Papers by Christopher Bean
Human Molecular Genetics, 2001
Despite the clinical importance of human aneuploidy, we know little of the causes of mammalian no... more Despite the clinical importance of human aneuploidy, we know little of the causes of mammalian non-disjunction. In part, this reflects the fact that, unlike lower organisms, segregation 'impaired' chromosomes are virtually non-existent in mammals. To address this issue, we have studied the mouse Y chromosome on the BALB/cWt ('Wt') inbred background, a system in which loss of the Y chromosome in gonadal tissue has been linked to hermaphroditism. Our results indicate that the Wt Y chromosome is stably transmitted during meiotic cell divisions, but non-disjoins at an extremely high frequency in mitosis. Surprisingly, the nondisjunction events are largely restricted to the earliest cleavage divisions, indicating that there is a temporal 'window' during which the Wt Y chromosome is susceptible to non-disjunction. The non-disjunction phenotype has both cis and trans components: the Wt Y chromosome malsegregates on a variety of genetic backgrounds, demonstrating an intrinsic defect; however, the incidence of non-disjunction is significantly influenced by strain background, indicating the existence of modifying loci and thus providing evidence for a genetic effect on mammalian nondisjunction. These studies suggest that the earliest cell divisions in mammals are non-disjunction-prone, an interpretation which provides an explanation for the high rate of chromosome mosaicism observed in studies of in vitro fertilization (IVF)-derived human preimplantation embryos. Further, our observations raise the possibility that the IVF setting adversely affects chromosome segregation and suggest that genetic quality be an important consideration in any attempt to improve or modify in vitro procedures for use on human eggs and embryos.
British Journal of Haematology, 2013
Genetic diversity at the human β-globin locus has been implicated as a modifier of sickle cell an... more Genetic diversity at the human β-globin locus has been implicated as a modifier of sickle cell anaemia (SCA) severity. However, haplotypes defined by restriction fragment length polymorphism sites across the β-globin locus have not been consistently associated with clinical phenotypes. To define the genetic structure at the β-globin locus more thoroughly, we performed high-density single nucleotide polymorphism (SNP) mapping in 820 children who were homozygous for the sickle cell mutation (HbSS). Genotyping results revealed very high linkage disequilibrium across a large region spanning the locus control region and the HBB (β-globin gene) cluster. We identified three predominant haplotypes accounting for 96% of the β S-carrying chromosomes in this population that could be distinguished using a minimal set of common SNPs. Consistent with previous studies, fetal haemoglobin level was significantly associated with β S-*
Public Health Genomics, 2014
Sickle cell disease (SCD) is an autosomal recessive genetic disorder, with persons heterozygous f... more Sickle cell disease (SCD) is an autosomal recessive genetic disorder, with persons heterozygous for the mutation said to have the sickle cell trait (SCT). Serious adverse effects are mainly limited to those with SCD, but the distinction between disease and trait is not always clear to the general population. We sought to determine the accuracy of self-reported SCD when compared to genetic confirmation. From stratified random samples of Southern Community Cohort Study participants, we sequenced the β- globin gene in 51 individuals reporting SCD and 75 individuals reporting no SCD. The median age of the group selected was 53 years (range 40-69) with 29% male. Only 5.9% of the 51 individuals reporting SCD were confirmed by sequencing, with the remaining 62.7% having SCT, 5.9% having hemoglobin C trait, and 25.5% having neither SCD nor trait. Sequencing results of the 75 individuals reporting no SCD by contrast were 100% concordant with self-report. Misreporting of SCD is common in an older adult population, with most persons reporting SCD in this study being carriers of the trait and a sizeable minority completely unaffected. The results from this pilot survey support the need for increased efforts to raise community awareness and knowledge of SCD.
Thrombosis Research, 2012
Venous thromboembolism (VTE) affects as many as 1 in 1000 individuals in the United States. Altho... more Venous thromboembolism (VTE) affects as many as 1 in 1000 individuals in the United States. Although Blacks are disproportionately affected by VTE, few genetic risk factors have been identified in this population. The inducible heme oxygenase-1 (HMOX1) gene encodes a key cytoprotective enzyme with anti-inflammatory, antioxidant and anticoagulant activity acting in the vascular system. A (GT)(n) microsatellite located in the promoter of the HMOX1 gene influences the level of response. Using the Genetic Attributes and Thrombosis Epidemiology (GATE) study, we examined the association between HMOX1 repeat length and VTE events in 883 Black and 927 White patients and matched controls. We found no association between HMOX1 genotypes and VTE in Whites. However, in Black patients, carrying two long (L) alleles (≥ 34 repeats) was significantly associated with provoked (odds ratio (OR) 1.86, 95% confidence interval (CI): 1.19-2.90) or recurrent (OR 3.13, 95% CI: 1.77-5.53) VTE events. We have demonstrated for the first time an association between genetic variation in HMOX1, and VTE in Blacks. Our results support a key role for the heme oxygenase system in protecting patients at increased risk for thrombosis and suggest a potential mechanism for targeted screening and intervention.
PLoS ONE, 2013
In pediatric sickle cell disease (SCD) patients, it has been reported that higher systolic blood ... more In pediatric sickle cell disease (SCD) patients, it has been reported that higher systolic blood pressure (SBP) is associated with increased risk of a silent cerebral infarction (SCI). SCI is a major cause of neurologic morbidity in children with SCD, and blood pressure is a potential modulator of clinical manifestations of SCD; however, the risk factors underlying these complications are not well characterized. The aim of this study was to identify genetic variants that influence SBP in an African American population in the setting of SCD, and explore the use of SBP as an endo-phenotype for SCI. We conducted a genome-wide meta-analysis for SBP using two SCD cohorts, as well as a candidate screen based on published SBP loci. A total of 1,617 patients were analyzed, and while no SNP reached genome-wide significance (P-value<5.0x10 -8 ), a number of suggestive candidate loci were identified. The most significant SNP, rs7952106 (P-value=8.57x10 -7 ), was in the DRD2 locus on chromosome 11. In a gene-based association analysis, MIR4301 (micro-RNA4301), which resides in an intron of DRD2, was the most significant gene (P-value=5.2x10 -5 ). Examining 27 of the previously reported SBP associated SNPs, 4 SNPs were nominally significant. A genetic risk score was constructed to assess the aggregated genetic effect of the published SBP variants, demonstrating a significant association (P=0.05). In addition, we also assessed whether these variants are associated with SCI, validating the use of SBP as an endo-phenotype for SCI. Three SNPs were nominally associated, and only rs2357790 (5' CACNB2) was significant for both SBP and SCI. None of these SNPs retained significance after Bonferroni correction. Taken together, our results suggest the importance of DRD2 genetic variation in the modulation of SBP, and extend the aggregated importance of previously reported SNPs in the modulation of SBP in an African American cohort, more specifically in children with SCD.
Pediatric Blood & Cancer, 2013
Nat Genet, 2003
The genetic imprinting of individual loci or whole chromosomes, as in imprinted X-chromosome inac... more The genetic imprinting of individual loci or whole chromosomes, as in imprinted X-chromosome inactivation in mammals 1,2 , is established and reset during gametogenesis; defects in this process in the parent can result in disease in the offspring 3 . We describe a sperm-specific chromatin-based imprinting of the X chromosome in the nematode Caenorhabditis elegans that is restricted to histone H3 modifications. The epigenetic imprint is established during spermatogenesis and its stability in the offspring is affected by the presence of a pairing partner during meiosis in the parental germ line. We observed that DNA lacking a pairing partner during meiosis, the normal situation for the X chromosome in males, is targeted for methylation of histone H3 at Lys9 (H3-Lys9) and can be silenced. Targeting unpaired DNA for silencing during meiosis, a potential hallmark of genome defense, could therefore have a conserved role in imprinted X-chromosome inactivation and, ultimately, in sex chromosome evolution.
Stroke, 2014
Background and Purpose-Although the prothrombin G20210A mutation has been implicated as a risk fa... more Background and Purpose-Although the prothrombin G20210A mutation has been implicated as a risk factor for venous thrombosis, its role in arterial ischemic stroke is unclear, particularly among young adults. To address this issue, we examined the association between prothrombin G20210A and ischemic stroke in a white case-control population and additionally performed a meta-analysis. Methods-From the population-based Genetics of Early Onset Stroke (GEOS) study, we identified 397 individuals of European ancestry aged 15 to 49 years with first-ever ischemic stroke and 426 matched controls. Logistic regression was used to calculate odds ratios (ORs) in the entire population and for subgroups stratified by sex, age, oral contraceptive use, migraine, and smoking status. A meta-analysis of 17 case-control studies (n=2305 cases <55 years) was also performed with and without GEOS data. Results-Within GEOS, the association of the prothrombin G20210A mutation with ischemic stroke did not achieve statistical significance (OR=2.5; 95% confidence interval [CI]=0.9-6.5; P=0.07). However, among adults aged 15 to 42 years (younger than median age), cases were significantly more likely than controls to have the mutation (OR=5.9; 95% CI=1.2-28.1; P=0.03), whereas adults aged 42 to 49 years were not (OR=1.4; 95% CI=0.4-5.1; P=0.94). In our meta-analysis, the mutation was associated with significantly increased stroke risk in adults ≤55 years (OR=1.4; 95% CI=1.1-1.9; P=0.02), with significance increasing with addition of the GEOS results (OR=1.5; 95% CI=1.1-2.0; P=0.005). Conclusions-The prothrombin G20210A mutation is associated with ischemic stroke in young adults and may have an even stronger association among those with earlier onset strokes. Our finding of a stronger association in the younger young adult population requires replication. (Stroke. 2014;45:961-967.)
PLoS ONE, 2012
Serum bilirubin levels have been associated with polymorphisms in the UGT1A1 promoter in normal p... more Serum bilirubin levels have been associated with polymorphisms in the UGT1A1 promoter in normal populations and in patients with hemolytic anemias, including sickle cell anemia. When hemolysis occurs circulating heme increases, leading to elevated bilirubin levels and an increased incidence of cholelithiasis. We performed the first genome-wide association study (GWAS) of bilirubin levels and cholelithiasis risk in a discovery cohort of 1,117 sickle cell anemia patients. We found 15 single nucleotide polymorphisms (SNPs) associated with total bilirubin levels at the genome-wide significance level (p value ,5610 28 ). SNPs in UGT1A1, UGT1A3, UGT1A6, UGT1A8 and UGT1A10, different isoforms within the UGT1A locus, were identified (most significant rs887829, p = 9.08610 225 ). All of these associations were validated in 4 independent sets of sickle cell anemia patients. We tested the association of the 15 SNPs with cholelithiasis in the discovery cohort and found a significant association (most significant p value 1.15610 24 ). These results confirm that the UGT1A region is the major regulator of bilirubin metabolism in African Americans with sickle cell anemia, similar to what is observed in other ethnicities.
Paediatric and Perinatal Epidemiology, 2012
Very preterm birth (VPTB) is a leading cause of infant mortality, morbidity and racial disparity ... more Very preterm birth (VPTB) is a leading cause of infant mortality, morbidity and racial disparity in the U.S. The underlying causes of VPTB are multiple and poorly understood. The California Very Preterm Birth Study was conducted to discover maternal and infant genetic and environmental factors associated with VPTB. This paper describes the study design, population, data and specimen collection, laboratory methods and characteristics of the study population. Using a large, population-based cohort created through record linkage of livebirths delivered from 2000 to 2007 in five counties of southern California, and existing data and banked specimens from state-wide prenatal and newborn screening, 1100 VPTB cases and 796 control mother-infant pairs were selected for study (385/200 White, 385/253 Hispanic and 330/343 Black cases/controls, respectively). Medical record abstraction of cases was conducted at over 50 hospitals to identify spontaneous VPTB, improve accuracy of gestational age, obtain relevant clinical data and exclude cases that did not meet eligibility criteria. VPTB was defined as birth at <32 weeks in Whites and Hispanics and <34 weeks in Blacks. Approximately 55% of all VPTBs were spontaneous and 45% had medical indications or other exclusions. Of the spontaneous VPTBs, approximately 41% were reported to have chorioamnionitis. While the current focus of the California Very Preterm Birth Study is to assess the role of candidate genetic markers on spontaneous VPTB, its design enables the pursuit of other research opportunities to identify social, clinical and biological determinants
Nature Genetics, 2004
The genetic imprinting of individual loci or whole chromosomes, as in imprinted X-chromosome inac... more The genetic imprinting of individual loci or whole chromosomes, as in imprinted X-chromosome inactivation in mammals 1,2 , is established and reset during gametogenesis; defects in this process in the parent can result in disease in the offspring 3 . We describe a sperm-specific chromatin-based imprinting of the X chromosome in the nematode Caenorhabditis elegans that is restricted to histone H3 modifications. The epigenetic imprint is established during spermatogenesis and its stability in the offspring is affected by the presence of a pairing partner during meiosis in the parental germ line. We observed that DNA lacking a pairing partner during meiosis, the normal situation for the X chromosome in males, is targeted for methylation of histone H3 at Lys9 (H3-Lys9) and can be silenced. Targeting unpaired DNA for silencing during meiosis, a potential hallmark of genome defense, could therefore have a conserved role in imprinted X-chromosome inactivation and, ultimately, in sex chromosome evolution.
Mechanisms of Development, 2005
RNA helicase A (RHA) is a multifunctional protein with established roles in chromatin regulation.... more RNA helicase A (RHA) is a multifunctional protein with established roles in chromatin regulation. The protein is conserved in worms, Drosophila, and mammals, but its role in worms has not been previously studied. We found that a deletion mutant lacking rha-1 has a temperature-sensitive defect in germline transcriptional silencing, consistent with RHA-1 having a function in transcription regulation. Transcriptional desilencing in these rha-1(tm329) mutants was associated with a loss of lysine 9 methylation on histone H3 that is normally associated with silenced chromatin. Other histone modifications are also mis-localized in the germ cells in the mutants. These defects in histone modifications suggest that there is a general transcription regulation defect in the mutant worms that results in a temperature-sensitive sterile phenotype. At the restrictive temperature, the extent of germ cell mitoses is reduced, and the mutants are sterile due to defects in meiosis and gametogenesis. Our results suggest that RHA-1 is a conserved transcription regulation protein that controls germline proliferation and development in C. elegans.
Mechanisms of Development, 2014
A v ai l abl e a t w w w . s c i e n c e d i r e c t. c o m ScienceDirect j o u r n a l h o m e p... more A v ai l abl e a t w w w . s c i e n c e d i r e c t. c o m ScienceDirect j o u r n a l h o m e p a g e : w w w . e l s e v i e r . c o m / l o c a t e / m o d o Please cite this article in press as: Walstrom, K.M. et al, Corrigendum to 'RNA helicase A is important for germline transcriptional control, proliferation, and meiosis in C. elegans' [Mechanisms of Development 122 (2005) 707-720], Mech. Dev. (2014), http://dx.
Journal of Women's Health, 2008
Preterm birth is one of the leading causes of infant mortality and the leading cause of infant mo... more Preterm birth is one of the leading causes of infant mortality and the leading cause of infant morbidity in the United States. It accounts for &amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;gt;70% of neonatal deaths and almost half of long-term neurological disabilities. The Centers for Disease Control and Prevention (CDC) is collaborating with state health departments, universities, communities, and healthcare providers to understand why preterm births occur and how to address preterm birth risk factors. These collaborations include identification of genetic and other biological markers for the early detection of women at high risk of preterm birth; improving understanding of the relationships among psychosocial stress, immune and inflammatory responses, and preterm risk; and designing community strategies to improve the health of pregnant women. By conducting public health research activities that explore the genetic, biological, clinical, behavioral, social, and community determinants of preterm birth, CDC will continue to elucidate the complex interactions of these factors and how they influence preterm birth.
Human Reproduction, 2002
BACKGROUND: We have been studying an unusual mouse-the BALB/cWt (Wt) male-in which the Y chromoso... more BACKGROUND: We have been studying an unusual mouse-the BALB/cWt (Wt) male-in which the Y chromosome is susceptible to high rates of mitotic non-disjunction, particularly at the first two cleavage divisions. As these are the same divisions that human embryos generated through assisted reproductive technology must complete in an artificial setting, analysis of the Wt Y chromosome allows us to examine the effect of fertilization and culture in vitro on mammalian chromosome segregation. METHODS: We performed standard mouse IVF, cultured embryos in 5% CO 2 in air or in a lowered oxygen atmosphere, and used fluorescence in-situ hybridization to examine the sex chromosome constitutions of 2-, 4-, 8-and 16-cell stage Wt Y-bearing embryos. RESULTS: We observed a significant increase in mosaic sex chromosome aneuploidy at each embryonic stage in embryos cultured in 5% CO 2 in air, but under lowered oxygen conditions mosaicism returned to control (in-vivo) levels. CONCLUSIONS: Our results demonstrate that slight alterations in in-vitro conditions may have a considerable impact on the genetic quality of assisted reproductive technology-derived embryos and suggest that the genetic quality of embryos should be a fundamental concern in the development of new culture systems for clinical use.
Human Genetics, 1997
Over the past few years, several groups have used fluorescence in situ hybridization (FISH) to st... more Over the past few years, several groups have used fluorescence in situ hybridization (FISH) to study aneuploidy in human sperm. Several important observations have derived from these studies, including the demonstration of chromosome-specific variation in non-disjunction frequencies, and the possible association of aneuploidy with environmental agents and with increasing paternal age. However, an important technical limitation of these studies has been the inability to distinguish between autosomal non-disjunction occurring at meiosis I and meiosis II. In the present report, we describe a simple FISH-based approach designed to overcome this limitation. Using oligonucleotide probes capable of distinguishing subtle differences in the alpha satellite sequences of chromosome 17, we demonstrate that (in appropriate heterozygotes) it is possible to simultaneously identify disomic sperm and to determine the meiotic stage of origin of the additional chromosome. This novel approach has important implications for future FISH sperm studies, since the ability to distinguish between meiosis I and meiosis II non-disjunction will make it possible to determine whether putative etiological agents affect chromosome segregation at both, or only one, of the two meiotic stages.
British Journal of Haematology, 2013
Genetic diversity at the human b-globin locus has been implicated as a modifier of sickle cell an... more Genetic diversity at the human b-globin locus has been implicated as a modifier of sickle cell anaemia (SCA) severity. However, haplotypes defined by restriction fragment length polymorphism sites across the b-globin locus have not been consistently associated with clinical phenotypes. To define the genetic structure at the b-globin locus more thoroughly, we performed high-density single nucleotide polymorphism (SNP) mapping in 820 children who were homozygous for the sickle cell mutation (HbSS). Genotyping results revealed very high linkage disequilibrium across a large region spanning the locus control region and the HBB (b-globin gene) cluster. We identified three predominant haplotypes accounting for 96% of the b S -carrying chromosomes in this population that could be distinguished using a minimal set of common SNPs. Consistent with previous studies, fetal haemoglobin level was significantly associated with b S -haplotypes. After controlling for covariates, an association was detected between haplotype and rate of hospitalization for acute chest syndrome (ACS) (incidence rate ratio 0Á51, 95% confidence interval 0Á29-0Á89) but not incidence rate of vaso-occlusive pain or presence of silent cerebral infarct (SCI). Our results suggest that these SNP-defined b S -haplotypes may be associated with ACS, but not pain or SCI in a study population of children with SCA.
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Papers by Christopher Bean