 20 June 2008; Accepted 20 August 2008 Article Note: (footnote) This study was supported in part by grants from Elsass Foundation, Denmark (to R.M.); funds from the Maternal-Fetal Group, LLC, Nashville, TN (to S.F., S.J.L.); and National Institutes of Health Grant T32-GM-080178 (to D.R.V.)., Cite this article as: Velez DR, Fortunato S, Thorsen P, et al. Spontaneous preterm birth in African Americans is associated with infection and inflammatory response gene variants. Am J Obstet Gynecol 2009;200:209.e1-209.e27.

To link to full-text access for this article, visit this link: http://dx.doi.org/10.1016/j.ajog.2008.02.033 Byline: Hyagriv N. Simhan (a), Kelli K. Ryckman (b), Scott M. Williams (b), Marijane A. Krohn (a) Keywords: antiinflammatory cytokine; cervix; gene; interleukin-10 Abstract: The purpose of this study was to evaluate the contribution of maternal genotype to the concentration of interleukin (IL)-4, -10, and -13 in the cervix during the first trimester in the context of bacterial vaginosis and cigarette smoking. Author Affiliation: (a) Division of Maternal-Fetal Medicine and the Division of Reproductive Infectious Diseases and Immunology, Department of Obstetrics, Gynecology, and Reproductive Sciences, University of Pittsburgh School of Medicine, Magee-Womens Research Institute, Pittsburgh, PA (b) Center for Human Genetics, Vanderbilt University School of Medicine, Nashville, TN. Article History: Received 20 September 2007; Accepted 21 February 2008 Article Note: (footnote) Cite this article as: Simhan HN, Ryckman KK, Williams SM, Krohn MA. Genetic regulation of cervical antiinflammatory cytokine concentrations during pregnancy. Am J Obstet Gynecol 2008;199:163.e1-163.e11. , Reprints not available from the authors., This study was supported by National Institute of Child Health and Human Development Grants 1 R01 HD41663-01A1, 1 R01 HD052732-01, and M01-RR000056.

To link to full-text access for this article, visit this link: http://dx.doi.org/10.1016/j.ajog.2008.02.003 Byline: Stephen J. Fortunato (a)(d), Ramkumar Menon (a)(c), Digna R. Velez (b), Poul Thorsen (c), Scott M. Williams (b) Keywords: African American women; gene-gene interactions; inflammatory cytokines; multifactor dimensionality reduction; prematurity rate; preterm delivery; white women Abstract: To understand the differences in genetic interactions among tumor necrosis factor-alpha, interleukin-6 and their receptor gene variants between black and white patients in spontaneous preterm birth. Author Affiliation: (a) Perinatal Research Center, Vanderbilt University School of Medicine, Nashville, TN (b) Center for Human Genetics Research, Vanderbilt University School of Medicine, Nashville, TN (c) Institute for Public Health, North Atlantic Neuro-Epidemiology Alliances, University of Aarhus, Aarhus, Denmark (d) Department of Obstetrics and Gynecology and Reproductive Science, Yale University School of Medicine, New Haven, CT. Article History: Received 11 July 2007; Revised 21 November 2007; Accepted 4 February 2008 Article Note: (footnote) This study was supported by grants from Thrasher Research Funds, Salt Lake City, UT (S. J. F.)., Cite this article as: Fortunato SJ, Menon R, Velez DR, et al. Racial disparity in maternal-fetal genetic epistasis in spontaneous preterm birth. Am J Obstet Gynecol 2008;198:666.e1-666.e10.

Aim:Antimalarial primaquine (PQ) eliminates liver hypnozoites of Plasmodium vivax.CYP2D6gene variation contributes to PQ therapeutic failure. Additional gene variation may contribute to PQ efficacy. Information on pharmacogenomic variation in Madagascar, with vivaxmalaria and a unique population admixture, is scanty. Methods:The authors performed genome-wide genotyping of 55 Malagasy samples and analyzed data with a focus on a set of 28 pharmacogenes most relevant to PQ. Results:Mainly, the study identified 110 coding or splicing variants, including those that, based on previous studies in other populations, may be implicated in PQ response and copy number variation, specifically in chromosomal regions that contain pharmacogenes. Conclusion:With this pilot information, larger genome-wide association analyses with PQ metabolism and response are substantially more feasible.

ABSTRACTAminoglycosides such as amikacin continue to be part of the backbone of treatment of multidrug-resistant tuberculosis (MDR-TB). We measured amikacin concentrations in 28 MDR-TB patients in Botswana receiving amikacin therapy together with oral levofloxacin, ethionamide, cycloserine, and pyrazinamide and calculated areas under the concentration-time curves from 0 to 24 h (AUC0–24). The patients were followed monthly for sputum culture conversion based on liquid cultures. The median duration of amikacin therapy was 184 (range, 28 to 866) days, at a median dose of 17.30 (range 11.11 to 19.23) mg/kg. Only 11 (39%) patients had sputum culture conversion during treatment; the rest failed. We utilized classification and regression tree analyses (CART) to examine all potential predictors of failure, including clinical and demographic features, comorbidities, and amikacin peak concentrations (Cmax), AUC0–24, and trough concentrations. The primary node for failure had two competing variables, Cmaxof <67 mg/liter and AUC0–24of <568.30 mg · h/L; weight of >41 kg was a secondary node with a score of 35% relative to the primary node. The area under the receiver operating characteristic curve for the CART model was an R2= 0.90 on posttest. In patients weighing >41 kg, sputum conversion was 3/3 (100%) in those with an amikacin Cmaxof ≥67 mg/liter versus 3/15 (20%) in those with a Cmaxof <67 mg/liter (relative risk [RR] = 5.00; 95% confidence interval [CI], 1.82 to 13.76). In all patients who had both amikacin Cmaxand AUC0–24below the threshold, 7/7 (100%) failed, compared to 7/15 (47%) of those who had these parameters above threshold (RR = 2.14; 95% CI, 1.25 to 43.68). These amikacin dose-schedule patterns and exposures are virtually the same as those identified in the hollow-fiber system model.

Supplemental Digital Content is available in the text.

The African Society of Human Genetics (AfSHG) was formed to provide a forum for human genetics and genomics scientists in Africa to interact, network, and collaborate. This is critical to facilitate development of solutions to the public health burden of many rare and common diseases across the continent. AfSHG fully supports the Black Lives Matter movement, which is dedicated to fighting racism and ensuring that society values the lives and humanity of Black people. The AfSHG would like to add its “voice” to the public outcry against racism sparked by George Floyd’s death and to declare its commitment to ensuring that injustice and systematic racism, as well as abuse and exploitation of Africans and their biological material, are no longer tolerated. This is particularly relevant now as African genomic variation is poised to make significant contributions across several disciplines including ancestry, personalized medicine, and novel drug discovery. “Black Lives Matter and Black Research Matters” is AfSHG’s call for the global community to support halting, and reversing, the perpetuation of exploitation of African people through neocolonial malpractices in genomic research. We also propose five key ways to curb racism in science, so that we can move forward together, with a common humanity, collectively embracing scientific endeavors.

Warfarin is a widely prescribed anticoagulant, and its effect depends on various patient factors including genotypes. Randomized controlled trials (RCTs) comparing genotype-guided dosing (GD) of warfarin with standard dosing have shown mixed efficacy and safety outcomes. We performed a meta-analysis of all published RCTs comparing GD vs standard dosing in adult patients with various indications of warfarin use.

ABSTRACTAminoglycosides, such as amikacin, are used to treat multidrug-resistant tuberculosis. However, ototoxicity is a common problem and is monitored using peak and trough amikacin concentrations based on World Health Organization recommendations. Our objective was to identify clinical factors predictive of ototoxicity using an agnostic machine learning method. We used classification and regression tree (CART) analyses to identify clinical factors, including amikacin concentration thresholds that predicted audiometry-confirmed ototoxicity among 28 multidrug-resistant pulmonary tuberculosis patients in Botswana. Amikacin concentrations were measured for all patients. The quantitative relationship between predictive factors and the probability of ototoxicity were then identified using probit analyses. The primary predictors of ototoxicity on CART analyses were cumulative days of therapy, followed by cumulative area under the concentration-time curve (AUC), which improved on the primary predictor by 87%. The area under the receiver operating curve was 0.97 on the test set. Peak and trough were not predictors in any tree. When algorithms were forced to pick peak and trough as primary predictors, the area under the receiver operating curve fell to 0.46. Probit analysis revealed that the probability of ototoxicity increased sharply starting after 6 months of therapy to near maximum at 9 months. A 10% probability of ototoxicity occurred with a threshold cumulative AUC of 87,232 days · mg · h/liter, while that of 20% occurred at 120,000 days · mg · h/liter. Thus, cumulative amikacin AUC and duration of therapy, and not peak and trough concentrations, should be used as the primary decision-making parameters to minimize the likelihood of ototoxicity in multidrug-resistant tuberculosis.

Williams, Sirugo, and Tishkoff discuss the recent article by Choudhury et al.1reporting the whole-genome sequencing of 426 sub-Saharan African individuals and its contribution to the study of genetic diversity to understand human evolutionary history and health.

Letter to the Editor

Natural selection shapes many human genes, including some related to complex diseases. Understanding how selection affects genes, especially pleiotropic ones, may be important in evaluating disease associations and the role played by environmental variation. This may be of particular interest for genes with antagonistic roles that cause divergent patterns of selection. The lectin-like low-density lipoprotein 1 receptor, encoded by OLR1, is exemplary. It has antagonistic functions in the cardiovascular and immune systems because the same protein domain binds oxidized low-density lipoprotein and bacterial cell wall proteins, the former contributing to atherosclerosis and the latter presumably protecting from infection. We studied patterns of selection in this gene, in humans and nonhuman primates, to determine whether variable selection can lead to conflicting results in cardiovascular disease association studies.

One-third of the world's population has hypertension and it is responsible for almost 50 of deaths from stroke or coronary heart disease. These statistics do not distinguish salt-sensitive from salt-resistant hypertension or include normotensives who are salt-sensitive even though salt sensitivity, independent of blood pressure, is a risk factor for cardiovascular and other diseases, including cancer. This review describes new personalized diagnostic tools for salt sensitivity.

We conducted a genome-wide association study to identify novel associations between genetic variants and circulating plasminogen activator inhibitor-1 (PAI-1) concentration, and examined functional implications of variants and genes that were discovered. A discovery meta-analysis was performed in 19 599 subjects, followed by replication analysis of genome-wide significant (P< 5 × 10−8) single nucleotide polymorphisms (SNPs) in 10 796 independent samples. We further examined associations with type 2 diabetes and coronary artery disease, assessed the functional significance of the SNPs for gene expression in human tissues, and conducted RNA-silencing experiments for one novel association. We confirmed the association of the 4G/5G proxy SNP rs2227631 in the promoter region of SERPINE1(7q22.1) and discovered genome-wide significant associations at 3 additional loci: chromosome 7q22.1 close to SERPINE1(rs6976053, discovery P= 3.4 × 10−10); chromosome 11p15.2 within ARNTL(rs6486122, discovery P= 3.0 × 10−8); and chromosome 3p25.2 within PPARG(rs11128603, discovery P= 2.9 × 10−8). Replication was achieved for the 7q22.1 and 11p15.2 loci. There was nominal association with type 2 diabetes and coronary artery disease at ARNTL(P< .05). Functional studies identified MUC3as a candidate gene for the second association signal on 7q22.1. In summary, SNPs in SERPINE1and ARNTLand an SNP associated with the expression of MUC3were robustly associated with circulating levels of PAI-1.

Vascular α2B-adrenergic receptors (α2B-ARs) mediate vasoconstriction and contribute to peripheral regulation of vascular tone. In vitro, a common 301–303 deletion in the α2B-AR gene, ADRA2B, results in loss of α2B-AR desensitization. We examined the hypothesis that ADRA2Bdel301–303 or other common ADRA2Bvariants alter vascular desensitization in vivo.

Prior to the discovery of chloride channel Kb with a variant threonine change to serine at position 481 (CLCNKB-T481S) there were no variants or clinical disorders associated with gain-of-function defects in thick ascending limb of the kidney channels or transporters. CLCNKB-T481S is a novel gain-of-function variant that has been associated with essential hypertension. This finding has not been replicated until our current study. In this study, we re-examined CLCNKB-T481S using a large homogenous population from Ghana, and coupled genetic analyses with the functional characterization of this polymorphism using a mammalian expression system.

The genetic basis of phenotypic variation across populations has not been well explained for most traits. Several factors may cause disparities, from variation in environments to divergent population genetic structure. We hypothesized that a population-level polygenic risk score (PRS) can explain phenotypic variation among geographic populations based solely on risk allele frequencies. We applied a population-specific PRS (psPRS) to 26 populations from the 1000 Genomes to four phenotypes: lactase persistence (LP), melanoma, multiple sclerosis (MS) and height. Our models assumed additive genetic architecture among the polymorphisms in the psPRSs, as is convention. Linear psPRSs explained a significant proportion of trait variance ranging from 0.32 for height in men to 0.88 for melanoma. The best models for LP and height were linear, while those for melanoma and MS were nonlinear. As not all variants in a PRS may confer similar, or even any, risk among diverse populations, we also filtered out SNPs to assess whether variance explained was improved using psPRSs with fewer SNPs. Variance explained usually improved with fewer SNPs in the psPRS and was as high as 0.99 for height in men using only 548 of the initial 4208 SNPs. That reducing SNPs improves psPRSs performance may indicate that missing heritability is partially due to complex architecture that does not mandate additivity, undiscovered variants or spurious associations in the databases. We demonstrated that PRS-based analyses can be used across diverse populations and phenotypes for population prediction and that these comparisons can identify the universal risk variants.

Black patients may be less responsive to -blockers than whites. Genetic variants in the 1-adrenergic receptor (1-AR) associated with lesser response to -blockers are more common in blacks than in whites. The purpose of this study was to determine whether ethnic differences in response to -blockade can be explained by differing distributions of functional genetic variants in the 1-AR.

More than 20 years after the identification of Helicobacter pylori as a human pathogen, gastric cancer continues to be a leading cause of cancer deaths worldwide. Genetic association studies have the potential for helping to identify those at greatest risk for developing gastric cancer subsequent to infection by H. pylori. IL1B promoter polymorphisms have been supported by several meta-analyses as being associated with gastric cancer risk. In this review, we discuss challenges in experimental design of gene association studies in gastric cancer, with attention to gene-environment interactions that may lead to inconsistency in findings across populations.

The 2B-adrenergic receptor (ADRA2B) plays an important role in vasoconstriction and blood pressure regulation. One common variant in the ADRA2Bgene (del301–303) has been identified, and results in markedly decreased receptor desensitization in vitrobut does not alter vascular sensitivity in vivo. Therefore, we fully characterized genetic variations in ADRA2Band related them to phenotype in vivo. We examined 5812 bp of contiguous sequence of ADRA2B(promoter, exonic, and 3′-untranslated region; 3′-UTR) using the polymerase chain reaction to amplify the genomic target followed by bidirectional sequencing (n68). Haplotypes were inferred using an expectation maximization algorithm. Vasoconstriction in response to increasing doses of the highly selective 2-adrenergic receptor agonist, dexmedetomidine (0.01–1000 ngmin) was measured in the dorsal hand vein using a linear variable differential transformer. The dose that produced 50 (ED50) of maximum venoconstriction (Emax) was determined for each subject from the individual dose–response curves. ED50and Emaxwere compared in subjects with and without variant alleles and haplotypes of interest. We identified 24 variable sites, 12 in the promoter region, five in the coding region (including two previously described as non-synonymous variants) and seven in the 3′-UTR region. Four haplotypes were inferred, representing approximately 95 of the cohort. One haplotype, characterized by two single nucleotide polymorphisms in the promoter region, and one in the 3′-UTR, occurred in seven of 38 African-Americans, and was associated with a lower Emax, 61.3 95 confidence interval (CI) 39.5–83.0, n7 compared to 78.1 (CI 73.8–82.5) in wild-types (n61) (P0.02). There was no association between the nine common variants and dexmedetomidine ED50. We have described novel variants and haplotypes of the ADRA2Bgene. These do not alter sensitivity to a selective 2-adrenergic receptor agonist but some may decrease maximal venoconstriction in vivo.

While hypertension is a complex disease with a well-documented genetic component, genetic studies often fail to replicate findings. One possibility for such inconsistency is that the underlying genetics of hypertension is not based on single genes of major effect, but on interactions among genes. To test this hypothesis, we studied both single locus and multilocus effects, using a case-control design of subjects from Ghana. Thirteen polymorphisms in eight candidate genes were studied. Each candidate gene has been shown to play a physiological role in blood pressure regulation and affects one of four pathways that modulate blood pressure: vasoconstriction (angiotensinogen, angiotensin converting enzyme – ACE, angiotensin II receptor), nitric oxide (NO) dependent and NO independent vasodilation pathways and sodium balance (G protein-coupled receptor kinase, GRK4). We evaluated single site allelic and genotypic associations, multilocus genotype equilibrium and multilocus genotype associations, using multifactor dimensionality reduction (MDR). For MDR, we performed systematic reanalysis of the data to address the role of various physiological pathways. We found no significant single site associations, but the hypertensive class deviated significantly from genotype equilibrium in more than 25% of all multilocus comparisons (2,162 of 8,178), whereas the normotensive class rarely did (11 of 8,178). The MDR analysis identified a two-locus model including ACE and GRK4 that successfully predicted blood pressure phenotype 70.5% of the time. Thus, our data indicate epistatic interactions play a major role in hypertension susceptibility. Our data also support a model where multiple pathways need to be affected in order to predispose to hypertension.

Factor XI is the zymogen of a plasma protease produced primarily in liver that is required for normal blood coagulation. We cloned ∼2600 base pairs of the human factor XI gene upstream of exon one, identified transcription start sites, and conducted a functional analysis. Luciferase reporter assays demonstrate that the 381 base pairs upstream of exon one are sufficient for maximum promoter activity in HepG2 hepatocellular carcinoma cells. The removal of 19 base pairs between −381 and −363 results in a nearly complete loss of promoter activity. This region contains the sequence ACTTTG, a motif required for binding of the transcription factor hepatocyte nuclear factor 4α (HNF-4α) to the promoters of several genes. Gel mobility shift assays using HepG2 or rat hepatocyte nuclear extract confirm HNF-4α binds between bp −375 and −360. Scrambling the ACTTTG motif completely abolishes promoter activity in luciferase assays. The factor XI promoter functions poorly when transfected into HeLa carcinoma cells, and gel mobility shift experiments with HeLa nuclear extracts demonstrate no HNF-4α binding to the ACTTTG sequence. When a rat HNF-4α expression construct is co-transfected into HeLa cells, factor XI promoter activity is enhanced ∼10-fold. We conclude that HNF-4α is required for hepatocyte-specific expression of factor XI.

We have identified, in four diverse human populations, five common single-nucleotide polymorphisms (SNPs) in the coding region of the gene for the blood coagulation protease factor XI. Each SNP has an allele frequency >5% in at least one population. Three of the SNPs (C472T, A844G, and T1234C), spread out over approximately 10 kb of genomic DNA, are in marked linkage disequilibrium (LD) with one another (P< 10−4). Interestingly, haplotypes associated with the linked SNPs are conserved across all populations studied, despite significantly different allele frequencies between populations. The presence of such common, widely dispersed haplotypes could complicate the interpretation of LD studies and emphasizes the need for a better understanding of general patterns of LD to facilitate identification of genes for common disorders.

True fruit flies belonging to the Rhagoletis pomonella(Diptera:Tephritidae) sibling species complex possess several attributes consistent with a history of sympatric divergence via host plant shifts. Here, we investigate whether hybridization and genetic introgression is occurring between two members of the group, Rhagoletis pomonella(Walsh), whose primary hosts are domestic apples (Malus pumila) and hawthorns (Crataegusspp., and R. zephyria(Snow) whose host is snowberries (Symphoricarposspp.). These flies are important because they appear to be at a transition stage between taxa reproductively isolated solely on the basis of host plant‐related adaptations and those that have evolved additional non‐host dependent sterility and inviability. Observing extensive hybridization and introgression between R. pomonellaand R. zephyriawould have major repercussions for current models of sympatric speciation.

Length variation of the ribosomal gene spacers of Drosophila melanogasterwas studied. Analysis of 47 Xchromosomal and 47 Ychromosomal linked rDNA arrays collected from five continents indicates that the arrays on the two chromosomes differ qualitatively. The Y-linked arrays from around the world share little or no similarity for either their overall length or the organization of their spacers. Most of the X-linked arrays do, however, share a major length spacer of 5.1 kb. In addition, those X-linked arrays that have a major 5.1-kb band have similar spacer organization as demonstrated by genomic DNA digestions with several restriction enzymes. These data strongly support the hypothesis that spacer length patterns on only X-linked genes are maintained primarily by natural selection.

Heterochromatin is an important component of eukaryotic chromosomes, comprising a significant portion of the total DNA in genomes. Despite its prevalence, long-standing cytological descriptions, and predominant composition of tandemly repeated DNA, no general theory unites heterochromatic structure with its functions. In an attempt to identify heterochromatic sequence tags, we have analysed heterochromatic sequences fromDrosophila melanogasterfor the presence of motifs that are known to define regions that anchor the chromosomal DNA to the scaffold (scaffold attachment regions or SARs). The SARs ofDrosophila melanogasterare characterized by the presence of a small conserved sequence (the A-box) that is clustered in overall A + T-rich regions. In comparing heterochromatic and euchromatic sequences we find that heterochromatic regions are several-fold enriched for these operationally defined SARs. This high density of SAR-associated sequences not only serves as a molecular tag for heterochromatin but also suggests a hypothesis for its special properties.

Hardy‐Weinberg equilibrium (HWE) is an important tool for understanding population structure. If certain assumptions are met, genotype and allele frequencies can be estimated from one generation to the next. In genetic association studies, HWE principles have been applied to detect genotyping error and disease susceptibility loci. The focus of this unit is to review the key principles and assumptions of HWE. There is a brief discussion on how the significance of HWE is tested, and a review of current applications of HWE in association studies. The applications discussed include estimating penetrance, evaluating genotyping errors, testing for population stratification, and testing for association. Curr. Protoc. Hum. Genet. 57:1.18.1‐1.18.11. © 2008 by John Wiley & Sons, Inc.