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Sample records for 5-httlpr allele homozygotes

  1. Does 5HTTLPR long allele prevent hospitalization? Test of Hardy-Weinberg equilibrium.

    PubMed

    Shinozaki, Gen; Kung, Simon; Mrazek, David A

    2014-02-01

    Many studies suggest an association of the serotonin transporter gene polymorphism (5HTTLPR) long allele with better antidepressant treatment response than the short allele. However, there is controversy over these findings. We hypothesized that if the long allele is associated with a better outcome, we would find fewer inpatients with the long allele compared with the short allele. Chart review identified 925 depressed inpatients and 201 outpatients genotyped for 5HTTLPR. The sample was primarily White (>90%). We tested potential departures from Hardy-Weinberg equilibrium for each sample. We analyzed three independent sets of inpatient samples separately and combined, a White subgroup of 791 patients of the total 925 inpatients, and 201 outpatients. There was no departure from Hardy-Weinberg equilibrium with any of these samples. We also compared 5HTTLPR genotype prevalence between 925 inpatients and 201 outpatients, which showed no statistically significant difference.

  2. Short Alleles, Bigger Smiles? The Effect of 5-HTTLPR on Positive Emotional Expressions

    PubMed Central

    Haase, Claudia M.; Beermann, Ursula; Saslow, Laura R.; Shiota, Michelle N.; Saturn, Sarina R.; Lwi, Sandy J.; Casey, James J.; Nguyen, Nguyen K.; Whalen, Patrick K.; Keltner, Dacher J.; Levenson, Robert W.

    2015-01-01

    The present research examined the effect of the 5-HTTLPR polymorphism in the serotonin transporter gene on objectively coded positive emotional expressions (i.e., laughing and smiling behavior objectively coded using the Facial Action Coding System). Three studies with independent samples of participants were conducted. Study 1 examined young adults watching still cartoons. Study 2 examined young, middle-aged, and older adults watching a thematically ambiguous yet subtly amusing film clip. Study 3 examined middle-aged and older spouses discussing an area of marital conflict (which typically produces both positive and negative emotion). Aggregating data across studies, results showed that the short allele of 5-HTTLPR predicted heightened positive emotional expressions. Results remained stable when controlling for age, gender, ethnicity, and depressive symptoms. These findings are consistent with the notion that the short allele of 5-HTTLPR functions as an emotion amplifier, which may confer heightened susceptibility to environmental conditions. PMID:26029940

  3. Is serotonin transporter polymorphism (5-HTTLPR) allele status a predictor for obsessive-compulsive disorder? A meta-analysis.

    PubMed

    Mak, Lauren; Streiner, David L; Steiner, Meir

    2015-06-01

    The serotonin transporter polymorphism has been implicated in obsessive-compulsive disorder (OCD). However, molecular genetic association studies have yielded inconsistent results. Variation may be due to lack of OCD subtype classification. The goal of this systematic review is to investigate the association of the S-allele of the serotonin transporter polymorphism with OCD and OCD subtypes. A total of 69 studies were initially found through a systematic search of the literature but only 13 with sufficient information to compute odds ratios were suitable for review. A total of 1991 participants with OCD and their 5-HTTLPR allele status were examined. The primary outcome measures were allele frequency and OCD diagnosis. A full meta-analysis was completed comparing the L- and S-alleles using a random effects model in RevMan 5.2.1. Further, a secondary meta-analysis stratified by sex and late-onset was conducted for S- versus L-allele frequency. In the primary meta-analysis, OCD was not associated with the S-allele of the 5-HTTLPR polymorphism (Z = 0.07, p = 0.94). Moreover, late-onset OCD was not associated with the S-allele (Z = 1.45, p = 0.15). However, when stratified by sex, there is an emerging sex-specific relationship. There was a trending association between the S-allele and OCD status in females (Z = 1.62, p = 0.10) but not in males (Z = 0.69, p = 0.49). The findings provide further support for the need of subtype classification of this heterogeneous disorder. Future studies should clearly examine sex differences and OCD age-of-onset. In particular, emphasis should be placed on the effect of female reproductive milestones on OCD onset and symptom exacerbation.

  4. Association of the Serotonin Transporter Gene Promoter Region (5-HTTLPR) Polymorphism with Biased Attention for Emotional Stimuli

    PubMed Central

    Beevers, Christopher G.; Wells, Tony T.; Ellis, Alissa J.; McGeary, John E.

    2010-01-01

    A deletion polymorphism in the serotonin transporter-linked polymorphic region (5-HTTLPR) has been associated with vulnerability to affective disorders, yet the mechanism by which this gene confers vulnerability remains unclear. Two studies examined associations between the 5-HTTLPR polymorphism and attentional bias for emotional stimuli among non-depressed adults. Biased attention, attention engagement, and difficulty with attention disengagement were assessed with a spatial cueing task using emotional stimuli. Results from Study 1 (N = 38) indicated that short 5-HTTLPR allele carriers experienced greater difficulty disengaging their attention from sad and happy stimuli compared to long allele homozygotes. Study 2 participants (N = 144) were genotyped for the 5-HTTLPR polymorphism, including single nucleotide polymorphism (SNP) rs25531 in the long allele of the 5-HTTLPR. Consistent with Study 1, individuals homozygous for the low expressing 5-HTTLPR alleles (i.e., S and LG) experienced greater difficulty disengaging attention from sad, happy, and fear stimuli than high expressing 5-HTTLPR homozygotes. Since this association exists in healthy adults, it may represent a susceptibility factor for affective disorders that becomes problematic during stressful life experiences. PMID:19685963

  5. Association of the serotonin transporter gene promoter region (5-HTTLPR) polymorphism with biased attention for emotional stimuli.

    PubMed

    Beevers, Christopher G; Wells, Tony T; Ellis, Alissa J; McGeary, John E

    2009-08-01

    A deletion polymorphism in the serotonin transporter-linked polymorphic region (5-HTTLPR) has been associated with vulnerability to affective disorders, yet the mechanism by which this gene confers vulnerability remains unclear. Two studies examined associations between the 5-HTTLPR polymorphism and attentional bias for emotional stimuli among nondepressed adults. Biased attention, attention engagement, and difficulty with attention disengagement were assessed with a spatial cuing task using emotional stimuli. Results from Study 1 (N = 38) indicated that short 5-HTTLPR allele carriers experienced greater difficulty disengaging their attention from sad and happy stimuli compared with long allele homozygotes. Study 2 participants (N = 144) were genotyped for the 5-HTTLPR polymorphism, including single nucleotide polymorphism rs25531 in the long allele of the 5-HTTLPR. Consistent with Study 1, individuals homozygous for the low-expressing 5-HTTLPR alleles (i.e., S and LG) experienced greater difficulty disengaging attention from sad, happy, and fear stimuli than high-expressing 5-HTTLPR homozygotes. Because this association exists in healthy adults, it may represent a susceptibility factor for affective disorders that becomes problematic during stressful life experiences.

  6. Boron-Doped Diamond Microelectrodes Reveal Reduced Serotonin Uptake Rates in Lymphocytes from Adult Rhesus Monkeys Carrying the Short Allele of the 5-HTTLPR

    PubMed Central

    2009-01-01

    Uptake resolved by high-speed chronoamperometry on a second-by-second basis has revealed important differences in brain serotonin transporter function associated with genetic variability. Here, we use chronoamperometry to investigate variations in serotonin transport in primary lymphocytes associated with the rhesus serotonin transporter gene-linked polymorphism (rh5-HTTLPR), a promoter polymorphism whose orthologues occur only in higher order primates including humans. Serotonin clearance by lymphocytes is Na+-dependent and inhibited by the serotonin-selective reuptake inhibitor paroxetine (Paxil), indicative of active uptake by serotonin transporters. Moreover, reductions in serotonin uptake rates are evident in lymphocytes from monkeys with one or two copies of the short ‘s’ allele of the rh5-HTTLPR (s/s < s/l < l/l). These findings illustrate that rh5-HTTLPR-related alterations in serotonin uptake are present during adulthood in peripheral blood cells natively expressing serotonin transporters. Moreover, they suggest that lymphocytes can be used as peripheral biomarkers for investigating genetic or pharmacologic alterations in serotonin transporter function. Use of boron-doped diamond microelectrodes for measuring serotonin uptake, in contrast to carbon fiber microelectrodes used previously in the brain, enabled these high-sensitivity and high-resolution measurements. Boron-doped diamond microelectrodes show excellent signal-to-noise and signal-to-background ratios due mainly to low background currents and are highly resistant to fouling when exposed to lymphocytes or high concentrations of serotonin. PMID:20352073

  7. Anxious behavior and fenfluramine-induced prolactin secretion in young rhesus macaques with different alleles of the serotonin reuptake transporter polymorphism (5HTTLPR).

    PubMed

    Bethea, Cynthia L; Streicher, John M; Coleman, Kristine; Pau, Francis K-Y; Moessner, Rainald; Cameron, Judy L

    2004-05-01

    Anxiety is a normal aspect of human personality, which can manifest in a variety of disorders and other negative traits. The primary treatment for anxiety is the class of drugs known as the selective serotonin reuptake inhibitors (SSRIs), which bind to the serotonin reuptake transporter. The upstream region of the gene that codes for this transporter contains a polymorphism that is an insertion/deletion event that in turn, produces long (l) and short (s) alleles in the population. This particular polymorphism in the serotonin transporter, the 5HTTLPR (serotonin transporter linked polymorphic region), is thought to be involved in the genesis of anxious traits and disorders. Most studies with human subjects have examined adult behavior, which may derive from diverse experiential and environmental backgrounds, as well as genetic differences. To better isolate the effect of genetics, we genotyped 128 infant and juvenile monkeys for the 5HTTLPR and tested for behavioral response in four testing paradigms designed to elicit fearful-anxious behaviors: a free play, remote-controlled car, human intruder, and novel fruit test. The s/s monkeys were found to be behaviorally inhibited in the free play test, engaged in more fear behaviors in the remote-controlled car test, and threatened more in the stare portion of the human intruder test, even though a small number of monkeys were assessed. There was no difference between genotypes of either sex in the prolactin response to fenfluramine. These data indicate greater anxiety in the s/s monkeys for distinct facets of anxious behavior, which are independent of a global neurohormonal challenge test. These neurobehavioral data support recent neuroimaging findings in humans indicating the importance of the 5HTTLPR for amygdala-dependent anxious behavior.

  8. Non-replication of the association between 5HTTLPR and response to psychological therapy for child anxiety disorders

    PubMed Central

    Lester, Kathryn J.; Roberts, Susanna; Keers, Robert; Coleman, Jonathan R. I.; Breen, Gerome; Wong, Chloe C. Y.; Xu, Xiaohui; Arendt, Kristian; Blatter-Meunier, Judith; Bögels, Susan; Cooper, Peter; Creswell, Cathy; Heiervang, Einar R.; Herren, Chantal; Hogendoorn, Sanne M.; Hudson, Jennifer L.; Krause, Karen; Lyneham, Heidi J.; McKinnon, Anna; Morris, Talia; Nauta, Maaike H.; Rapee, Ronald M.; Rey, Yasmin; Schneider, Silvia; Schneider, Sophie C.; Silverman, Wendy K.; Smith, Patrick; Thastum, Mikael; Thirlwall, Kerstin; Waite, Polly; Wergeland, Gro Janne; Eley, Thalia C.

    2016-01-01

    Background We previously reported an association between 5HTTLPR genotype and outcome following cognitive–behavioural therapy (CBT) in child anxiety (Cohort 1). Children homozygous for the low-expression short-allele showed more positive outcomes. Other similar studies have produced mixed results, with most reporting no association between genotype and CBT outcome. Aims To replicate the association between 5HTTLPR and CBT outcome in child anxiety from the Genes for Treatment study (GxT Cohort 2, n = 829). Method Logistic and linear mixed effects models were used to examine the relationship between 5HTTLPR and CBT outcomes. Mega-analyses using both cohorts were performed. Results There was no significant effect of 5HTTLPR on CBT outcomes in Cohort 2. Mega-analyses identified a significant association between 5HTTLPR and remission from all anxiety disorders at follow-up (odds ratio 0.45, P = 0.014), but not primary anxiety disorder outcomes. Conclusions The association between 5HTTLPR genotype and CBT outcome did not replicate. Short-allele homozygotes showed more positive treatment outcomes, but with small, non-significant effects. Future studies would benefit from utilising whole genome approaches and large, homogenous samples. PMID:26294368

  9. COMT Val158Met × SLC6A4 5-HTTLPR interaction impacts on gray matter volume of regions supporting emotion processing

    PubMed Central

    El-Hage, Wissam; Monté, Gemma C.; Gohier, Benedicte; Tropeano, Maria; Phillips, Mary L.; Surguladze, Simon A.

    2014-01-01

    There have been several reports on the association between the Val158Met genetic polymorphism of the catechol-O-methyltransferase (COMT) gene, as well as the serotonin transporter-linked polymorphic region (5-HTTLPR) of the serotonin transporter gene (SLC6A4), and frontolimbic region volumes, which have been suggested to underlie individual differences in emotion processing or susceptibility to emotional disorders. However, findings have been somewhat inconsistent. This study used diffeomorphic anatomic registration through exponentiated Lie algebra (DARTEL) whole-brain voxel-based morphometry to study the genetic effects of COMT Val158Met and SLC6A4 5-HTTLPR, as well as their interaction, on the regional gray matter volumes of a sample of 91 healthy volunteers. An interaction of COMT Val158Met × SLC6A4 5-HTTLPR genotypes with gray matter volume was found in bilateral parahippocampal gyrus, amygdala, hippocampus, vermis of cerebellum and right putamen/insula. In particular, the gray matter volume in these regions was smaller in individuals who were both COMT-Met and 5-HTTLPR-S carriers, or both COMT-Val and 5-HTTLPR-L homozygotes, as compared with individuals with intermediate combinations of alleles. The interaction of COMT Val158Met and SLC6A4 5-HTTLPR adds to the understanding of individual differences in emotion processing. PMID:23748501

  10. On the evolution of the serotonin transporter linked polymorphic region (5-HTTLPR) in primates

    PubMed Central

    Dobson, Seth D.; Brent, Lauren J. N.

    2013-01-01

    Some allelic variants of the serotonin transporter linked polymorphic region (5-HTTLPR) result in lower levels of expression of the serotonin transporter gene (SLC6A4). These low-expressing (LE) alleles are associated with mental-health disorders in a minority of humans that carry them. Humans are not the only primates that exhibit this polymorphism; other species, including some monkeys, also have LE and high-expressing (HE) variants of 5-HTTLPR. We propose a behavioral genetic framework to explain the adaptive evolution of this polymorphism in primates, including humans. We hypothesize that both LE and HE alleles are maintained by balancing selection in species characterized by short-term fluctuations in social competition levels. More specifically, we propose that LE carriers benefit from their hypervigilant tendencies during periods of elevated competition, whereas HE homozygotes cope best when competition levels do not deviate from the norm. Thus, both alleles have long-term benefits when competition levels tend to vary substantially over relatively short timescales within a social group. We describe this hypothesis in detail and outline a series of predictions to test it. Some of these predictions are supported by findings in the current literature, while others remain areas of future research. PMID:24312034

  11. 5-HTTLPR/rs25531 polymorphism and neuroticism are linked by resting state functional connectivity of amygdala and fusiform gyrus.

    PubMed

    Kruschwitz, J D; Walter, M; Varikuti, D; Jensen, J; Plichta, M M; Haddad, L; Grimm, O; Mohnke, S; Pöhland, L; Schott, B; Wold, A; Mühleisen, T W; Heinz, A; Erk, S; Romanczuk-Seiferth, N; Witt, S H; Nöthen, M M; Rietschel, M; Meyer-Lindenberg, A; Walter, H

    2015-07-01

    The s/s-genotype of the 5-HTTLPR polymorphism and the personality trait of neuroticism have both been associated with experiences of negative affect, anxiety and mood disorders, as well as an emotional processing bias towards negative facial emotions. On a neural level, this bias can be characterized by altered amygdala and fusiform gyrus (FFG) activity during perception of negative facial expressions. Using resting-state functional magnetic resonance imaging in a multi-center-sample of 178 healthy subjects of European descent, this study investigated the association of 5-HTTLPR (short s- and long l-allele) including the genotype of the single nucleotide polymorphism (SNP) rs25531 (A/G) within this region polymorphism, and trait neuroticism on resting-state functional connectivity (rs-FC) between amygdala and the FFG. Moreover, we aimed to identify additional brain regions with associations of 5-HTTLPR/rs25531 (combined according to its expression; low: s/s; high: l(A)/l(A); intermediate: s/l(A), s/l(G), l(G)/l(G), l(A)/l(G)) and trait neuroticism to amygdala rs-FC. Separate analyses for 5-HTTLPR/rs25531 and neuroticism (controlling for age, gender, handedness, and research site) revealed that s/s-homozygotes and individuals high in neuroticism obtained altered amygdala rs-FC in the right occipital face area, which is considered to be a "core component" of the face processing system. Importantly, effects of neuroticism were replicated across three independent research sites. Additionally, associations of 5-HTTLPR/rs25531 genotype and amygdala rs-FC were observed in the anterior and posterior cingulate cortex, whereas neuroticism was not related to rs-FC in these areas. The presented data implies that 5-HTTLPR/rs25531 variants and neuroticism are linked by resting state functional connectivity of amygdala and fusiform gyrus and suggests that variants of 5-HTTLPR/rs25531 genotype and different levels of neuroticism may partly account for altered processing of

  12. The 5-HTTLPR polymorphism, early and recent life stress, and cognitive endophenotypes of depression.

    PubMed

    Kruijt, Anne-Wil; Putman, Peter; Van der Does, Willem

    2014-01-01

    Studies associating interactions of 5-HTTLPR and life adversities with depression have yielded equivocal results. Studying endophenotypes may constitute a more powerful approach. In the current study, it was assessed whether interactions of 5-HTTLPR with childhood emotional abuse (CEA) and recent negative life events (RNLE) affect possible cognitive endophenotypes of depression, namely, attention-allocation bias and the ability to recognise others' mind states in 215 young adults of North-West European descent. The ability to classify others' negative mind states was found to be increased with increasing RNLE in carriers of low-expressing Serotonin Transporter Linked Polymorphic Region (5-HTTLPR) alleles. Carriers of two low-expressing alleles also preferentially oriented attention towards negative information. Gene-environment interactions were not observed for attention allocation bias. No effects involving CEA were observed. These results suggest that low-expressing 5-HTTLPR alleles may confer increased risk for depression through enhanced recognition of negative facial expressions following RNLE.

  13. Bone growth in juvenile rhesus monkeys is influenced by 5HTTLPR polymorphisms and interactions between 5HTTLPR polymorphisms and fluoxetine.

    PubMed

    Golub, Mari S; Bulleri, Alicia M; Hogrefe, Casey E; Sherwood, Richard J

    2015-10-01

    Male rhesus monkeys received a therapeutic oral dose of the selective serotonin reuptake inhibitor (SSRI) fluoxetine daily from 1 to 3 years of age. Puberty is typically initiated between 2 and 3 years of age in male rhesus and reproductive maturity is reached at 4 years. The study group was genotyped for polymorphisms in the monoamine oxidase A (MAOA) and serotonin transporter (SERT) genes that affect serotonin neurotransmission. Growth was assessed with morphometrics at 4 month intervals and radiographs of long bones were taken at 12 month intervals to evaluate skeletal growth and maturation. No effects of fluoxetine, or MAOA or SERT genotype were found for growth during the first year of the study. Linear growth began to slow during the second year of the study and serotonin reuptake transporter (SERT) long polymorphic region (5HTTLPR) polymorphism effects with drug interactions emerged. Monkeys with two SERT 5HTTLPR L alleles (LL, putative greater transcription) had 25-39% less long bone growth, depending on the bone, than monkeys with one S and one L allele (SL). More advanced skeletal maturity was also seen in the LL group, suggesting earlier onset of puberty. An interaction between 5HTTLPR polymorphisms and fluoxetine was identified for femur and tibia growth; the 5HTTLPR effect was seen in controls (40% less growth for LL) but not in the fluoxetine treated group (10% less growth for LL). A role for serotonin in peripubertal skeletal growth and maturation has not previously been investigated but may be relevant to treatment of children with SSRIs.

  14. The association between the 5-HTTLPR and neural correlates of fear conditioning and connectivity.

    PubMed

    Klucken, Tim; Schweckendiek, Jan; Blecker, Carlo; Walter, Bertram; Kuepper, Yvonne; Hennig, Juergen; Stark, Rudolf

    2015-05-01

    Strong evidence links the 5-HTTLPR genotype to the modulation of amygdala reactivity during fear conditioning, which is considered to convey the increased vulnerability for anxiety disorders in s-allele carriers. In addition to amygdala reactivity, the 5-HTTLPR has been shown to be related to alterations in structural and effective connectivity. The aim of this study was to investigate the effects of 5-HTTLPR genotype on amygdala reactivity and effective connectivity during fear conditioning, as well as structural connectivity [as measured by diffusion tensor imaging (DTI)]. To integrate different classification strategies, we used the bi-allelic (s-allele vs l/l-allele group) as well as the tri-allelic (low-functioning vs high-functioning) classification approach. S-allele carriers showed exaggerated amygdala reactivity and elevated amygdala-insula coupling during fear conditioning (CS + > CS-) compared with the l/l-allele group. In addition, DTI analysis showed increased fractional anisotropy values in s-allele carriers within the uncinate fasciculus. Using the tri-allelic classification approach, increased amygdala reactivity and amygdala insula coupling were observed in the low-functioning compared with the high-functioning group. No significant differences between the two groups were found in structural connectivity. The present results add to the current debate on the influence of the 5-HTTLPR on brain functioning. These differences between s-allele and l/l-allele carriers may contribute to altered vulnerability for psychiatric disorders.

  15. Children’s attentional biases and 5-HTTLPR genotype: Potential mechanisms linking mother and child depression

    PubMed Central

    Gibb, Brandon E.; Benas, Jessica S.; Grassia, Marie; McGeary, John

    2014-01-01

    We examined the roles of specific cognitive (attentional bias) and genetic (5-HTTLPR) risk factors in the intergenerational transmission of depression. Focusing first on the link between maternal history of major depressive disorder (MDD) and children’s attentional biases, we found that children of mothers with a history of MDD during their children’s lives, compared to children of mothers with no depression history, exhibited greater attentional avoidance of sad faces. This attention bias was specific to sad, rather than happy or angry, faces. There was also preliminary evidence that this relation is stronger among children carrying the 5-HTTLPR S or LG allele than among those homozygous for the LA allele. Next, conceptualizing mothers’ levels of depressive symptoms during the multi-wave prospective follow-up within a vulnerability-stress framework, we found evidence for a three-way child 5-HTTLPR × attentional bias × mother depressive symptom interaction predicting children’s depressive symptoms. Specifically, the relation between mother and child depressive symptom levels over time was strongest among children carrying the 5-HTTLPR S or LG allele who also exhibited attentional avoidance of sad faces. These findings provide initial support for role of children’s 5-HTTLPR genotype and attentional biases for sad faces in the intergenerational transmission of depression. PMID:19437301

  16. Prefrontal morphology, 5-HTTLPR polymorphism and biased attention for emotional stimuli.

    PubMed

    Beevers, C G; Pacheco, J; Clasen, P; McGeary, J E; Schnyer, D

    2010-03-01

    Biased attention for emotional stimuli has been associated with vulnerability to psychopathology. This study examines the neural substrates of biased attention. Twenty-three adult women completed high-resolution structural imaging followed by a standard behavioral measure of biased attention (i.e. spatial cueing task). Participants were also genotyped for the serotonin transporter-linked promoter region (5-HTTLPR) gene. Results indicated that lateral prefrontal cortex (lPFC) morphology was inversely associated with maintained attention for positive and negative stimuli, but only among short 5-HTTLPR allele carriers. No such associations were observed for the medial prefrontal cortex (mPFC) or the amygdala. Results from this study suggest that brain regions involved in cognitive control of emotion are also associated with attentional biases for emotion stimuli among short 5-HTTLPR allele carriers.

  17. Therapygenetics: 5-HTTLPR genotype predicts the response to exposure therapy for agoraphobia.

    PubMed

    Knuts, Inge; Esquivel, Gabriel; Kenis, Gunter; Overbeek, Thea; Leibold, Nicole; Goossens, Lies; Schruers, Koen

    2014-08-01

    This study was intended to assess the extent to which the low-expression allele of the serotonin transporter gene promoter predicts better response to exposure-based behavior therapy in patients with panic disorder with agoraphobia (PDA). Ninety-nine patients with PDA underwent a 1-week in vivo exposure-based behavior therapy program and provided saliva samples to extract genomic DNA and classify individuals according to four allelic forms (SA, SG, LA, LG) of the 5-HTT-linked polymorphic region (5-HTTLPR). We determined whether the 5-HTTLPR genotype predicted change in avoidance behavior in PDA following treatment. After controlling for pre-treatment avoidance behavior, the 5-HTTLPR low-expression genotypes showed a more favorable response to exposure therapy two weeks following treatment, compared to the other patients. This study suggests a genetic contribution to treatment outcome following behavior therapy and implicates the serotonergic system in response to exposure-based treatments in PDA.

  18. Phobic anxiety in late-life in relationship to cognition and 5HTTLPR polymorphism.

    PubMed

    Schultz, Susan K; Moser, David J; Bishop, Jeffrey R; Ellingrod, Vicki L

    2005-12-01

    Anxiety in late-life may functionally impair the older adult. In this study the polymorphic region 5HTTLPR of the SLC6A4 gene was examined in relation to phobic anxiety and cognitive function. Sixty-four community-dwelling older adults were genotyped for the 5HTTLPR polymorphism to examine whether late-life phobias are associated with the short (s) allele and whether cognitive impairment may precipitate phobic behaviors in association with the s allele. Our findings suggested that phobic anxiety symptoms are significantly related to lower cognitive function. However, in this sample we did not detect a significant association between phobic anxiety and the 5HTTLPR genotype. The interaction between age-related changes in cognition and anxiety remain an important area for future studies.

  19. No Moderating Effect of 5-HTTLPR on Associations between Antenatal Anxiety and Infant Behavior

    ERIC Educational Resources Information Center

    Braithwaite, Elizabeth C.; Ramchandani, Paul G.; O'Connor, Thomas G.; van IJzendoorn, Marinus H.; Bakermans-Kranenburg, Marian J.; Glover, Vivette; Netsi, Elena; Evans, Jonathan; Meaney, Michael J.; Murphy, Susannah E.

    2013-01-01

    Objective: Maternal antenatal anxiety is associated with an increased risk of behavioral disturbances in offspring. Recent work has suggested that the effect of maternal antenatal anxiety on infant temperament at 6 months is moderated by the serotonin transporter polymorphism 5-HTTLPR, with carriers of the short allele more susceptible to the…

  20. 5-HTTLPR X Stress in Adolescent Depression: Moderation by MAOA and Gender

    ERIC Educational Resources Information Center

    Priess-Groben, Heather A.; Hyde, Janet Shibley

    2013-01-01

    Depression surges in adolescence, especially among girls. Most evidence indicates that the short allele of a polymorphism in the promoter region of the serotonin transporter gene (5-HTTLPR) interacts with stress to influence the onset of depression. This effect appears to be less robust in adolescents, particularly among boys, and may be moderated…

  1. The 5HTTLPR polymorphism, prior maltreatment and dramatic–erratic personality manifestations in women with bulimic syndromes

    PubMed Central

    Steiger, Howard; Richardson, Jodie; Joober, Ridha; Gauvin, Lise; Israel, Mimi; Bruce, Kenneth R.; Ying Kin, N.M.K Ng; Howard, Heidi; Young, Simon N.

    2007-01-01

    Background Low-function alleles of the serotonin transporter promoter polymorphism (5HTTLPR) have been linked to various psychopathological entities, especially in individuals exposed to prior stressors. In women with bulimic syndromes, we explored associations with personality pathology of 5HTTLPR and prior sexual or physical maltreatment. Methods Ninety-two women with bulimic syndromes were genotyped for 5HTTLPR short (S) and long (LG and LA) alleles and were then assessed for eating symptoms, dimensional personality disturbances, history of sexual or physical abuse and borderline personality disorder (BPD). Results With a classification based on a biallelic model of 5HTTLPR (i.e., presence or absence of at least 1 S-allele copy), multiple regression analyses indicated significant proportions of variance in stimulus seeking and insecure attachment to be explained by abuse × genotype interaction effects, with greater psychopathology always occurring in S-allele carriers who had been abused. Likewise, a logistic regression analysis linked BPD to significant main effects of genotype and abuse. Analyses that aggregated carriers according to a triallelic model of 5HTTLPR (i.e., presence or absence of at least 1 copy of a presumably low-function S or LG allele) produced similar patterns but no statistically significant effects. Conclusions Traits such as sensation seeking and insecure attachment are, on average, elevated in 5HTTLPR S-allele carriers with bulimic syndromes who report prior physical or sexual maltreatment. These results add to the literature associating pronounced psychopathological manifestations, with conjoint effects of stress and the 5HTTLPR polymorphism. PMID:17823651

  2. Stressful life events, perceived stress, and 12-month course of geriatric depression: direct effects and moderation by the 5-HTTLPR and COMT Val158Met polymorphisms.

    PubMed

    Zannas, Anthony S; McQuoid, Douglas R; Steffens, David C; Chrousos, George P; Taylor, Warren D

    2012-07-01

    Although the relation between stressful life events (SLEs) and risk of major depressive disorder is well established, important questions remain about the effects of stress on the course of geriatric depression. Our objectives were (1) to examine how baseline stress and change in stress is associated with course of geriatric depression and (2) to test whether polymorphisms of serotonin transporter (5-HTTLPR) and catechol-O-methyltransferase (COMT Val158Met) genes moderate this relation. Two-hundred and sixteen depressed subjects aged 60 years or older were categorized by remission status (Montgomery-Asberg depression rating scale≤6) at 6 and 12 months. At 6 months, greater baseline numbers of self-reported negative and total SLEs and greater baseline perceived stress severity were associated with lower odds of remission. At 12 months, only baseline perceived stress predicted remission. When we examined change in stress, 12-month decrease in negative SLEs and level of perceived stress were associated with improved odds of 12-month remission. When genotype data were included, COMT Val158Met genotype did not influence these relations. However, when compared with 5-HTTLPR L/L homozygotes, S allele carriers with greater baseline numbers of negative SLEs and with greater decrease in negative SLEs were more likely to remit at 12 months. This study demonstrates that baseline SLEs and perceived stress severity may influence the 12-month course of geriatric depression. Moreover, changes in these stress measures over time correlate with depression outcomes. 5-HTTLPR S carriers appear to be more susceptible to both the effects of enduring stress and the benefit of interval stress reduction.

  3. Children's attentional biases and 5-HTTLPR genotype: potential mechanisms linking mother and child depression.

    PubMed

    Gibb, Brandon E; Benas, Jessica S; Grassia, Marie; McGeary, John

    2009-05-01

    In this study, we examined the roles of specific cognitive (attentional bias) and genetic (5-HTTLPR) risk factors in the intergenerational transmission of depression. Focusing first on the link between maternal history of major depressive disorder (MDD) and children's attentional biases, we found that children of mothers with a history of MDD during their children's lives, compared to children of mothers with no depression history, exhibited greater attentional avoidance of sad faces. This attention bias was specific to sad, rather than happy or angry, faces. There was also preliminary evidence that this relation is stronger among children carrying the 5-HTTLPR S or L(G) allele than among those homozygous for the L(A) allele. Next, conceptualizing mothers' levels of depressive symptoms during the multi-wave prospective follow-up within a vulnerability-stress framework, we found evidence for a three-way child 5-HTTLPR x attentional bias x mother depressive symptom interaction predicting children's depressive symptoms. Specifically, the relation between mother and child depressive symptom levels over time was strongest among children carrying the 5-HTTLR S or L(G) allele who also exhibited attentional avoidance of sad faces. These findings provide initial support for role of children's 5-HTTLPR genotype and attentional biases for sad faces in the intergenerational transmission of depression.

  4. Individual differences in neural correlates of fear conditioning as a function of 5-HTTLPR and stressful life events.

    PubMed

    Klucken, Tim; Alexander, Nina; Schweckendiek, Jan; Merz, Christian J; Kagerer, Sabine; Osinsky, Roman; Walter, Bertram; Vaitl, Dieter; Hennig, Juergen; Stark, Rudolf

    2013-03-01

    Fear learning is a crucial process in the pathogeneses of psychiatric disorders, which highlights the need to identify specific factors contributing to interindividual variation. We hypothesized variation in the serotonin transporter gene (5-HTTLPR) and stressful life events (SLEs) to be associated with neural correlates of fear conditioning in a sample of healthy male adults (n = 47). Subjects were exposed to a differential fear conditioning paradigm after being preselected regarding 5-HTTLPR genotype and SLEs. Individual differences in brain activity as measured by functional magnetic resonance imaging (fMRI), skin conductance responses and preference ratings were assessed. We report significant variation in neural correlates of fear conditioning as a function of 5-HTTLPR genotype. Specifically, the conditioned stimulus (CS(+)) elicited elevated activity within the fear-network (amygdala, insula, thalamus, occipital cortex) in subjects carrying two copies of the 5-HTTLPR S' allele. Moreover, our results revealed preliminary evidence for a significant gene-by-environment interaction, such as homozygous carriers of the 5-HTTLPR S' allele with a history of SLEs demonstrated elevated reactivity to the CS(+) in the occipital cortex and the insula. Our findings contribute to the current debate on 5-HTTLPR x SLEs interaction by investigating crucial alterations on an intermediate phenotype level which may convey an elevated vulnerability for the development of psychopathology.

  5. Association between the serotonin transporter promoter polymorphism (5-HTTLPR) and adult unresolved attachment

    PubMed Central

    Caspers, Kristin M; Paradiso, Sergio; Yucuis, Rebecca; Troutman, Beth; Arndt, Stephan; Philibert, Robert

    2013-01-01

    Research on antecedents of organized attachment has focused on the quality of caregiving received during childhood. In recent years, research has begun to examine the influence of genetic factors on quality of infant attachment. However, no published studies report on the association between specific genetic factors and adult attachment. This study examined the link between the 5-HTTLPR promoter polymorphism of the serotonin transporter gene and adult unresolved attachment assessed with the Adult Attachment Interview. Genetic material and information on attachment-related loss or trauma were available for 86 participants. Multivariate regression analyses showed an association between the short 5-HTTLPR allele and increased risk for unresolved attachment. Temperament traits and psychological symptoms did not affect the association between 5-HTTLPR and unresolved attachment. The authors hypothesize that the increased susceptibility to unresolved attachment among carriers of the short allele of 5-HTTLPR is consistent with the role of serotonin in modulation of frontal–amygdala circuitry. The findings challenge current thinking by demonstrating significant genetic influences on a phenomenon previously thought to be largely environmentally driven. PMID:19209991

  6. Face and emotion expression processing and the serotonin transporter polymorphism 5-HTTLPR/rs22531.

    PubMed

    Hildebrandt, A; Kiy, A; Reuter, M; Sommer, W; Wilhelm, O

    2016-06-01

    Face cognition, including face identity and facial expression processing, is a crucial component of socio-emotional abilities, characterizing humans as highest developed social beings. However, for these trait domains molecular genetic studies investigating gene-behavior associations based on well-founded phenotype definitions are still rare. We examined the relationship between 5-HTTLPR/rs25531 polymorphisms - related to serotonin-reuptake - and the ability to perceive and recognize faces and emotional expressions in human faces. For this aim we conducted structural equation modeling on data from 230 young adults, obtained by using a comprehensive, multivariate task battery with maximal effort tasks. By additionally modeling fluid intelligence and immediate and delayed memory factors, we aimed to address the discriminant relationships of the 5-HTTLPR/rs25531 polymorphisms with socio-emotional abilities. We found a robust association between the 5-HTTLPR/rs25531 polymorphism and facial emotion perception. Carriers of two long (L) alleles outperformed carriers of one or two S alleles. Weaker associations were present for face identity perception and memory for emotional facial expressions. There was no association between the 5-HTTLPR/rs25531 polymorphism and non-social abilities, demonstrating discriminant validity of the relationships. We discuss the implications and possible neural mechanisms underlying these novel findings.

  7. Association between the serotonin transporter promoter polymorphism (5-HTTLPR) and adult unresolved attachment.

    PubMed

    Caspers, Kristin M; Paradiso, Sergio; Yucuis, Rebecca; Troutman, Beth; Arndt, Stephan; Philibert, Robert

    2009-01-01

    Research on antecedents of organized attachment has focused on the quality of caregiving received during childhood. In recent years, research has begun to examine the influence of genetic factors on quality of infant attachment. However, no published studies report on the association between specific genetic factors and adult attachment. This study examined the link between the 5-HTTLPR promoter polymorphism of the serotonin transporter gene and adult unresolved attachment assessed with the Adult Attachment Interview. Genetic material and information on attachment-related loss or trauma were available for 86 participants. Multivariate regression analyses showed an association between the short 5-HTTLPR allele and increased risk for unresolved attachment. Temperament traits and psychological symptoms did not affect the association between 5-HTTLPR and unresolved attachment. The authors hypothesize that the increased susceptibility to unresolved attachment among carriers of the short allele of 5-HTTLPR is consistent with the role of serotonin in modulation of frontal-amygdala circuitry. The findings challenge current thinking by demonstrating significant genetic influences on a phenomenon previously thought to be largely environmentally driven.

  8. 5-HTTLPR moderates effects of current life events on neuroticism: differential susceptibility to environmental influences.

    PubMed

    Pluess, Michael; Belsky, Jay; Way, Baldwin M; Taylor, Shelley E

    2010-08-16

    Research chronicling links between a polymorphism in the serotonin-transporter gene (5-HTTLPR) and neuroticism has yielded inconsistent results. One possible explanation for this inconsistency is that any gene-phenotype association is obscured by a gene-X-environment (GXE) interaction. We studied a healthy non-clinical sample (N=118) to determine whether the 5-HTTLPR interacts with current life events in predicting neuroticism. The differential-susceptibility hypothesis led to the prediction of such an interaction, reflecting the fact that individuals with short alleles would be affected more by both negative and positive life events than those homozygous for long alleles. Participants completed questionnaires concerning recent life events and neuroticism. The 5-HTTLPR was genotyped using a standard protocol with DNA extracted from oral fluid. For those homozygous for the short allele, more negative life events proved related to greater neuroticism, whereas more positive life events proved related to less neuroticism. No such association emerged in the case of those homozygous for the long allele. Whereas neuroticism is likely to be an especially stable trait in individuals homozygous for the long allele, this may be less so the case for those carrying short alleles.

  9. Differential influence of the 5-HTTLPR genotype, neuroticism and real-life acute stress exposure on appetite and energy intake.

    PubMed

    Capello, Aimée E M; Markus, C Rob

    2014-06-01

    Stress or negative mood often promotes energy intake and overeating. Since the serotonin transporter-linked polymorphic region (5-HTTLPR) is found to mediate stress vulnerability as well as to influence energy intake, this gene may also influence the negative effects of stress exposure on overeating. Moreover, since stress proneness also reflects cognitive stress vulnerability - as often defined by trait neuroticism - this may additionally predispose for stress-induced overeating. In the present study it was investigated whether the 5-HTTLPR genotype interacted with neuroticism on changes in mood, appetite and energy intake following exposure to a real-life academic examination stressor. In a balanced-experimental design, homozygous S-allele and L-allele carriers (N = 94) with the lowest and highest neuroticism scores were selected from a large database of 5-HTTLPR genotyped students. Mood, appetite and energy intake were measured before and after a 2-hour academic examination and compared with a control day. Examination influenced appetite for particular sweet snacks differently depending on 5-HTTLPR genotype and neuroticism. S/S compared with L/L subjects reported greater examination stress, and this was accompanied by a more profound post-stress increase in appetite for sweet snacks. Data also revealed a 5-HTTLPR genotype by trait neuroticism interaction on energy intake, regardless of examination. These results consolidate previous assumptions of 5-HTTLPR involvement in stress vulnerability and suggest 5-HTTLPR and neuroticism may influence stress-induced overeating depending on the type of food available. These findings furthermore link previous findings of increased risk for weight gain in S/S-allele carriers, particularly with high scores on trait neuroticism, to increased energy intake.

  10. Threat-related amygdala functional connectivity is associated with 5-HTTLPR genotype and neuroticism.

    PubMed

    Madsen, Martin Korsbak; Mc Mahon, Brenda; Andersen, Sofie Bech; Siebner, Hartwig Roman; Knudsen, Gitte Moos; Fisher, Patrick MacDonald

    2016-01-01

    Communication between the amygdala and other brain regions critically regulates sensitivity to threat, which has been associated with risk for mood and affective disorders. The extent to which these neural pathways are genetically determined or correlate with risk-related personality measures is not fully understood. Using functional magnetic resonance imaging, we evaluated independent and interactive effects of the 5-HTTLPR genotype and neuroticism on amygdala functional connectivity during an emotional faces paradigm in 76 healthy individuals. Functional connectivity between left amygdala and medial prefrontal cortex (mPFC) and between both amygdalae and a cluster including posterior cingulate cortex, precuneus and visual cortex was significantly increased in 5-HTTLPR S' allele carriers relative to L(A)L(A) individuals. Neuroticism was negatively correlated with functional connectivity between right amygdala and mPFC and visual cortex, and between both amygdalae and left lateral orbitofrontal (lOFC) and ventrolateral prefrontal cortex (vlPFC). Notably, 5-HTTLPR moderated the association between neuroticism and functional connectivity between both amygdalae and left lOFC/vlPFC, such that S' carriers exhibited a more negative association relative to L(A)L(A) individuals. These findings provide novel evidence for both independent and interactive effects of 5-HTTLPR genotype and neuroticism on amygdala communication, which may mediate effects on risk for mood and affective disorders.

  11. Variations in Maternal 5-HTTLPR Affect Observed Sensitive Parenting

    ERIC Educational Resources Information Center

    Cents, Rolieke A. M.; Kok, Rianne; Tiemeier, Henning; Lucassen, Nicole; Székely, Eszter; Bakermans-Kranenburg, Marian J.; Hofman, Albert; Jaddoe, Vincent W. V.; IJzendoorn, Marinus H.; Verhulst, Frank C.; Lambregtse-van den Berg, Mijke P.

    2014-01-01

    Background: Little is known about the genetic determinants of sensitive parenting. Two earlier studies examined the effect of the serotonin transporter polymorphism (5-HTTLPR) on sensitive parenting, but reported opposite results. In a large cohort we further examined whether 5-HTTLPR is a predictor of observed maternal sensitivity and whether…

  12. Association of Anxiety Symptoms in Offspring of Bipolar Parents with Serotonin Transporter-Linked Polymorphic Region (5-HTTLPR) Genotype

    PubMed Central

    Park, Min-Hyeon; Sanders, Erica; Howe, Meghan; Singh, Manpreet; Hallmayer, Joachim; Kim, Eunjoo

    2015-01-01

    Abstract Objective: Offspring of parents with bipolar disorder (BD) have been shown to be at high risk for BD. Anxiety symptoms, even at subclinical levels, have been associated with increased risk for BD in these youth. The s-allele of the serotonin transporter-linked polymorphic region (5-HTTLPR) has been implicated in the pathophysiology of both BD and anxiety disorders and has been associated with pharmacological treatment response and increased risk for antidepressant side effects. Therefore, we aimed to explore 1) whether anxiety symptoms in offspring of BD parents were associated with presence of the 5-HTTLPR s-allele and 2) whether anxiety symptoms in the offspring of BD parents according to the 5-HTTLPR genotypes are related to antianxiety medication status. Methods: A total of 64 offspring of BD parents (mean age: 13.7 years) and 51 healthy controls (HC) (mean age: 13.7 years) were compared genetically and on the Multidimensional Anxiety Scale for Children (MASC). Results: Offspring of BD parents showed higher levels of overall anxiety than did the HC group. Only antianxiety medication naïve offspring of BD parents were found to have an association between 5-HTTLPR genotypes and anxiety symptoms. The antianxiety medication naïve offspring of BD parents with the s-allele showed higher level of overall anxiety than offspring of BD parents with the l/l genotype. No significant differences in anxiety symptoms or their association with the 5-HTTLPR genotype were found in the HC group. Conclusions: This study indicated that there may be an association between 5-HTTLPR genotypes and anxiety symptoms in offspring of BD parents, and that antianxiety medication status may affect anxiety symptoms in the offspring of BD patients according to genotype. PMID:26218602

  13. 5-HTTLPR Polymorphism Impacts Task-Evoked and Resting-State Activities of the Amygdala in Han Chinese

    PubMed Central

    Li, Sufang; Zou, Qihong; Li, Jun; Li, Jin; Wang, Deyi; Yan, Chaogan; Dong, Qi; Zang, Yu-Feng

    2012-01-01

    Background Prior research has shown that the amygdala of carriers of the short allele (s) of the serotonin transporter (5-HTT) gene (5-HTTLPR) have a larger response to negative emotional stimuli and higher spontaneous activity during the resting state than non-carriers. However, recent studies have suggested that the effects of 5-HTTLPR may be specific to different ethnic groups. Few studies have been conducted to address this issue. Methodology/Principal Findings Blood oxygenation level dependent (BOLD) functional magnetic resonance imaging (fMRI) was conducted on thirty-eight healthy Han Chinese subjects (l/l group, n = 19; s/s group, n = 19) during the resting state and during an emotional processing task. Compared with the s/s group, the l/l group showed significantly increased regional homogeneity or local synchronization in the right amygdala during the resting state (|t|>2.028, p<0.05, corrected), but no significant difference was found in the bilateral amygdala in response to negative stimuli in the emotional processing task. Conclusions/Significance 5-HTTLPR can alter the spontaneous activity of the amygdala in Han Chinese. However, the effect of 5-HTTLPR on the amygdala both in task state and resting state in Asian population was no similar with Caucasians. They suggest that the effect of 5-HTTLPR on the amygdala may be modulated by ethnic differences. PMID:22574175

  14. Relational Security Moderates the Effect of Serotonin Transporter Gene Polymorphism (5-HTTLPR) on Stress Generation and Depression among Adolescents

    ERIC Educational Resources Information Center

    Starr, Lisa R.; Hammen, Constance; Brennan, Patricia A.; Najman, Jake M.

    2013-01-01

    Previous research demonstrates that carriers of the short allele of the serotonin transporter gene (5-HTTLPR) show both greater susceptibility to depression in response to stressful life events and higher rates of generation of stressful events in response to depression. The current study examines relational security (i.e., self-reported beliefs…

  15. Gene × environment interaction on intergroup bias: the role of 5-HTTLPR and perceived outgroup threat.

    PubMed

    Cheon, Bobby K; Livingston, Robert W; Hong, Ying-Yi; Chiao, Joan Y

    2014-09-01

    Perceived threat from outgroups is a consistent social-environmental antecedent of intergroup bias (i.e. prejudice, ingroup favoritism). The serotonin transporter gene polymorphism (5-HTTLPR) has been associated with individual variations in sensitivity to context, particularly stressful and threatening situations. Here, we examined how 5-HTTLPR and environmental factors signaling potential outgroup threat dynamically interact to shape intergroup bias. Across two studies, we provide novel evidence for a gene-environment interaction on the acquisition of intergroup bias and prejudice. Greater exposure to signals of outgroup threat, such as negative prior contact with outgroups and perceived danger from the social environment, were more predictive of intergroup bias among participants possessing at least one short allele (vs two long alleles) of 5-HTTLPR. Furthermore, this gene x environment interaction was observed for biases directed at diverse ethnic and arbitrarily-defined outgroups across measures reflecting intergroup biases in evaluation and discriminatory behavior. These findings reveal a candidate genetic mechanism for the acquisition of intergroup bias, and suggest that intergroup bias is dually inherited and transmitted through the interplay of social (i.e. contextual cues of outgroup threat) and biological mechanisms (i.e. genetic sensitivity toward threatening contexts) that regulate perceived intergroup threats.

  16. Peer Problems and Hyperactivity-Impulsivity Among Norwegian and American Children: The Role of 5-HTTLPR.

    PubMed

    Stenseng, Frode; Li, Zhi; Belsky, Jay; Hygen, Beate W; Skalicka, Vera; Guzey, Ismail C; Wichstrøm, Lars

    2017-03-10

    Peer problems are linked to attention deficit hyperactivity disorder (ADHD) symptoms and the serotonin system is thought to be involved in ADHD-related behavior. Hence, from a Gene × Environment perspective, the serotonin transporter 5-HTTLPR may play a moderating role. In two large community samples, the moderating role of 5-HTTLPR was examined related to more hyperactivity-impulsivity symptoms (HI symptoms) predicted by more peer problems. In Study 1, involving 642 Norwegian children, results indicated that for s-allele carriers only, caregiver-reported peer problems at age 4 predicted more parent-reported HI symptoms at age 6. In Study 2, similar results emerged involving 482 American children. Discussion focuses on differential sensitivity to the adverse effects of poor peer relations.

  17. Accurate, large-scale genotyping of 5HTTLPR and flanking SNPs in an association study of depression, anxiety and personality measures

    PubMed Central

    Wray, Naomi R; James, Michael R; Gordon, Scott D; Dumenil, Troy; Ryan, Leanne; Coventry, William L; Statham, Dixie J; Pergadia, Michele L; Madden, Pamela AF; Heath, Andrew C; Montgomery, Grant W; Martin, Nicholas G

    2011-01-01

    Background 5HTTLPR, the length polymorphism repeat in the promoter region of the serotonin transporter gene (5HTT renamed SLC6A4) is one of the most studied polymorphisms for association with a range of psychiatric and personality phenotypes. However, the original 5HTTLPR assay is prone to bias toward short allele calling. Methods We designed new assays for the 5HTTLPR suitable for large scale genotyping projects and we genotyped 13 SNPs in a 38kb region around the 5HTTLPR including SNP rs25531, a polymorphism of the 5HTTLPR long allele. Association analysis was conducted for major depression and/or anxiety disorder in unrelated cases (N = 1161) and controls (N = 1051) identified through psychiatric interviews administered to a large population sample of Australian twin families. Participants had been scored for personality traits of neuroticism, extraversion and harm avoidance several years earlier (N ≥ 2643 unrelated individuals). Results Using the linkage disequilibrium (LD) between markers we identified a two SNP haplotype proxy for 5HTTLPR; the CA haplotype of SNPs rs4251417 and rs2020934 is coupled with the short allele of 5HTTLPR (r2 = 0.72). We found evidence for association (p=0.0062, after accounting for multiple testing) for SLC6A4 SNPs rs6354 and rs2020936 (positioned in a different LD block about 15.5kb from 5HTTLPR) with anxiety and/or depression and neuroticism, with the strongest association for recurrent depression with onset in young adulthood (OR = 1.55, 95% CI 1.16–2.06). Conclusions The associated SNPs are in the same LD block as the VNTR STin2, for which association has previously been reported. PMID:19541292

  18. 5-HTTLPR Expression Outside the Skin: An Experimental Test of the Emotional Reactivity Hypothesis in Children

    PubMed Central

    Weeland, Joyce; Slagt, Meike; Brummelman, Eddie; Matthys, Walter; de Castro, Bram Orobio; Overbeek, Geertjan

    2015-01-01

    Background There is increasing evidence that variation in the promoter region of the serotonin transporter gene SLC6A4 (i.e., the 5-HTTLPR polymorphism) moderates the impact of environmental stressors on child psychopathology. Emotional reactivity −the intensity of an individual’s response to other’s emotions− has been put forward as a possible mechanism underlying these gene-by-environment interactions (i.e., G×E). Compared to children homozygous for the L-allele (LL-genotypes), children carrying an S-allele (SS/SL-genotypes), specifically when they have been frequently exposed to negative emotions in the family environment, might be more emotionally reactive and therefore more susceptible to affective environmental stressors. However, the association between 5-HTTLPR and emotional reactivity in children has not yet been empirically tested. Therefore, the goal of this study was to test this association in a large-scale experiment. Methods Children (N = 521, 52.5% boys, Mage = 9.72 years) were genotyped and randomly assigned to happy, angry or neutral dynamic facial expressions and vocalizations. Motor and affective emotional reactivity were assessed through children’s self-reported negative and positive affect (n = 460) and facial electromyography activity (i.e., fEMG: the zygomaticus or “smile” muscle and the corrugator or “frown” muscle, n = 403). Parents reported on their negative and positive parenting behaviors. Results Children mimicked and experienced the emotion they were exposed to. However, neither motor reactivity nor affective reactivity to these emotions depended on children’s 5-HTTLPR genotype: SS/SL-genotypes did not manifest any stronger response to emotional stimuli than LL-genotypes. This finding remained the same when taking the broader family environment into account, controlling for kinship, age, gender and genetic ancestry, and when including a tri-allelic factor. Conclusions We found no evidence for an association

  19. 5-HTTLPR, anxiety and gender interaction moderates right amygdala volume in healthy subjects.

    PubMed

    Cerasa, Antonio; Quattrone, Aldo; Piras, Fabrizio; Mangone, Graziella; Magariello, Angela; Fagioli, Sabrina; Girardi, Paolo; Muglia, Maria; Caltagirone, Carlo; Spalletta, Gianfranco

    2014-10-01

    Genetic variants within the serotonin transporter gene (5-HTTLPR) impact the neurobiology and risk for anxiety-related behaviours. There are also gender differences in the prevalence of anxiety-related behaviours. Although numerous studies have investigated the influence of 5-HTTLPR genotype on the neural systems involved in emotional regulation, none have investigated how these effects are modulated by gender and anxiety. We investigated this issue using two complementary region of interest-based structural neuroimaging approaches (voxel-based morphometry and Freesurfer) in 138 healthy individuals categorized into 'no anxiety' and 'subclinical anxiety' groups based on the Hamilton Rating Scale for Anxiety (HAM-A). Preliminarily, using anxiety as a continuous variable, we found a significant interaction effect of genotype by gender on anxiety. Females homozygous for the Short allele showed the highest HAM-A scores and males the lowest. In addition, a three-way significant interaction among genotype, gender and anxiety category was found for the right amygdala volume. Post hoc tests revealed that homozygous females carrying the Short variant with a subclinical anxiety condition had larger volume. The reported interaction effects demonstrate that gender strongly modulates the relationship between 5-HTTLPR genotype and subclinical expression of anxiety acting on amygdala, one region of the emotional neural network specifically involved in the anxiety-like behaviours.

  20. 5-HTTLPR, anxiety and gender interaction moderates right amygdala volume in healthy subjects

    PubMed Central

    Cerasa, Antonio; Quattrone, Aldo; Piras, Fabrizio; Mangone, Graziella; Magariello, Angela; Fagioli, Sabrina; Girardi, Paolo; Muglia, Maria; Caltagirone, Carlo

    2014-01-01

    Genetic variants within the serotonin transporter gene (5-HTTLPR) impact the neurobiology and risk for anxiety-related behaviours. There are also gender differences in the prevalence of anxiety-related behaviours. Although numerous studies have investigated the influence of 5-HTTLPR genotype on the neural systems involved in emotional regulation, none have investigated how these effects are modulated by gender and anxiety. We investigated this issue using two complementary region of interest-based structural neuroimaging approaches (voxel-based morphometry and Freesurfer) in 138 healthy individuals categorized into ‘no anxiety’ and ‘subclinical anxiety’ groups based on the Hamilton Rating Scale for Anxiety (HAM-A). Preliminarily, using anxiety as a continuous variable, we found a significant interaction effect of genotype by gender on anxiety. Females homozygous for the Short allele showed the highest HAM-A scores and males the lowest. In addition, a three-way significant interaction among genotype, gender and anxiety category was found for the right amygdala volume. Post hoc tests revealed that homozygous females carrying the Short variant with a subclinical anxiety condition had larger volume. The reported interaction effects demonstrate that gender strongly modulates the relationship between 5-HTTLPR genotype and subclinical expression of anxiety acting on amygdala, one region of the emotional neural network specifically involved in the anxiety-like behaviours. PMID:23986266

  1. The Association Between Serotonin Transporter Gene Promoter Polymorphism (5-HTTLPR), Self-Reported Symptoms, and Dental Mercury Exposure

    PubMed Central

    Heyer, Nicholas J.; Echeverria, Diana; Farin, Federico M.; Woods, James S.

    2008-01-01

    The associations between a polymorphism of the serotonin transporter gene (5-HTTLPR), dental mercury exposure, and self-reported symptoms were evaluated among 157 male dentists and 84 female dental assistants. Self-reported symptoms and detailed work histories were obtained by computerized questionnaire. Spot urine samples were collected and analyzed for mercury concentrations to evaluate recent exposures, whereas a chronic mercury exposure index was created from the work histories. 5-HTTLPR polymorphism status was determined using a polymerase chain reaction (PCR)-based assay. Scores for current, recent, and chronic self-reported symptom groups were evaluated with respect to recent and chronic mercury exposure and 5-HTTLPR polymorphism status. Multiple regression analysis controlled for age, socioeconomic status, tobacco and alcohol use, self-reported health problems, and medications. Analyses were restricted to Caucasian subjects due to the highly skewed distribution of the 5-HTTLPR polymorphism. Separate evaluations were conducted for dentists and dental assistants. In contrast to previous reports, no consistent associations were found between either urinary mercury concentration or the chronic index of mercury exposure and any category of symptoms. However, both significant and consistent associations were observed between increased symptoms and the 5-HTTLPR polymorphism involving two copies of the short or “s” allele (full mutation), but not with the polymorphism involving only one copy (heterozygous), demonstrating a gene–dose relationship for symptom reporting. These findings suggest that within this restricted population increased symptoms of depression, anxiety, and memory are associated with the 5-HTTLPR polymorphism among both males and females. PMID:18686203

  2. Association Between 5-HTTLPR Polymorphism and Tics after Treatment with Methylphenidate in Korean Children with Attention-Deficit/Hyperactivity Disorder

    PubMed Central

    Park, Seo Yeon; Kim, Eun Joo

    2015-01-01

    Abstract Objectives: The purpose of this study is to examine the relationship between 5-HTTLPR polymorphism (44-bp insertion/deletion polymorphism of serotonin transporter gene) and methylphenidate (MPH) treatment response, as well as the association between the adverse events of MPH treatment and 5-HTTLPR polymorphism in children with attention-deficit/hyperactivity disorder (ADHD). Methods: A total of 114 children with ADHD (mean age 9.08 ± 1.94 years) were recruited from the child psychiatric clinic in a hospital in South Korea. We have extracted the genomic DNA of the subjects from their blood lymphocytes and analyzed 5-HTTLPR polymorphism of the SLC6A4 gene. All children were treated with MPH for 8 weeks, with clinicians monitoring both the improvement of ADHD symptoms and the side effects. We compared the response to MPH treatment and adverse events among those with the genotype of 5-HRRLPR polymorphism. Results: There was no significant association between the 5-HTTLPR genotype and the response to MPH treatment in children with ADHD. Subjects with the S/L+L/L genotype tended to have tics and nail biting (respectively, p < 0.001, p = 0.017). Conclusions: The results of this study do not support the association between the 5-HTTLPR polymorphism and treatment response with MPH in ADHD. However, our findings suggest the association between 5-HTTLPR polymorphism and the occurrence of tics and nail-biting as an adverse event of methylphenidate. This may aid in our understanding of the genetic contribution and genetic susceptibility of a particular allele in those ADHD patients with tics or nail biting. PMID:26402385

  3. Cognitive appraisal and life stress moderate the effects of the 5-HTTLPR polymorphism on amygdala reactivity.

    PubMed

    Lemogne, Cédric; Gorwood, Philip; Boni, Claudette; Pessiglione, Mathias; Lehéricy, Stéphane; Fossati, Philippe

    2011-11-01

    The short allele of the serotonin-transporter-linked promoter region (5-HTTLPR) polymorphism is associated with increased amygdala activation in response to emotional stimuli. Although top-down processes may moderate this association, available evidence is conflicting, showing the genotype influence on amygdala reactivity to be either decreased or increased during emotion regulation. Because the effects of the 5-HTTLPR polymorphism on amygdala reactivity are also conditional on self-reported life stress, differences in life stress exposure may account for this apparent discrepancy. Here, we hypothesized that self-reported life stress would moderate the relationships between genotype, cognitive appraisal, and amygdala reactivity. Forty-five healthy never-depressed subjects were presented with emotional stimuli and performed two cognitive tasks: a self-referential task and an emotion-labeling task. Life-stress exposure was measured through a semistructured interview. First, there was a genotype × condition interaction in the right amygdala: short allele carriers displayed increased amygdala activation and decreased functional connectivity with the subgenual anterior cingulate cortex in self-referential processing versus emotion labeling. Second, in line with our hypothesis, there was a genotype × condition × stress interaction in bilateral amygdala the amygdala activation during self-referential processing was negatively correlated with self-reported life stress in short allele carriers and positively in individuals homozygous for the long allele, whereas an opposite pattern was observed during emotion labeling. These results confirm that the influence of the 5-HTTLPR polymorphism on amygdala reactivity is at least partially under cognitive control. Additionally, they suggest that measuring life stress exposure is a critical step when imaging genetics.

  4. The association between serotonin transporter gene promotor polymorphism (5-HTTLPR) and elemental mercury exposure on mood and behavior in humans.

    PubMed

    Echeverria, Diana; Woods, James S; Heyer, Nicholas J; Martin, Michael D; Rohlman, Dianne S; Farin, Federico M; Li, Tingting

    2010-01-01

    A functional polymorphism in the serotonin transporter (5-HTT) gene-linked polymorphic region (5-HTTLPR) is reported to affect mood and behavior in humans. In this study, the effects of 5-HTTLPR polymorphism on neurobehavioral and mood domains that are known to be affected by elemental mercury (Hg degrees ) exposure in human subjects were examined. The Behavioral Evaluation for Epidemiologic Studies (BEES) test battery was administered concurrently with urine and buccal-cell collections for 164 male dentists (DD) and 101 female dental assistants (DA) with occupational exposure to Hg degrees for an average of 19 and 10 yr, respectively. Geometric mean urinary mercury (Hg) levels in DD and DA were 2.52 (2.22) microg/L and 1.98 (1.98) microg/L, respectively. Corresponding indices of chronic occupational Hg degrees exposure, weighted for historical exposure, were 1212 (1877) and 316 (429). 5-HTTLPR status was 40% and 20% wild type, 40% and 56% single allelic substitution, and 20% and 24% double allelic substitution for the two genders. DD and DA were evaluated separately. Regression analyses controlled for age, premorbid intelligence, frequency of alcohol per week, and education. 5-HTTLPR polymorphism was associated with 5 behavioral measures in DD and with 12 behavioral measures in DA. Mood scores were more consistently associated with the variant in both groups. The strongest evidence for an additive effect for urinary Hg and 5-HTTLPR polymorphism in both groups was for tests of Finger Tap(Alternate) and Hand Steadiness(Factor1). Other significant additive effects that were less consistent across groups were also observed. These results add to the growing evidence of genetic determinants of mood and behavior that potentially increase susceptibility to Hg toxicity in humans.

  5. 5-HTTLPR polymorphism is linked to neural mechanisms of selective attention in preschoolers from lower socioeconomic status backgrounds.

    PubMed

    Isbell, Elif; Stevens, Courtney; Hampton Wray, Amanda; Bell, Theodore; Neville, Helen J

    2016-12-01

    While a growing body of research has identified experiential factors associated with differences in selective attention, relatively little is known about the contribution of genetic factors to the skill of sustained selective attention, especially in early childhood. Here, we assessed the association between the serotonin transporter linked polymorphic region (5-HTTLPR) genotypes and the neural mechanisms of selective attention in young children from lower socioeconomic status (SES) backgrounds. Event-related potentials (ERPs) were recorded during a dichotic listening task from 121 children (76 females, aged 40-67 months), who were also genotyped for the short and long allele of 5-HTTLPR. The effect of selective attention was measured as the difference in ERP mean amplitudes elicited by identical probe stimuli embedded in stories when they were attended versus unattended. Compared to children homozygous for the long allele, children who carried at least one copy of the short allele showed larger effects of selective attention on neural processing. These findings link the short allele of the 5-HTTLPR to enhanced neural mechanisms of selective attention and lay the groundwork for future studies of gene-by-environment interactions in the context of key cognitive skills.

  6. 5HTTLPR genotype moderates the longitudinal impact of early caregiving on externalizing behavior

    PubMed Central

    Smyke, Anna T.; Gleason, Mary Margaret; Nelson, Charles A.; Zeanah, Charles H.; Fox, Nathan A; Drury, Stacy S.

    2014-01-01

    We examined caregiver report of externalizing behavior from 12 to 54 months of age in 102 children randomized to care as usual in institutions or to newly-created high quality foster care. At baseline no differences by group or genotype in externalizing were found. However, changes in externalizing from baseline to 42 months of age were moderated by 5HTTLPR genotype and intervention group, where the slope for s/s individuals differed as a function of intervention group. The slope for individuals carrying the l allele did not significantly differ between groups. At 54 months of age, s/s children in the foster care group had the lowest levels of externalizing behavior, while children with the s/s genotype in the care as usual group demonstrated the highest rates of externalizing behavior. No intervention group differences were found in externalizing behavior among children who carried the l allele. These findings, within a randomized control trial of foster care compared to continued care as usual, indicate that 5HTTLPR genotype moderates the relation between early caregiving environments to predict externalizing behavior in children exposed to early institutional care in a manner most consistent with differential susceptibility. PMID:25640827

  7. COMT val158met and 5-HTTLPR Genetic Polymorphisms Moderate Executive Control in Cannabis Users

    PubMed Central

    Verdejo-García, Antonio; Beatriz Fagundo, Ana; Cuenca, Aida; Rodriguez, Joan; Cuyás, Elisabet; Langohr, Klaus; de Sola Llopis, Susana; Civit, Ester; Farré, Magí; Peña-Casanova, Jordi; de la Torre, Rafael

    2013-01-01

    The adverse effects of cannabis use on executive functions are still controversial, fostering the need for novel biomarkers able to unveil individual differences in the cognitive impact of cannabis consumption. Two common genetic polymorphisms have been linked to the neuroadaptive impact of Δ9-tetrahydrocannabinol (THC) exposure and to executive functions in animals: the catechol-O-methyltransferase (COMT) gene val158met polymorphism and the SLC6A4 gene 5-HTTLPR polymorphism. We aimed to test if these polymorphisms moderate the harmful effects of cannabis use on executive function in young cannabis users. We recruited 144 participants: 86 cannabis users and 58 non-drug user controls. Both groups were genotyped and matched for genetic makeup, sex, age, education, and IQ. We used a computerized neuropsychological battery to assess different aspects of executive functions: sustained attention (CANTAB Rapid Visual Information Processing Test, RVIP), working memory (N-back), monitoring/shifting (CANTAB ID/ED set shifting), planning (CANTAB Stockings of Cambridge, SOC), and decision-making (Iowa Gambling Task, IGT). We used general linear model-based analyses to test performance differences between cannabis users and controls as a function of genotypes. We found that: (i) daily cannabis use is not associated with executive function deficits; and (ii) COMT val158met and 5-HTTLPR polymorphisms moderate the link between cannabis use and executive performance. Cannabis users carrying the COMT val/val genotype exhibited lower accuracy of sustained attention, associated with a more strict response bias, than val/val non-users. Cannabis users carrying the COMT val allele also committed more monitoring/shifting errors than cannabis users carrying the met/met genotype. Finally, cannabis users carrying the 5-HTTLPR s/s genotype had worse IGT performance than s/s non-users. COMT and SLC6A4 genes moderate the impact of cannabis use on executive functions. PMID:23449176

  8. 5-HTTLPR moderates naltrexone and psychosocial treatment responses in heavy drinking men who have sex with men

    PubMed Central

    Chen, Andrew C.H.; Davis, Christine M.; Kahler, Christopher W.; Kuerbis, Alexis N.; Covault, Jonathan; Kranzler, Henry R.; Morgenstern, Jon

    2014-01-01

    Background A functional polymorphism (5-HTTLPR) in the promoter region of the serotonin transporter gene has been widely studied as a risk factor and moderator of treatment for a variety of psychopathologic conditions. To evaluate whether 5-HTTLPR moderates the effects of treatment to reduce heavy drinking, we studied 112 high-functioning European-American men who have sex with men (MSM). Subjects participated in a randomized clinical trial of naltrexone (NTX) and cognitive behavioral therapy (CBT) for problem drinking. Methods Subjects were treated for 12 weeks with 100 mg/day of oral NTX or placebo. All participants received medical management with adjusted Brief Behavioral Compliance Enhancement Treatment (BBCET) alone or in combination with Modified Behavioral Self-Control Therapy (MBSCT, an amalgam of motivational interviewing and CBT). Participants were genotyped for the tri-allelic 5-HTTLPR polymorphism (i.e., low-activity S′ or high-activity L′ alleles). Results During treatment, the number of weekly heavy drinking days (HDD, defined as 5 or more standard drinks per day) was significantly lower in subjects with the L′L′ (N=26, p=0.015) or L′S′ (N=52, p=0.016) genotype than those with the S′S′ (N=34) genotype regardless of treatment type. There was a significant interaction of genotype with treatment: For subjects with the S′S′ genotype, the effects of MBSCT or NTX on HDD were significantly greater than the minimal intervention (i.e., BBCET or placebo, p=0.007 and p=0.049, respectively). In contrast, for subjects with one or two L′ alleles, the effects of the more intensive psychosocial treatment (MBSCT) or NTX did not significantly differ from BBCET or placebo. Conclusions These preliminary findings support the utility of the 5-HTTLPR polymorphism for personalizing treatment selection in problem drinkers. PMID:25070809

  9. Effects of acute psychosocial stress exposure on endocrine and affective reactivity in college students differing in the 5-HTTLPR genotype and trait neuroticism.

    PubMed

    Verschoor, Ellen; Markus, C Rob

    2011-07-01

    Enhanced stress vulnerability has been implicated in the pathogenesis of affective disorders. Although both genetic (5-HTTLPR) and cognitive (neuroticism) factors are known to increase stress vulnerability, no experimental study has investigated the interaction between these two factors on psychobiological reactivity following acute stress exposure. This study used a balanced experimental design to examine the interaction between the 5-HTTLPR genotype and trait neuroticism in neuroendocrine and affective stress responses. From a large group of 771 students, 48 carriers of the short/short (S/S) allele and 48 carriers of the long/long (L/L) allele with the lowest and the highest neuroticism scores (77 females, 19 males; mean age ± SD: 20.6 ± 2 years) were selected and exposed to an acute psychosocial stressor. Mood was assessed before and after the stressor, and salivary cortisol concentrations were measured before and at 20, 30, and 60 min after stressor onset. Acute stress increased salivary cortisol concentration regardless of either 5-HTTLPR genotype or neuroticism, but it caused a less profound negative mood change in L/L compared to S/S-allele carriers with the lowest neuroticism scores. The 5-HTTLPR genotype influences affective reactivity to acute stress conditional upon neuroticism, improving resilience to acute stress in L/L-allele carriers if they do not already possess high cognitive-affective (neuroticism) vulnerability.

  10. An integrative review of methylation at the serotonin transporter gene and its dialogue with environmental risk factors, psychopathology and 5-HTTLPR.

    PubMed

    Palma-Gudiel, H; Fañanás, L

    2017-01-01

    Gene-environment (G×E) interactions have largely been regarded as the root of many complex disorders, including several psychiatric disorders. In this regard, it has been hypothesized that epigenetic mechanisms may be the main mediators of such interactions. Of particular interest is the previously described interaction between psychosocial stress and genetic variability of the serotonin transporter gene (SLC6A4) in its polymorphic region 5-HTTLPR. Here we review the literature concerning SLC6A4 methylation in association with environmental, clinical or genetic variables. While SLC6A4 hypermethylation has typically been described to be independently associated with both early life stress and depressive disorders, only a few papers address whether methylation could mediate the interaction between stress and 5-HTTLPR in predicting psychopathological risk. Nevertheless, research preliminarily indicates a methylation-driven increased vulnerability of carriers of the short allele of 5-HTTLPR to psychiatric disorders when exposed to early stress or soon after exposure to stress.

  11. A study of blood serotonin and serotonin transporter promoter variant (5-HTTLPR) polymorphism in Egyptian autistic children

    PubMed Central

    Meguid, Nagwa A.; Gebril, Ola H.; Khalil, Rehab O.

    2015-01-01

    Background: Autism spectrum disorder (ASD) is a complex, heterogeneous neurodevelopmental disorder with onset during early childhood. Most studies have reported an elevation in platelet serotonin in persons with autism. The serotonin (5-hydroxytryptamine; 5-HT) transporter in the brain uptakes 5-HT from extracellular spaces. It is also present in platelets, where it takes up 5-HT from plasma. Polymorphisms in serotonin transporter gene (SLC6A4) were frequently studied in many neuropsychiatric disorders. Materials and Methods: We have measured the plasma 5-HT levels in 20 autistic male children and 20 control male children by the enzyme-linked immunosorbent assay (ELISA) method. In addition, the SLC6A4 promoter region (5-HTTLPR) insertion/deletion (I/D) polymorphism was studied, using whole genomic DNA. Results: Plasma serotonin was significantly low in autistic children compared to control (P = 0.001), although correlation to severity of autism was not significant. The frequency of short (S) allele in autism cases was 10% and in the control group it was absent. Conclusion: Our study demonstrated an increased prevalence of 5-HTTLPR S allele in autism subjects. Significantly decreased plasma serotonin was detected in autism subjects, with no significant relationship between 5-HTTLPR genotype and plasma 5-HT being evident. PMID:26015920

  12. Lack of homozygotes for the most frequent disease allele in carbohydrate-deficient glycoprotein syndrome type 1A.

    PubMed

    Matthijs, G; Schollen, E; Van Schaftingen, E; Cassiman, J J; Jaeken, J

    1998-03-01

    Carbohydrate-deficient-glycoprotein syndrome type 1 (CDG1; also known as "Jaeken syndrome") is an autosomal recessive disorder characterized by defective glycosylation. Most patients show a deficiency of phosphomannomutase (PMM), the enzyme that converts mannose 6-phosphate to mannose 1-phosphate in the synthesis of GDP-mannose. The disease is linked to chromosome 16p13, and mutations have recently been identified in the PMM2 gene in CDG1 patients with a PMM deficiency (CDG1A). The availability of the genomic sequences of PMM2 allowed us to screen for mutations in 56 CDG1 patients from different geographic origins. By SSCP analysis and by sequencing, we identified 23 different missense mutations and 1 single-base-pair deletion. In total, mutations were found on 99% of the disease chromosomes in CDG1A patients. The R141H substitution is present on 43 of the 112 disease alleles. However, this mutation was never observed in the homozygous state, suggesting that homozygosity for these alterations is incompatible with life. On the other hand, patients were found homozygous for the D65Y and F119L mutations, which must therefore be mild mutations. One particular genotype, R141H/D188G, which is prevalent in Belgium and the Netherlands, is associated with a severe phenotype and a high mortality. Apart from this, there is only a limited relation between the genotype and the clinical phenotype.

  13. Lack of homozygotes for the most frequent disease allele in carbohydrate-deficient glycoprotein syndrome type 1A.

    PubMed Central

    Matthijs, G; Schollen, E; Van Schaftingen, E; Cassiman, J J; Jaeken, J

    1998-01-01

    Carbohydrate-deficient-glycoprotein syndrome type 1 (CDG1; also known as "Jaeken syndrome") is an autosomal recessive disorder characterized by defective glycosylation. Most patients show a deficiency of phosphomannomutase (PMM), the enzyme that converts mannose 6-phosphate to mannose 1-phosphate in the synthesis of GDP-mannose. The disease is linked to chromosome 16p13, and mutations have recently been identified in the PMM2 gene in CDG1 patients with a PMM deficiency (CDG1A). The availability of the genomic sequences of PMM2 allowed us to screen for mutations in 56 CDG1 patients from different geographic origins. By SSCP analysis and by sequencing, we identified 23 different missense mutations and 1 single-base-pair deletion. In total, mutations were found on 99% of the disease chromosomes in CDG1A patients. The R141H substitution is present on 43 of the 112 disease alleles. However, this mutation was never observed in the homozygous state, suggesting that homozygosity for these alterations is incompatible with life. On the other hand, patients were found homozygous for the D65Y and F119L mutations, which must therefore be mild mutations. One particular genotype, R141H/D188G, which is prevalent in Belgium and the Netherlands, is associated with a severe phenotype and a high mortality. Apart from this, there is only a limited relation between the genotype and the clinical phenotype. PMID:9497260

  14. Biallelic and Triallelic 5-Hydroxytyramine Transporter Gene-Linked Polymorphic Region (5-HTTLPR) Polymorphisms and Their Relationship with Lifelong Premature Ejaculation: A Case-Control Study in a Chinese Population

    PubMed Central

    Huang, Yuanyuan; Zhang, Xiansheng; Gao, Jingjing; Tang, Dongdong; Gao, Pan; Li, Chao; Liu, Weiqun; Liang, Chaozhao

    2016-01-01

    Background This study aimed to explore the relationship between premature ejaculation (PE) and the serotonin transporter gene-linked polymorphic region (5-HTTLPR) with respect to the biallelic and triallelic classifications. Material/Methods A total of 115 outpatients who complained of ejaculating prematurely and who were diagnosed as having lifelong premature ejaculation (LPE) and 101 controls without PE complaint were recruited. All subjects completed a detailed questionnaire and were genotyped for 5-HTTLPR polymorphism using PCR-based technology. We evaluated the associations between 5-HTTLPR allelic and genotypic frequencies and their association with LPE, as well as the intravaginal ejaculation latency time (IELT) of different 5-HTTLPR genotypes among LPE patients. Results The patients and controls did not differ significantly in terms of any characteristic except age. The results showed no significant difference regarding biallelic 5-HTTLPR. According to the triallelic classification, no significant difference was found when comparing the genotypic distribution (P=0.091). However, the distribution of the S, LG, and LA alleles in the cases was significantly different from the controls (P=0.018). We found a significantly lower frequency of LA allele and higher frequency of LG allele in patients. Based on another classification by expression, we found a significantly lower frequency of the L’L’ genotype (OR=0.37; 95%CI=0.15–0.91, P=0.025) in patients with LPE. No significant association was detected between IELT of LPE and different genotypes. Conclusions Contrary to the general classification based on S/L alleles, triallelic 5-HTTLPR was associated with LPE. Triallelic 5-HTTLPR may be a promising field for genetic research in PE to avoid false-negative results in future studies. PMID:27311544

  15. Biallelic and Triallelic 5-Hydroxytyramine Transporter Gene-Linked Polymorphic Region (5- HTTLPR) Polymorphisms and Their Relationship with Lifelong Premature Ejaculation: A Case-Control Study in a Chinese Population.

    PubMed

    Huang, Yuanyuan; Zhang, Xiansheng; Gao, Jingjing; Tang, Dongdong; Gao, Pan; Li, Chao; Liu, Weiqun; Liang, Chaozhao

    2016-06-17

    BACKGROUND This study aimed to explore the relationship between premature ejaculation (PE) and the serotonin transporter gene-linked polymorphic region (5-HTTLPR) with respect to the biallelic and triallelic classifications. MATERIAL AND METHODS A total of 115 outpatients who complained of ejaculating prematurely and who were diagnosed as having lifelong premature ejaculation (LPE) and 101 controls without PE complaint were recruited. All subjects completed a detailed questionnaire and were genotyped for 5-HTTLPR polymorphism using PCR-based technology. We evaluated the associations between 5-HTTLPR allelic and genotypic frequencies and their association with LPE, as well as the intravaginal ejaculation latency time (IELT) of different 5-HTTLPR genotypes among LPE patients. RESULTS The patients and controls did not differ significantly in terms of any characteristic except age. The results showed no significant difference regarding biallelic 5-HTTLPR. According to the triallelic classification, no significant difference was found when comparing the genotypic distribution (P=0.091). However, the distribution of the S, LG, and LA alleles in the cases was significantly different from the controls (P=0.018). We found a significantly lower frequency of LA allele and higher frequency of LG allele in patients. Based on another classification by expression, we found a significantly lower frequency of the L'L' genotype (OR=0.37; 95%CI=0.15-0.91, P=0.025) in patients with LPE. No significant association was detected between IELT of LPE and different genotypes. CONCLUSIONS Contrary to the general classification based on S/L alleles, triallelic 5-HTTLPR was associated with LPE. Triallelic 5-HTTLPR may be a promising field for genetic research in PE to avoid false-negative results in future studies.

  16. A Serotonin Transporter Gene Polymorphism (5-HTTLPR), Drinking-to-Cope Motivation, and Negative Life Events Among College Students*

    PubMed Central

    Armeli, Stephen; Conner, Tamlin S.; Covault, Jonathan; Tennen, Howard; Kranzler, Henry R.

    2008-01-01

    Objective: This study was performed to examine whether a polymorphism (5-HTTLPR) in the serotonin transporter gene was related to college students' reports of relief drinking (drinking-to-cope motives) and whether it moderated the associations between negative life events and drinking to cope. We examined reward drinking (drinkingto-enhance motives) as a comparison and to see whether these effects varied across gender. Method: Using an Internet-based survey, college students (N = 360; 192 women) self-reported on drinking motives and negative life events for up to 4 years. Study participants provided saliva for genotyping the triallelic (LA vs LG or S) variants of 5-HTTLPR. Results: Among men, individuals with two risk alleles (LG or S), compared with individuals with the LA/LA allele, displayed lower drinking-to-cope motives. Among women, individuals with one risk allele (either LG or S), compared with individuals with the LA/LA allele, displayed stronger drinking-to-enhance motives. The association between yearly changes in negative life events and drinking-to-cope motives varied across 5-HT-TLPR genotype and gender and was strongest in the positive direction for women with the LA/LA variant. Conclusions: Our findings are not consistent with prior speculation that stronger positive associations between life stress and alcohol use among individuals with the LG or S allele are the result of increased use of alcohol as a method for coping with stress. The importance of examining gender differences in the relations between 5-HTTLPR, substance use, and related constructs is also noted. PMID:18925339

  17. Meta-Analyses of the 5-HTTLPR Polymorphisms and Post-Traumatic Stress Disorder

    PubMed Central

    Navarro-Mateu, Fernando; Escámez, Teresa; Koenen, Karestan C.; Alonso, Jordi; Sánchez-Meca, Julio

    2013-01-01

    Objective To conduct a meta-analysis of all published genetic association studies of 5-HTTLPR polymorphisms performed in PTSD cases Methods Data Sources Potential studies were identified through PubMed/MEDLINE, EMBASE, Web of Science databases (Web of Knowledge, WoK), PsychINFO, PsychArticles and HuGeNet (Human Genome Epidemiology Network) up until December 2011. Study Selection: Published observational studies reporting genotype or allele frequencies of this genetic factor in PTSD cases and in non-PTSD controls were all considered eligible for inclusion in this systematic review. Data Extraction: Two reviewers selected studies for possible inclusion and extracted data independently following a standardized protocol. Statistical analysis: A biallelic and a triallelic meta-analysis, including the total S and S' frequencies, the dominant (S+/LL and S'+/L'L') and the recessive model (SS/L+ and S'S'/L'+), was performed with a random-effect model to calculate the pooled OR and its corresponding 95% CI. Forest plots and Cochran's Q-Statistic and I2 index were calculated to check for heterogeneity. Subgroup analyses and meta-regression were carried out to analyze potential moderators. Publication bias and quality of reporting were also analyzed. Results 13 studies met our inclusion criteria, providing a total sample of 1874 patients with PTSD and 7785 controls in the biallelic meta-analyses and 627 and 3524, respectively, in the triallelic. None of the meta-analyses showed evidence of an association between 5-HTTLPR and PTSD but several characteristics (exposure to the same principal stressor for PTSD cases and controls, adjustment for potential confounding variables, blind assessment, study design, type of PTSD, ethnic distribution and Total Quality Score) influenced the results in subgroup analyses and meta-regression. There was no evidence of potential publication bias. Conclusions Current evidence does not support a direct effect of 5-HTTLPR polymorphisms on PTSD

  18. Collaborative meta-analysis finds no evidence of a strong interaction between stress and 5-HTTLPR genotype contributing to the development of depression.

    PubMed

    Culverhouse, R C; Saccone, N L; Horton, A C; Ma, Y; Anstey, K J; Banaschewski, T; Burmeister, M; Cohen-Woods, S; Etain, B; Fisher, H L; Goldman, N; Guillaume, S; Horwood, J; Juhasz, G; Lester, K J; Mandelli, L; Middeldorp, C M; Olié, E; Villafuerte, S; Air, T M; Araya, R; Bowes, L; Burns, R; Byrne, E M; Coffey, C; Coventry, W L; Gawronski, K A B; Glei, D; Hatzimanolis, A; Hottenga, J-J; Jaussent, I; Jawahar, C; Jennen-Steinmetz, C; Kramer, J R; Lajnef, M; Little, K; Zu Schwabedissen, H M; Nauck, M; Nederhof, E; Petschner, P; Peyrot, W J; Schwahn, C; Sinnamon, G; Stacey, D; Tian, Y; Toben, C; Van der Auwera, S; Wainwright, N; Wang, J-C; Willemsen, G; Anderson, I M; Arolt, V; Åslund, C; Bagdy, G; Baune, B T; Bellivier, F; Boomsma, D I; Courtet, P; Dannlowski, U; de Geus, E J C; Deakin, J F W; Easteal, S; Eley, T; Fergusson, D M; Goate, A M; Gonda, X; Grabe, H J; Holzman, C; Johnson, E O; Kennedy, M; Laucht, M; Martin, N G; Munafò, M R; Nilsson, K W; Oldehinkel, A J; Olsson, C A; Ormel, J; Otte, C; Patton, G C; Penninx, B W J H; Ritchie, K; Sarchiapone, M; Scheid, J M; Serretti, A; Smit, J H; Stefanis, N C; Surtees, P G; Völzke, H; Weinstein, M; Whooley, M; Nurnberger, J I; Breslau, N; Bierut, L J

    2017-04-04

    The hypothesis that the S allele of the 5-HTTLPR serotonin transporter promoter region is associated with increased risk of depression, but only in individuals exposed to stressful situations, has generated much interest, research and controversy since first proposed in 2003. Multiple meta-analyses combining results from heterogeneous analyses have not settled the issue. To determine the magnitude of the interaction and the conditions under which it might be observed, we performed new analyses on 31 data sets containing 38 802 European ancestry subjects genotyped for 5-HTTLPR and assessed for depression and childhood maltreatment or other stressful life events, and meta-analysed the results. Analyses targeted two stressors (narrow, broad) and two depression outcomes (current, lifetime). All groups that published on this topic prior to the initiation of our study and met the assessment and sample size criteria were invited to participate. Additional groups, identified by consortium members or self-identified in response to our protocol (published prior to the start of analysis) with qualifying unpublished data, were also invited to participate. A uniform data analysis script implementing the protocol was executed by each of the consortium members. Our findings do not support the interaction hypothesis. We found no subgroups or variable definitions for which an interaction between stress and 5-HTTLPR genotype was statistically significant. In contrast, our findings for the main effects of life stressors (strong risk factor) and 5-HTTLPR genotype (no impact on risk) are strikingly consistent across our contributing studies, the original study reporting the interaction and subsequent meta-analyses. Our conclusion is that if an interaction exists in which the S allele of 5-HTTLPR increases risk of depression only in stressed individuals, then it is not broadly generalisable, but must be of modest effect size and only observable in limited situations

  19. BDNF Val 66 Met and 5-HTTLPR genotype moderate the impact of early psychosocial adversity on plasma brain-derived neurotrophic factor and depressive symptoms: a prospective study.

    PubMed

    Buchmann, Arlette F; Hellweg, Rainer; Rietschel, Marcella; Treutlein, Jens; Witt, Stephanie H; Zimmermann, Ulrich S; Schmidt, Martin H; Esser, Günter; Banaschewski, Tobias; Laucht, Manfred; Deuschle, Michael

    2013-08-01

    Recent studies have emphasized an important role for neurotrophins, such as brain-derived neurotrophic factor (BDNF), in regulating the plasticity of neural circuits involved in the pathophysiology of stress-related diseases. The aim of the present study was to examine the interplay of the BDNF Val⁶⁶Met and the serotonin transporter promoter (5-HTTLPR) polymorphisms in moderating the impact of early-life adversity on BDNF plasma concentration and depressive symptoms. Participants were taken from an epidemiological cohort study following the long-term outcome of early risk factors from birth into young adulthood. In 259 individuals (119 males, 140 females), genotyped for the BDNF Val⁶⁶Met and the 5-HTTLPR polymorphisms, plasma BDNF was assessed at the age of 19 years. In addition, participants completed the Beck Depression Inventory (BDI). Early adversity was determined according to a family adversity index assessed at 3 months of age. Results indicated that individuals homozygous for both the BDNF Val and the 5-HTTLPR L allele showed significantly reduced BDNF levels following exposure to high adversity. In contrast, BDNF levels appeared to be unaffected by early psychosocial adversity in carriers of the BDNF Met or the 5-HTTLPR S allele. While the former group appeared to be most susceptible to depressive symptoms, the impact of early adversity was less pronounced in the latter group. This is the first preliminary evidence indicating that early-life adverse experiences may have lasting sequelae for plasma BDNF levels in humans, highlighting that the susceptibility to this effect is moderated by BDNF Val⁶⁶Met and 5-HTTLPR genotype.

  20. Association of serotonin transporter promoter gene polymorphism (5-HTTLPR) with depression in Costa Rican schizophrenic patients.

    PubMed

    Contreras, Javier; Hernández, Sandra; Quezada, Paulina; Dassori, Albana; Walss-Bass, Consuelo; Escamilla, Michael; Raventos, Henriette

    2010-07-01

    Depression and suicidal behavior are frequently observed in patients with schizophrenia. The serotonin transporter protein regulates serotonergic signaling at synapses and is encoded by a single gene (SLC6A4; Locus Link ID: 6532), located at 17q11.1-q12 with two polymorphic variants (the short and the long allele). The short allele of serotonin transporter gene has been associated with depression and suicidality in individuals who suffered negative life events and with depression in individuals with chronic psychosis.. Subjects were recruited from a genetic study of schizophrenia conducted in Costa Rica. The authors replicated their previous research, using a more narrow phenotype (only schizophrenic subjects) and a more ethnically homogenous sample (only Costa Rican schizophrenic individuals who were not included in the previous study). The authors hypothesized that subjects with at least one copy of the serotonin transporter promoter gene polymorphism (5-HTTLPR) "s" allele would have a greater history of lifetime depression and suicidability rate than those who had an "l/l" genotype. The authors analyzed 155 subjects with a DSM-IV (Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition) diagnosis of schizophrenia (73% male, age at interview 38.3, SD = 11.23). The genotype distribution was "ss" 58 (37%), "sl" 69 (45%), and "ll" 28 (18%). In the secondary analysis, the authors explored association of the "s" allele with lifetime history of suicide behavior in 173 subjects (18 more subjects than primary analysis because schizophrenic individuals were included regardless of history of depression). The authors found that subjects carrying at least one short allele had a significant increased lifetime risk for depressive syndromes (chi(2) = 5.4, df = 1, P = 0.02; odds ratio [OR] = 2.7, 95% confidence interval [CI] = 1.15-6.3). No association was found for suicidal behavior in the same sample (chi(2) = 0.928, P = 0.629). In conclusion, the genotype at the

  1. Lack of association between the Serotonin Transporter Promoter Polymorphism (5-HTTLPR) and Panic Disorder: a systematic review and meta-analysis

    PubMed Central

    Blaya, Carolina; Salum, Giovanni A; Lima, Maurício S; Leistner-Segal, Sandra; Manfro, Gisele G

    2007-01-01

    Background The aim of this study is to assess the association between the Serotonin Transporter Promoter Polymorphism (5-HTTLPR) and Panic Disorder (PD). Methods This is a systematic review and meta-analysis of case-control studies with unrelated individuals of any ethnic origin examining the role of the 5-HTTLPR in PD according to standard diagnostic criteria (DSM or ICD). Articles published in any language between January 1996 and April 2007 were eligible. The electronic databases searched included PubMed, PsychInfo, Lilacs and ISI. Two separate analyses were performed: an analysis by alleles and a stratified analysis separating studies by the quality of control groups. Asymptotic DerSimonian and Laird's Q test were used to assess heterogeneity. Results of individual studies were combined using the fixed effect model with respective 95% confidence intervals. Results Nineteen potential articles were identified, and 10 studies were included in this meta-analysis. No statistically significant association between 5-HTTLPR and PD was found, OR = 0.91 (CI95% 0.80 to 1.03, p = 0.14). Three sub-analyses divided by ethnicity, control group quality and Agoraphobia comorbidity also failed to find any significant association. No evidence of heterogeneity was found between studies in the analyses. Conclusion Results from this systematic review do not provide evidence to support an association between 5-HTTLPR and PD. However, more studies are needed in different ethnic populations in order to evaluate a possible minor effect. PMID:17705872

  2. Children’s Inferential Styles, 5-HTTLPR Genotype, and Maternal Expressed Emotion-Criticism: An Integrated Model for the Intergenerational Transmission of Depression

    PubMed Central

    Gibb, Brandon E.; Uhrlass, Dorothy J.; Grassia, Marie; Benas, Jessica S.; McGeary, John

    2010-01-01

    We tested a model for the intergenerational transmission of depression integrating specific genetic (5-HTTLPR), cognitive (inferential style), and environmental (mother depressive symptoms and expressed-emotion criticism) risk factors. Supporting the hypothesis that maternal depression is associated with elevated levels of stress in children’s lives, mothers with a history of major depressive disorder (MDD) exhibited higher depressive symptoms across a 6-month multi-wave follow-up than mothers with no depression history. In addition, partially supporting our hypothesis, levels of maternal criticism during the follow-up were significantly related to mothers’ current depressive symptoms, but not history of MDD. Finally, we found support for an integrated gene × cognition × environment model of risk. Specifically, among children with negative inferential styles regarding their self-characteristics, there was a clear dose response of 5-HTTLPR genotype moderating the relation between maternal criticism and children’s depressive symptoms, with the highest depressive symptoms during the follow-up observed among children carrying two copies of the 5-HTTLPR lower expressing alleles (S or LG) who also exhibited negative inferential styles for self-characteristics and who experienced high levels of EE-Crit. In contrast, children with positive inferential styles exhibited low depressive symptoms regardless of 5-HTTLPR genotype or level of maternal criticism. PMID:19899843

  3. Lack of association between the serotonin transporter promoter polymorphism (5-HTTLPR) and personality traits in asymptomatic patients with panic disorder.

    PubMed

    Wachleski, Cláudia; Blaya, Carolina; Salum, Giovanni Abrahão; Vargas, Verônica; Leistner-Segal, Sandra; Manfro, Gisele Gus

    2008-01-31

    The serotonin transporter promoter polymorphism (5-HTTLPR) has been investigated regarding its association with neuroticism, which, in its turn, is a personality dimension often found in patients with panic disorder (PD). It has been recently evidenced that the long 5-HTTLPR polymorphism has a genetic variation (Lg), which is related to its lower expression. The objective of this study was to assess the association between the 5-HTTLPR polymorphism in the triallelic system and the neurotic personality traits in patients in PD remission. Sixty-seven Caucasian patients with PD diagnosis according to the DSM-IV-TR assessed with the MINI (mini international neuropsychiatric interview) were included. The MMPI (Minnesota multiphasic personality inventory) was used to assess the personality. The remission of PD symptoms was defined as CGI (clinical global impression) alleles in these patients was as follows: S 58 (43.3%), Lg 17 (12.7%) and La 59 (44.0%). There were no significant differences on the MMPI scales between different genotype classifications and allele analyses. Larger samples are necessary to exclude the less relevant genetic influences on these traits. In addition, other polymorphisms should be considered in the characterization of a heritable phenotype in the PD.

  4. Memory monitoring performance and PFC activity are associated with 5-HTTLPR genotype in older adults

    PubMed Central

    Pacheco, Jennifer; Beevers, Christopher G.; McGeary, John E.; Schnyer, David M.

    2012-01-01

    Older adults show extensive variability in cognitive performance, including episodic memory. A portion of this variability could potentially be explained by genetic factors. Recent literature shows that the neurotransmitter serotonin plays an important role in memory processes, as enhancements of brain serotonin have led to memory improvement. Here, we have begun to explore genetic contributions to the performance and underlying brain activity associated with source memory monitoring. Using a source recognition memory task during fMRI scanning, this study offers evidence that older adults who carry a short allele (S-car) of the serotonin transporter linked polymorphic region (5-HTTLPR) in the SLC6A4 gene show specific deficits in source memory monitoring relative to older adults who are homozygous for the long allele (LL). These deficits are accompanied by less neural activity in regions of prefrontal cortex that have been shown to support accurate memory monitoring. Moreover, while the older adult LL group’s behavioral performance does not differ from younger adults, their brain activation reveals evidence of compensatory activation that likely supports their higher performance level. These results provide preliminary evidence that the long-allele homozygous profile is cognitively beneficial to older adults, particularly for memory functioning. PMID:22705442

  5. The 5-HTTLPR Polymorphism in the Serotonin Transporter Gene Moderates the Association between Emotional Behavior and Changes in Marital Satisfaction over Time

    PubMed Central

    Haase, Claudia M.; Saslow, Laura R.; Bloch, Lian; Saturn, Sarina R.; Casey, James J.; Seider, Benjamin H.; Lane, Jessica; Coppola, Giovanni; Levenson, Robert W.

    2014-01-01

    Why do some individuals become dissatisfied with their marriages when levels of negative emotion are high and levels of positive emotions are low, whereas others remain unaffected? Using data from a 13-year longitudinal study of middle-aged and older adults in long-term marriages, we examined whether the 5-HTTLPR polymorphism in the serotonin transporter gene moderates the association between negative and positive emotional behavior (objectively measured during marital conflict) and changes in marital satisfaction over time. For individuals with two short alleles of 5-HTTLPR, higher negative and lower positive emotional behavior at Time 1 predicted declines in marital satisfaction over time (even after controlling for depression and other covariates). For individuals with one or two long alleles, emotional behavior did not predict changes in marital satisfaction. We also found evidence for a crossover interaction (individuals with two short alleles of 5-HTTLPR and low levels of negative or high levels of positive emotion had the highest levels of marital satisfaction). These findings provide the first evidence of a specific genetic polymorphism that moderates the association between emotional behavior and changes in marital satisfaction over time and are consistent with increasing evidence that the short allele of this polymorphism serves as a susceptibility factor that amplifies sensitivity to both negative and positive emotional influences. PMID:24098925

  6. Children’s 5-HTTLPR genotype moderates the link between maternal criticism and attentional biases specifically for facial displays of anger

    PubMed Central

    Gibb, Brandon E.; Johnson, Ashley L.; Benas, Jessica S.; Uhrlass, Dorothy J.; Knopik, Valerie S.; McGeary, John E.

    2011-01-01

    Theorists have proposed that negative experiences in childhood may contribute to the development of experience-specific information-processing biases, including attentional biases. There are also clear genetic influences on cognitive processes, with evidence that polymorphisms in specific candidate genes may moderate the impact of environmental stress on attentional biases (e.g., a functional polymorphism in the serotonin transporter gene [5-HTTLPR]). In the current study, we tested a gene × environment (G × E) model of risk for attentional biases. We hypothesized that children whose mothers exhibit high levels of expressed emotion criticism (EE-Crit) would display attentional biases specifically for angry, but not happy or sad, faces, and that this link would be stronger among children carrying one or two copies of the 5-HTTLPR short allele than among those homozygous for the long allele. Results generally supported these hypotheses, though we found that carriers of the 5-HTTLPR short allele who also had a critical mother exhibited attentional avoidance of angry faces rather than preferential attention. PMID:21895572

  7. Diurnal cortisol rhythms in youth from risky families: effects of cumulative risk exposure and variation in the serotonin transporter gene-linked polymorphic region (5-HTTLPR) [corrected].

    PubMed

    Willner, Cynthia J; Morris, Pamela A; McCoy, Dana Charles; Adam, Emma K

    2014-11-01

    Building on research on cumulative risk and psychopathology, this study examines how cumulative risk exposure is associated with altered diurnal cortisol rhythms in an ethnically diverse, low-income sample of youth. In addition, consistent with a diathesis-stress perspective, this study explores whether the effect of environmental risk is moderated by allelic variation in the promoter region of the serotonin transporter gene-linked polymorphic region (5-HTTLPR). Results show that youth with greater cumulative risk exposure had flatter diurnal cortisol slopes, regardless of 5-HTTLPR genotype. However, the association of cumulative risk with average cortisol output (area under the curve [AUC]) was moderated by the 5-HTTLPR genotype. Among youth homozygous for the long allele, greater cumulative risk exposure was associated with lower cortisol AUC, driven by significant reductions in cortisol levels at waking. In contrast, there was a trend-level association between greater cumulative risk and higher cortisol AUC among youth carrying the short allele, driven by a trend-level increase in bedtime cortisol levels. Findings are discussed with regard to the relevance of dysregulated diurnal cortisol rhythms for the development of psychopathology and the implications of genetically mediated differences in psychophysiological adaptations to stress.

  8. The 5-HTTLPR and BDNF polymorphisms moderate the association between uncinate fasciculus connectivity and antidepressants treatment response in major depression.

    PubMed

    Tatham, Erica L; Hall, Geoff B C; Clark, Darren; Foster, Jane; Ramasubbu, Rajamannar

    2017-03-01

    Symptom improvement in depression due to antidepressant treatment is highly variable and clinically unpredictable. Linking neuronal connectivity and genetic risk factors in predicting antidepressant response has clinical implications. Our investigation assessed whether indices of white matter integrity, serotonin transporter-linked polymorphism (5-HTTLPR) and brain-derived neurotrophic factor (BDNF) val66met polymorphism predicted magnitude of depression symptom change following antidepressant treatment. Fractional anisotropy (FA) was used as an indicator of white matter integrity and was assessed in the uncinate fasciculus and superior longitudinal fasciculus using tract-based spatial statistics (TBSS) and probabilistic tractography. Forty-six medication-free patients with major depressive disorder participated in a diffusion tensor imaging scan prior to completing an 8-week treatment regime with citalopram or quetiapine XR. Indexed improvements in Hamilton Depression Rating Scale score from baseline to 8-week endpoint were used as an indicator of depression improvement. Carriers of the BDNF met allele exhibited lower FA values in the left uncinate fasciculus relative to val/val individuals [F(1, 40) = 7.314, p = 0.009]. Probabilistic tractography identified that higher FA in the left uncinate fasciculus predicted percent change in depression severity, with BDNF moderating this association [F(3, 30) = 3.923, p = 0.018]. An interaction between FA in the right uncinate fasciculus and 5-HTTLPR also predicted percent change in depression severity [F(5, 25) = 5.315, p = 0.002]. Uncorrected TBSS results revealed significantly higher FA in hippocampal portions of the cingulum bundle in responders compared to non-responders (p = 0.016). The predictive value of prefrontal and amygdala/hippocampal WM connectivity on antidepressant treatment response may be influenced by 5-HTTLPR and BDNF polymorphisms in MDD.

  9. Interaction between serotonin transporter polymorphism (5-HTTLPR) and stressful life events in adolescents' trajectories of anxious/depressed symptoms.

    PubMed

    Petersen, Isaac T; Bates, John E; Goodnight, Jackson A; Dodge, Kenneth A; Lansford, Jennifer E; Pettit, Gregory S; Latendresse, Shawn J; Dick, Danielle M

    2012-09-01

    Caspi et al. (2003) found an interaction between the serotonin transporter polymorphism gene (5-HTTLPR) and stressful life events on depression. Subsequent attempts to replicate have been inconsistent. The present research included long allele variants modified by SNP rs25531 and tested the interaction on adolescents' trajectories of anxious/depressed symptoms, with consideration of possible age effects. Adolescents (N = 574), of whom 436 were genotyped, were followed from ages 12 to 17. Analyses demonstrated a G × E interaction in predicting the development of anxious/depressed symptoms. Specifically, adolescents with lower serotonin transcriptional efficiency (TE) genotypes whose mothers reported more stressful events were reported to show more anxious/depressed symptoms and greater increases in the development of symptoms of anxiety and depression than were higher TE adolescents, particularly at ages 16 and 17. Interactions did not differ by gender. Findings demonstrate that stress may affect adolescents' likelihood of experiencing anxious/depressed symptoms when they have a low serotonin TE (A/G-modified 5-HTTLPR) genotype and suggest that the vulnerability may be stronger in late than early adolescence.

  10. Physiological and affective reactivity to a 35% CO₂ inhalation challenge in individuals differing in the 5-HTTLPR genotype and trait neuroticism.

    PubMed

    Verschoor, Ellen; Markus, C Rob

    2012-08-01

    The inhalation of 35% carbon dioxide (CO₂) results in an acute stress response in healthy individuals and may accordingly provide a good paradigm to examine potential vulnerability factors for stress reactivity and stress-related psychopathology. It has been proposed that CO₂ reactivity is moderated by genetic (5-HTTLPR) and personality (neuroticism) factors, yet no experimental study has investigated their effects on CO₂ reactivity simultaneously. The current study examined the singular and interactive effects of the 5-HTTLPR genotype and neuroticism in predicting the affective and physiological response to a 35% CO₂ challenge in a healthy sample of male and female students. From a large group of 771 students, 48 carriers of the low/low expressing allele (S/S, S/Lg, Lg/Lg) and 48 carriers of the high/high expressing allele (La/La) with the lowest and the highest neuroticism scores (77 females, 19 males; mean age ± SD: 20.6 ± 2 years) were selected and underwent a 35% CO₂ inhalation. Visual analogue scales for anxiety and discomfort and the Panic Symptom List were used to assess affective symptomatology, while salivary samples and heart rate were assessed to establish the physiological response. A typical pattern of responses to CO₂ was observed, characterised by increases in anxiogenic symptoms and physical panic symptomatology and a reduction in heart rate; however, no effect on salivary cortisol concentration was observed. Additionally, the CO₂ reactivity did not differ between groups divided by the 5-HTTLPR genotype or neuroticism. Findings of the current study do not support a role for singular or interactive effects of the 5-HTTLPR genotype and trait neuroticism on affective and physiological reactivity to a 35% CO₂ inhalation procedure.

  11. 5-HTTLPR genotype potentiates the effects of war zone stressors on the emergence of PTSD, depressive and anxiety symptoms in soldiers deployed to iraq.

    PubMed

    Telch, Michael J; Beevers, Christopher G; Rosenfield, David; Lee, Han-Joo; Reijntjes, Albert; Ferrell, Robert E; Hariri, Ahmad R

    2015-06-01

    Exposure to war zone stressors is common, yet only a minority of soldiers experience clinically meaningful disturbance in psychological function. Identification of biomarkers that predict vulnerability to war zone stressors is critical for developing more effective treatment and prevention strategies not only in soldiers but also in civilians who are exposed to trauma. We investigated the role of the serotonin transporter linked polymorphic region (5-HTTLPR) genotype in predicting the emergence of post-traumatic stress disorder (PTSD), depressive and anxiety symptoms as a function of war zone stressors. A prospective cohort of 133 U.S. Army soldiers with no prior history of deployment to a war zone, who were scheduled to deploy to Iraq, was recruited. Multilevel regression models were used to investigate associations between 5-HTTLPR genotype, level of war zone stressors, and reported symptoms of PTSD, depression and anxiety while deployed to Iraq. Level of war zone stressors was associated with symptoms of PTSD, depression and anxiety. Consistent with its effects on stress responsiveness, 5-HTTLPR genotype moderated the relationship between level of war zone stressors and symptoms of emotional disturbance. Specifically, soldiers carrying one or two low functioning alleles (S or LG ) reported heightened symptoms of PTSD, depression and anxiety in response to increased levels of exposure to war zone stressors, relative to soldiers homozygous for the high functioning allele (LA ). These data suggest that 5-HTTLPR genotype moderates individual sensitivity to war zone stressors and the expression of emotional disturbance including PTSD symptoms. Replication of this association along with identification of other genetic moderators of risk can inform the development of biomarkers that can predict relative resilience vs. vulnerability to stress.

  12. 5-HTTLPR genotype potentiates the effects of war zone stressors on the emergence of PTSD, depressive and anxiety symptoms in soldiers deployed to iraq

    PubMed Central

    Telch, Michael J; Beevers, Christopher G; Rosenfield, David; Lee, Han-Joo; Reijntjes, Albert; Ferrell, Robert E; Hariri, Ahmad R

    2015-01-01

    Exposure to war zone stressors is common, yet only a minority of soldiers experience clinically meaningful disturbance in psychological function. Identification of biomarkers that predict vulnerability to war zone stressors is critical for developing more effective treatment and prevention strategies not only in soldiers but also in civilians who are exposed to trauma. We investigated the role of the serotonin transporter linked polymorphic region (5-HTTLPR) genotype in predicting the emergence of post-traumatic stress disorder (PTSD), depressive and anxiety symptoms as a function of war zone stressors. A prospective cohort of 133 U.S. Army soldiers with no prior history of deployment to a war zone, who were scheduled to deploy to Iraq, was recruited. Multilevel regression models were used to investigate associations between 5-HTTLPR genotype, level of war zone stressors, and reported symptoms of PTSD, depression and anxiety while deployed to Iraq. Level of war zone stressors was associated with symptoms of PTSD, depression and anxiety. Consistent with its effects on stress responsiveness, 5-HTTLPR genotype moderated the relationship between level of war zone stressors and symptoms of emotional disturbance. Specifically, soldiers carrying one or two low functioning alleles (S or LG) reported heightened symptoms of PTSD, depression and anxiety in response to increased levels of exposure to war zone stressors, relative to soldiers homozygous for the high functioning allele (LA). These data suggest that 5-HTTLPR genotype moderates individual sensitivity to war zone stressors and the expression of emotional disturbance including PTSD symptoms. Replication of this association along with identification of other genetic moderators of risk can inform the development of biomarkers that can predict relative resilience vs. vulnerability to stress. PMID:26043338

  13. 5-HTTLPR Genotype and Anxiety-Related Personality Traits: A meta-analysis and new data

    PubMed Central

    Munafò, Marcus R.; Freimer, Nelson B.; Ng, Whitney; Ophoff, Roel; Veijola, Juha; Miettunen, Jouko; Järvelin, Marjo-Riitta; Taanila, Anja; Flint, Jonathan

    2008-01-01

    We investigated the strength of evidence for association of the 5-HTTLPR polymorphism and the personality trait of Harm Avoidance. We used new primary data from a large sample of adults drawn from the Finnish population. We also applied meta-analytic techniques to synthesize existing published data. The large number studies of the 5-HTTLPR polymorphism allowed us to apply a formal test of publication bias, as well as formally investigate the impact of potential moderating factors such as measurement instrument. Univariate ANOVA of primary data (n = 3,872), with 5-HTTLPR genotype as a between-groups factor, indicated no evidence of association with Harm Avoidance (p = 0.99). Meta-analysis indicated no evidence of significant association of 5-HTTLPR with Harm Avoidance (d = 0.02, p = 0.37), or EPQ Neuroticism (d = 0.01, p = 0.71), although there was evidence of association with NEO Neuroticism (d = 0.18, p < 0.001). Our analyses indicate that the 5-HTTLPR variant is not associated with Harm Avoidance. Together with our previous analyses of a large sample of participants with extreme Neuroticism scores (defined by the EPQ), we have data that excludes a meaningful genetic effect of the 5-HTTLPR on two measures of anxiety-related personality traits. There remains the possibility that the variant influences the NEO personality questionnaire measure of Neuroticism. However, a large, well-powered primary study is required to test this hypothesis directly and adequately. PMID:18546120

  14. Genetic sensitivity to the caregiving context: The influence of 5httlpr and BDNF val66met on indiscriminate social behavior

    PubMed Central

    Drury, Stacy S; Gleason, Mary Margaret; Theall, Katherine; Smyke, Anna T; Nelson, Charles A; Fox, Nathan A; Zeanah, Charles H

    2014-01-01

    Evidence that gene x environment interactions can reflect differential sensitivity to the environmental context, rather than risk or resilience, is increasing. To test this model, we examined the genetic contribution to indiscriminate social behavior, in the setting of a randomized controlled trial of foster care compared to institutional rearing. Children enrolled in the Bucharest Early Intervention Project (BEIP) were assessed comprehensively before the age of 30 months and subsequently randomized to either care as usual (CAUG) or high quality foster care (FCG). Indiscriminate social behavior was assessed at four time points, baseline, 30 months, 42 months and 54 months of age, using caregiver report with the Disturbances of Attachment Interview (DAI). General linear mixed-effects models were used to examine the effect of the interaction between group status and functional polymorphisms in Brain Derived Neurotrophic Factor (BDNF) and the Serotonin Transporter (5htt) on levels of indiscriminate behavior over time. Differential susceptibility, relative to levels of indiscriminate behavior, was demonstrated in children with either the s/s 5httlpr genotype or met 66 BDNF allele carriers. Specifically children with either the s/s 5httlpr genotype or met66 carriers in BDNF demonstrated the lowest levels of indiscriminate behavior in the FCG and the highest levels in the CAUG. Children with either the long allele of the 5httlpr or val/val genotype of BDNF demonstrated little difference in levels of indiscriminate behaviors over time and no group x genotype interaction. Children with both plasticity genotypes had the most signs of indiscriminate behavior at 54 months if they were randomized to the CAUG in the institution, while those with both plasticity genotypes randomized to the FCG intervention had the fewest signs at 54 months. Strikingly children with no plasticity alleles demonstrated no intervention effect on levels of indiscriminate behavior at 54 months. These

  15. Affective and neuroendocrine stress reactivity to an academic examination: influence of the 5-HTTLPR genotype and trait neuroticism.

    PubMed

    Verschoor, Ellen; Markus, C Rob

    2011-07-01

    The current study examined the singular and interactive effects of the 5-HTTLPR genotype and trait neuroticism on affective and physiological stress responses to an academic examination in healthy undergraduate students. From 771 students, 46 short/short (S/S)-allele carriers and 48 long/long (L/L)-allele carriers with the lowest and the highest neuroticism scores (80 females, 14 males; mean age±SD: 20.3±1.7 years) were selected. Salivary cortisol concentrations, mood and perceived stress were assessed before and after a 2-h written examination and compared with a control day. Negative mood, perceived stress and cortisol significantly increased during the examination compared to the control day. Negative stress effects on mood and perceived stress were significantly larger for S/S-allele carriers compared to L/L-allele carriers, regardless of trait neuroticism. Since vulnerability to real-life stressors is an important risk factor for depression pathogenesis, this may be a mediating factor making S/S-allele carriers more susceptible for depression symptoms.

  16. Interaction of 5-HTTLPR and Idiographic Stressors Predicts Prospective Depressive Symptoms Specifically among Youth in a Multiwave Design

    ERIC Educational Resources Information Center

    Hankin, Benjamin L.; Jenness, Jessica; Abela, John R. Z.; Smolen, Andrew

    2011-01-01

    5-HTTLPR, episodic stressors, depressive and anxious symptoms were assessed prospectively (child and parent report) every 3 months over 1 year (5 waves of data) among community youth ages 9 to 15 (n = 220). Lagged hierarchical linear modeling analyses showed 5-HTTLPR interacted with idiographic stressors (increases relative to the child's own…

  17. Association of a serotonin transporter gene (SLC6A4) 5-HTTLPR polymorphism with body mass index categories but not type 2 diabetes mellitus in Mexicans

    PubMed Central

    Peralta-Leal, Valeria; Leal-Ugarte, Evelia; Meza-Espinoza, Juan P.; Dávalos-Rodríguez, Ingrid P.; Bocanegra-Alonso, Anabel; Acosta-González, Rosa I.; Gonzales, Enrique; Nair, Saraswathy; Durán-González, Jorge

    2012-01-01

    The serotonergic system has been hypothesized to contribute to the biological susceptibility to type 2 diabetes mellitus (T2DM) and body-mass index (BMI) categories. We investigate a possible association of 5-HTTLPR polymorphism (L and S alleles) in the promoter region of the serotonin transporter gene (SLC6A4) with the development of T2DM and/or higher BMI by analyzing a sample of 138 individuals diagnosed with T2DM and 172 unrelated controls from the Mexican general population. In the total sample genotypes were distributed according to Hardy-Weinberg equilibrium, and S allele frequency was 0.58. There was no statistical association between 5-HTTLPR polymorphism and the development of T2DM in this Mexican population sample (p = 0.12). Nevertheless, logistic regression analysis of the L allele and increased BMI disclosed an association, after adjusting for age, sex and T2DM (p = 0.02, OR 1.74, 95% CI: 1.079–2.808). PMID:23055796

  18. Genetic Sensitivity to Peer Behaviors: "5HTTLPR", Smoking, and Alcohol Consumption

    ERIC Educational Resources Information Center

    Daw, Jonathan; Shanahan, Michael; Harris, Kathleen Mullan; Smolen, Andrew; Haberstick, Brett; Boardman, Jason D.

    2013-01-01

    We investigate whether the serotonin transporter-linked polymorphic region ("5HTTLPR"), a gene associated with environmental sensitivity, moderates the association between smoking and drinking patterns at adolescents' schools and their corresponding risk for smoking and drinking themselves. Drawing on the school-based design of the National…

  19. Thyroid-stimulating hormone, 5-HTTLPR genotype, and antidepressant response in depressed women.

    PubMed

    Gressier, Florence; Trabado, Séverine; Verstuyft, Céline; Bouaziz, Elodie; Hardy, Patrick; Fève, Bruno; Becquemont, Laurent; Corruble, Emmanuelle

    2011-10-01

    Basal serum thyroid-stimulating hormone (TSH) levels may predict antidepressant efficacy in patients with major depressive episodes (MDE), but data are inconsistent. As the SS genotype of the 5-HTTLPR polymorphism has been associated with a lower antidepressant efficacy in women with MDE, we aimed at assessing the relationship between normal basal TSH, 5-HTTLPR, and antidepressant efficacy in women. A total of 71 women and 28 men, with normal baseline TSH serum levels, hospitalized for a MDE, were assessed for 5-HTTLPR genotypes and prospectively followed for short-term antidepressant efficacy. Women with SS genotype had higher TSH levels (P=0.002) and a worse antidepressant response (P=0.046) than the women with LL/LS genotype, whereas no significant difference was shown in men. In multivariate analyses, antidepressant response in women was explained by TSH and 5-HTTLPR, but not by other variables. Further research is needed to understand the underlying mechanism explaining interactions between sex, TSH, and serotonergic function.

  20. The effect of the serotonin transporter polymorphism (5-HTTLPR) on amygdala function: a meta-analysis.

    PubMed

    Murphy, S E; Norbury, R; Godlewska, B R; Cowen, P J; Mannie, Z M; Harmer, C J; Munafò, M R

    2013-04-01

    The 5-HTTLPR polymorphism has been widely regarded as a potential genetic risk factor for affective disorders. Consistent with this, this polymorphism has been associated with altered amygdala responses at rest and in response to aversive stimuli. However, the strength of this association remains uncertain. We sought to synthesize existing data on the association between the 5-HTTLPR polymorphism and amygdala activation and ascertain the strength of evidence for this association. Meta-analytic techniques were applied to data from relevant published studies and unpublished data sets to obtain an estimate of the likely magnitude of effect of any association. The large number of studies allowed us to apply a formal test of publication bias, as well as explore the impact of various study-level characteristics on the magnitude of the observed effect size. Our meta-analysis indicated that there is a statistically significant but small effect of 5-HTTLPR on left and right amygdala activity. However, there was considerable between-study heterogeneity, which could not be fully accounted for by the study design and sample characteristics that we investigated. In addition, there was evidence of excess statistical significance among published studies. These findings indicate that the association between the 5-HTTLPR and amygdala activation is smaller than originally thought, and that the majority of previous studies have been considerably under powered to reliably demonstrate an effect of this size.

  1. 5-HTTLPR Moderates the Effect of Relational Peer Victimization on Depressive Symptoms in Adolescent Girls

    ERIC Educational Resources Information Center

    Benjet, Corina; Thompson, Renee J.; Gotlib, Ian H.

    2010-01-01

    Background: Relational peer victimization is associated with internalizing symptoms. Compared to boys, girls are more likely to be both relationally victimized by peers and distressed by the victimization. While previous studies have reported that a functional polymorphism in the promoter region of the serotonin transporter gene (5-HTTLPR)…

  2. Serotonin Transporter (5-HTTLPR) Genotype, Childhood Abuse, and Suicide Attempts in Adult Psychiatric Inpatients

    ERIC Educational Resources Information Center

    Gibb, Brandon E.; McGeary, John E.; Beevers, Christopher G.; Miller, Ivan W.

    2006-01-01

    There is growing evidence that a functional polymorphism in the serotonin transporter gene (5-HTTLPR) moderates the impact of negative life events (e.g., childhood abuse) on the development of depression. However, it is unclear whether the gene x environment interaction predicts suicide attempts specifically. In addition, previous studies have not…

  3. Children's Attentional Biases and "5-HTTLPR" Genotype: Potential Mechanisms Linking Mother and Child Depression

    ERIC Educational Resources Information Center

    Gibb, Brandon E.; Benas, Jessica S.; Grassia, Marie; McGeary, John

    2009-01-01

    In this study, we examined the roles of specific cognitive (attentional bias) and genetic ("5-HTTLPR") risk factors in the intergenerational transmission of depression. Focusing first on the link between maternal history of major depressive disorder (MDD) and children's attentional biases, we found that children of mothers with a history…

  4. Ondansetron and sertraline may interact with 5-HTTLPR and DRD4 polymorphisms to reduce drinking in non-treatment seeking alcohol-dependent women: exploratory findings.

    PubMed

    Kenna, George A; Zywiak, William H; Swift, Robert M; McGeary, John E; Clifford, James S; Shoaff, Jessica R; Fricchione, Samuel; Brickley, Michael; Beaucage, Kayla; Haass-Koffler, Carolina L; Leggio, Lorenzo

    2014-09-01

    The purpose of this exploratory study was to examine the interaction of 5-HTTLPR and DRD4 exon III polymorphisms with gender in non-treatment seeking alcohol-dependent (AD) individuals while alternately taking ondansetron and sertraline. Evidence suggests that alcohol dependence may be influenced by a genetic interaction that may be gender-specific with temporal changes making pharmacological treatment with serotonergic drugs complex. The main trial was a within-subject double-blind placebo-controlled human laboratory study with 77 non-treatment-seeking AD individuals randomized (55 completed, 49 complete data) to receive 200 mg/day of sertraline or 0.5 mg/day of ondansetron for 3 weeks followed by an alcohol self-administration experiment (ASAE), then placebo for 3 weeks followed by a second ASAE, then receive the alternate drug, in a counterbalanced order, for 3 weeks followed by a third ASAE. Results for men were not significant. Women with the LL 5-HTTLPR genotype receiving ondansetron and SS/SL 5-HTTLPR genotype receiving sertraline (matched), drank significantly fewer drinks per drinking day (DDD) during the 7 days prior to the first and third ASAEs than women receiving the mismatched medication (i.e., sertraline to LL and ondansetron to SS/SL). In a 3-way interaction, 5-HTTLPR alleles by DRD4 alleles by medications, women with the LL genotype who received ondansetron and had DRD4≥7 exon III repeats drank significantly fewer DDD as did SS/SL women who received sertraline but conversely had DRD4<7 repeats in the 7-day period leading up to the first and third ASAEs. Consistent with these data was a significant reduction of milliliters consumed ad libitum during these same ASAEs. These exploratory findings add possible support to gender and genetic differences among AD individuals in response to serotonergic pharmacotherapies. Future trials should be powerful enough to take into account that endophenotypes and a targeting of serotonergic interactions may be

  5. Effect of sub chronic tryptophan supplementation on stress-induced cortisol and appetite in subjects differing in 5-HTTLPR genotype and trait neuroticism.

    PubMed

    Capello, Aimée E M; Markus, C Rob

    2014-07-01

    Stress or negative effect often increases preference for, and intake of, palatable snack foods and this may be influenced by cognitive and genetic factors related to stress and 5-HT vulnerability. The short (S) compared to the long (L) allele of the 5-HT transporter linked polymorphic region (5-HTTLPR) has been associated (i) with decreased 5-HT transporter function and availability and hence, with 5-HT vulnerability, and (ii) with greater stress-responsiveness. Stress-proneness is furthermore promoted by cognitive stress-vulnerability, a key feature of trait neuroticism. Brain 5-HT function can be manipulated by dietary administration of its amino acid precursor tryptophan (Trp), and the beneficial effects of dietary Trp on stress experience and emotional eating may be greatest following repeated administration in both stress- and 5-HT-vulnerable subjects. The aim was to examine the influence of repeated Trp administration on stress responsiveness and emotional eating in homozygous 5-HTTLPR S-allele (N=60) and L-allele (N=58) carriers with high and low neuroticism. Following seven days of Trp or PLC intake, mood, cortisol and appetite were assessed before and after exposure to acute stress and snack intake and preference were measured post-stress. It was hypothesized that Trp would reduce stress experience and emotional eating particularly in S-allele carriers with high neuroticism. Results revealed Trp treatment caused a clear reduction in stress-induced cortisol levels in S/S-allele carriers exclusively, and prevented a stress-induced increase in appetite only in S/S-allele carriers with high trait neuroticism. The findings reveal an advantageous effect of sub chronic Trp treatment on stress experience and appetite depending on stress and (genetic) serotonergic vulnerability.

  6. Serotonin transporter gene-linked polymorphic region (5-HTTLPR) influences decision making under ambiguity and risk in a large Chinese sample.

    PubMed

    He, Qinghua; Xue, Gui; Chen, Chuansheng; Lu, Zhonglin; Dong, Qi; Lei, Xuemei; Ding, Ni; Li, Jin; Li, He; Chen, Chunhui; Li, Jun; Moyzis, Robert K; Bechara, Antoine

    2010-11-01

    Risky decision making is a complex process that involves weighing the probabilities of alternative options that can be desirable, undesirable, or neutral. Individuals vary greatly in how they make decisions either under ambiguity and/or under risk. Such individual differences may have genetic bases. Based on previous studies on the genetic basis of decision making, two decision making tasks [i.e., the Iowa Gambling Task (IGT) and Loss Aversion Task (LAT)] were used to test the effect of 5-HTTLPR polymorphism on decision making under ambiguity and under risk in a large Han Chinese sample (572 college students, 312 females). Basic intelligence and memory tests were also included to control for the influence of basic cognitive abilities on decision making. We found that 5-HTTLPR polymorphism significantly influenced performance in both IGT and LAT. After controlling for intelligence and memory abilities, subjects homozygous for s allele had lower IGT scores than l carriers in the first 40 trials of the IGT task. They also exhibited higher loss aversion than l carriers in the LAT task. Moreover, the effects of 5-HTTLPR were stronger for males than for females. These results extend the literature on the important role of emotion in decision making under ambiguity and risk, and shed additional lights on how decision making is influenced by culture as well as sex differences. Combining our results with existing literature, we propose that these effects might be mediated by a neural circuitry that comprises the amygdala, ventromedial prefrontal cortex, and insular cortex. Understanding the genetic factors affecting decision making in healthy subjects may allow us to better identify at-risk individuals, and better target the development of new potential treatments for specific disorders such as schizophrenia, addiction, and depression.

  7. Incremental effect for antisocial personality disorder genetic risk combining 5-HTTLPR and 5-HTTVNTR polymorphisms.

    PubMed

    Garcia, Luis F; Aluja, Anton; Fibla, Joan; Cuevas, Lara; García, Oscar

    2010-05-15

    As the serotonin transporter gene (SLC6A4 or 5-HTT) is a key regulator of central serotonergic activity, several association studies between Antisocial Personality Disorder (APD) and the SLC6A4 polymorphisms have been conducted in the last decade. In the present study, the role of both 5-HTTLPR and 5-HTTVNTR polymorphisms of the SLC6A4 gene in APD is investigated. A sample of 147 male inmates was analyzed. APD was assessed by Aluja's Antisocial Personality Disorder Scale, a measure that correlates 0.73 with the dimensional score of DSM-IV APD and 0.62 with factor II of the Psychopathy Checklist-Revised. Inmates presenting both 5-HTTLPR S/S+S/L and 5-HTTVNTR 12/12 had a higher risk of being classified in the APD group (Odds ratio=3.48). The results also showed that the genotype and haplotype distribution was more dissimilar when extreme groups were compared with odds ratios up to 6.50. Our results supported that, in addition to the widely investigated 5-HTTLPR polymorphism, the 5-HTTVNTR polymorphism might be an interesting candidate for association studies with APD. Results also suggested that previous failures to replicate the association between serotonin transporter gene polymorphisms and APD, or similar phenotypes, could have been due to an under-representation of extremely high APD subjects in the samples analyzed.

  8. Brain-Derived Neurotrophic Factor (Val66Met) and Serotonin Transporter (5-HTTLPR) Polymorphisms Modulate Plasticity in Inhibitory Control Performance Over Time but Independent of Inhibitory Control Training

    PubMed Central

    Enge, Sören; Fleischhauer, Monika; Gärtner, Anne; Reif, Andreas; Lesch, Klaus-Peter; Kliegel, Matthias; Strobel, Alexander

    2016-01-01

    Several studies reported training-induced improvements in executive function tasks and also observed transfer to untrained tasks. However, the results are mixed and there is a large interindividual variability within and across studies. Given that training-related performance changes would require modification, growth or differentiation at the cellular and synaptic level in the brain, research on critical moderators of brain plasticity potentially explaining such changes is needed. In the present study, a pre-post-follow-up design (N = 122) and a 3-weeks training of two response inhibition tasks (Go/NoGo and Stop-Signal) was employed and genetic variation (Val66Met) in the brain-derived neurotrophic factor (BDNF) promoting differentiation and activity-dependent synaptic plasticity was examined. Because Serotonin (5-HT) signaling and the interplay of BDNF and 5-HT are known to critically mediate brain plasticity, genetic variation in the 5-HTT gene-linked polymorphic region (5-HTTLPR) was also addressed. The overall results show that the kind of training (i.e., adaptive vs. non-adaptive) did not evoke genotype-dependent differences. However, in the Go/NoGo task, better inhibition performance (lower commission errors) were observed for BDNF Val/Val genotype carriers compared to Met-allele ones supporting similar findings from other cognitive tasks. Additionally, a gene-gene interaction suggests a more impulsive response pattern (faster responses accompanied by higher commission error rates) in homozygous l-allele carriers relative to those with the s-allele of 5-HTTLPR. This, however, is true only in the presence of the Met-allele of BDNF, while the Val/Val genotype seems to compensate for such non-adaptive responding. Intriguingly, similar results were obtained for the Stop-Signal task. Here, differences emerged at post-testing, while no differences were observed at T1. In sum, although no genotype-dependent differences between the relevant training groups emerged

  9. Meta-analysis of the serotonin transporter promoter variant (5-HTTLPR) in relation to adverse environment and antisocial behavior.

    PubMed

    Tielbeek, Jorim J; Karlsson Linnér, Richard; Beers, Koko; Posthuma, Danielle; Popma, Arne; Polderman, Tinca J C

    2016-07-01

    Several studies have suggested an association between antisocial, aggressive, and delinquent behavior and the short variant of the serotonin transporter gene polymorphism (5-HTTLPR). Yet, genome wide and candidate gene studies in humans have not convincingly shown an association between these behaviors and 5-HTTLPR. Moreover, individual studies examining the effect of 5-HTTLPR in the presence or absence of adverse environmental factors revealed inconsistent results. We therefore performed a meta-analysis to test for the robustness of the potential interaction effect of the "long-short" variant of the 5-HTTLPR genotype and environmental adversities, on antisocial behavior. Eight studies, comprising of 12 reasonably independent samples, totaling 7,680 subjects with an effective sample size of 6,724, were included in the meta-analysis. Although our extensive meta-analysis resulted in a significant interaction effect between the 5-HTTLPR genotype and environmental adversities on antisocial behavior, the methodological constraints of the included studies hampered a confident interpretation of our results, and firm conclusions regarding the direction of effect. Future studies that aim to examine biosocial mechanisms that influence the etiology of antisocial behavior should make use of larger samples, extend to genome-wide genetic risk scores and properly control for covariate interaction terms, ensuring valid and well-powered research designs. © 2016 Wiley Periodicals, Inc.

  10. Prevention Effects Moderate the Association of 5-HTTLPR and Youth Risk Behavior Initiation: Gene x Environment Hypotheses Tested via a Randomized Prevention Design

    ERIC Educational Resources Information Center

    Brody, Gene H.; Beach, Steven R. H.; Philibert, Robert A.; Chen, Yi-Fu; Murry, Velma McBride

    2009-01-01

    A randomized prevention design was used to investigate a moderation effect in the association between a polymorphism in the "SCL6A4"("5HTT") gene at 5-HTTLPR and increases in youths' risk behavior initiation. Participation in the Strong African American Families (SAAF) program was hypothesized to attenuate the link between 5-HTTLPR status and risk…

  11. Genetic correlates of behavioral endophenotypes in Alzheimer disease: role of COMT, 5-HTTLPR and APOE polymorphisms.

    PubMed

    Borroni, B; Grassi, M; Agosti, C; Costanzi, C; Archetti, S; Franzoni, S; Caltagirone, C; Di Luca, M; Caimi, L; Padovani, A

    2006-11-01

    Several studies have been conducted to understand the genetic correlates of Alzheimer disease (AD)-related behavioral and psychological symptoms in dementia (BPSD). However, given that BPSD rarely occur in isolation, it has been suggested that targeting BPSD individually is too narrow of an approach if one wants to accurately define all the associated risk factors. To date, we know of no work on genetic polymorphisms related to behavioral endophenotypes in AD. The present study sought to evaluate the relationship between such behavioral endophenotypes in AD and genetic variations in dopamine- or serotonin-related genes, such as catechol-O-methyltransferase (COMT) or 5-HTT gene-linked promoter region (5-HTTLPR), and apolipoprotein E (APOE). Among 232 AD patients who underwent clinical and neuropsychological examination, a behavioral and psychiatric evaluation, and genotyping at COMT, 5-HTTPLR, and APOE; 66.4% showed more than one behavioral symptom. By Principal Component Analysis of Neuropsychiatric Inventory (NPI) symptoms four endophenotypes were identified, these were termed "psychosis", "moods", "apathy", and "frontal". Modeling NPI symptom-endophenotype-genotype relationships, and taking into account possible confounds (i.e. demographic characteristics, comorbidities, concomitant pharmacological treatments, and disease severity) by latent variable models, COMT and 5-HTTLPR genetic variations correlated with "frontal" and "psychosis" endophenotypes. APOE genotype did not correlate with any endophenotype. These findings suggest that the possibility of identifying distinct phenotypes on a genetic basis among AD patients exists, and suggest that clustering of BPSD into endophenotypes might provide a new strategy for guiding future research on this issue.

  12. How and Why Does the 5-HTTLPR Gene Moderate Associations between Maternal Unresponsiveness and Children's Disruptive Problems?

    ERIC Educational Resources Information Center

    Davies, Patrick T.; Cicchetti, Dante

    2014-01-01

    This study tested the 5-HTTLPR gene as a moderator in the relation between maternal unresponsiveness and child externalizing symptoms in a disadvantaged, predominantly Black sample of two hundred and one 2-year-old children and their mothers. Using a multimethod, prospective design, structural equation model analyses indicated that maternal…

  13. Therapygenetics: anterior cingulate cortex-amygdala coupling is associated with 5-HTTLPR and treatment response in panic disorder with agoraphobia.

    PubMed

    Lueken, Ulrike; Straube, Benjamin; Wittchen, Hans-Ulrich; Konrad, Carsten; Ströhle, Andreas; Wittmann, André; Pfleiderer, Bettina; Arolt, Volker; Kircher, Tilo; Deckert, Jürgen; Reif, Andreas

    2015-01-01

    Variation in the 5'-flanking promoter region of the serotonin transporter gene SLC6A4, the 5-HTT-linked polymorphic region (5-HTTLPR) has been inconclusively associated with response to cognitive-behavioural therapy (CBT). As genomic functions are stronger related to neural than to behavioural markers, we investigated the association of treatment response, 5-HTTLPR and functional brain connectivity in patients with panic disorder with agoraphobia (PD/AG). Within the national research network PANIC-NET 231 PD/AG patients who provided genetic information underwent a manualized exposure-based CBT. A subset of 41 patients participated in a functional magnetic resonance imaging (fMRI) add-on study prior to treatment applying a differential fear conditioning task. Neither the treatment nor the reduced fMRI sample showed a direct effect of 5-HTTLPR on treatment response as defined by a reduction in the Hamilton Anxiety Scale score ≥50 % from baseline to post assessment. On a neural level, inhibitory anterior cingulate cortex (ACC)-amygdala coupling during fear conditioning that had previously been shown to characterize treatment response in this sample was driven by responders with the L/L genotype. Building upon conclusive evidence from basic and preclinical findings on the association of the 5-HTTLPR polymorphism with emotion regulation and related brain connectivity patterns, present findings translate these to a clinical sample of PD/AG patients and point towards a potential intermediate connectivity phenotype modulating response to exposure-based CBT.

  14. Does 5HTTLPR Genotype Moderate the Association of Family Environment With Child Attention-Deficit Hyperactivity Disorder Symptomatology?

    PubMed

    Elmore, Alexis L; Nigg, Joel T; Friderici, Karen H; Jernigan, Katherine; Nikolas, Molly A

    2016-01-01

    Problematic family dynamics are common among youth with attention-deficit hyperactivity disorder (ADHD). Multiple mechanisms, including diathesis-stress (vulnerability) and differential susceptibility Gene × Environment interaction effects (G × E), have been proposed to account for this association. G × E effects for ADHD were examined via interactions between a genetic marker hypothesized to influence sensitivity to the environment (the promoter polymorphism of the serotonin transporter gene -5HTTLPR) and family conflict and cohesion in predicting ADHD symptoms. There were 498 youth ages 6-17 years (251 ADHD, 213 non-ADHD) and their parents who completed a multistage, multi-informant assessment (including parent and youth reports on the Family Environment Scale), and saliva sample collection for genotyping. Linear regression analyses examined interactions between 5HTTLPR genotype and the Family Environment Scale scales of conflict and cohesion reported by parent and child. Criteria laid out by Roisman et al. ( 2012 ) were applied to evaluate diathesis stress versus differential susceptibility G × E mechanisms. Results demonstrated interactions between 5HTTLPR genotype and both conflict and cohesion in predicting inattention but not hyperactivity-impulsivity. Both interactions were highly consistent with differential susceptibility models of G × E effects. 5HTTLPR genotype appeared to moderate the relationship between family conflict/cohesion and inattentive symptoms. Interactions highlight the role of 5HTTLPR genotype as a potential marker of environmental sensitivity and provide support for differential susceptibility models of G × E effects for ADHD.

  15. Effects of stressful life events, maternal depression and 5-HTTLPR genotype on emotional symptoms in pre-adolescent children.

    PubMed

    Araya, Ricardo; Hu, Xianzhang; Heron, Jon; Enoch, Mary-Anne; Evans, Jonathan; Lewis, Glyn; Nutt, David; Goldman, David

    2009-07-05

    There has been a large but inconsistent literature on interactions between the 5-HTTLPR polymorphism of the serotonin transporter gene and adversity on emotional disorders. We investigated these interactions in 4,334 children from a birth longitudinal cohort: the Avon Longitudinal Study of Parents and Children (ALSPAC). We measured emotional symptoms at 7 years with the Strengths and Difficulties Questionnaire. Mothers rated stressful life events between ages 5 and 7 years. Maternal depression was defined as a score > or =12 on the Edinburgh Postnatal Depression Scale at 2 or 8 months postnatally. Triallelic genoptyping of the 5-HTTLPR polymorphism was performed. We found strong associations between stressful life events (OR 1.19; 1.12-1.26; P < 0.01) and maternal postnatal depression (OR 1.91; 1.63-2.24; P < 0.01) with emotional symptoms in the children. There were no main 5-HTTLPR genotype effects or significant interactions between genotype and life events or maternal postnatal depression on emotional symptoms. There was marginal evidence (P = 0.08) for an interaction between stressful life events and genotype in boys only, with those in the low and high 5-HTTLPR expression groups showing stronger associations. In these 7-year-old children, we did not replicate previously reported G x E interactions between 5-HTTLPR and life events for emotional symptoms. Gene by environment interactions may be developmentally dependent and show variation depending on the type and levels of exposure and sex. Young cohorts are essential to improve our understanding of the impact of development on gene and environment interactions.

  16. Three-way interaction effect of 5-HTTLPR, BDNF Val66Met, and childhood adversity on depression: a replication study.

    PubMed

    Comasco, Erika; Åslund, Cecilia; Oreland, Lars; Nilsson, Kent W

    2013-10-01

    Both the serotonin transporter linked promoter region (5-HTTLPR) and the brain-derived neurotrophic factor (BDNF) Val66Met polymorphisms have been shown to interact with unfavourable environment in relation to depression symptoms and to depression diagnosis. Several attempts have been made to study a three-way interaction effect of these factors on depression, however with contradictory results. We aimed to test the hypothesis of a three-way interaction effect and to attempt at replication in an independent population-based sample. Family maltreatment, sexual abuse and depression were self-reported by an adolescent population-based cohort (N=1393) from the county of Västmanland, Sweden. DNA was isolated from saliva, and used for genotyping of the 5-HTTLPR and BDNF Val66Met polymorphisms. Neither 5-HTTLPR or BDNF genotypes separately, nor in interaction with each other had any relation to depression, however in an environment adjusted model a two-way interaction and a three-way interaction effect was found. Both 5-HTTLPR and BDNF Val66Met interacted with unfavourable environment in relation to depressive symptoms (Adj R²=0.19). Depressive symptoms and depression were more common among carriers of either the ss/sl+Val/Val or the ll+Met genotypes in the presence of early-life adversities. This three-way effect was more pronounced among girls. The current study, with a virtually similar set-up compared to previous studies, can partially confirm previous findings and their generalizability. The study also shows the importance of genetic plasticity in individuals with different environmental exposure, for different phenotypic expression.

  17. How the cerebral serotonin homeostasis predicts environmental changes: a model to explain seasonal changes of brain 5-HTT as intermediate phenotype of the 5-HTTLPR.

    PubMed

    Kalbitzer, Jan; Kalbitzer, Urs; Knudsen, Gitte Moos; Cumming, Paul; Heinz, Andreas

    2013-12-01

    Molecular imaging studies with positron emission tomography have revealed that the availability of serotonin transporter (5-HTT) in the human brain fluctuates over the course of the year. This effect is most pronounced in carriers of the short allele of the 5-HTT promoter region (5-HTTLPR), which has in several previous studies been linked to an increased risk to develop mood disorders. We argue that long-lasting fluctuations in the cerebral serotonin transmission, which is regulated via the 5-HTT, are responsible for mediating responses to environmental changes based on an assessment of the expected "safety" of the environment; this response is obtained in part through serotonergic modulation of the hypothalamic-pituitary-adrenal (HPA) axis. We posit that the intermediate phenotype of the s-allele may properly be understood as mediating a trade-off, wherein increased responsiveness of cerebral serotonin transmission to seasonal and other forms of environmental change imparts greater behavioral flexibility, at the expense of increased vulnerability to stress. This model may explain the somewhat higher prevalence of the s-allele in some human populations dwelling at geographic latitudes with pronounced seasonal climatic changes, while this hypothesis does not rule out that genetic drift plays an additional or even exclusive role. We argue that s-allele manifests as an intermediate phenotype in terms of an increased responsiveness of the 5-HTT expression to number of daylight hours, which may serve as a stable surrogate marker of other environmental factors, such as availability of food and safety of the environment in populations that live closer to the geographic poles.

  18. Maintenance of Chronic Fatigue Syndrome (CFS) in Young CFS Patients Is Associated with the 5-HTTLPR and SNP rs25531 A > G Genotype

    PubMed Central

    Meyer, Benedicte; Nguyen, Chinh Bkrong Thuy; Moen, Aurora; Fagermoen, Even; Sulheim, Dag; Nilsen, Hilde; Wyller, Vegard Bruun; Gjerstad, Johannes

    2015-01-01

    Earlier studies have shown that genetic variability in the SLC6A4 gene encoding the serotonin transporter (5-HTT) may be important for the re-uptake of serotonin (5-HT) in the central nervous system. In the present study we investigated how the 5-HTT genotype i.e. the short (S) versus long (L) 5-HTTLPR allele and the SNP rs25531 A > G affect the physical and psychosocial functioning in patients with chronic fatigue syndrome (CFS). All 120 patients were recruited from The Department of Paediatrics at Oslo University Hospital, Norway, a national referral center for young CFS patients (12–18 years). Main outcomes were number of steps per day obtained by an accelerometer and disability scored by the Functional Disability Inventory (FDI). Patients with the 5-HTT SS or SLG genotype had a significantly lower number of steps per day than patients with the 5-HTT LALG, SLA or LALA genotype. Patients with the 5-HTT SS or SLG genotype also had a significantly higher FDI score than patients with the 5-HTT LALG, SLA or LALA genotype. Thus, CFS patients with the 5-HTT SS or SLG genotype had worse 30 weeks outcome than CFS patients with the 5-HTT LALG, SLA or LALA genotype. The present study suggests that the 5-HTT genotype may be a factor that contributes to maintenance of CFS. PMID:26473596

  19. Homozygotes for the autosomal dominant neoplasia syndrome (MEN1)

    SciTech Connect

    Brandi, M.L.; Falchetti, A.; Tonelli, F. ); Weber, G.; Svensson, A.; Larsson, C. ); Castello, R.; Furlani, L.; Scappaticci, S.; Fraccaro, M.

    1993-12-01

    Families in which both parents are heterozygotes for the same autosomal dominant neoplasia syndrome are extremely unusual. Recently, the authors had the unique opportunity to evaluate three symptomatic siblings from the union between two unrelated individuals affected by multiple endocrine neoplasia type 1 (MEN1). When the three siblings and their parents and relatives were genotyped for 12 markers tightly linked to the MEN1 locus, at 11q13, two of the siblings were found to be homozygotes, and one a heterozygote, for MEN1. With regard to the MEN1 syndrome, no phenotypic differences were observed between the two homozygotes and the heterozygotes. However, the two homozygotes showed unexplained infertility, which was not the case for any of the heterozygotes. Thus, MEN1 appears to be a disease with complete dominance, and the presence of two MEN1 alleles with mutations of the type that occur constitutionally may be insufficient for tumor development. 28 refs., 2 figs.

  20. Interaction between 5-HTTLPR polymorphism and abuse history on adolescent African-American females' condom use behavior following participation in an HIV prevention intervention.

    PubMed

    Sales, Jessica M; DiClemente, Ralph J; Brody, Gene H; Philibert, Robert A; Rose, Eve

    2014-06-01

    Not everyone exposed to an efficacious human immunodeficiency virus (HIV) intervention will reduce sexual risk behaviors, yet little is known about factors associated with "failure to change" high-risk sexual behaviors post-intervention. History of abuse and polymorphisms in the serotonin transporter gene (5-HTT) may be associated with non-change. The current study sought to identify genetic, life history, and psychosocial factors associated with adolescents' failure to change condom use behaviors post-participation in an HIV prevention intervention. A sub-set of participants from a clinic-based sample of adolescent African-American females (N = 254) enrolled in a randomized trial of an HIV-prevention was utilized for the current study. Forty-four percent did not increase their condom use from baseline levels 6 months after participating in the sexually transmitted infection (STI)/HIV prevention intervention. In multivariable logistic regression analysis, an interaction between abuse and 5-HTTLPR group was significantly associated with non-change status, along with partner communication frequency scores at follow-up. Follow-up tests found that having a history of abuse was significantly associated with greater odds of non-change in condom use post-intervention for only those with the s allele. For those with ll allele, participants with higher partner communication frequency scores were at decreased odds of non-change in condom use post-intervention. Thus, STI/HIV interventions for adolescent females may consider providing a more in-depth discussion and instruction on how to manage and overcome fear or anxiety related to being assertive in sexual decisions or sexual situations. Doing so may improve the efficacy of STI/HIV prevention programs for adolescent women who have experienced abuse in their lifetime.

  1. Anxiety disorders and anxiety-related traits and serotonin transporter gene-linked polymorphic region (5-HTTLPR) in adolescents: case-control and trio studies.

    PubMed

    Bortoluzzi, Andressa; Blaya, Carolina; Salum, Giovanni A; Cappi, Carolina; Leistner-Segal, Sandra; Manfro, Gisele G

    2014-08-01

    The role of the serotonin transporter gene-linked polymorphic region (5-HTTLPR) in anxiety disorder and anxiety-related traits is controversial. Besides this study, few studies have evaluated the triallelic genotype in adolescents. The aim of this study was to investigate whether anxiety disorders and anxiety-related traits are associated with 5-HTTLPR (biallelic and triallelic) in adolescents, integrating both case-control-based and family-based designs in a community sample. This is a cross-sectional community study of 504 individuals and their families: 225 adolescents (129 adolescents with anxiety disorder and 96 controls) and their biological families. We assessed psychiatric diagnosis using the Kiddie Schedule for Affective Disorders and Schizophrenia. The Temperament and Character Inventory and the Resnick Behavioral Inhibition Scale were used to evaluate harm avoidance and behavioral inhibition. DNA was extracted from saliva and genotyped, including biallelic and triallelic 5-HTTLPR classification, by PCR-RFLP followed by agarose gel electrophoresis. We were not able to find any associations between 5-HTTLPR and anxiety-related phenotypes in both case-control and trio analyses. Further investigation and meta-analytic studies are needed to better clarify the inconsistent results with regard to the association between 5-HTTLPR and anxiety-related phenotypes in adolescents.

  2. The Generation R Study: A Review of Design, Findings to Date, and a Study of the 5-HTTLPR by Environmental Interaction from Fetal Life Onward

    ERIC Educational Resources Information Center

    Tiemeier, Henning; Velders, Fleur P.; Szekely, Eszter; Roza, Sabine J.; Dieleman, Gwen; Jaddoe, Vincent W. V.; Uitterlinden, Andre G.; White, Tonya J. H.; Bakermans-Kranenburg, Marian J.; Hofman, Albert; Van IJzendoorn, Marinus H.; Hudziak, James J.; Verhulst, Frank C.

    2012-01-01

    Objective: First, we give an overview of child psychiatric research in the Generation R Study, a population-based cohort from fetal life forward. Second, we examine within Generation R whether the functional polymorphism (5-HTTLPR) in the promoter of the serotonin transporter gene interacts with prenatal maternal chronic difficulties, prenatal…

  3. No association between lithium full responders and the DRD1, DRD2, DRD3, DAT1, 5-HTTLPR and HTR2A genes in a Sardinian sample.

    PubMed

    Manchia, Mirko; Congiu, Donatella; Squassina, Alessio; Lampus, Simona; Ardau, Raffaella; Chillotti, Caterina; Severino, Giovanni; Del Zompo, Maria

    2009-09-30

    Polymorphisms within the DRD1, DRD2, DRD3, DAT1, 5-HTTLPR and HTR2A genes are being studied for association with lithium prophylaxis in a sample of 155 Sardinian unrelated probands affected by bipolar disorder (BP). No significant association was shown between the polymorphisms of the genes studied and response to lithium treatment.

  4. Serotonin Transporter-Linked Polymorphic Region (5-HTTLPR) Genotype and Stressful Life Events Interact to Predict Preschool-Onset Depression: A Replication and Developmental Extension

    ERIC Educational Resources Information Center

    Bogdan, Ryan; Agrawal, Arpana; Gaffrey, Michael S.; Tillman, Rebecca; Luby, Joan L.

    2014-01-01

    Background: Scientific enthusiasm about gene × environment interactions, spurred by the 5-HTTLPR (serotonin transporter-linked polymorphic region) × SLEs (stressful life events) interaction predicting depression, have recently been tempered by sober realizations of small effects and meta-analyses reaching opposing conclusions. These mixed findings…

  5. Financial difficulties but not other types of recent negative life events show strong interactions with 5-HTTLPR genotype in the development of depressive symptoms

    PubMed Central

    Gonda, X; Eszlari, N; Kovacs, D; Anderson, I M; Deakin, J F W; Juhasz, G; Bagdy, G

    2016-01-01

    Several studies indicate that 5-HTTLPR mediates the effect of childhood adversity in the development of depression, while results are contradictory for recent negative life events. For childhood adversity the interaction with genotype is strongest for sexual abuse, but not for other types of childhood maltreatment; however, possible interactions with specific recent life events have not been investigated separately. The aim of our study was to investigate the effect of four distinct types of recent life events in the development of depressive symptoms in a large community sample. Interaction between different types of recent life events measured by the List of Threatening Experiences and the 5-HTTLPR genotype on current depression measured by the depression subscale and additional items of the Brief Symptom Inventory was investigated in 2588 subjects in Manchester and Budapest. Only a nominal interaction was found between life events overall and 5-HTTLPR on depression, which failed to survive correction for multiple testing. However, subcategorising life events into four categories showed a robust interaction between financial difficulties and the 5-HTTLPR genotype, and a weaker interaction in the case of illness/injury. No interaction effect for the other two life event categories was present. We investigated a general non-representative sample in a cross-sectional approach. Depressive symptoms and life event evaluations were self-reported. The 5-HTTLPR polymorphism showed a differential interaction pattern with different types of recent life events, with the strongest interaction effects of financial difficulties on depressive symptoms. This specificity of interaction with only particular types of life events may help to explain previous contradictory findings. PMID:27138797

  6. Financial difficulties but not other types of recent negative life events show strong interactions with 5-HTTLPR genotype in the development of depressive symptoms.

    PubMed

    Gonda, X; Eszlari, N; Kovacs, D; Anderson, I M; Deakin, J F W; Juhasz, G; Bagdy, G

    2016-05-03

    Several studies indicate that 5-HTTLPR mediates the effect of childhood adversity in the development of depression, while results are contradictory for recent negative life events. For childhood adversity the interaction with genotype is strongest for sexual abuse, but not for other types of childhood maltreatment; however, possible interactions with specific recent life events have not been investigated separately. The aim of our study was to investigate the effect of four distinct types of recent life events in the development of depressive symptoms in a large community sample. Interaction between different types of recent life events measured by the List of Threatening Experiences and the 5-HTTLPR genotype on current depression measured by the depression subscale and additional items of the Brief Symptom Inventory was investigated in 2588 subjects in Manchester and Budapest. Only a nominal interaction was found between life events overall and 5-HTTLPR on depression, which failed to survive correction for multiple testing. However, subcategorising life events into four categories showed a robust interaction between financial difficulties and the 5-HTTLPR genotype, and a weaker interaction in the case of illness/injury. No interaction effect for the other two life event categories was present. We investigated a general non-representative sample in a cross-sectional approach. Depressive symptoms and life event evaluations were self-reported. The 5-HTTLPR polymorphism showed a differential interaction pattern with different types of recent life events, with the strongest interaction effects of financial difficulties on depressive symptoms. This specificity of interaction with only particular types of life events may help to explain previous contradictory findings.

  7. Identification and functional characterization of three novel alleles for the serotonin transporter-linked polymorphic region.

    PubMed

    Ehli, E A; Hu, Y; Lengyel-Nelson, T; Hudziak, J J; Davies, G E

    2012-02-01

    A promoter polymorphism in the serotonin transporter gene (5-HTTLPR) has been reported to confer relative risk for phenotypes (depression/anxiety) and endophenotypes (amygdala reactivity). In this report, we identify and characterize three rare 5-HTTLPR alleles not previously described in the human literature. The three novel alleles were identified while genotyping 5-HTTLPR in a family-based attention deficit hyperactivity disorder clinical population. Two of the novel alleles are longer than the common 16-repeat long (L) allele (17 and 18 repeats) and the third is significantly smaller than the 14-repeat short (S) allele (11 repeats). The sequence and genetic architecture of each novel allele is described in detail. We report a significant decrease in the expression between the XL₁₇ (17r) allele and the L(A) (16r) allele. The XS₁₁ (11r) allele showed similar expression with the S (14r) allele. A 1.8-fold increase in expression was observed with the L(A)(16r) allele compared with the L(G) (16r) allele, which replicates results from earlier 5-HTTLPR expression experiments. In addition, transcription factor binding site (TFBS) analysis was performed using MatInspector (Genomatix) that showed the presence or absence of different putative TFBSs between the novel alleles and the common L (16r) and S (14r) alleles. The identification of rare variants and elucidation of their functional impact could potentially lead to understanding the contribution that the rare variant may have on the inheritance/susceptibility of multifactorial common diseases.

  8. Serotonin transporter (5-HTTLPR) and monoamine oxidase (MAOA) promoter polymorphisms in women with severe alcoholism.

    PubMed

    Gokturk, Camilla; Schultze, Stefan; Nilsson, Kent W; von Knorring, Lars; Oreland, Lars; Hallman, Jarmila

    2008-12-01

    The serotonin system is known to play a pivotal role for mood, behaviour and psychic illness as e.g. alcoholism. Alcoholism in both males and females has been associated with polymorphisms in genes encoding for proteins of importance for central serotonergic function. Genotyping of two functional polymorphisms in the promoter region of the serotonin transporter and monoamine oxidase-A, respectively, (5-HTT-LPR and MAOA-VNTR), was performed in a group of women with severe alcohol addiction. A large sample of adolescent females from a normal population was used as controls. A significantly higher frequency of the LL 5-HTT genotype (high activity) was found in female addicts without a known co-morbid psychiatric disorder than in the controls. Genotype of the MAOA-VNTR polymorphism did not differ significantly between addicts and controls. However, within the group of alcoholics, when the patients with known co-morbid psychiatric disorders were excluded, aggressive anti-social behaviour was significantly linked to the presence of the high activity MAOA allele. The pattern of associations between genotypes of 5-HTT-LPR and MAOA-VNTR in women with severe alcoholism differs from most corresponding studies on males.

  9. Predictors for self-directed aggression in Italian prisoners include externalizing behaviors, childhood trauma and the serotonin transporter gene polymorphism 5-HTTLPR.

    PubMed

    Gorodetsky, E; Carli, V; Sarchiapone, M; Roy, A; Goldman, D; Enoch, M-A

    2016-06-01

    Suicidal behavior and self-mutilation can be regarded as the expression of self-directed aggression and both are common in prison populations. We investigated the influence of externalizing behaviors, depressive symptoms, childhood trauma, 5-HTTLPR variants on self-directed aggression (N = 145) in a group of 702 male Italian prisoners. Participants were comprehensively evaluated, including for psychiatric disorders, impulsive traits, lifetime aggressive behavior [Brown-Goodwin Lifetime History of Aggression (BGHA)], hostility, violent behavior during incarceration, depressive symptomatology [Hamilton Depression Rating Scale (HDRS)], childhood trauma [Childhood Trauma Questionnaire (CTQ)]. Logistic regression analysis showed false discovery rate corrected independent main effects of externalizing behaviors: BGHA (P = 0.001), violent behavior in jail (P = 0.007), extraversion (P = 0.015); HDRS (P = 0.0004), Axis I disorders (P = 0.015), CTQ (P = 0.004) and 5-HTTLPR genotype (P = 0.02). Carriers of 5-HTTLPR high (LA LA ), intermediate (LA LG , SLA ) activity variants were more likely to have exhibited self-directed aggression relative to the low activity (LG LG , SLG , SS) variant: high/low: odds ratio (OR) = 2.3, 95% confidence interval (CI) 1.27-4.68, P = 0.007; intermediate/low: OR = 1.96, 95% CI 1.09-3.68, P = 0.025. The CTQ main effect was driven by physical abuse. There was no interactive effect of 5-HTTLPR and CTQ. Secondary logistic regression analyses in (1) all suicide attempters (N = 88) and (2) all self-mutilators (N = 104), compared with controls showed that in both groups, childhood trauma (P = 0.008-0.01), depression (P = 0.0004-0.001) were strong predictors. BGHA, violent behavior in jail predicted self-mutilation (P = 0.002) but not suicide attempts (P = 0.1). This study was able to distinguish differing influences on self-directed aggression between groups of closely related

  10. Panic Disorder is Associated with the Serotonin Transporter Gene (SLC6A4) But Not the Promoter Region (5-HTTLPR)

    PubMed Central

    Strug, Lisa J.; Suresh, Rathi; Fyer, Abby; Talati, Ardesheer; Adams, Philip B.; Li, Weili; Hodge, Susan E.; Gilliam, T. Conrad; Weissman, Myrna M.

    2008-01-01

    Panic disorder (PD) and social anxiety disorder (SAD) are moderately heritable anxiety disorders. We analyzed five genes, derived from pharmacological or translational mouse models, in a new case-control study of PD and SAD in European Americans: (1) the serotonin transporter (SLC6A4), (2) the serotonin receptor 1A (HTR1A), (3) catechol-o-methyltransferase (COMT), (4) a regulator of g-protein signalling, RGS2, and (5) the gastrin releasing peptide receptor (GRPR). Cases were interviewed using the Schedule for Affective disorders and Schizophrenia (SADS-LA-IV) and were required to have a probable or definite lifetime diagnosis of PD (N = 179), SAD (161) or both (140), with first onset by age 31 and a family history of anxiety. Final diagnoses were determined using the best estimate procedure, blind to genotyping data. Controls were obtained from the NIMH Human Genetics Initiative; only subjects above 25 years of age who screened negative for all psychiatric symptoms were included (N = 470). A total of 45 SNPs were successfully genotyped over the 5 selected genes using Applied Biosystems SNPlex protocol. SLC6A4 provided strong and consistent evidence of association with the PD and PD+SAD groups, with the most significant association in both groups being at rs140701 (χ2=10.72, p=0.001 with PD and χ2=8.59, p=0.003 in the PD+SAD group). This association remained significant after multiple test correction. Those carrying at least one copy of the haplotype A-A-G constructed from rs3794808, rs140701 and rs4583306 have 1.7 times the odds of PD than those without the haplotype (90%CI 1.2-2.3). The SAD only group did not provide evidence of association, suggesting a PD driven association. The findings remained after adjustment for age and sex, and there was no evidence that the association was due to population stratification. The promoter region of the gene, 5-HTTLPR, did not provide any evidence of association, regardless of whether analyzed as a triallelic or biallelic

  11. A functional polymorphism in a serotonin transporter gene (5-HTTLPR) interacts with 9/11 to predict gun-carrying behavior.

    PubMed

    Barnes, J C; Beaver, Kevin M; Boutwell, Brian B

    2013-01-01

    On September 11, 2001, one of the deadliest terrorist attacks in US history took place on American soil and people around the world were impacted in myriad ways. Building on prior literature which suggests individuals are more likely to purchase a gun for self-protection if they are fearful of being victimized, the authors hypothesized that the terrorist attacks of 9/11 would lead to an increase in gun carrying among US residents. At the same time, a line of research has shown that a polymorphism in the 5-HTT gene (i.e., 5-HTTLPR) interacts with environmental stressors to predict a range of psychopathologies and behaviors. Thus, it was hypothesized that 9/11 and 5-HTTLPR would interact to predict gun carrying. The results supported both hypotheses by revealing a positive association between 9/11 and gun carrying (b = .426, odds ratio = 1.531, standard error for b = .194, z = 2.196, p = .028) in the full sample of respondents (n = 15,052) and a statistically significant interaction between 9/11 and 5-HTTLPR in the prediction of gun carrying (b = -1.519, odds ratio = .219, standard error for b = .703, z = -2.161, p = .031) in the genetic subsample of respondents (n = 2,350). This is one of the first studies to find an association between 9/11 and gun carrying and, more importantly, is the first study to report a gene-environment interaction (GxE) between a measured gene and a terrorist attack.

  12. Functional polymorphism (5-HTTLPR) in the serotonin transporter gene is associated with subjective well-being: evidence from a US nationally representative sample.

    PubMed

    De Neve, Jan-Emmanuel

    2011-06-01

    Variation in the promotor region of the serotonin transporter gene (5-HTTLPR) is a promising candidate for better understanding individual heterogeneity in subjective well-being or happiness, as measured by life satisfaction. This functional polymorphism has previously been associated with mental health and selective processing of positive and negative emotional stimuli. A case-control association study on a representative sample of Americans (N=2574) finds that individuals with the transcriptionally more efficient version of the serotonin transporter gene, report significantly higher levels of life satisfaction (P=0.01). This new finding may help explain the important genetic component of the individual baseline levels of happiness.

  13. The Association Between Breastfeeding Exposure and Duration, Neuropsychological Deficits, and Psychopathic Personality Traits in Offspring: The Moderating Role of 5HTTLPR.

    PubMed

    Jackson, Dylan B; Beaver, Kevin M

    2016-03-01

    A wealth of research has revealed that a shorter duration of breastfeeding during infancy can increase the risk of various maladaptive traits, including neuropsychological deficits. Despite the number of studies that have been conducted on the topic, few studies have explored whether the effects of breastfeeding on neuropsychological functioning and personality features persist into adulthood. Furthermore, very little research to date has examined whether this relationship is moderated by specific indicators of genetic risk. The current study examines the direct and interactive effects of breastfeeding experiences and the serotonin transporter polymorphism (5HTTLPR) on neuropsychological deficits and psychopathic personality traits. Using data from the National Longitudinal study of Adolescent Health, we find that no exposure to breastfeeding and a shorter duration of breastfeeding significantly increase the risk of exhibiting neuropsychological deficits during adolescence and early adulthood as well as psychopathic personality traits during adulthood. The results also reveal a number of gene × environment interactions between 5HTTLPR, breastfeeding exposure and breastfeeding duration in the prediction of neuropsychological deficits, but not in the prediction of psychopathic personality traits.

  14. The influence of psychiatric screening in healthy populations selection: a new study and meta-analysis of functional 5-HTTLPR and rs25531 polymorphisms and anxiety-related personality traits

    PubMed Central

    2011-01-01

    Background A genetic liability for anxiety-related personality traits in healthy subjects has been associated with the functional serotonin transporter promoter polymorphism (5-HTTLPR), although the data are somewhat conflicting. Moreover, only one study has investigated the functional significance of the 5-HTTLPR/rs25531 haplotypes in relation to anxiety traits in healthy subjects. We tested whether the 5-HTTLPR polymorphism and the 5-HTTLPR/rs25531 haplotypes are linked to Harm Avoidance (HA) using an association study (STUDY I) and a meta-analytic approach (STUDY II). Methods STUDY I: A total of 287 unrelated Italian volunteers were screened for DSM-IV Axis I disorders and genotyped for the 5-HTTLPR and rs25531 (A/G) polymorphisms. Different functional haplotype combinations were also analyzed. STUDY II: A total of 44 studies were chosen for a meta-analysis of the putative association between 5-HTTLPR and anxiety-related personality traits. Results STUDY I: In the whole sample of 287 volunteers, we found that the SS genotype and S'S' haplotypes were associated with higher scores on HA. However, because the screening assessed by Mini-International Neuropsychiatric Interview (M.I.N.I.) showed the presence of 55 volunteers affected by depression or anxiety disorders, we analyzed the two groups ("disordered" and "healthy") separately. The data obtained did indeed confirm that in the "healthy" group, the significant effects of the SS genotype and S'S' haplotypes were lost, but they remained in the "disordered" group. STUDY II: The results of the 5-HTTLPR meta-analysis with anxiety-related traits in the whole sample confirmed the association of the SS genotype with higher anxiety-related traits scores in Caucasoids; however, when we analyzed only those studies that used structured psychiatric screening, no association was found. Conclusions This study demonstrates the relevance to perform analyses on personality traits only in DSM-IV axis I disorder-free subjects

  15. Residual recombination in Neurospora crassa spo11 deletion homozygotes occurs during meiosis.

    PubMed

    Bowring, F J; Yeadon, P J; Catcheside, D E A

    2013-09-01

    Spo11 is considered responsible for initiation of meiotic recombination in higher organisms, but previous analysis using spo11 (RIP) mutants suggests that the his-3 region of Neurospora crassa experiences spo11-independent recombination. However, despite possessing several stop codons, it is conceivable that the mutants are not completely null. Also, since lack of spo11 interferes with chromosomal pairing and proper segregation at Meiosis I, spores can be partially diploid for a period after meiosis. Thus, it is possible that the recombination observed could be an abnormal event, occurring during the period of aneuploidy rather than during meiosis. To test the former hypothesis, we generated spo11 deletion homozygotes. Using crosses heteroallelic for his-3 mutations, we showed that His(+) progeny are generated in spo11 deletion homozygotes at a frequency at least as high as in wild type and, as in the spo11 (RIP) mutants, local crossing over is not reduced. To test the latter hypothesis, we utilised mutations in either end of a histone H1-GFP fusion gene, inserted between the recombination hotspot cog and his-3, in which GFP(+) spores arise as a result of recombination in a cross between the two GFP alleles. In a control cross homozygous for spo11 (+), the frequency at which GFP(+) spores arise is comparable to the frequency of His(+) spores and glowing nuclei first appear during prophase, prior to metaphase I, as expected for a product of meiotic recombination. Similarly in spo11 deletion homozygotes, GFP(+) spores arise at high frequency and glowing nuclei are first seen before metaphase, indicating that allelic recombination occurs during meiosis in the absence of spo11. We have therefore shown that spo11 is not essential for either his-3 allelic recombination or crossing over in the vicinity of his-3, and that spo11-independent allelic recombination is meiotic, indicating that there is a spo11-independent mechanism for initiation of recombination in Neurospora.

  16. Clinical manifestations of hemochromatosis in HFE C282Y homozygotes identified by screening

    PubMed Central

    McLaren, Gordon D; McLaren, Christine E; Adams, Paul C; Barton, James C; Reboussin, David M; Gordeuk, Victor R; Acton, Ronald T; Harris, Emily L; Speechley, Mark R; Sholinsky, Phyliss; Dawkins, Fitzroy W; Snively, Beverly M; Vogt, Thomas M; Eckfeldt, John H

    2008-01-01

    BACKGROUND: Patients with hemochromatosis may suffer organ damage from iron overload, often with serious clinical consequences. OBJECTIVE: To assess prevalences of self-reported symptoms and clinical signs and conditions in persons homozygous for the hemochromatosis gene (HFE) mutation (C282Y) identified by screening. METHODS: Participants were adults 25 years of age or older enrolled in the Hemochromatosis and Iron Overload Screening (HEIRS) Study. C282Y homozygotes (n=282) were compared with control participants without the HFE C282Y or H63D alleles (ie, wild type/wild type; n=364). RESULTS: Previously diagnosed C282Y homozygotes and newly diagnosed homozygotes with elevated serum ferritin levels had higher prevalences of certain symptoms such as chronic fatigue (OR 2.8; 95% CI 1.34 to 5.95, and OR 2.0; 95% CI 1.07 to 3.75, respectively), and had more hyperpigmentation on physical examination (OR 4.7; 95% CI 1.50 to 15.06, and OR 3.7; 95% CI 1.10 to 12.16, respectively) and swelling or tenderness of the second and third metacarpophalangeal joints (OR 4.2; 95% CI 1.37 to 13.03, and OR 3.3; 95% CI 1.17 to 9.49, respectively) than control subjects. Joint stiffness was also more common among newly diagnosed C282Y homozygotes with elevated serum ferritin than among control subjects (OR 2.7; 95% CI 1.38 to 5.30). However, the sex- and age-adjusted prevalences of self-reported symptoms and signs of liver disease, heart disease, diabetes and most other major clinical manifestations of hemochromatosis were similar in C282Y homozygotes and control subjects. CONCLUSIONS: Some symptoms and conditions associated with hemochromatosis were more prevalent among C282Y homozygotes identified by screening than among control subjects, but prevalences of most outcomes were similar in C282Y homozygotes and controls in this primary care-based study. PMID:19018338

  17. Genotypes Do Not Confer Risk For Delinquency ut Rather Alter Susceptibility to Positive and Negative Environmental Factors: Gene-Environment Interactions of BDNF Val66Met, 5-HTTLPR, and MAOA-uVNTR

    PubMed Central

    Comasco, Erika; Hodgins, Sheilagh; Oreland, Lars; Åslund, Cecilia

    2015-01-01

    Background: Previous evidence of gene-by-environment interactions associated with emotional and behavioral disorders is contradictory. Differences in findings may result from variation in valence and dose of the environmental factor, and/or failure to take account of gene-by-gene interactions. The present study investigated interactions between the brain-derived neurotrophic factor gene (BDNF Val66Met), the serotonin transporter gene-linked polymorphic region (5-HTTLPR), the monoamine oxidase A (MAOA-uVNTR) polymorphisms, family conflict, sexual abuse, the quality of the child-parent relationship, and teenage delinquency. Methods: In 2006, as part of the Survey of Adolescent Life in Västmanland, Sweden, 1 337 high-school students, aged 17–18 years, anonymously completed questionnaires and provided saliva samples for DNA analyses. Results: Teenage delinquency was associated with two-, three-, and four-way interactions of each of the genotypes and the three environmental factors. Significant four-way interactions were found for BDNF Val66Met × 5-HTTLPR×MAOA-uVNTR × family conflicts and for BDNF Val66Met × 5-HTTLPR×MAOA-uVNTR × sexual abuse. Further, the two genotype combinations that differed the most in expression levels (BDNF Val66Met Val, 5-HTTLPR LL, MAOA-uVNTR LL [girls] and L [boys] vs BDNF Val66Met Val/Met, 5-HTTLPR S/LS, MAOA-uVNTR S/SS/LS) in interaction with family conflict and sexual abuse were associated with the highest delinquency scores. The genetic variants previously shown to confer vulnerability for delinquency (BDNF Val66Met Val/Met × 5-HTTLPR S × MAOA-uVNTR S) were associated with the lowest delinquency scores in interaction with a positive child-parent relationship. Conclusions: Functional variants of the MAOA-uVNTR, 5-HTTLPR, and BDNF Val66Met, either alone or in interaction with each other, may be best conceptualized as modifying sensitivity to environmental factors that confer either risk or protection for teenage delinquency. PMID

  18. Serotonin transporter polymorphism modulates neural correlates of real-life joint action. An investigation with functional near-infrared spectroscopy (fNIRS).

    PubMed

    Herrmann, M J; Bogon, J; Quester, S; Cordes, A; Stenneken, P; Reif, A; Ehlis, A-C

    2015-04-30

    A functional polymorphism (5-HTTLPR) within the serotonin transporter gene (SERT) has been associated with personality dimensions such as neuroticism, with emotional reactivity to negative events, and with an increased risk of affective disorders. More specifically, the short (S) allele of 5-HTTLPR has been linked to increased amygdala activity and has been identified as a risk allele for depressive disorders. Recently, Homberg and Lesch (2011) urged for a conceptual change in the current deficit-oriented connotation of the 5-HTTLPR S-allele and argued that the S-allele could be considered adaptive in certain contexts. They postulated that S-allele carriers show hypervigilant behavior in social situations and should thus show increased social conformity. Therefore, we tested whether 5-HTTLPR modulates the neural correlates of real-life social joint action through functional near-infrared spectroscopy (fNIRS). Thirty participants, homozygote for 5-HTTLPR, were measured and analyzed while they were involved in a previously published joint-action paradigm, which reliably leads to an activation of the left parietal cortex. We found that homozygote S-allele carriers showed increased inferior parietal lobe activation, compared to the LL-allele carriers for the contrast "joint action greater solo action". Therefore, our results provide evidence for beneficial effects of the S-allele on the neural correlates of social interactions.

  19. Serotonin Transporter Gene Promoter Region Polymorphism and Selective Processing of Emotional Images

    PubMed Central

    Beevers, Christopher G.; Ellis, Alissa J.; Wells, Tony T.; McGeary, John E.

    2009-01-01

    Several studies have now documented that the serotonin transporter promoter region (5-HTTLPR) polymorphism predicts neural response to affective images in brain regions involved in the experience of emotion. However, the behavioral consequences of this genetic effect are less well known. The current study used eye-tracking methodology to examine how individuals genotyped for the 5-HTTLPR allocated their attention when simultaneously presented an array of positive and negative emotional scenes. Short 5-HTTLPR allele homozygotes displayed a bias to focus on positive images, particularly in the first half of the 30-second trial. In contrast, long 5-HTTLPR allele homozygotes viewed the stimuli in a more evenhanded fashion. Thus, short 5-HTTLPR allele homozygotes may be attempting to regulate greater reactivity to negative stimuli by purposefully turning their attention towards positive stimuli. Although this sensitivity may have benefits under benign conditions, it may also increase vulnerability to affective disorders when cognitive resources needed to turn attention away from negative stimuli are compromised. PMID:19715738

  20. Genetic and neural correlates of romantic relationship satisfaction.

    PubMed

    Luo, Siyang; Yu, Dian; Han, Shihui

    2016-02-01

    Romantic relationship satisfaction (RRS) is important for mental/physical health but varies greatly across individuals. To date, we have known little about the biological (genetic and neural) correlates of RRS. We tested the hypothesis that the serotonin transporter promoter polymorphism (5-HTTLPR), the promoter region of the gene SLC6A4 that codes for the serotonin transporter protein, is associated with individuals' RRS. Moreover, we investigated neural activity that mediates 5-HTTLPR association with RRS by scanning short-short (s/s) and long-long (l/l) homozygotes of 5-HTTLPR, using functional MRI, during a Cyberball game that resulted in social exclusion. l/l compared with s/s allele carriers reported higher RRS but lower social interaction anxiety. l/l compared with s/s carriers showed stronger activity in the right ventral prefrontal cortex (RVPFC) and stronger functional connectivity between the dorsal and rostral ACC when being excluded from the Cyberball game. Moreover, the 5-HTTLPR association with RRS was mediated by the RVPFC activity and the 5-HTTLPR association with social interaction anxiety was mediated by both the dorsal-rostral ACC connectivity and RVPFC activity. Our findings suggest that 5-HTTLPR is associated with satisfaction of one's own romantic relationships and this association is mediated by the neural activity in the brain region related to emotion regulation.

  1. Genetic and neural correlates of romantic relationship satisfaction

    PubMed Central

    Luo, Siyang; Yu, Dian

    2016-01-01

    Romantic relationship satisfaction (RRS) is important for mental/physical health but varies greatly across individuals. To date, we have known little about the biological (genetic and neural) correlates of RRS. We tested the hypothesis that the serotonin transporter promoter polymorphism (5-HTTLPR), the promoter region of the gene SLC6A4 that codes for the serotonin transporter protein, is associated with individuals’ RRS. Moreover, we investigated neural activity that mediates 5-HTTLPR association with RRS by scanning short-short (s/s) and long-long (l/l) homozygotes of 5-HTTLPR, using functional MRI, during a Cyberball game that resulted in social exclusion. l/l compared with s/s allele carriers reported higher RRS but lower social interaction anxiety. l/l compared with s/s carriers showed stronger activity in the right ventral prefrontal cortex (RVPFC) and stronger functional connectivity between the dorsal and rostral ACC when being excluded from the Cyberball game. Moreover, the 5-HTTLPR association with RRS was mediated by the RVPFC activity and the 5-HTTLPR association with social interaction anxiety was mediated by both the dorsal–rostral ACC connectivity and RVPFC activity. Our findings suggest that 5-HTTLPR is associated with satisfaction of one’s own romantic relationships and this association is mediated by the neural activity in the brain region related to emotion regulation. PMID:26385612

  2. Negative BOLD response and serotonin concentration within rostral subgenual portion of the anterior cingulate cortex for long-allele carriers during perceptual processing of emotional tasks

    NASA Astrophysics Data System (ADS)

    Hadi, Shamil M.; Siadat, Mohamad R.; Babajani-Feremi, Abbas

    2012-03-01

    We investigated the effect of synaptic serotonin concentration on hemodynamic responses. The stimuli paradigm involved the presentation of fearful and threatening facial expressions to a set of 24 subjects who were either5HTTLPR long- or short-allele carriers (12 of each type in each group). The BOLD signals of the rACC from subjects of each group were averaged to increase the signal-to-noise ratio. We used a Bayesian approach to estimate the parameters of the underlying hemodynamic model. Our results, during this perceptual processing of emotional task, showed a negative BOLD signal in the rACC in the subjects with long-alleles. In contrast, the subjects with short-alleles showed positive BOLD signals in the rACC. These results suggest that high synaptic serotonin concentration in the rACC inhibits neuronal activity in a fashion similar to GABA, and a consequent negative BOLD signal ensues.

  3. Genetic moderation of child maltreatment effects on depression and internalizing symptoms by serotonin transporter linked polymorphic region (5-HTTLPR), brain-derived neurotrophic factor (BDNF), norepinephrine transporter (NET), and corticotropin releasing hormone receptor 1 (CRHR1) genes in African American children.

    PubMed

    Cicchetti, Dante; Rogosch, Fred A

    2014-11-01

    Genetic moderation of the effects of child maltreatment on depression and internalizing symptoms was investigated in a sample of low-income maltreated and nonmaltreated African American children (N = 1,096). Lifetime child maltreatment experiences were independently coded from Child Protective Services records and maternal report. Child depression and internalizing problems were assessed in the context of a summer research camp by self-report on the Children's Depression Inventory and adult counselor report on the Teacher Report Form. DNA was obtained from buccal cell or saliva samples and genotyped for polymorphisms of the following genes: serotonin transporter linked polymorphic region (5-HTTLPR), brain-derived neurotrophic factor (BDNF), norepinephrine transporter, and corticotropin releasing hormone receptor 1. Analyses of covariance with age and gender as covariates were conducted, with maltreatment status and respective polymorphism as main effects and their Gene × Environment (G × E) interactions. Maltreatment consistently was associated with higher Children's Depression Inventory and Teacher Report Form symptoms. The results for child self-report symptoms indicated a G × E interaction for BDNF and maltreatment. In addition, BDNF and triallelic 5-HTTLPR interacted with child maltreatment in a G × G × E interaction. Analyses for counselor report of child anxiety/depression symptoms on the Teacher Report Form indicated moderation of child maltreatment effects by triallelic 5-HTTLPR. These effects were elaborated based on variation in developmental timing of maltreatment experiences. Norepinephrine transporter was found to further moderate the G × E interaction of 5-HTTLPR and maltreatment status, revealing a G × G × E interaction. This G × G × E was extended by consideration of variation in maltreatment subtype experiences. Finally, G × G × E effects were observed for the co-action of BDNF and the corticotropin releasing hormone receptor 1

  4. Efficiency of the inbreeding coefficient f and other estimators in detecting null alleles, as revealed by empirical data of locus oke3 across 65 populations of chum salmon Oncorhynchus keta.

    PubMed

    Zhivotovsky, L A; Kordicheva, S Yu; Shaikhaev, E G; Rubtsova, G A; Afanasiev, K I; Shitova, M V; Fuller, S A; Shaikhaev, G O; Gharrett, A J

    2015-01-01

    A survey of 65 populations of chum salmon Oncorhynchus keta across the species range revealed homozygote excess (947 homozygotes in 2954 fish) at a polymerase chain reaction (PCR)-based simple sequence repeat (SSR) locus oke3 with multiple alleles, whereas re-designed PCR primers indicated that 328 of these homozygotes were actually heterozygotes. Statistically significant high positive values of inbreeding coefficients, f, in multiple populations appeared to be a reliable predictor of null alleles. Based on these data, three methods were checked for their ability to estimate null-allele frequencies.

  5. Different outcome of six homozygotes for prothrombin A20210A gene variant

    PubMed Central

    Di Micco, Pierpaolo; Di Fiore, Rosanna; Niglio, Alferio; Quaranta, Sandro; Angiolillo, Antonella; Cardillo, Giuseppe; Castaldo, Giuseppe

    2008-01-01

    Prothrombin G20210A gene variant (FII G20210A) is a risk factor for venous thrombotic disease while conflicting results have been reported for the risk of arterial thrombotic events. However, vascular episodes were absent in up to 40% of the 67 homozygotes for the G20210A described so far, which indicates that the clinical expression depends on additional risk/trigger factors. We describe six homozygotes for the G20210A variant, among which the first pair of siblings (cases n. 3 and 4) reported so far that displayed a strongly heterogeneous clinical outcome. Case 1, a female of 27 years, developed a full thrombosis of common femoral, superficial and popliteal veins. She assumed oral contraceptives in the last two years. Case n. 2, 34 years old, suffered of recurrent pregnancy loss in absence of any causative alteration. Cases n. 3 and n. 5 experienced arterial thrombotic disease, i.e., juvenile myocardial infarction (40 years old) and stroke (48 years old), respectively, in absence of other risk factors. Finally, cases n. 4 and 6 identified as homozygotes for the FII G20210A variant being consanguineous of symptomatic subjects bearing the variant, did not experience any episode of venous nor arterial disease. Both of them have chronic liver disease with an impairement of the prothrombin time INR. Thus, homozygotes for the G20210A are at risk for arterial (in addition to venous) thromobotic events; chronic liver disease might modulate this risk. PMID:18627609

  6. The homozygote p.V27I/p.E114G variant of GJB2 is a putative indicator of nonsyndromic hearing loss in Chinese infants.

    PubMed

    Chen, Wen-Xia; Huang, Yue; Yang, Xiao-Lin; Duan, Bo; Lu, Ping; Wang, Yan; Xu, Zheng-Min

    2016-05-01

    The gap junction β2 (GJB2) gene is associated with more than half of the recessive forms of hereditary hearing loss (HHL). However, the correlation between p.V27I and p.E114G variants of GJB2 and hearing phenotype remains controversial. This study aimed to clarify possible roles of these variants in Chinese infants with nonsyndromic hearing loss (NSHL). Hearing and gene tests were conducted in 300 infants (aged 0-3 months) with NSHL and 484 normal infants (aged 0-3 months). The p.V27I and p.E114G variants appeared frequently in both NSHL patients and normal controls. The allele and haplotype frequencies of p.V27I and p.E114G in patients and controls were compared, but no significant difference was observed (p=0.44 and p=0.26, respectively). Moreover, genotype frequencies of the p.V27I variant showed no significant difference between the two groups (p=0.66). Interestingly, more homozygote p.V27I/p.E114G subjects were found in NSHL infants than in controls (5/484 and 13/300, respectively), most of whom (61.54%) had mild or moderate hearing losses. Our results indicate that homozygote p.V27I/p.E114G is associated with mild and moderate HHL.

  7. HFE C282Y homozygotes are at increased risk of breast and colorectal cancer

    PubMed Central

    Osborne, Nicholas J.; Gurrin, Lyle C; Allen, Katrina J.; Constantine, Clare C; Delatycki, Martin B.; McLaren, Christine E.; Gertig, Dorota M; Anderson, Gregory J; Southey, Melissa C; Olynyk, John K; Powell, Lawrie W.; Hopper, John L; Giles, Graham G; English, Dallas R

    2013-01-01

    The evidence that mutations in the HFE gene are associated with increased cancer risk is inconsistent. The Melbourne Collaborative Cohort Study is a prospective cohort study that commenced recruitment in 1990. Participants of born in Australia, New Zealand, the United Kingdom or Ireland (n = 28,509) were genotyped for the HFE C282Y variant. Incident cancers were ascertained from Australian cancer registries during an average of 14 years follow up. Hazard ratios, confidence intervals and p-values were obtained from separate Cox regression analyses for colorectal, breast and prostate cancers, all other solid cancers and all cancers. Compared with those with no C282Y variant, C282Y homozygotes were at increased risk of colorectal cancer (HR 2·28; 95% CI 1·22, 4·25; p = 0.01) and female C282Y homozygotes were at increased risk of developing breast cancer (HR 2·39; 95% CI 1·24, 4·61; p = 0.01) but male C282Y homozygotes were not at increased risk for prostate cancer (HR 0·96; 95% CI 0·43, 2·15; p = 0.92). C282Y/H63D compound heterozygotes were not at increased risk for colorectal cancer, (HR 1 27; 95% CI 0·80, 2·01); breast cancer, (HR 1·16; 95% CI 0·74, 1·84); or prostate cancer (HR 1·08; 95% CI 0·68, 1·70). Conclusion HFE C282Y homozygotes have twice the risk of colorectal and breast cancer compared with those without the C282Y variant. PMID:20099304

  8. p53 centrosomal localization diagnoses ataxia-telangiectasia homozygotes and heterozygotes

    PubMed Central

    Prodosmo, Andrea; De Amicis, Andrea; Nisticò, Cecilia; Gabriele, Mario; Di Rocco, Giuliana; Monteonofrio, Laura; Piane, Maria; Cundari, Enrico; Chessa, Luciana; Soddu, Silvia

    2013-01-01

    Ataxia-telangiectasia (A-T) is an autosomal recessive neurodegenerative disorder characterized by radiosensitivity, genomic instability, and predisposition to cancer. A-T is caused by biallelic mutations in the ataxia-telangiectasia mutated (ATM) gene, but heterozygous carriers, though apparently healthy, are believed to be at increased risk for cancer and more sensitive to ionizing radiation than the general population. Despite progress in functional and sequencing-based assays, no straightforward, rapid, and inexpensive test is available for the identification of A-T homozygotes and heterozygotes, which is essential for diagnosis, genetic counseling, and carrier prediction. The oncosuppressor p53 prevents genomic instability and centrosomal amplification. During mitosis, p53 localizes at the centrosome in an ATM-dependent manner. We capitalized on the latter finding and established a simple, fast, minimally invasive, reliable, and inexpensive test to determine mutant ATM zygosity. The percentage of mitotic lymphoblasts or PBMCs bearing p53 centrosomal localization clearly discriminated among healthy donors (>75%), A-T heterozygotes (40%–56%), and A-T homozygotes (<30%). The test is specific for A-T, independent of the type of ATM mutations, and recognized tumor-associated ATM polymorphisms. In a preliminary study, our test confirmed that ATM is a breast cancer susceptibility gene. These data open the possibility of cost-effective, early diagnosis of A-T homozygotes and large-scale screenings for heterozygotes. PMID:23454770

  9. Deep resequencing of CFTR in 762 F508del homozygotes reveals clusters of non-coding variants associated with cystic fibrosis disease traits

    PubMed Central

    Vecchio-Pagán, Briana; Blackman, Scott M; Lee, Melissa; Atalar, Melis; Pellicore, Matthew J; Pace, Rhonda G; Franca, Arianna L; Raraigh, Karen S; Sharma, Neeraj; Knowles, Michael R; Cutting, Garry R

    2016-01-01

    Extensive phenotypic variability is commonly observed in individuals with Mendelian disorders, even among those with identical genotypes in the disease-causing gene. To determine whether variants within and surrounding CFTR contribute to phenotypic variability in cystic fibrosis (CF), we performed deep sequencing of CFTR in 762 patients homozygous for the common CF-causing variant, F508del. In phase 1, ~200 kb encompassing CFTR and extending 10 kb 5′ and 5 kb 3′ of the gene was sequenced in 486 F508del homozygotes selected from the extremes of sweat chloride concentration. In phase 2, a 510 kb region, which included the entire topologically associated domain of CFTR, was sequenced in 276 F508del homozygotes drawn from extremes of lung function. An additional 163 individuals who carried F508del and a different CF-causing variant were sequenced to inform haplotype construction. Region-based burden testing of both common and rare variants revealed seven regions of significance (α=0.01), five of which overlapped known regulatory elements or chromatin interactions. Notably, the −80 kb locus known to interact with the CFTR promoter was associated with variation in both CF traits. Haplotype analysis revealed a single rare recombination event (1.9% frequency) in intron 15 of CFTR bearing the F508del variant. Otherwise, the majority of F508del chromosomes were markedly similar, consistent with a single origin of the F508del allele. Together, these high-resolution variant analyses of the CFTR locus suggest a role for non-coding regulatory motifs in trait variation among individuals carrying the common CF allele. PMID:27917292

  10. [A search for null alleles at the microsatellite locus of chum salmon (Oncorhynchus keta Walbaum)].

    PubMed

    Kordicheva, S Iu; Rubtsova, G A; Shitova, M V; Shaĭkhaev, G O; Afanas'ev, K I; Zhivotovskiĭ, L A

    2010-08-01

    Population studies with the use of microsatellite markers face a problem of null alleles, i.e., the absence of a PCR product, caused by the mutations in the microsatellite flanking regions, which serve as the sites of primer hybridization. In this case, the microsatellite primer associated with such mutation is not amplified, leading to false homozygosity in heterozygous individuals. This, in turn, results in biased population genetic estimates, including the excess of homozygotes at microsatellite loci. Analysis of the population structure of a Pacific salmon species, chum salmon (Oncorhynchus keta Walbaum), revealed the presence of null alleles at the Oke3 microsatellite locus in the population samples, in which an excess of homozygotes was observed. The analysis was performed using different combinations of modified primers chosen to match the Oke3 locus. The use of these primers enabled identification of true heterozygotes among those individuals, which were previously diagnosed as homozygotes with the use of standard primers. Removal of null alleles eliminated the excess homozygotes in the chum salmon samples described. In addition to the exclusion of false homozygosity, the use of modified primers makes it possible to introduce polymorphic primer variants associated with certain microsatellite alleles into population studies.

  11. A common allele on chromosome 9 associated with coronary heartdisease

    SciTech Connect

    McPherson, Ruth; Pertsemlidis, Alexander; Kavaslar, Nihan; Stewart, Alexandre; Roberts, Robert; Cox, David R.; Hinds, David; Pennachio, Len; Tybjaerg-Hansen, Anne; Folsom, Aaron R.; Boerwinkle,Eric; Hobbs, Helen H.; Cohen, Jonathan C.

    2007-03-01

    Coronary heart disease (CHD) is a major cause of death in Western countries. Here we used genome-wide association scanning to identify a 58 kb interval on chromosome 9 that was consistently associated with CHD in six independent samples. The interval contains no annotated genes and is not associated with established CHD risk factors such as plasma lipoproteins, hypertension or diabetes. Homozygotes for the risk allele comprise 20-25% of Caucasians and have a {approx}30-40% increased risk of CHD. These data indicate that the susceptibility allele acts through a novel mechanism to increase CHD risk in a large fraction of the population.

  12. Effect of MC1R variant allele status on MSH-ligand induction of dopachrome tautomerase in melanocytes co-cultured with keratinocytes.

    PubMed

    Ainger, Stephen A; Wong, Shu S; Roberts, Donald W; Leonard, J Helen; Sturm, Richard A

    2011-08-01

    A co-culture system of melanocytic cells and keratinocytes was used to examine dendricity and dopachrome tautomerase (DCT) responses in low penetrant 'r' homozygote and 'R/+' heterozygote MC1R variant allele expressing cells compared to that of wild-type (WT) cells. The V60L-/- homozygote r variant cells showed similar responses to ligand as WT MC1R strains, while V92M-/- homozygote r variant cells were generally shown to have greater dendricity and express higher DCT than the WT cells, even at basal levels. The R151C+/- heterozygote cells showed similar responses to WT cells, while the R160W+/- and D294H+/- variant cells were reduced in their responses to NDP-MSH, but still had an active cAMP response with forskolin treatment. These responses are consistent with the dominant negative effect of these alleles on the MC1R WT allele that has previously been demonstrated genetically and biochemically.

  13. The conditioning of intervention effects on early adolescent alcohol use by maternal involvement and dopamine receptor D4 (DRD4) and serotonin transporter linked polymorphic region (5-HTTLPR) genetic variants.

    PubMed

    Cleveland, H Harrington; Schlomer, Gabriel L; Vandenbergh, David J; Feinberg, Mark; Greenberg, Mark; Spoth, Richard; Redmond, Cleve; Shriver, Mark D; Zaidi, Arslan A; Hair, Kerry L

    2015-02-01

    Data drawn from the in-home subsample of the PROSPER intervention dissemination trial were used to investigate the moderation of intervention effects on underage alcohol use by maternal involvement and candidate genes. The primary gene examined was dopamine receptor D4 (DRD4). Variation in this gene and maternal involvement were hypothesized to moderate the influence of intervention status on alcohol use. The PROSPER data used were drawn from 28 communities randomly assigned to intervention or comparison conditions. Participating youth were assessed in five in-home interviews from sixth to ninth grades. A main effect of sixth-grade pretest maternal involvement on ninth-grade alcohol use was found. Neither intervention status nor DRD4 variation was unconditionally linked to ninth-grade drinking. However, moderation analyses revealed a significant three-way interaction among DRD4 status, maternal involvement, and intervention condition. Follow-up analyses revealed that prevention reduced drinking risk, but only for youth with at least one DRD4 seven-repeat allele who reported average or greater pretest levels of maternal involvement. To determine if this conditional pattern was limited to the DRD4 gene, we repeated analyses using the serotonin transporter linked polymorphic region site near the serotonin transporter gene. The results for this supplemental analysis revealed a significant three-way interaction similar but not identical to that found for DRD4.

  14. Genetic and hormonal sensitivity to threat: Testing a serotonin transporter genotype × testosterone interaction

    PubMed Central

    Josephs, Robert A.; Telch, Michael J.; Hixon, J. Gregory; Evans, Jacqueline J.; Lee, Hanjoo; Knopik, Valerie S.; McGeary, John E.; Hariri, Ahmad R.; Beevers, Christopher G.

    2011-01-01

    Summary Background Striking parallels are observed when comparing the literature on the 5-HTTLPR of the serotonin transporter gene (SLC6A4) to the testosterone (T) literature on measures of stress reactivity and neural activity. Short (S) allele carriers and individuals higher in testosterone levels show exaggerated stress responses, amygdala hyperactivity, and reduction of amygdala-prefrontal cortex coupling when exposed to threat. Methods Three studies tested the hypothesis that higher T, S carriers would show increased cortisol responses to threat. Results Supporting the hypothesis, a T × 5-HTTLPR interaction was obtained across all studies. Threats to status via social exclusion (Study 1), cognitive/perceptual failure (Study 2), and physical competence (Study 3) all produced elevated cortisol levels in S carriers with higher T levels. An unexpected result was that 5-HTTLPR long (L) allele homozygotes with higher T showed lower cortisol levels in response to threat--a pattern of response that closely parallels that reported for psychopathic individuals. Finally, combining effect sizes across studies showed that the likelihood that these effects were due to Type 1 errors was quite low. Conclusions What emerges from these studies is a novel yet reliable, and synergistic relationship between 5-HTTLPR genotype and testosterone on stress reactivity, possibly conferring vulnerability for multiple neuropsychiatric disorders. PMID:21978869

  15. Preclinical cognitive decline in late middle-aged asymptomatic apolipoprotein E-e4/4 homozygotes: a replication study.

    PubMed

    Caselli, R J; Osborne, D; Reiman, E M; Hentz, J G; Barbieri, C J; Saunders, A M; Hardy, J; Graff-Radford, N R; Hall, G R; Alexander, G E

    2001-08-15

    In a previous cross-sectional study of 100 asymptomatic individuals aged 49-69, we reported age-related decline in immediate and delayed memory that was steeper in apolipoprotein E (apoE)-e4/4 homozygotes than in members of other genetic subgroups. These findings were preliminarily based upon the statistical problem of multiple comparisons. We therefore sought to replicate these findings in a new cohort. From 1998 to 2000, 80 asymptomatic residents of Maricopa County, AZ were recruited through newspaper ads. 20 apoE-e4/4 homozygotes, 20 e3/4 heterozygotes, and 40 e4 noncarriers were matched (1:1:2) by age, gender, and years of education. All had normal neurologic and psychiatric examinations, including Folstein minimental status exam (MMSE) and Hamilton depression scale, and underwent a battery of neuropsychological tests identical to those in our previous study. The groups were well-matched for age (55.9+/-5.9 years), gender (60% women), and education (15.9+/-2.2 years), and were demographically similar to our previous cohort. Complex figure test recall was lower in e3/4 heterozygotes than noncarriers, but there was no significant difference between e4/4 homozygotes and noncarriers. There were no other significant differences in mean test scores between groups, but Wechsler adult intelligence scale-revised (WAIS-R) digit span showed a significant negative correlation with age in the e4/4 homozygote group relative to e4 noncarriers (p=0.008) as we had found in our previous study. In conclusion, we found a significant negative correlation of WAIS-R digit span with age in apoE-e4/4 homozygotes relative to e4 noncarriers in two separate cohorts, possibly reflecting an age-related effect on frontal lobe function in this genetic subgroup.

  16. Potyviral resistance derived from cultivars of Phaseolus vulgaris carrying bc-3 is associated with the homozygotic presence of a mutated eIF4E allele

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Eukaryotic translation initiation factors (eIFs) play a central role in potyviral infection. Accordingly, mutations in the gene encoding eIF4E have been identified as a source of recessive resistance in several plant species. In common bean, Phaseolus vulgaris, four recessive genes, bc-1, bc-2, bc-3...

  17. Human fear acquisition deficits in relation to genetic variants of the corticotropin releasing hormone receptor 1 and the serotonin transporter.

    PubMed

    Heitland, Ivo; Groenink, Lucianne; Bijlsma, Elisabeth Y; Oosting, Ronald S; Baas, Johanna M P

    2013-01-01

    The ability to identify predictors of aversive events allows organisms to appropriately respond to these events, and failure to acquire these fear contingencies can lead to maladaptive contextual anxiety. Recently, preclinical studies demonstrated that the corticotropin-releasing factor and serotonin systems are interactively involved in adaptive fear acquisition. Here, 150 healthy medication-free human subjects completed a cue and context fear conditioning procedure in a virtual reality environment. Fear potentiation of the eyeblink startle reflex (FPS) was measured to assess both uninstructed fear acquisition and instructed fear expression. All participants were genotyped for polymorphisms located within regulatory regions of the corticotropin releasing hormone receptor 1 (CRHR1 - rs878886) and the serotonin transporter (5HTTLPR). These polymorphisms have previously been linked to panic disorder and anxious symptomology and personality, respectively. G-allele carriers of CRHR1 (rs878886) showed no acquisition of fear conditioned responses (FPS) to the threat cue in the uninstructed phase, whereas fear acquisition was present in C/C homozygotes. Moreover, carrying the risk alleles of both rs878886 (G-allele) and 5HTTLPR (short allele) was associated with increased FPS to the threat context during this phase. After explicit instructions regarding the threat contingency were given, the cue FPS and context FPS normalized in all genotype groups. The present results indicate that genetic variability in the corticotropin-releasing hormone receptor 1, especially in interaction with the 5HTTLPR, is involved in the acquisition of fear in humans. This translates prior animal findings to the human realm.

  18. 'True' null allele detection in microsatellite loci: a comparison of methods, assessment of difficulties and survey of possible improvements.

    PubMed

    Dąbrowski, M J; Bornelöv, S; Kruczyk, M; Baltzer, N; Komorowski, J

    2015-05-01

    Null alleles are alleles that for various reasons fail to amplify in a PCR assay. The presence of null alleles in microsatellite data is known to bias the genetic parameter estimates. Thus, efficient detection of null alleles is crucial, but the methods available for indirect null allele detection return inconsistent results. Here, our aim was to compare different methods for null allele detection, to explain their respective performance and to provide improvements. We applied several approaches to identify the 'true' null alleles based on the predictions made by five different methods, used either individually or in combination. First, we introduced simulated 'true' null alleles into 240 population data sets and applied the methods to measure their success in detecting the simulated null alleles. The single best-performing method was ML-NullFreq_frequency. Furthermore, we applied different noise reduction approaches to improve the results. For instance, by combining the results of several methods, we obtained more reliable results than using a single one. Rule-based classification was applied to identify population properties linked to the false discovery rate. Rules obtained from the classifier described which population genetic estimates and loci characteristics were linked to the success of each method. We have shown that by simulating 'true' null alleles into a population data set, we may define a null allele frequency threshold, related to a desired true or false discovery rate. Moreover, using such simulated data sets, the expected null allele homozygote frequency may be estimated independently of the equilibrium state of the population.

  19. Analysis and interpretation of short tandem repeat microvariants and three-banded allele patterns using multiple allele detection systems.

    PubMed

    Crouse, C A; Rogers, S; Amiott, E; Gibson, S; Masibay, A

    1999-01-01

    The Palm Beach County Sheriffs Office (PBSO) Crime Laboratory and the Alabama Department of Forensic Sciences (ADFS) have validated and implemented analysis of short tandem repeat (STR) sequences on casework using silver staining kit and SYBR Green I detection systems and are presently validating fluorescently tagged STR alleles using the Hitachi FMBIO 100 instrument. Concurrently, the Broward County Sheriff's Office (BSO) Crime Laboratory is validating the ABI Prism310 Genetic Analyzer capillary electrophoresis STR detection system (ABI CE310) from Perkin Elmer Applied BioSystems. During the course of analyzing over 10,000 individuals for the STR loci CSF1PO, TPOX and THO1 (CTT) using silver staining for allele detection, 42 samples demonstrated alleles that were "off ladder," contained three-banded patterns at a single locus, or exhibited an apparent THO1 "9.3,10" allele pattern. PBSO, ADFS and BSO Crime Laboratories have collaborated on the verification of the allele patterns observed in these 42 samples using the following allele detection systems: (1) manual silver staining, (2) SYBR Green I staining, and/or (3) fluorescently tagged amplified products separated by polyacrylamide gel electrophoresis or capillary electrophoresis followed by laser detection. Regardless of the CTT allele detection system utilized, concordant results were obtained for 41 of the 42 samples. The only exception was a sample in which a wide band within the THO1 locus was identified as a THO1 "9.3, 10" genotype by silver staining kit and SYBR Green I staining but was verified to be a THO1 "9.3" homozygote by all other allele detection systems. Manual allele detection could readily identify microvariants, as a visual assessment of stained gels clearly shows that alleles do not migrate coincident with well-characterized allele size standards. As would be predicted, however, the manual detection systems did not provide adequate resolution to approximate the basepair size for off

  20. Genotoxic investigation of a thiazolidinedione PPARγ agonist using the in vitro micronucleus test and the in vivo homozygotization assay.

    PubMed

    Morais, Janicélle Fernandes; Sant'Anna, Juliane Rocha de; Pereira, Tais Susane; Franco, Claudinéia Conationi da Silva; Mathias, Paulo Cezar de Freitas; de Castro-Prado, Marialba Avezum Alves

    2016-07-01

    Pioglitazone (PTZ) is an oral antidiabetic agent whose anti-cancer properties have been described recently. Since PTZ increases the production of reactive oxygen species in mammalian cells, the aim of current study was to evaluate the cytotoxic, mutagenic and recombinogenic effects of PTZ using respectively the in vitro mitotic index assay and the in vitro mammalian cell micronucleus test in human peripheral lymphocytes, and the in vivo homozygotization assay in Aspergillus nidulans, which detects the loss of heterozygosity due to somatic recombination. Although the lowest PTZ concentrations (4-36 μM) did not show any significant rise in the micronucleus production, the higher PTZ concentration (108 μM) produced a statistically higher number of micronuclei than the negative control and significantly altered the cell-proliferation kinetics, demonstrating the mutagenic and antiproliferative effects of PTZ, respectively. The recombinogenic activity of PTZ, demonstrated here for the first time, was observed at the highest tested concentration (400 μM) through the homozygotization index rates significantly different from the negative control. Taken together, our results show that PTZ is genotoxic at a concentration higher than the therapeutic plasma concentration. This PTZ genotoxicity may be a potential benefit to its previously described antitumour activity.

  1. Phenotypic effects of an allele causing obligate parthenogenesis in a rotifer.

    PubMed

    Scheuerl, Thomas; Riss, Simone; Stelzer, Claus-Peter

    2011-01-01

    Transitions to obligate asexuality have been documented in almost all metazoan taxa, yet the conditions favoring such transitions remained largely unexplored. We address this problem in the rotifer Brachionus calyciflorus. In this species, a polymorphism at a single locus, op, can result in transitions to obligate parthenogenesis. Homozygotes for the op allele reproduce strictly by asexual reproduction, whereas heterozygous clones (+/op) and wild-type clones (+/+) are cyclical parthenogens that undergo sexual reproduction at high population densities. Here, we examine dosage effects of the op allele by analyzing various life-history characteristics and population traits in 10 clones for each of the 3 possible genotypes (op/op, +/op, and +/+). For most traits, we found that op/op clones differed significantly (P < 0.05) from the 2 cyclical parthenogenetic genotypes (+/+ and +/op). By contrast, the 2 cyclical parthenogenetic genotypes were almost indistinguishable, except that heterozygote individuals were slightly but significantly smaller in body size compared with wild-type individuals. Overall, this indicates that the op allele is selectively neutral in the heterozygous state. Thus, selective sweeps of this allele in natural populations would first require conditions favoring the generation of homozygotes. This may be given by inbreeding in very small populations or by double mutants in very large populations.

  2. Platelet serotonin uptake and paroxetine binding among allelic genotypes of the serotonin transporter in alcoholics.

    PubMed

    Javors, Martin A; Seneviratne, Chamindi; Roache, John D; Ait-Daoud, Nassima; Bergeson, Susan E; Walss-Bass, M Consuelo; Akhtar, Fatema Z; Johnson, Bankole A

    2005-01-01

    Expression rates of long (L) and short (S) alleles of the serotonin (5-HT) transporter (5-HTT) gene have been shown to differ under various circumstances. We compared 5-HTT uptake (function) level and paroxetine binding (density) in platelets of alcoholics as indices of 5-HTT expression rate among LL, LS, and SS genotypes. Concentration curves of [3H]5-HT and [3H]paroxetine were used to quantify the equilibrium constant (Km) and maximum 5-HT uptake rate (Vmax) for 5-HTT uptake into intact platelets and the dissociation constant (Kd) and maximum specific binding density (Bmax) for paroxetine binding to platelet membranes, respectively. Genotypes were determined using electrophoresis with fluorescent markers. Vmax for 5-HTT uptake did not correlate with Bmax for paroxetine binding (r=-0.095, P=0.415). Means of Vmax and Bmax did not differ in a statistically significant manner among LL, LS, and SS genotypes in these alcoholic subjects. However, Vmax for LL and SS appeared to have a bimodal distribution, so the percentage of subjects with Vmax <200 fmol/min-10(7) platelets was statistically significantly higher in LL than in SS (51.5% vs. 22.7%, respectively), with an odds ratio of 3.6 (P<0.05). The percentage of Vmax <200 fmol/min-10(7) platelets for LS was 39.3% (not significant vs. LL or SS). Previous studies of healthy human controls have shown that 5-HTT density in raphe nuclei and 5-HTT uptake in platelets are higher in the LL genotype than in S carriers. Our findings in currently drinking alcoholics support the hypothesis that those with the LL genotype of the 5'-HTTLPR region of the 5-HTT gene have reduced 5-HTT function.

  3. Ethnic variation of the HLA-G*0105N allele in two Chinese populations.

    PubMed

    Lin, A; Li, M; Xu, D-P; Zhang, W-G; Yan, W-H

    2009-03-01

    Unlike high polymorphic classical human leukocyte antigen (HLA) class I molecules, the genetic polymorphism of HLA-G is very limited. However, the prevalence of HLA-G alleles among different ethnic populations varied dramatically. The HLA-G null allele (HLA-G*0105N) is defined by a cytosine deletion (Delta C) at position 1597 in exon 3, which disrupts the reading frame and alters the expression of HLA-G proteins. The HLA-G*0105N allelic frequency was investigated in previous studies and possible roles were addressed. In the current study, a total of 310 Chinese Han and 260 Chinese She ethnic minority population had been genotyped for the G*0105N polymorphism. Marked difference was observed that the G*0105N allelic frequency in Chinese Han was 1.61%, while no copy of the null allele was observed in the Chinese She minority population (P(c) = 0.0073). Data also revealed that no homozygote of HLA-G*0105N allele exists in this Chinese Han population. Furthermore, significant difference was found for the frequencies of HLA-G*0105N both in Chinese Han and in Chinese She populations when compared with other ethnic populations. Taken together, our results indicated that ethnic variation of the HLA-G*0105N polymorphism among different ethnic populations is possibly the result of evolution. However, the advantages of the selection of this allele are necessary to be further investigated.

  4. Sensorineural hearing loss with brainstem auditory evoked responses changes in homozygote and heterozygote sickle cell patients in Guadeloupe (France).

    PubMed

    Jovanovic-Bateman, L; Hedreville, R

    2006-08-01

    This prospective study involved 79 homozygote and heterozygote sickle cell anaemia patients (16 to 50 years old) and a control group of 40 people.All patients underwent ENT, audiological and brainstem auditory evoked responses (BSER) examinations in order to evaluate the incidence of sensorineural hearing loss (SNHL), to identify the changes at the level of the cochlear nerve and the central pathways, and to determine the most vulnerable group, in order to intervene with early prevention and rehabilitation for this condition.A hearing loss of greater than 20 dB at two or more frequencies was found in 36 (45.57 per cent) sickle cell patients (19 (47.22 per cent) HbSC patients and 17 (43.59 per cent) HbSS patients) and three (7.5 per cent) members of the control group. Homozygote and heterozygote patients, as well as both sexes, were equally affected. Bilateral hearing loss occurred in 19 (52.78 per cent) patients, unilateral right-sided hearing loss in five (13.89 per cent) patients and unilateral left-sided hearing loss in 12 (33.33 per cent) patients. Brainstem auditory evoked potential demonstrated a prolonged I-V (III-V) interpeak latency in 13 (25.35 per cent) sickle cell patients (11 men (eight with HbSS) and two women). The hearing loss in HbSS patients was neural in nature and of earlier onset; the hearing loss in HbSC patients was usually cochlear in nature and of later onset. Despite high medical standards and 100 per cent social security cover, the high incidence of SNHL in our sickle cell affected patients (the majority with the Benin haplotype) was probably due to their specific haematological profile and to the original geographical distribution of the disease in the tropics. Our results highlight the necessity for early and regular hearing assessment of sickle cell patients, including BSER examination, especially in male patients with SNHL.

  5. A new mib allele with a chromosomal deletion covering foxc1a exhibits anterior somite specification defect

    PubMed Central

    Hsu, Chia-Hao; Lin, Ji-Sheng; Po Lai, Keng; Li, Jing-Woei; Chan, Ting-Fung; You, May-Su; Tse, William Ka Fai; Jiang, Yun-Jin

    2015-01-01

    mibnn2002, found from an allele screen, showed early segmentation defect and severe cell death phenotypes, which are different from previously known mib mutants. Despite distinct morphological phenotypes, the typical mib molecular phenotypes: her4 down-regulation, neurogenic phenotype and cold sensitive dlc expression pattern, still remained. The linkage analysis also indicated that mibnn2002 is a new mib allele. Failure of specification in anterior 7-10 somites is likely due to lack of foxc1a expression in mibnn2002 homozygotes. Somites and somite markers gradually appeared after 7-10 somite stage, suggesting that foxc1a is only essential for the formation of anterior 7-10 somites. Apoptosis began around 16-somite stage with p53 up-regulation. To find the possible links of mib, foxc1a and apoptosis, transcriptome analysis was employed. About 140 genes, including wnt3a, foxc1a and mib, were not detected in the homozygotes. Overexpression of foxc1a mRNA in mibnn2002 homozygotes partially rescued the anterior somite specification. In the process of characterizing mibnn2002 mutation, we integrated the scaffolds containing mib locus into chromosome 2 (or linkage group 2, LG2) based on synteny comparison and transcriptome results. Genomic PCR analysis further supported the conclusion and showed that mibnn2002 has a chromosomal deletion with the size of about 9.6 Mbp. PMID:26039894

  6. Natural Allelic Variations in Highly Polyploidy Saccharum Complex

    PubMed Central

    Song, Jian; Yang, Xiping; Resende, Marcio F. R.; Neves, Leandro G.; Todd, James; Zhang, Jisen; Comstock, Jack C.; Wang, Jianping

    2016-01-01

    Sugarcane (Saccharum spp.) is an important sugar and biofuel crop with high polyploid and complex genomes. The Saccharum complex, comprised of Saccharum genus and a few related genera, are important genetic resources for sugarcane breeding. A large amount of natural variation exists within the Saccharum complex. Though understanding their allelic variation has been challenging, it is critical to dissect allelic structure and to identify the alleles controlling important traits in sugarcane. To characterize natural variations in Saccharum complex, a target enrichment sequencing approach was used to assay 12 representative germplasm accessions. In total, 55,946 highly efficient probes were designed based on the sorghum genome and sugarcane unigene set targeting a total of 6 Mb of the sugarcane genome. A pipeline specifically tailored for polyploid sequence variants and genotype calling was established. BWA-mem and sorghum genome approved to be an acceptable aligner and reference for sugarcane target enrichment sequence analysis, respectively. Genetic variations including 1,166,066 non-redundant SNPs, 150,421 InDels, 919 gene copy number variations, and 1,257 gene presence/absence variations were detected. SNPs from three different callers (Samtools, Freebayes, and GATK) were compared and the validation rates were nearly 90%. Based on the SNP loci of each accession and their ploidy levels, 999,258 single dosage SNPs were identified and most loci were estimated as largely homozygotes. An average of 34,397 haplotype blocks for each accession was inferred. The highest divergence time among the Saccharum spp. was estimated as 1.2 million years ago (MYA). Saccharum spp. diverged from Erianthus and Sorghum approximately 5 and 6 MYA, respectively. The target enrichment sequencing approach provided an effective way to discover and catalog natural allelic variation in highly polyploid or heterozygous genomes. PMID:27375658

  7. Natural Allelic Variations in Highly Polyploidy Saccharum Complex.

    PubMed

    Song, Jian; Yang, Xiping; Resende, Marcio F R; Neves, Leandro G; Todd, James; Zhang, Jisen; Comstock, Jack C; Wang, Jianping

    2016-01-01

    Sugarcane (Saccharum spp.) is an important sugar and biofuel crop with high polyploid and complex genomes. The Saccharum complex, comprised of Saccharum genus and a few related genera, are important genetic resources for sugarcane breeding. A large amount of natural variation exists within the Saccharum complex. Though understanding their allelic variation has been challenging, it is critical to dissect allelic structure and to identify the alleles controlling important traits in sugarcane. To characterize natural variations in Saccharum complex, a target enrichment sequencing approach was used to assay 12 representative germplasm accessions. In total, 55,946 highly efficient probes were designed based on the sorghum genome and sugarcane unigene set targeting a total of 6 Mb of the sugarcane genome. A pipeline specifically tailored for polyploid sequence variants and genotype calling was established. BWA-mem and sorghum genome approved to be an acceptable aligner and reference for sugarcane target enrichment sequence analysis, respectively. Genetic variations including 1,166,066 non-redundant SNPs, 150,421 InDels, 919 gene copy number variations, and 1,257 gene presence/absence variations were detected. SNPs from three different callers (Samtools, Freebayes, and GATK) were compared and the validation rates were nearly 90%. Based on the SNP loci of each accession and their ploidy levels, 999,258 single dosage SNPs were identified and most loci were estimated as largely homozygotes. An average of 34,397 haplotype blocks for each accession was inferred. The highest divergence time among the Saccharum spp. was estimated as 1.2 million years ago (MYA). Saccharum spp. diverged from Erianthus and Sorghum approximately 5 and 6 MYA, respectively. The target enrichment sequencing approach provided an effective way to discover and catalog natural allelic variation in highly polyploid or heterozygous genomes.

  8. Etude de l’hémogramme dans la drépanocytose homozygote: à propos de 87 patients

    PubMed Central

    Dahmani, Fatima; Benkirane, Souad; Kouzih, Jaafar; Woumki, Aziz; Mamad, Hassan; Masrar, Azlarab

    2016-01-01

    La drépanocytose homozygote, fait partie des hémoglobinopathies les plus fréquentes au Maroc. La drépanocytose est caractérisée par une grande variabilité d’expressions clinique et biologique qui dépendent des facteurs génétiques modulateurs et environnementaux. Elle se manifeste par une anémie régénérative de gravité très variable selon les individus. L’évolution spontanée en l’absence de traitement est le décès précoce. La drépanocytose est caractérisée par une grande variabilité d’expression clinique et biologique qui dépend des facteurs génétiques et environnementaux. Un tableau clinique sévère marqué par une fréquence de transfusion élevée et précoce, des complications infectieuses graves et une mortalité précoce. Un état inflammatoire constant caractérisé par des protéines inflammatoires élevées et état nutritionnel compromis. L’objectif est de déterminer le profil des paramètres hématologiques du drépanocytaire homozygote (SS) marocain au cours des stades stationnaires. Nous avons fait une étude descriptive transversale de 87 patients drépanocytaires (SS). Nous avons réalisé une étude biologique comportant: l’hémogramme avec étude morphologique des globules rouges en coloration MGG et numération automatique des réticulocytes. Les électrophorèses de l’hémoglobine à pH alcalin (8.8) sur gel d’agarose avec intégration densitométrique. L’âge moyen est de 13.22 ans ± 16.36 avec un sex- ratio (H/F) de 1.175 et des extrêmes allant de 0.6 à 36 ans. La répercussion de l’anémie sur le plan biologique, est intense chez 88.5% des patients, 67.8% ont une anémie normocytaire contre 29.9% présentant une microcytose, et 2.3% qui présentaient une macrocytose. Le degré d’anisocytose est lié au degré d’anémie, très évocatrice chez les drépanocytaires homozygotes S/S (95,4%). Une réticulocytose était observée chez nos patients (81,6%) et 52.9% présentaient une

  9. Undiagnosed diabetes and impaired fasting glucose in HFE C282Y homozygotes and HFE wild-type controls in the HEIRS Study

    PubMed Central

    Barton, James C; Barton, J Clayborn; Adams, Paul C; Acton, Ronald T

    2016-01-01

    Objective To determine prevalences and predictors of undiagnosed diabetes mellitus (UDM) and impaired fasting glucose (IFG) in non-Hispanic whites with HFE p.C282Y homozygosity and controls without common HFE mutations identified in population screening. Research design and methods We analyzed these observations in a postscreening examination: age; sex; body mass index; systolic/diastolic blood pressure; metacarpophalangeal joint hypertrophy; hepatomegaly; blood neutrophils; alanine and aspartate aminotransferase; elevated C reactive protein; transferrin saturation; serum ferritin; and Field Center. Results There were 223 p.C282Y homozygotes and 449 controls without diagnosed diabetes (43.9% men). Mean age of p.C282Y homozygotes was 52±13 years (controls 57±14 years; p<0.0001). Mean transferrin saturation in p.C282Y homozygotes was 67±26% (controls 34±14%; p<0.0001). Mean serum ferritin in p.C282Y homozygotes was 607 pmol/L (95% CI 497 to 517; controls 274 pmol/L (247 to 301); p<0.0001). Overall prevalences of UDM (4.0% vs 4.2%) and IFG (23.8% vs 25.6%) did not differ significantly between p.C282Y homozygotes and wt/wt controls, respectively. In logistic regressions, male sex, body mass index, and alanine aminotransferase were significantly associated with UDM. ORs were 2.7 (1.2 to 2.8); 1.0 (1.0 to 1.1); and 1.0 (1.0 to 1.0), respectively. Age, male sex, and body mass index were significantly associated with IFG. ORs were 1.0 (1.0 to 1.1); 2.8 (1.9 to 4.2); and 1.0 (1.0 to 1.1), respectively. Conclusions Prevalences of UDM and IFG were similar in p.C282Y homozygotes and controls in a postpopulation screening examination. Male sex was the strongest predictor of UDM and IFG. PMID:28074138

  10. Genetic Associations with Performance on a Behavioral Measure of Distress Intolerance

    PubMed Central

    Amstadter, Ananda B.; Daughters, Stacey B.; MacPherson, Laura; Reynolds, Elizabeth K.; Danielson, Carla Kmett; Wang, Frances; Potenza, Marc N.; Gelernter, Joel; Lejuez, C. W.

    2013-01-01

    Both theory and empirical evidence support possible associations between two candidate genetic polymorphisms (SLC6A4 5-HTTLPR l/s and COMT Val158Met – rs4680 variants) and emotion-regulation difficulties. One particular form of emotion-regulation difficulty, distress intolerance, has been measured using a behavioral assessment in youth; data indicate a relationship with poor psychological functioning. No prior study has investigated genetic influences on emotion-regulation difficulties in youth. As part of a larger longitudinal study on adolescent risk behaviors, 218 10-14 year-old youths from the metropolitan Washington, D.C., area completed a measure of distress intolerance, the Behavioral Indicator of Resilience to Distress (BIRD), and provided saliva samples for DNA extraction and genotyping. Results indicate that those with one or two copies of the s allele of the 5-HTTLPR polymorphism were more likely to perform poorly on the task (i.e., choose to quit) than were those homozygous for the l allele. Participants who were Val allele carriers of the COMT Val158Met polymorphism were also more likely to quit the task compared to Met homozygotes. A summative risk allele score was created to combine the two polymorphisms, and each risk allele was associated with a 1.75 fold increased likelihood of quitting the task. Exploratory analyses revealed that emotional abuse moderated the relationship between the 5-HTTLPR and BIRD performance, as well as the genetic risk allele and the BIRD. This is the first investigation of genetic predictors of a behavioral measure of tolerance to distress. Results suggest that distress tolerance is at least partially regulated by specific genetic variants. Implications are discussed. PMID:22024485

  11. Host mating system and the spread of a disease-resistant allele in a population

    USGS Publications Warehouse

    DeAngelis, D.L.; Koslow, Jennifer M.; Jiang, J.; Ruan, S.

    2008-01-01

    The model presented here modifies a susceptible-infected (SI) host-pathogen model to determine the influence of mating system on the outcome of a host-pathogen interaction. Both deterministic and stochastic (individual-based) versions of the model were used. This model considers the potential consequences of varying mating systems on the rate of spread of both the pathogen and resistance alleles within the population. We assumed that a single allele for disease resistance was sufficient to confer complete resistance in an individual, and that both homozygote and heterozygote resistant individuals had the same mean birth and death rates. When disease invaded a population with only an initial small fraction of resistant genes, inbreeding (selfing) tended to increase the probability that the disease would soon be eliminated from a small population rather than become endemic, while outcrossing greatly increased the probability that the population would become extinct due to the disease.

  12. Clinical spectrum in homozygotes and compound heterozygotes inheriting cystic fibrosis mutation 3849+10kbC>T: Significance for geneticists

    SciTech Connect

    Gilbert, F.; Li, Zhen; Arzimanoglou, I.

    1995-09-25

    We describe patients inheriting cystic fibrosis (CF) mutation 3849+10kbC>T as homozygotes or compound heterozygotes. Three unrelated homozygotes for this mutation were all pancreatic-sufficient and sweat test-negative or inconclusive. Among the compound heterozygotes, both pancreatic sufficiency and insufficiency, as well as positive and negative/inconclusive sweat test results are reported, expanding the range of clinical expression associated with inheritance of this mutation. 3849+10kbC>T is one of several CF mutations that can result in atypical or variant forms of CF. For geneticists, the diagnosis of variant CF has implications for recurrence risk and prognosis counseling of the families of affected individuals, and possibly for CF carrier screening in the general population. 19 refs., 1 tab.

  13. Three cadherin alleles associated with resistance to Bacillus thuringiensis in pink bollworm

    PubMed Central

    Morin, Shai; Biggs, Robert W.; Sisterson, Mark S.; Shriver, Laura; Ellers-Kirk, Christa; Higginson, Dawn; Holley, Daniel; Gahan, Linda J.; Heckel, David G.; Carrière, Yves; Dennehy, Timothy J.; Brown, Judith K.; Tabashnik, Bruce E.

    2003-01-01

    Evolution of resistance by pests is the main threat to long-term insect control by transgenic crops that produce Bacillus thuringiensis (Bt) toxins. Because inheritance of resistance to the Bt toxins in transgenic crops is typically recessive, DNA-based screening for resistance alleles in heterozygotes is potentially much more efficient than detection of resistant homozygotes with bioassays. Such screening, however, requires knowledge of the resistance alleles in field populations of pests that are associated with survival on Bt crops. Here we report that field populations of pink bollworm (Pectinophora gossypiella), a major cotton pest, harbored three mutant alleles of a cadherin-encoding gene linked with resistance to Bt toxin Cry1Ac and survival on transgenic Bt cotton. Each of the three resistance alleles has a deletion expected to eliminate at least eight amino acids upstream of the putative toxin-binding region of the cadherin protein. Larvae with two resistance alleles in any combination were resistant, whereas those with one or none were susceptible to Cry1Ac. Together with previous evidence, the results reported here identify the cadherin gene as a leading target for DNA-based screening of resistance to Bt crops in lepidopteran pests. PMID:12695565

  14. apo B gene knockout in mice results in embryonic lethality in homozygotes and neural tube defects, male infertility, and reduced HDL cholesterol ester and apo A-I transport rates in heterozygotes.

    PubMed Central

    Huang, L S; Voyiaziakis, E; Markenson, D F; Sokol, K A; Hayek, T; Breslow, J L

    1995-01-01

    apo B is a structural constituent of several classes of lipoprotein particles, including chylomicrons, VLDL, and LDL. To better understand the role of apo B in the body, we have used gene targeting in embryonic stem cells to create a null apo B allele in the mouse. Homozygous apo B deficiency led to embryonic lethality, with resorption of all embryos by gestational day 9. Heterozygotes showed an increased tendency to intrauterine death with some fetuses having incomplete neural tube closure and some live-born heterozygotes developing hydrocephalus. The majority of male heterozygotes were sterile, although the genitourinary system and sperm were grossly normal. Viable heterozygotes had normal triglycerides, but total, LDL, and HDL cholesterol levels were decreased by 37, 37, and 39%, respectively. Hepatic and intestinal apo B mRNA levels were decreased in heterozygotes, presumably contributing to the decreased LDL levels through decreased synthesis of apo B-containing lipoproteins. Kinetic studies indicated that heterozygotes had decreased transport rates of HDL cholesterol ester and apo A-I. As liver and intestinal apo A-I mRNA levels were unchanged, the mechanism for decreased apo A-I transport must be posttranscriptional. Heterozygotes also had normal cholesterol absorption and a normal response of the plasma lipoprotein pattern to chronic consumption of a high fat, high cholesterol, Western-type diet. In summary, we report a mouse model for apo B deficiency with several phenotypic features that were unexpected based on clinical studies of apo B-deficient humans, such as embryonic lethality in homozygotes and neural tube closure defects, male infertility, and a major defect in HDL production in heterozygotes. This model presents an opportunity to study the mechanisms underlying these phenotypic changes. Images PMID:7593600

  15. Allele frequencies of microsatellite loci for genetic characterization of a Sicilian bovine population.

    PubMed

    Cosenza, M; Reale, S; Lupo, T; Vitale, F; Caracappa, S

    2015-01-30

    Short tandem repeats are used as an effective method to trace DNA markers in genotyping. Using a standardized kit, we tested 11 microsatellite markers recommended by the International Society for Animal Genetics (ISAG) in a sample of 495 Sicilian cattle. The aim of this study was to investigate the allele frequencies in the Sicilian cattle population to provide a reference database and at the same time to assess the use of the ISAG microsatellite panel for pedigree analysis. DNA samples were collected from blood and amplified in an 11-plex polymerase chain reaction (PCR); PCR products were injected in a 3130 Genetic Analyzer. All loci showed high mean polymorphism information content (0.768), and the observed mean heterozygosity was less than the expected value (0.732 vs 0.794, respectively). The exact test for Hardy-Weinberg proportions, allele number, and inbreeding coefficient were calculated. Our results indicated that equilibrium was not always maintained. The observed mean homozygote value exceeded the expected value (132.81 vs 102.14), but no evidence for allele dropout was found. These results could be explained by a non-random mating; further studies using a larger number of animals could confirm or invalidate this hypothesis. The probability of identity and exclusion of a locus were also estimated and proved to be useful in paternity testing. The ISAG microsatellite panel is useful to screen the Sicilian bovine kinship. Currently, an allele frequency database is being constructed.

  16. Interaction between SLC6A4 promoter variants and childhood trauma on the age at onset of bipolar disorders

    PubMed Central

    Etain, B.; Lajnef, M.; Henrion, A.; Dargél, A.A.; Stertz, L.; Kapczinski, F.; Mathieu, F.; Henry, C.; Gard, S.; Kahn, J. P.; Leboyer, M.; Jamain, S.; Bellivier, F.

    2015-01-01

    Age at onset (AAO) of bipolar disorders (BD) could be influenced both by a repeat length polymorphism (5HTTLPR) in the promoter region of the serotonin transporter gene (SLC6A4) and exposure to childhood trauma. We assessed 308 euthymic patients with BD for the AAO of their first mood episode and childhood trauma. Patients were genotyped for the 5HTTLPR (long/short variant) and the rs25531. Genotypes were classified on functional significance (LL, LS, SS). A sample of 126 Brazilian euthymic patients with BD was used for replication. In the French sample, the correlation between AAO and trauma score was observed only among ‘SS’ homozygotes (p = 0.002) but not among ‘L’ allele carriers. A history of at least one trauma decreased the AAO only in ‘SS’ homozygotes (p = 0.001). These results remained significant after correction using FDR. Regression models suggested an interaction between emotional neglect and ‘SS’ genotype on the AAO (p = 0.009) and no further interaction with other trauma subtypes. Partial replication was obtained in the Brazilian sample, showing an interaction between emotional abuse and ‘LS’ genotype on the AAO (p = 0.02). In conclusion, an effect of childhood trauma on AAO of BD was observed only in patients who carry a specific stress responsiveness-related SLC6A4 promoter genotype. PMID:26542422

  17. What Is a Recessive Allele?

    ERIC Educational Resources Information Center

    American Biology Teacher, 1991

    1991-01-01

    Presents four misconceptions students have concerning the concepts of recessive and dominant alleles. Discusses the spectrum of dominant-recessive relationships, different levels of analysis between phenotype and genotype, possible causes of dominance, and an example involving wrinkled peas. (MDH)

  18. Molecular characterization of the human delta-aminolevulinate dehydratase 2 (ALAD2) allele: implications for molecular screening of individuals for genetic susceptibility to lead poisoning.

    PubMed Central

    Wetmur, J G; Kaya, A H; Plewinska, M; Desnick, R J

    1991-01-01

    The second enzyme in the heme biosynthetic pathway, delta-aminolevulinate dehydratase (ALAD), is a homooctameric protein encoded by a gene localized to human chromosome 9q34. Expression of the two common alleles, ALAD1 (p = .9) and ALAD2 (q = .1), results in a polymorphic enzyme system with three distinct charge isozymes, designated 1-1, 1-2, and 2-2. Individuals heterozygous (2pq = .18) or homozygous (q2 = .01) for the ALAD2 allele have significantly higher blood lead levels than do ALAD1 homozygotes, when exposed to low or high levels of lead in the environment. To investigate the molecular nature of this common polymorphism, total RNA from an ALAD2 homozygote was oligo-dT primed and reverse transcribed, and then the ALAD2 cDNA was amplified, subcloned, and sequenced. Compared with the ALAD1 sequence, the only difference in the ALAD2 cDNA was a G-to-C transversion of nucleotide 177 in the coding region, which created an MspI restriction site. This base substitution predicted the replacement of a positively charged lysine by a neutral asparagine (K59N), an amino acid change consistent with the more electronegative charge of the ALAD-2 subunit. The ALAD1 and ALAD2 alleles were easily detected by amplification of a 916-bp region of genomic DNA and MspI digestion which results in 582- and 511-bp products, respectively. Molecular analysis of 85 ALAD1/ALAD2 heterozygotes and of eight ALAD2 homozygotes revealed no discrepancy between the predicted genotype and the erythrocyte isozyme phenotype, indicating that all the ALAD2 alleles analyzed had the G-to-C transversion.(ABSTRACT TRUNCATED AT 250 WORDS) Images Figure 2 PMID:1716854

  19. Choreography of Ig allelic exclusion.

    PubMed

    Cedar, Howard; Bergman, Yehudit

    2008-06-01

    Allelic exclusion guarantees that each B or T cell only produces a single antigen receptor, and in this way contributes to immune diversity. This process is actually initiated in the early embryo when the immune receptor loci become asynchronously replicating in a stochastic manner with one early and one late allele in each cell. This distinct differential replication timing feature then serves an instructive mark that directs a series of allele-specific epigenetic events in the immune system, including programmed histone modification, nuclear localization and DNA demethylation that ultimately bring about preferred rearrangement on a single allele, and this decision is temporally stabilized by feedback mechanisms that inhibit recombination on the second allele. In principle, these same molecular components are also used for controlling monoallelic expression at other genomic loci, such as those carrying interleukins and olfactory receptor genes that require the choice of one gene out of a large array. Thus, allelic exclusion appears to represent a general epigenetic phenomenon that is modeled on the same basis as X chromosome inactivation.

  20. Preproghrelin gene polymorphisms in obese Japanese women. Minor homozygotes are light eaters, do not prefer protein or fat, and apparently have a poor appetite.

    PubMed

    Takezawa, Jun; Yamada, Kouichi; Miyachi, Motohiko; Morita, Akemi; Aiba, Naomi; Sasaki, Satoshi; Watanabe, Shaw

    2013-04-01

    Preproghrelin gene single-nucleotide polymorphisms are possible predisposing factors to obesity and other metabolic syndromes. To study the correlation between genotypes and obesity, we recruited 117 obese Japanese women (BMI, 25.0-41.1; average, 31.1). Minor homozygotes for five preproghrelin gene polymorphisms, namely, -1500C>G (rs3755777), -1062G>C (rs26311), -994C>T (rs26312) (promoter region), Leu72Met (rs696217) (exon 2), and +3056T>C (rs2075356) (intron 2), had high values of total and visceral fat areas, waist circumference, and BMI, indicating significant correlation of the polymorphisms with obesity and fat metabolism. Here, we studied the relationship between the genotypes and dietary tendency. Self-administered Diet History Questionnaire showed that total food intake, sugar, and dairy product intake were low in +3056C/C women. Their energy, protein, fat, and meat intake was also low. Energy balance calculation showed considerably reduced fat and protein consumption. Dietary habits were surveyed using Sakata's Questionnaire on Eating Behavior. Of the genotypes, -1062C/C women showed low scores for "motivation for eating" and "eating because of stress or something else." Thus, surprisingly, it was revealed that minor homozygotes for preproghrelin gene polymorphisms were light eaters, did not prefer fat or protein, and apparently had a poor appetite, although they were predisposed to obesity.

  1. Serotonin transporter gene polymorphisms and treatment-resistant depression.

    PubMed

    Bonvicini, Cristian; Minelli, Alessandra; Scassellati, Catia; Bortolomasi, Marco; Segala, Matilde; Sartori, Riccardo; Giacopuzzi, Mario; Gennarelli, Massimo

    2010-08-16

    Major Depression Disorder (MDD) is a serious mental illness that is one of the most disabling diseases worldwide. In addition, approximately 15% of depression patients are defined treatment-resistant (TRD). Preclinical and genetic studies show that serotonin modulation dysfunction exists in patients with TRD. Some polymorphisms in the promoter region of the serotonin transporter gene (SLC6A4) are likely to be involved in the pathogenesis/treatment of MDD; however, no data are available concerning TRD. Therefore, in order to investigate the possible influence of SLC6A4 polymorphisms on the risk of TRD, we genotyped 310 DSM-IV MDD treatment-resistant patients and 284 healthy volunteers. We analysed the most studied polymorphism 5-HTTLPR (L/S) and a single nucleotide substitution, rs25531 (A/G), in relation to different functional haplotype combinations. However the correct mapping of rs25531 is still debated whether it is within or outside the insertion. Our sequencing analysis showed that rs25531 is immediately outside of the 5-HTTLPR segment. Differences in 5-HTTLPR allele (p=0.04) and in L allele carriers (p<0.05) were observed between the two groups. Concerning the estimated haplotype analyses, L(A)L(A) homozygote haplotype was more represented among the control subjects (p=0.01, OR=0.64 95%CI: 0.45-0.91). In conclusion, this study reports a protective effect of the L(A)L(A) haplotype on TRD, supporting the hypothesis that lower serotonin transporter transcription alleles are correlated to a common resistant depression mechanism.

  2. Cytochrome P450 CYP2D6 genotypes: association with hair colour, Breslow thickness and melanocyte stimulating hormone receptor alleles in patients with malignant melanoma.

    PubMed

    Strange, R C; Ellison, T; Ichii-Jones, F; Bath, J; Hoban, P; Lear, J T; Smith, A G; Hutchinson, P E; Osborne, J; Bowers, B; Jones, P W; Fryer, A A

    1999-06-01

    We previously identified associations between polymorphism in the cytochrome P450 CYP2D6 gene and outcome in several cancers. We have now examined the hypothesis that homozygosity for the mutant alleles, CYP2D6*4 and CYP2D6*3, is associated with susceptibility and outcome in malignant melanoma. Outcome was assessed by Breslow thickness. We first confirmed previous reports that these mutant alleles are associated with increased susceptibility to malignant melanoma. For example, the frequency of homozygosity for CYP2D6*4 was significantly greater (P = 0.006, chi-squared 1 d.f. = 7.4, odds ratio 2.2, 95% confidence interval 1.2, 3.9) in cases (9.1%) than in control individuals (4.3%). The frequency of homozygosity for the mutant alleles was next examined in the malignant melanoma cases grouped on the basis of characteristics associated with malignant melanoma risk. Homozygosity was significantly more common (P = 0.038) in cases with red/blonde hair than in those with brown/black hair. We found no associations between the CYP2D6 genotype and sex, skin type or eye colour. The possible association of CYP2D6 with outcome was assessed by comparing genotype frequencies in patients with tumours of Breslow thickness < 1.5 mm with those whose tumours were > or = 1.5 mm. In patients with red/blonde, but not brown or black hair, homozygosity for CYP2D6*4 was significantly associated with thicker lesions in a multivariate model (P = 0.036). We further examined the association of CYP2D6*4 homozygosity with red/blonde hair by classifying patients on the basis of homo- or heterozygosity for wild-type or val92met, asp294his or asp84glu melanocyte stimulating hormone receptor (MC1R) alleles. None of the nine patients with brown/black hair with the asp294his allele were homozygotes for CYP2D6*4. By contrast, in the patients with red/blonde hair, three of five cases with asp294his were homozygotes for the mutant CYP2D6 allele. The difference in the frequency of CYP2D6*4 homozygotes in

  3. Recurrent Muscle Weakness with Rhabdomyolysis, Metabolic Crises, and Cardiac Arrhythmia Due to Bi-allelic TANGO2 Mutations

    PubMed Central

    Lalani, Seema R.; Liu, Pengfei; Rosenfeld, Jill A.; Watkin, Levi B.; Chiang, Theodore; Leduc, Magalie S.; Zhu, Wenmiao; Ding, Yan; Pan, Shujuan; Vetrini, Francesco; Miyake, Christina Y.; Shinawi, Marwan; Gambin, Tomasz; Eldomery, Mohammad K.; Akdemir, Zeynep Hande Coban; Emrick, Lisa; Wilnai, Yael; Schelley, Susan; Koenig, Mary Kay; Memon, Nada; Farach, Laura S.; Coe, Bradley P.; Azamian, Mahshid; Hernandez, Patricia; Zapata, Gladys; Jhangiani, Shalini N.; Muzny, Donna M.; Lotze, Timothy; Clark, Gary; Wilfong, Angus; Northrup, Hope; Adesina, Adekunle; Bacino, Carlos A.; Scaglia, Fernando; Bonnen, Penelope E.; Crosson, Jane; Duis, Jessica; Maegawa, Gustavo H.B.; Coman, David; Inwood, Anita; McGill, Jim; Boerwinkle, Eric; Graham, Brett; Beaudet, Art; Eng, Christine M.; Hanchard, Neil A.; Xia, Fan; Orange, Jordan S.; Gibbs, Richard A.; Lupski, James R.; Yang, Yaping

    2016-01-01

    The underlying genetic etiology of rhabdomyolysis remains elusive in a significant fraction of individuals presenting with recurrent metabolic crises and muscle weakness. Using exome sequencing, we identified bi-allelic mutations in TANGO2 encoding transport and Golgi organization 2 homolog (Drosophila) in 12 subjects with episodic rhabdomyolysis, hypoglycemia, hyperammonemia, and susceptibility to life-threatening cardiac tachyarrhythmias. A recurrent homozygous c.460G>A (p.Gly154Arg) mutation was found in four unrelated individuals of Hispanic/Latino origin, and a homozygous ∼34 kb deletion affecting exons 3–9 was observed in two families of European ancestry. One individual of mixed Hispanic/European descent was found to be compound heterozygous for c.460G>A (p.Gly154Arg) and the deletion of exons 3–9. Additionally, a homozygous exons 4–6 deletion was identified in a consanguineous Middle Eastern Arab family. No homozygotes have been reported for these changes in control databases. Fibroblasts derived from a subject with the recurrent c.460G>A (p.Gly154Arg) mutation showed evidence of increased endoplasmic reticulum stress and a reduction in Golgi volume density in comparison to control. Our results show that the c.460G>A (p.Gly154Arg) mutation and the exons 3–9 heterozygous deletion in TANGO2 are recurrent pathogenic alleles present in the Latino/Hispanic and European populations, respectively, causing considerable morbidity in the homozygotes in these populations. PMID:26805781

  4. Identification of null alleles and deletions from SNP genotypes for an intercross between domestic and wild chickens.

    PubMed

    Crooks, Lucy; Carlborg, Örjan; Marklund, Stefan; Johansson, Anna M

    2013-08-07

    We analyzed genotypes from ~10K single-nucleotide polymorphisms (SNPs) in two families of an F2 intercross between Red Junglefowl and White Leghorn chickens. Possible null alleles were found by patterns of incompatible and missing genotypes. We estimated that 2.6% of SNPs had null alleles compared with 2.3% with genotyping errors and that 40% of SNPs in which a parent and offspring were genotyped as different homozygotes had null alleles. Putative deletions were identified by null alleles at adjacent markers. We found two candidate deletions that were supported by fluorescence intensity data from a 60K SNP chip. One of the candidate deletions was from the Red Junglefowl, and one was present in both the Red Junglefowl and White Leghorn. Both candidate deletions spanned protein-coding regions and were close to a previously detected quantitative trait locus affecting body weight in this population. This study demonstrates that the ~50K SNP genotyping arrays now available for several agricultural species can be used to identify null alleles and deletions in data from large families. We suggest that our approach could be a useful complement to linkage analysis in experimental crosses.

  5. A silent allele in the locus D5S818 contained within the PowerPlex®21 PCR Amplification Kit.

    PubMed

    Chen, Ling; Tai, Yunchun; Qiu, Pingming; Du, Weian; Liu, Chao

    2015-11-01

    Three paternity tests cases were found with a single locus mismatch at the locus D5S818 with PowerPlex®21 PCR Amplification Kit (Promega). Forward and reverse primers were redesigned to type the samples again and to evaluate if there were alleles dropped out. The results showed the existence of a silent allele 12 in all the three families, due to a point mutation that changed cytosine to adenine at 90 nucleotides upstream from the 5' end of the AGAT repeat sequences in all the six individuals. A single locus mismatch due to a silent allele may occur in any locus using any kit. Therefore, we recommend using multiple kits to confirm the results in paternity testing cases with mismatches, especially when there is a single locus mismatch with homozygote involved.

  6. A maximum-likelihood method to correct for allelic dropout in microsatellite data with no replicate genotypes.

    PubMed

    Wang, Chaolong; Schroeder, Kari B; Rosenberg, Noah A

    2012-10-01

    Allelic dropout is a commonly observed source of missing data in microsatellite genotypes, in which one or both allelic copies at a locus fail to be amplified by the polymerase chain reaction. Especially for samples with poor DNA quality, this problem causes a downward bias in estimates of observed heterozygosity and an upward bias in estimates of inbreeding, owing to mistaken classifications of heterozygotes as homozygotes when one of the two copies drops out. One general approach for avoiding allelic dropout involves repeated genotyping of homozygous loci to minimize the effects of experimental error. Existing computational alternatives often require replicate genotyping as well. These approaches, however, are costly and are suitable only when enough DNA is available for repeated genotyping. In this study, we propose a maximum-likelihood approach together with an expectation-maximization algorithm to jointly estimate allelic dropout rates and allele frequencies when only one set of nonreplicated genotypes is available. Our method considers estimates of allelic dropout caused by both sample-specific factors and locus-specific factors, and it allows for deviation from Hardy-Weinberg equilibrium owing to inbreeding. Using the estimated parameters, we correct the bias in the estimation of observed heterozygosity through the use of multiple imputations of alleles in cases where dropout might have occurred. With simulated data, we show that our method can (1) effectively reproduce patterns of missing data and heterozygosity observed in real data; (2) correctly estimate model parameters, including sample-specific dropout rates, locus-specific dropout rates, and the inbreeding coefficient; and (3) successfully correct the downward bias in estimating the observed heterozygosity. We find that our method is fairly robust to violations of model assumptions caused by population structure and by genotyping errors from sources other than allelic dropout. Because the data sets

  7. Cerebellar microfolia and other abnormalities of neuronal growth, migration, and lamination in the Pit1dw-J homozygote mutant mouse

    NASA Technical Reports Server (NTRS)

    Sekiguchi, M.; Abe, H.; Moriya, M.; Tanaka, O.; Nowakowski, R. S.

    1998-01-01

    The Snell dwarf mouse (Pit1dw-J homozygote) has a mutation in the Pit1 gene that prevents the normal formation of the anterior pituitary. In neonates and adults there is almost complete absence of growth hormone (GH), prolactin (PRL), thyroxin (T4), and thyroid-stimulating hormone (TSH). Since these hormones have been suggested to play a role in normal development of the central nervous system (CNS), we have investigated the effects of the Pit1dw-J mutation on the cerebellum and hippocampal formation. In the cerebellum, there were abnormalities of both foliation and lamination. The major foliation anomalies were 1) changes in the relative size of specific folia and also the proportional sizes of the anterior vs posterior cerebellum; and 2) the presence of between one and three microfolia per half cerebellum. The microfolia were all in the medial portion of the hemisphere in the caudal part of the cerebellum. Each microfolium was just rostral to a normal fissure and interposed between the fissure and a normal gyrus. Lamination abnormalities included an increase in the number of single ectopic granule cells in the molecular layer in both cerebellar vermis (86%) and hemisphere (40%) in comparison with the wild-type mouse. In the hippocampus of the Pit1dw-J homozygote mouse, the number of pyramidal cells was decreased, although the width of the pyramidal cell layer throughout areas CA1-CA3 appeared to be normal, but less densely populated than in the wild-type mouse. Moreover, the number of granule cells that form the granule cell layer was decreased from the wild-type mouse and some ectopic granule cells (occurring both as single cells and as small clusters) were observed in the innermost portion of the molecular layer. The abnormalities observed in the Pit1dw-J homozygote mouse seem to be caused by both direct and indirect effects of the deficiency of TSH (or T4), PRL, or GH rather than by a direct effect of the deletion of Pit1.

  8. Distribution of the HIV resistance CCR5-Delta32 allele among Egyptians and Syrians.

    PubMed

    Salem, Abdel-Halim; Batzer, Mark A

    2007-03-01

    A mutant allele of the beta-chemokine receptor gene CCR5 bearing a 32-basepair (bp) deletion that prevents cell invasion by the primary transmitting strain of HIV-1 has recently been characterized. Individuals homozygous for the mutation are resistant to infection, even after repeated high-risk exposure, but this resistance appears not absolute, as isolated cases of HIV-positive deletion homozygotes are emerging. The consequence of the heterozygous state is not clear, but it may delay the progression to AIDS in infected individuals. In order to evaluate the frequency distribution of CCR5-Delta32 polymorphism among Egyptians, a total of 200 individuals (154 from Ismailia and 46 from Sinai) were tested. Only two heterozygous individuals from Ismailia carried the CCR5-Delta32 allele (0.6%), and no homozygous (Delta32/Delta32) individuals were detected among the tested samples. The presence of the CCR5-Delta32 allele among Egyptians may be attributed to the admixture with people of European descent. Thus we conclude that the protective deletion CCR5-Delta32 is largely absent in the Egyptian population.

  9. [Association of allelic polymorphisms of genes matrix Gla-protein system with ischemic atherothrombotic stroke].

    PubMed

    Garbuzova, V Yu; Stroy, D A; Dosenko, V E; Dubovyk, Ye I; Borodenko, A O; Shimko, K A; Obukhova, O A; Ataman, O V

    2015-01-01

    There are results of the determination of 10 polymorphisms of matrix Gla-protein system (gene MGP-T(-138)-->C (rs1800802), G(-7)-->A (rs1800801), Thr83-->Ala (rs4236), gene VDR-FokI (rs2228570), BsmI (rs1544410), ApaI (rs7975232), TaqI (rs731236), gene GGCX-Arg325-->Gln (rs699664), gene VKORS1-T(2255)-->C (rs2359612), gene BMP-2-Ser37-->Ala (rs2273073)) into 170 patients with ischemic atherothrombotic stroke (IATS) and 124 healthy individual is (control group). It is established that there is a connection between the IATS and polymorphic variants of genes MGP (G(-7)-->A) and VKORC1 (T(2255)-->C). The risk of IATS in carriers of minor allele A/A (G(-7)-->A polymorphism) in 2.6 times higher than in carriers of the major allele (G/A + G/G), and C/C genotype (T(2255)-->C polymorphism) in 2.2 times higher than the homozygotes of major allele. The coincidence of patients T/C and G/G, C/C and G/A genotypes, and A/A genotype (G(-7)-->A polymorphism) with any genotype T(2255)-->C polymorphism are increases the risk of IATS.

  10. Neonatal screening for hereditary fructose intolerance: frequency of the most common mutant aldolase B allele (A149P) in the British population.

    PubMed

    James, C L; Rellos, P; Ali, M; Heeley, A F; Cox, T M

    1996-10-01

    Hereditary fructose intolerance (HFI) causes severe and sometimes fatal metabolic disturbances in infants and children but responds to dietary treatment. To determine the practicability of screening newborn infants for HFI, we have investigated the frequency of the most common and widespread mutant allele of aldolase B, A149P, in the neonatal population. The polymerase chain reaction was used to amplify aldolase B exon 5 genomic sequences in DNA present in dried blood specimens preserved on Guthrie cards. The A149P mutation was identified by discriminatory hybridisation to allele specific oligonucleotides and confirmed independently by digestion with the restriction endonuclease BsaHI. Twenty-seven A149P heterozygotes were identified by the molecular analysis of aldolase B genes in blood samples obtained from a random cohort of 2050 subjects born in 1994 and 1995, 1.32 +/- 0.49% (95% confidence level). Although no A149P homozygotes were identified, the data allow the frequency of 1 in 23,000 homozygotes for this allele to be predicted. Our findings have implications for establishing an interventional mass screening programme to identify newborn infants with HFI in the UK.

  11. Risk Factors for Insulin Resistance, Metabolic Syndrome, and Diabetes in 248 HFE C282Y Homozygotes Identified by Population Screening in the HEIRS Study

    PubMed Central

    Barton, J. Clayborn; Adams, Paul C.; Acton, Ronald T.

    2016-01-01

    Abstract Background: We sought to identify risk factors for insulin resistance, metabolic syndrome (MetS), and diabetes mellitus in 248 non-Hispanic white HFE C282Y homozygotes identified by population screening. Methods: We analyzed observations obtained prospectively in a postscreening examination: age; sex; body mass index (BMI); systolic/diastolic blood pressure; metacarpophalangeal (MP) joint hypertrophy; hepatomegaly; complete blood counts; alanine/aspartate aminotransferase levels; elevated C-reactive protein (>0.5 mg/dL); transferrin saturation; serum ferritin; homeostasis model assessment-insulin resistance (HOMA-IR); and MetS. Results: Twenty-six participants (10.5%) had diabetes diagnoses. A significant trend across HOMA-IR quartiles was observed only for blood neutrophils. Logistic regression on HOMA-IR fourth quartile revealed positive associations: age (P = 0.0002); male sex (P = 0.0022); and BMI (P < 0.0001). HOMA-IR fourth quartile predicted MetS (P < 0.0001). Logistic regression on diabetes revealed positive associations: age (P = 0.0012); male sex (P = 0.0068); MP joint hypertrophy (P = 0.0167); neutrophils (P = 0.0342); and MetS (P = 0.0298). Serum ferritin did not predict HOMA-IR fourth quartile, MetS, or diabetes. Conclusions: In screening C282Y homozygotes, age, male sex, and BMI predicted HOMA-IR fourth quartile. HOMA-IR fourth quartile alone predicted MetS. Diabetes was associated with greater age, male sex, MP joint hypertrophy, greater blood neutrophil counts, and MetS. PMID:26771691

  12. Interplay between stress response genes associated with attention-deficit hyperactivity disorder and brain volume.

    PubMed

    van der Meer, D; Hoekstra, P J; Bralten, J; van Donkelaar, M; Heslenfeld, D J; Oosterlaan, J; Faraone, S V; Franke, B; Buitelaar, J K; Hartman, C A

    2016-09-01

    The glucocorticoid receptor plays a pivotal role in the brain's response to stress; a haplotype of functional polymorphisms in the NR3C1 gene encoding this receptor has been associated with attention-deficit hyperactivity disorder (ADHD). The serotonin transporter (5-HTT) gene polymorphism 5-HTTLPR is known to influence the relation between stress exposure and ADHD severity, which may be partly because of its reported effects on glucocorticoid levels. We therefore investigated if NR3C1 moderates the relation of stress exposure with ADHD severity and brain structure, and the potential role of 5-HTTLPR. Neuroimaging, genetic and stress exposure questionnaire data were available for 539 adolescents and young adults participating in the multicenter ADHD cohort study NeuroIMAGE (average age: 17.2 years). We estimated the effects of genetic variation in NR3C1 and 5-HTT, stress exposure and their interactions on ADHD symptom count and gray matter volume. We found that individuals carrying the ADHD risk haplotype of NR3C1 showed significantly more positive relation between stress exposure and ADHD severity than non-carriers. This gene-environment interaction was significantly stronger for 5-HTTLPR L-allele homozygotes than for S-allele carriers. These two- and three-way interactions were reflected in the gray matter volume of the cerebellum, parahippocampal gyrus, intracalcarine cortex and angular gyrus. Our findings illustrate how genetic variation in the stress response pathway may influence the effects of stress exposure on ADHD severity and brain structure. The reported interplay between NR3C1 and 5-HTT may further explain some of the heterogeneity between studies regarding the role of these genes and hypothalamic-pituitary-adrenal axis activity in ADHD.

  13. Variation in key genes of serotonin and norepinephrine function predicts gamma-band activity during goal-directed attention.

    PubMed

    Enge, Sören; Fleischhauer, Monika; Lesch, Klaus-Peter; Reif, Andreas; Strobel, Alexander

    2014-05-01

    Recent evidence shows that genetic variations in key regulators of serotonergic (5-HT) signaling explain variance in executive tasks, which suggests modulatory actions of 5-HT on goal-directed selective attention as one possible underlying mechanism. To investigate this link, 130 volunteers were genotyped for the 5-HT transporter gene-linked polymorphic region (5-HTTLPR) and for a variation (TPH2-703 G/T) of the TPH2 gene coding for the rate-limiting enzyme of 5-HT synthesis in the brain. Additionally, a functional polymorphism of the norepinephrine transporter gene (NET -3081 A/T) was considered, which was recently found to predict attention and working memory processes in interaction with serotonergic genes. The flanker-based Attention Network Test was used to assess goal-directed attention and the efficiency of attentional networks. Event-related gamma-band activity served to indicate selective attention at the intermediate phenotype level. The main findings were that 5-HTTLPR s allele and TPH2 G-allele homozygotes showed increased induced gamma-band activity during target processing when combined with the NET A/A genotype compared with other genotype combinations, and that gamma activity mediates the genotype-specific effects on task performance. The results further support a modulatory role of 5-HT and NE function in the top-down attentional selection of motivationally relevant over competing or irrelevant sensory input.

  14. Effects of the Serotonin Transporter Polymorphism and History of Major Depression on Overgeneral Autobiographical Memory

    PubMed Central

    Sumner, Jennifer A.; Vrshek-Schallhorn, Suzanne; Mineka, Susan; Zinbarg, Richard E.; Craske, Michelle G.; Redei, Eva E.; Wolitzky-Taylor, Kate; Adam, Emma K.

    2013-01-01

    Overgeneral autobiographical memory (OGM) is a key memory deficit in major depressive disorder (MDD). Much research has examined cognitive mechanisms underlying OGM, but little work has investigated potential neurobiological influences. There is preliminary evidence that a genetic serotonergic vulnerability coupled with depressive symptoms may be associated with other memory impairments, and experimental research suggests a role for serotonin in OGM. We investigated whether a polymorphism in the promoter region of the serotonin transporter gene (5-HTTLPR) was associated with OGM in interaction with a lifetime history of MDD in 370 young adults in a longitudinal study of risk for emotional disorders. There was a significant interaction between 5-HTTLPR genotype and lifetime history of MDD in predicting OGM. Among S allele homozygotes, MDD history was associated with greater OGM, whereas no significant relationship between MDD history and OGM emerged among L carriers. Furthermore, there was evidence that a greater number of S alleles was associated with greater memory specificity in individuals without a history of MDD. Implications for understanding cognitive and biological risk for depression are discussed. PMID:24341893

  15. Effects of the serotonin transporter polymorphism and history of major depression on overgeneral autobiographical memory.

    PubMed

    Sumner, Jennifer A; Vrshek-Schallhorn, Suzanne; Mineka, Susan; Zinbarg, Richard E; Craske, Michelle G; Redei, Eva E; Wolitzky-Taylor, Kate; Adam, Emma K

    2014-01-01

    Overgeneral autobiographical memory (OGM) is a key memory deficit in major depressive disorder (MDD). Much research has examined cognitive mechanisms underlying OGM, but little work has investigated potential neurobiological influences. There is preliminary evidence that a genetic serotonergic vulnerability coupled with depressive symptoms may be associated with other memory impairments, and experimental research suggests a role for serotonin in OGM. We investigated whether a polymorphism in the promoter region of the serotonin transporter gene (5-HTTLPR) was associated with OGM in interaction with a lifetime history of MDD in 370 young adults in a longitudinal study of risk for emotional disorders. There was a significant interaction between 5-HTTLPR genotype and lifetime history of MDD in predicting OGM. Among S allele homozygotes, MDD history was associated with greater OGM, whereas no significant relationship between MDD history and OGM emerged among L carriers. Furthermore, there was evidence that a greater number of S alleles were associated with greater memory specificity in individuals without a history of MDD. Implications for understanding cognitive and biological risk for depression are discussed.

  16. Link-Polymorphism of 5-HTT Promoter Region Is Associated with Autoantibodies in Patients with Systemic Lupus Erythematosus

    PubMed Central

    Li, Shu; Chen, Fan; Cheng, Yuqi; Lai, Aiyun; Lu, Zhaoping

    2016-01-01

    Serotonin transporter linked polymorphic region (5-HTTLPR) was reported to associate with depression in systemic lupus erythematosus (SLE) patients by our team. To explore whether 5-HTTLPR plays a role in the pathogenesis of SLE, we tested 138 SLE patients and 138 age and sex matched health controls (HCs) for 5-HTTLPR by polymerase chain reaction (PCR) and agarose gel electrophoresis. Interestingly, the results suggest that the frequencies of SS genotype and S allele in SLE patients with positive anti-Sm antibody and anti-U1RNP antibody were both significantly higher than the other genotypes and alleles. However, the frequencies of 5-HTTLPR genotypes and alleles were of no significant difference between SLE patients and HCs. This suggested that 5-HTTLPR was not a high-risk susceptible gene in SLE but might relate to SLE by affecting production of some autoantibodies, especially anti-Sm and anti-U1RNP antibody. PMID:27819008

  17. Molecular lesions associated with alleles of decapentaplegic identify residues necessary for TGF/{beta}/BMP cell signaling in Drosophila melanogaster

    SciTech Connect

    Wharton, K.; Ray, R.P.; Gelbart, W.M.

    1996-02-01

    We have identified the molecular lesions associated with six point mutations in the Drosophila TGF-{beta} homologue decapentaplegic (dpp). The sites of these mutations define residues within both the pro and ligand regions that are essential for dpp function in vivo. While all of these mutations affect residues that are highly conserved among TGF-{beta} superfamily members, the phenotypic consequences of the different alleles are quite distinct. Through an analysis of these mutant phenotypes, both in cuticle preparations and with molecular probes, we have assessed the functional significance of specific residues that are conserved among the different members of the superfamily. In addition, we have tested for conditional genetic interactions between the different alleles. We show that two of the alleles are temperature sensitive for the embryonic functions of dpp, such that these alleles are not only embryonic viable as homozygotes but also partially complement other dpp hypomorphs at low temperatures. Our results are discussed with regard to in vitro mutagenesis data on other TGF-{beta}-like molecules, as well as with regard to the regulation of dpp cell signaling in Drosophila. 57 refs., 4 figs., 3 tabs.

  18. Expansion of the Parkinson disease-associated SNCA-Rep1 allele upregulates human alpha-synuclein in transgenic mouse brain.

    PubMed

    Cronin, Kenneth D; Ge, Dongliang; Manninger, Paul; Linnertz, Colton; Rossoshek, Anna; Orrison, Bonnie M; Bernard, David J; El-Agnaf, Omar M A; Schlossmacher, Michael G; Nussbaum, Robert L; Chiba-Falek, Ornit

    2009-09-01

    Alpha-synuclein (SNCA) gene has been implicated in the development of rare forms of familial Parkinson disease (PD). Recently, it was shown that an increase in SNCA copy numbers leads to elevated levels of wild-type SNCA-mRNA and protein and is sufficient to cause early-onset, familial PD. A critical question concerning the molecular pathogenesis of PD is what contributory role, if any, is played by the SNCA gene in sporadic PD. The expansion of SNCA-Rep1, an upstream, polymorphic microsatellite of the SNCA gene, is associated with elevated risk for sporadic PD. However, whether SNCA-Rep1 is the causal variant and the underlying mechanism with which its effect is mediated by remained elusive. We report here the effects of three distinct SNCA-Rep1 variants in the brains of 72 mice transgenic for the entire human SNCA locus. Human SNCA-mRNA and protein levels were increased 1.7- and 1.25-fold, respectively, in homozygotes for the expanded, PD risk-conferring allele compared with homozygotes for the shorter, protective allele. When adjusting for the total SNCA-protein concentration (endogenous mouse and transgenic human) expressed in each brain, the expanded risk allele contributed 2.6-fold more to the SNCA steady-state than the shorter allele. Furthermore, targeted deletion of Rep1 resulted in the lowest human SNCA-mRNA and protein concentrations in murine brain. In contrast, the Rep1 effect was not observed in blood lysates from the same mice. These results demonstrate that Rep1 regulates human SNCA expression by enhancing its transcription in the adult nervous system and suggest that homozygosity for the expanded Rep1 allele may mimic locus multiplication, thereby elevating PD risk.

  19. More than one mutant allele causes infantile Tay-Sachs disease in French-Canadians

    PubMed Central

    Hechtman, Peter; Kaplan, Feige; Bayleran, Janet; Boulay, Bernard; Andermann, Eva; de Braekeleer, Marc; Melançon, Serge; Lambert, Marie; Potier, Michel; Gagné, Richard; Kolodny, Edwin; Clow, Carol; Capua, Aniceta; Prevost, Claude; Scriver, Charles

    1990-01-01

    Two Tay-Sachs disease (TSD) patients of French-Canadian origin were shown by Myerowitz and Hogikyan to be homozygous for a 7.6-kb deletion mutation at the 5' end of the hexosaminidase A α-subunit gene. In order to determine whether all French-Canadian TSD patients were homozygotes for the deletion allele and to assess the geographic origins of TSD in this population, we ascertained 12 TSD families of French-Canadian origin and screened for occurrence of mutations associated with infantile TSD. DNA samples were obtained from 12 French-Canadian TSD families. Samples were analyzed using polymerase-chain-reaction (PCR) amplification followed by hybridization to allele-specific oligonucleotides (ASO) or by restriction analysis of PCR products. In some cases Southern analysis of genomic DNA was performed. Eighteen of the 22 independently segregating mutant chromosomes in this sample carried the 7.6-kb deletion mutation at the 5' end of the gene. One chromosome carried the 4-nucleotide insertion in exon 11 (a “Jewish” mutation). In this population no individuals were detected who had the substitution at the splice junction of exon 12 previously identified in Ashkenazi Jews. One chromosome carried an undescribed B1 mutation; this allele came from a parent of non-French-Canadian origin. Patients in three families carried TSD alleles different from any of the above mutations. The 5' deletion mutation clusters in persons originating in southeastern Quebec (Gaspé) and adjacent counties of northern New Brunswick. ImagesFigure 3Figure 4Figure 5Figure 6 PMID:2220821

  20. The genetic basis of asymptomatic codon 8 frame-shift (HBB:c25_26delAA) β(0) -thalassaemia homozygotes.

    PubMed

    Jiang, Zhihua; Luo, Hong-Yuan; Huang, Shengwen; Farrell, John J; Davis, Lance; Théberge, Roger; Benson, Katherine A; Riolueang, Suchada; Viprakasit, Vip; Al-Allawi, Nasir A S; Ünal, Sule; Gümrük, Fatma; Akar, Nejat; Başak, A Nazli; Osorio, Leonor; Badens, Catherine; Pissard, Serge; Joly, Philippe; Campbell, Andrew D; Gallagher, Patrick G; Steinberg, Martin H; Forget, Bernard G; Chui, David H K

    2016-03-01

    Two 21-year old dizygotic twin men of Iraqi descent were homozygous for HBB codon 8, deletion of two nucleotides (-AA) frame-shift β(0) -thalassaemia mutation (FSC8; HBB:c25_26delAA). Both were clinically well, had splenomegaly, and were never transfused. They had mild microcytic anaemia (Hb 120-130 g/l) and 98% of their haemoglobin was fetal haemoglobin (HbF). Both were carriers of Hph α-thalassaemia mutation. On the three major HbF quantitative trait loci (QTL), the twins were homozygous for G>A HBG2 Xmn1 site at single nucleotide polymorphism (SNP) rs7482144, homozygous for 3-bp deletion HBS1L-MYB intergenic polymorphism (HMIP) at rs66650371, and heterozygous for the A>C BCL11A intron 2 polymorphism at rs766432. These findings were compared with those found in 22 other FSC8 homozygote patients: four presented with thalassaemia intermedia phenotype, and 18 were transfusion dependent. The inheritance of homozygosity for HMIP 3-bp deletion at rs66650371 and heterozygosity for Hph α-thalassaemia mutation was found in the twins and not found in any of the other 22 patients. Further studies are needed to uncover likely additional genetic variants that could contribute to the exceptionally high HbF levels and mild phenotype in these twins.

  1. White matter alterations related to attention-deficit hyperactivity disorder and COMT val158met polymorphism: children with valine homozygote attention-deficit hyperactivity disorder have altered white matter connectivity in the right cingulum (cingulate gyrus)

    PubMed Central

    Kabukcu Basay, Burge; Buber, Ahmet; Basay, Omer; Alacam, Huseyin; Ozturk, Onder; Suren, Serkan; Izci Ay, Ozlem; Acikel, Cengizhan; Agladıoglu, Kadir; Erdal, Mehmet Emin; Ercan, Eyup Sabri; Herken, Hasan

    2016-01-01

    Introduction In this article, the COMT gene val158met polymorphism and attention-deficit hyperactivity disorder (ADHD)-related differences in diffusion-tensor-imaging-measured white matter (WM) structure in children with ADHD and controls were investigated. Patients and methods A total of 71 children diagnosed with ADHD and 24 controls aged 8–15 years were recruited. Using diffusion tensor imaging, COMT polymorphism and ADHD-related WM alterations were investigated, and any interaction effect between the COMT polymorphism and ADHD was also examined. The effects of age, sex, and estimated total IQ were controlled by multivariate analysis of covariance (MANCOVA). Results First, an interaction between the COMT val158met polymorphism and ADHD in the right (R) cingulum (cingulate gyrus) (CGC) was found. According to this, valine (val) homozygote ADHD-diagnosed children had significantly lower fractional anisotropy (FA) and higher radial diffusivity (RD) in the R-CGC than ADHD-diagnosed methionine (met) carriers, and val homozygote controls had higher FA and lower RD in the R-CGC than val homozygote ADHD patients. Second, met carriers had higher FA and axial diffusivity in the left (L)-uncinate fasciculus and lower RD in the L-posterior corona radiata and L-posterior thalamic radiation (include optic radiation) than the val homozygotes, independent of ADHD diagnosis. Third, children with ADHD had lower FA in the L-CGC and R-retrolenticular part of the internal capsule than the controls, independent of the COMT polymorphism. Conclusion Significant differences reported here may be evidence that the COMT gene val158met polymorphism variants, as well as ADHD, could affect brain development. ADHD and the COMT polymorphism might be interactively affecting WM development in the R-CGC to alter the WM connectivity in children with val homozygote ADHD. PMID:27143897

  2. Association between the Serotonin Transporter Promoter Polymorphism (5-HTTLPR) and Adult Unresolved Attachment

    ERIC Educational Resources Information Center

    Caspers, Kristin M.; Paradiso, Sergio; Yucuis, Rebecca; Troutman, Beth; Arndt, Stephan; Philibert, Robert

    2009-01-01

    Research on antecedents of organized attachment has focused on the quality of caregiving received during childhood. In recent years, research has begun to examine the influence of genetic factors on quality of infant attachment. However, no published studies report on the association between specific genetic factors and adult attachment. This…

  3. Mutant alleles of small effect are primarily responsible for the loss of fitness with slow inbreeding in Drosophila melanogaster.

    PubMed

    Latter, B D

    1998-03-01

    Multilocus simulation is used to identify genetic models that can account for the observed rates of inbreeding and fitness decline in laboratory populations of Drosophila melanogaster. The experimental populations were maintained under crowded conditions for approximately 200 generations at a harmonic mean population size of Nh approximately 65-70. With a simulated population size of N = 50, and a mean selective disadvantage of homozygotes at individual loci approximately 1-2% or less, it is demonstrated that the mean effective population size over a 200-generation period may be considerably greater than N, with a ratio matching the experimental estimate of Ne/Nh approximately 1.4. The buildup of associative overdominance at electrophoretic marker loci is largely responsible for the stability of gene frequencies and the observed reduction in the rate of inbreeding, with apparent selection coefficients in favor of the heterozygote at neutral marker loci increasing rapidly over the first N generations of inbreeding to values approximately 5-10%. The observed decline in fitness under competitive conditions in populations of size approximately 50 in D. melanogaster therefore primarily results from mutant alleles with mean effects on fitness as homozygotes of sm < or = 0.02. Models with deleterious recessive mutants at the background loci require that the mean selection coefficient against heterozygotes is at most hsm approximately 0.002, with a minimum mutation rate for a single Drosophila autosome 100 cM in length estimated to be in the range 0.05-0.25, assuming an exponential distribution of s. A typical chromosome would be expected to carry at least 100-200 such mutant alleles contributing to the decline in competitive fitness with slow inbreeding.

  4. Mytilus galloprovincialis-type foot-protein-1 alleles occur at low frequency among mussels in the Dutch Wadden Sea

    NASA Astrophysics Data System (ADS)

    Luttikhuizen, Pieternella C.; Koolhaas, Anita; Bol, Anneke; Piersma, Theunis

    2002-11-01

    The presence of M. galloprovincialis-type genes among the population of mussels in the Dutch Wadden Sea, historically described as M. edulis, was assessed. We applied the molecular technique in which a fragment of the gene coding for an adhesive protein of the byssus of mussels is amplified by PCR and assayed for length using electrophoresis. Among 321 individual mussels collected in August-October 2001 at 14 sites (5 intertidal, 9 subtidal) widely dispersed over the Dutch Wadden Sea, 6 specimens (collected at 5 sites) were found that showed a heterozygote genotype with both the M. edulis- and the M. galloprovincialis-type alleles being amplified; all others were identified as homozygotes for the M. edulis-type allele. Differentiation in frequencies of heterozygotes among sites was not detected. The fact that the M. galloprovincialis-type allele was present at low frequency (0.0093) may be attributed to one of three possible, and not mutually exclusive, causes: incomplete diagnosticity of this marker, an historically stable introgression zone in the Wadden Sea, or a recent invasion.

  5. Detecting low frequent loss-of-function alleles in genome wide association studies with red hair color as example.

    PubMed

    Liu, Fan; Struchalin, Maksim V; Duijn, Kate van; Hofman, Albert; Uitterlinden, André G; Duijn, Cornelia van; Aulchenko, Yurii S; Kayser, Manfred

    2011-01-01

    Multiple loss-of-function (LOF) alleles at the same gene may influence a phenotype not only in the homozygote state when alleles are considered individually, but also in the compound heterozygote (CH) state. Such LOF alleles typically have low frequencies and moderate to large effects. Detecting such variants is of interest to the genetics community, and relevant statistical methods for detecting and quantifying their effects are sorely needed. We present a collapsed double heterozygosity (CDH) test to detect the presence of multiple LOF alleles at a gene. When causal SNPs are available, which may be the case in next generation genome sequencing studies, this CDH test has overwhelmingly higher power than single SNP analysis. When causal SNPs are not directly available such as in current GWA settings, we show the CDH test has higher power than standard single SNP analysis if tagging SNPs are in linkage disequilibrium with the underlying causal SNPs to at least a moderate degree (r²>0.1). The test is implemented for genome-wide analysis in the publically available software package GenABEL which is based on a sliding window approach. We provide the proof of principle by conducting a genome-wide CDH analysis of red hair color, a trait known to be influenced by multiple loss-of-function alleles, in a total of 7,732 Dutch individuals with hair color ascertained. The association signals at the MC1R gene locus from CDH were uniformly more significant than traditional GWA analyses (the most significant P for CDH = 3.11×10⁻¹⁴² vs. P for rs258322 = 1.33×10⁻⁶⁶). The CDH test will contribute towards finding rare LOF variants in GWAS and sequencing studies.

  6. A novel measurement of allele discrimination for assessment of allele-specific silencing by RNA interference.

    PubMed

    Takahashi, Masaki; Hohjoh, Hirohiko

    2014-11-01

    Allele-specific silencing by RNA interference (ASP-RNAi) is an atypical RNAi that is capable of discriminating target alleles from non-target alleles, and may be therapeutically useful for specific inhibition of disease-causing alleles without affecting their corresponding normal alleles. However, it is difficult to design and select small interfering RNA (siRNAs) that confer ASP-RNAi. A major problem is that there are few appropriate measures in determining optimal allele-specific siRNAs. Here we show two novel formulas for calculating a new measure of allele-discrimination, named "ASP-score". The formulas and ASP-score allow for an unbiased determination of optimal siRNAs, and may contribute to characterizing such allele-specific siRNAs.

  7. Profil hématologique et nutritionnel du drépanocytaire homozygote SS âgé de 6 à 59 mois à Lubumbashi, République Démocratique du Congo

    PubMed Central

    Shongo, Mick Ya Pongombo; Mukuku, Olivier; Mutombo, Augustin Mulangu; Lubala, Toni Kasole; Ilunga, Paul Makinko; Sombodi, Winnie Umumbu; Wembonyama, Stanislas Okitotsho; Luboya, OscarNumbi

    2015-01-01

    Introduction La drépanocytose est une maladie génétique très polymorphe et la moitié des drépanocytaires homozygotes SS en Afrique meurt avant l’âge de 5 ans. Le but de cette étude est de déterminer les paramètres nutritionnels et hématologiques des jeunes drépanocytaires homozygotes (SS) congolais au cours de la phase stationnaire. Méthodes Nous avons fait à une étude descriptive comparative de deux groupes de patients dont l'un avec 41 sujets drépanocytaires (SS) d’âge moyen de 39,1mois et l'autre, groupe contrôle, avec 82 patients avec hémoglobine AA et d’âge moyen de 35,0 mois. Nous avons eu recours à un automate ABX Micros 60 pour l’évaluation hématologique. Pour l’évaluation nutritionnel nous avons étudiés le poids, la taille, l’âge ainsi que le sexe. Résultats Nous n'avons pas observé de différence significative entre les deux groupes par rapport à l’état nutritionnel (p > 0,05). L'hémogramme des homozygotes SS révèle une anémie chronique avec un taux moyen d'Hémoglobine à 8,33 ± 1,35g/dL. Cette anémie est normocytaire (VGM = 83,86 µm3), et régénérative (réticulocytes = 4,23±4,26%). Conclusion Nos résultats rencontrent ce qui est souvent décrit dans le syndrome drépanocytaire majeur sur les homozygotes SS avec haplotype bantu. PMID:26587126

  8. Allelic selection of human IL-2 gene.

    PubMed

    Matesanz, F; Delgado, C; Fresno, M; Alcina, A

    2000-12-01

    The allelic expression of mouse IL-2 cannot be definitely extrapolated to what might happen in humans. Therefore, we investigated the regulation of allelic expression of the IL-2 gene in non-genetically manipulated human T lymphocytes by following natural allelic polymorphisms. We found a phenotypically silent punctual change in the human IL-2 at position 114 after the first nucleotide of the initiation codon, which represents a dimorphic polymorphism at the first exon of the IL-2 gene. This allowed the study by single-cell PCR of the regulation of the human IL-2 allelic expression in heterozygous CD4(+) T cells, which was found to be tightly controlled monoallelically. These findings may be used as a suitable marker for monitoring the IL-2 allelic contribution to effector activities and in immune responses against different infections or in pathological situations.

  9. Variants of the mannose-binding lectin gene in the Benin population: heterozygosity for the p.G57E allele may confer a selective advantage.

    PubMed

    Dossou-Yovo, Omer Placide; Lapoumeroulie, Claudine; Hauchecorne, Michelle; Zaccaria, Isabelle; Ducrocq, Rolande; Krishnamoorthy, Rajagopal; Rahimy, Mohamed Chérif; Elion, Jacques

    2007-12-01

    Human mannose-binding lectin (MBL) plays an important role in innate immunity. MBL deficiency is associated with mutations in the promoter region and in exon 1 of the MBL2 gene. Such deficiency has been correlated with elevated incidence of infections in infancy and in immunocompromised adults. We determined the distribution profile of the MBL2 gene variants in the general population of Benin (West Africa) and in a vulnerable subset of children with sickle cell disease (SCD) (SS homozygotes). Five hundred forty-two healthy individuals (274 newborns, 268 adults) and 128 patients with SCD (35 newborns, 93 children) were screened for the common variant alleles in the MBL2 secretor haplotype region (exon 1 and promoter). The p.G57E variant allele was the most frequent allele compared to p.G54D (27.5% vs. 1.6%, respectively). The p.R52C allele was not found in this population. There was no difference in allele or genotype frequencies between healthy newborns and newborns with SCD. Alleles associated with MBL deficiency were more frequent in adults than in newborns (69.8% vs. 57.3%, respectively; p = 0.002). This enrichment was exclusively due to an elevated proportion of heterozygotes for the p.G57E allele (47.0% vs. 35.3%, respectively; p = 0.004), supporting a potential selective advantage of this genotype. Our results, compared to those reported in other African countries, support the implication of the MBL2 gene in various major infections in Africa, such as meningitis and tuberculosis in HIV-positive patients.

  10. Variants of the mannose-binding lectin gene in the Benin population: heterozygosity for the p.G57E allele may confer a selective advantage. 2007.

    PubMed

    Dossou-Yovo, Omer Placide; Lapoumeroulie, Claudine; Hauchecorne, Michelle; Zaccaria, Isabelle; Ducrocq, Rolande; Krishnamoorthy, Rajagopal; Rahimy, Mohamed Chérif; Elion, Jacques

    2009-12-01

    Human mannose- binding lectin (MBL) plays an important role in innate immunity. MBL deficiency is associated with mutations in the promoter region and in exon 1 of the MBL2 gene. Such deficiency has been correlated with elevated incidence of infections in infancy and in immunocompromised adults. We determined the distribution profile of the MBL2 gene variants in the general population of Benin (West Africa) and in a vulnerable subset of children with sickle cell disease (SCD) (SS homozygotes). Five hundred forty-two healthy individuals (274 newborns, 268 adults) and 128 patients with SCD (35 newborns, 93 children) were screened for the common variant alleles in the MBL2 secretor haplotype region (exon 1 and promoter). The p.G57E variant allele was the most frequent allele compared to p.G54D (27.5% vs. 1.6%, respectively). The p.R52C allele was not found in this population. There was no difference in allele or genotype frequencies between healthy newborns and newborns with SCD. Alleles associated with MBL deficiency were more frequent in adults than in newborns (69.8% vs. 57.3%, respectively; p=0.002). This enrichment was exclusively due to an elevated proportion of heterozygotes for the p.G57E allele (47.0% vs. 35.3%,respectively; p=0.004), supporting a potential selective advantage of this genotype. Our results, compared to those reported in other African countries, support the implication of the MBL2 gene in various major infections in Africa, such as meningitis and tuberculosis in HIV- positive patients.

  11. Frequencies of 32 base pair deletion of the (Delta 32) allele of the CCR5 HIV-1 co-receptor gene in Caucasians: a comparative analysis.

    PubMed

    Lucotte, Gérard

    2002-05-01

    The CCR5 gene encodes for the co-receptor for the major macrophage-tropics strains of human immunodeficiency virus (HIV-1), and a mutant allele of this gene (Delta 32) provide to homozygotes a strong resistance against infection by HIV. The frequency of the Delta 32 allele was investigated in 40 populations of 8842 non-infected subjects coming from Europe, the Middle-East and North Africa. A clear north-south decreasing gradient was evident for Delta 32 frequencies, with a significant correlation coefficient (r=0.83). The main frequency value of Delta 32 for Sweden, Norway, Denmark, Finland and Iceland (0.134) is significantly (chi(2)=63.818, P<0.001) highest than the Delta 32 mean value, indicating that probably the Vikings might have been instrumental in disseminating the Delta 32 allele during the eighth to the tenth centuries during historical times. Possibly variola virus has discriminated the Delta 32 carriers in Europe since the eighth century AD, explaining the high frequency of the Delta 32 allele in Europe today.

  12. Molecular basis of alpha 1-antitrypsin deficiency and emphysema associated with the alpha 1-antitrypsin Mmineral springs allele.

    PubMed Central

    Curiel, D T; Vogelmeier, C; Hubbard, R C; Stier, L E; Crystal, R G

    1990-01-01

    The Mmineral springs alpha 1-antitrypsin (alpha 1AT) allele, causing alpha 1AT deficiency and emphysema, is unique among the alpha 1AT-deficiency alleles in that it was observed in a black family, whereas most mutations causing alpha 1AT deficiency are confined to Caucasian populations of European descent. Immobilized pH gradient analysis of serum demonstrated that alpha 1AT Mmineral springs migrated cathodal to the normal M2 allele. Evaluation of Mmineral springs alpha 1AT as an inhibitor of neutrophil elastase, its natural substrate, demonstrated markedly lower than normal function. Characterization of the alpha 1AT Mmineral springs gene demonstrated that it differed from the common normal M1(Ala213) allele by a single-base substitution causing the amino acid substitution Gly-67 (GGG)----Glu-67 (GAG). Capitalizing on the fact that this mutation creates a polymorphism for the restriction endonuclease AvaII, family analysis demonstrated that the Mmineral springs alpha 1AT allele was transmitted in an autosomal-codominant fashion. Evaluation of genomic DNA showed that the index case was homozygous for the alpha 1AT Mmineral springs allele. Cytoplasmic blot analysis of blood monocytes of the Mmineral springs homozygote demonstrated levels of alpha 1AT mRNA transcripts comparable to those in cells of a normal M1 (Val213) homozygote control. Evaluation of in vitro translation of Mmineral springs alpha 1AT mRNA transcripts demonstrated a normal capacity to direct the translation of alpha 1AT. Evaluation of secretion of alpha 1AT by the blood monocytes by pulse-chase labeling with [35S]methionine, however, demonstrated less secretion by the Mmineral springs cells than normal cells. To characterize the posttranslational events causing the alpha 1AT-secretory defect associated with the alpha 1AT Mmineral springs gene, retroviral gene transfer was used to establish polyclonal populations of murine fibroblasts containing either a normal human M1 alpha 1AT cDNA or an Mmineral

  13. Characterization of the treefrog null allele, 1991

    SciTech Connect

    Guttman, S.I.

    1992-04-01

    Spring peeper (Hyla crucifer) tadpoles collected from the waste storage area during the Biological and Ecological Site Characterization of the Feed Materials Production Center (FEMP) in 1986 and 1987 appeared to be unique. A null (inactive) allele was found at the glucose phosphate isomerase enzyme locus in significant frequencies (approximately 20%) each year; this allele did not appear to occur in the offsite sample collected approximately 15km from the FEMP. Null alleles at this locus have not been reported in other amphibian populations; when they have been found in other organisms they have invariably been lethal in the homozygous condition.

  14. Characterization of the treefrog null allele

    SciTech Connect

    Guttman, S.I. . Dept. of Zoology)

    1990-12-01

    As part of the authors intensive year-long baseline ecological study, they characterized the degree of genetic polymorphism and heterozygosity in selected Feed Materials Production Center (FMPC) populations using electrophoretic techniques. These data are being used as an indicator of stress by comparing populations on and off the FMPC site. The current study was initiated to determine whether this GPI null allele is lethal, when homozygous, in spring peepers. Also, a sampling protocol was implemented to determine whether a linear effect occurs relative to the frequency of the null allele offsite and to determine the origination site of the null allele. 18 refs., 2 figs., 4 tabs.

  15. Nucleotide variation and identification of novel blast resistance alleles of Pib by allele mining strategy.

    PubMed

    Ramkumar, G; Madhav, M S; Devi, S J S Rama; Prasad, M S; Babu, V Ravindra

    2015-04-01

    Pib is one of significant rice blast resistant genes, which provides resistance to wide range of isolates of rice blast pathogen, Magnaporthe oryzae. Identification and isolation of novel and beneficial alleles help in crop enhancement. Allele mining is one of the best strategies for dissecting the allelic variations at candidate gene and identification of novel alleles. Hence, in the present study, Pib was analyzed by allele mining strategy, and coding and non-coding (upstream and intron) regions were examined to identify novel Pib alleles. Allelic sequences comparison revealed that nucleotide polymorphisms at coding regions affected the amino acid sequences, while the polymorphism at upstream (non-coding) region affected the motifs arrangements. Pib alleles from resistant landraces, Sercher and Krengosa showed better resistance than Pib donor variety, might be due to acquired mutations, especially at LRR region. The evolutionary distance, Ka/Ks and phylogenetic analyzes also supported these results. Transcription factor binding motif analysis revealed that Pib (Sr) had a unique motif (DPBFCOREDCDC3), while five different motifs differentiated the resistance and susceptible Pib alleles. As the Pib is an inducible gene, the identified differential motifs helps to understand the Pib expression mechanism. The identified novel Pib resistant alleles, which showed high resistance to the rice blast, can be used directly in blast resistance breeding program as alternative Pib resistant sources.

  16. A novel TaqMAMA assay for allelic discrimination of TLR9 rs352140 polymorphism.

    PubMed

    Bergallo, Massimiliano; Montanari, Paola; Mareschi, Katia; Rassu, Marco; Galliano, Ilaria; Ravanini, Paolo

    2017-05-01

    TaqMAMA is an allele-specific PCR-based (ASPCR) method that may be suitable for broad and cost-effective genotyping applications in all types of laboratories. There is evidence that interactions between some toll like receptors (TLRs) with viruses influence both the immune response and outcome of HCMV infection. We developed a TaqMAMA genotyping assay for the detection of rs352140 TLR9 polymorphism in transplant recipients with and without HCMV infections. Performance parameters to ensure a solid pre-validation protocol have been here argued. We analysed a population of 74 kidney transplants recipients subdivided in 58 HCMV PCR positive and 16 HCMV PCR negative in the post-transplant routine control. All 74 samples were tested with 31/74 (41.9%) homozygotes (11 CC and 20 TT) and 43/74 (58.1%) heterozygotes (CT). Our preliminary data suggest that there is no correlation between TLR9 rs352140 polymorphism and frequency of HCMV infection.

  17. Comparison of HLA allelic imputation programs.

    PubMed

    Karnes, Jason H; Shaffer, Christian M; Bastarache, Lisa; Gaudieri, Silvana; Glazer, Andrew M; Steiner, Heidi E; Mosley, Jonathan D; Mallal, Simon; Denny, Joshua C; Phillips, Elizabeth J; Roden, Dan M

    2017-01-01

    Imputation of human leukocyte antigen (HLA) alleles from SNP-level data is attractive due to importance of HLA alleles in human disease, widespread availability of genome-wide association study (GWAS) data, and expertise required for HLA sequencing. However, comprehensive evaluations of HLA imputations programs are limited. We compared HLA imputation results of HIBAG, SNP2HLA, and HLA*IMP:02 to sequenced HLA alleles in 3,265 samples from BioVU, a de-identified electronic health record database coupled to a DNA biorepository. We performed four-digit HLA sequencing for HLA-A, -B, -C, -DRB1, -DPB1, and -DQB1 using long-read 454 FLX sequencing. All samples were genotyped using both the Illumina HumanExome BeadChip platform and a GWAS platform. Call rates and concordance rates were compared by platform, frequency of allele, and race/ethnicity. Overall concordance rates were similar between programs in European Americans (EA) (0.975 [SNP2HLA]; 0.939 [HLA*IMP:02]; 0.976 [HIBAG]). SNP2HLA provided a significant advantage in terms of call rate and the number of alleles imputed. Concordance rates were lower overall for African Americans (AAs). These observations were consistent when accuracy was compared across HLA loci. All imputation programs performed similarly for low frequency HLA alleles. Higher concordance rates were observed when HLA alleles were imputed from GWAS platforms versus the HumanExome BeadChip, suggesting that high genomic coverage is preferred as input for HLA allelic imputation. These findings provide guidance on the best use of HLA imputation methods and elucidate their limitations.

  18. Comparison of HLA allelic imputation programs

    PubMed Central

    Shaffer, Christian M.; Bastarache, Lisa; Gaudieri, Silvana; Glazer, Andrew M.; Steiner, Heidi E.; Mosley, Jonathan D.; Mallal, Simon; Denny, Joshua C.; Phillips, Elizabeth J.; Roden, Dan M.

    2017-01-01

    Imputation of human leukocyte antigen (HLA) alleles from SNP-level data is attractive due to importance of HLA alleles in human disease, widespread availability of genome-wide association study (GWAS) data, and expertise required for HLA sequencing. However, comprehensive evaluations of HLA imputations programs are limited. We compared HLA imputation results of HIBAG, SNP2HLA, and HLA*IMP:02 to sequenced HLA alleles in 3,265 samples from BioVU, a de-identified electronic health record database coupled to a DNA biorepository. We performed four-digit HLA sequencing for HLA-A, -B, -C, -DRB1, -DPB1, and -DQB1 using long-read 454 FLX sequencing. All samples were genotyped using both the Illumina HumanExome BeadChip platform and a GWAS platform. Call rates and concordance rates were compared by platform, frequency of allele, and race/ethnicity. Overall concordance rates were similar between programs in European Americans (EA) (0.975 [SNP2HLA]; 0.939 [HLA*IMP:02]; 0.976 [HIBAG]). SNP2HLA provided a significant advantage in terms of call rate and the number of alleles imputed. Concordance rates were lower overall for African Americans (AAs). These observations were consistent when accuracy was compared across HLA loci. All imputation programs performed similarly for low frequency HLA alleles. Higher concordance rates were observed when HLA alleles were imputed from GWAS platforms versus the HumanExome BeadChip, suggesting that high genomic coverage is preferred as input for HLA allelic imputation. These findings provide guidance on the best use of HLA imputation methods and elucidate their limitations. PMID:28207879

  19. Allele Workbench: transcriptome pipeline and interactive graphics for allele-specific expression.

    PubMed

    Soderlund, Carol A; Nelson, William M; Goff, Stephen A

    2014-01-01

    Sequencing the transcriptome can answer various questions such as determining the transcripts expressed in a given species for a specific tissue or condition, evaluating differential expression, discovering variants, and evaluating allele-specific expression. Differential expression evaluates the expression differences between different strains, tissues, and conditions. Allele-specific expression evaluates expression differences between parental alleles. Both differential expression and allele-specific expression have been studied for heterosis (hybrid vigor), where the hybrid has improved performance over the parents for one or more traits. The Allele Workbench software was developed for a heterosis study that evaluated allele-specific expression for a mouse F1 hybrid using libraries from multiple tissues with biological replicates. This software has been made into a distributable package, which includes a pipeline, a Java interface to build the database, and a Java interface for query and display of the results. The required input is a reference genome, annotation file, and one or more RNA-Seq libraries with optional replicates. It evaluates allelic imbalance at the SNP and transcript level and flags transcripts with significant opposite directional allele-specific expression. The Java interface allows the user to view data from libraries, replicates, genes, transcripts, exons, and variants, including queries on allele imbalance for selected libraries. To determine the impact of allele-specific SNPs on protein folding, variants are annotated with their effect (e.g., missense), and the parental protein sequences may be exported for protein folding analysis. The Allele Workbench processing results in transcript files and read counts that can be used as input to the previously published Transcriptome Computational Workbench, which has a new algorithm for determining a trimmed set of gene ontology terms. The software with demo files is available from https://code.google.com/p/allele

  20. Ten novel HLA-DRB1 alleles and one novel DRB3 allele.

    PubMed

    Lazaro, A M; Steiner, N K; Moraes, M E; Moraes, J R; Ng, J; Hartzman, R J; Hurley, C K

    2005-10-01

    Ten novel HLA-DRB1 and one DRB3 alleles are described. Eight of the variants are single-nucleotide substitutions, four resulting in an amino acid change (DRB1*1145, *1148, *0828 and *1514) and four with silent substitutions (DRB1*040504, *130103, *160502 and DRB3*020204). Two alleles differ by two nucleotide changes altering one (DRB1*1447 and *1361) amino acid and one allele alters three nucleotides and two amino acids.

  1. Abnormal segregation of alleles in CEPH pedigree DNAs arising from allele loss in lymphoblastoid DNA

    SciTech Connect

    Royle, N.J.; Armour, J.A.L.; Crosier, M.; Jeffreys, A.J. )

    1993-01-01

    Somatic events that result in the reduction to hemior homozygosity at all loci affected by the event have been identified in lymphoblastoid DNA from mothers of two CEPH families. Using suitably informative probes, the allele deficiencies were detected by the abnormal transmission of alleles from grandparents to grandchildren, with the apparent absence of the alleles from the parent. Undetected somatic deficiencies in family DNAs could result in misscoring of recombination events and consequently introduce errors into linkage analysis. 15 refs., 2 figs.

  2. Ten Novel HLA-DRB1 Alleles and One Novel DRB3 Allele

    DTIC Science & Technology

    2006-05-31

    BRIEF COMMUNICATION Ten novel HLA-DRB1 alleles and one novel DRB3 allele A. M. Lazaro1, N. K. Steiner1, M. E. Moraes2, J. R. Moraes2, J. Ng1, R. J...accepted for publication 31 May 2005 doi: 10.1111/j.1399-0039.2005.00459.x Abstract Ten novel HLA-DRB1 and one DRB3 alleles are described. Eight of the...substitutions (DRB1*040504, *130103, *160502 and DRB3 *020204). Two alleles differ by two nucleotide changes altering one (DRB1*1447 and *1361) amino acid and

  3. Association between serotonin transporter genotype and extraversion.

    PubMed

    Gillihan, Seth J; Farah, Martha J; Sankoorikal, Geena Mary V; Breland, Jessica; Brodkin, Edward S

    2007-12-01

    Despite the long-standing recognition that extraversion is partially heritable, few specific genes have been found to be associated significantly with this personality trait. The purpose of this study was to examine the association between a functional genetic polymorphism of the serotonin transporter promoter region (5-HTTLPR) and extraversion. Caucasian participants (N=183) were genotyped for the 5-HTTLPR; extraversion scores for participants homozygous for the short allele (s/s) were compared with those participants carrying at least one long allele (s/l and l/l). An s/s genotype at 5-HTTLPR was significantly associated with self ratings of reduced extraversion (P=0.012); presence versus absence of the long allele explained 3.4% of the variance in extraversion. These findings provide support for the effect of the 5-HTTLPR, and for the serotonergic system more broadly, on behaviors related to extraversion.

  4. Human fear acquisition deficits in relation to genetic variants of the corticotropin-releasing hormone receptor 1 and the serotonin transporter--revisited.

    PubMed

    Heitland, I; Groenink, L; van Gool, J M; Domschke, K; Reif, A; Baas, J M P

    2016-02-01

    We recently showed that a genetic polymorphism (rs878886) in the human corticotropin-releasing hormone receptor 1 (CRHR1) is associated with reduced fear-conditioned responses to a threat cue. This is a potentially important finding considering that the failure to acquire fear contingencies can leave an individual in a maladaptive state of more generalized anxiety. Consistent with that idea, the CRHR1-dependent fear acquisition deficit translated into heightened contextual anxiety when taking genetic variability within the serotonin transporter long polymorphic region (5-HTTLPR) into account. To replicate our previous findings, we conducted a replication study in 224 healthy medication-free human subjects using the exact same cue and context virtual reality fear-conditioning procedure as in study by Heitland et al. (2013). In the replication study, consistent with the original findings, CRHR1 rs878886 G-allele carriers showed reduced acquisition of cue-specific fear-conditioned responses compared with C/C homozygotes. Also, in this larger sample the cue acquisition deficit of G-allele carriers translated into heightened contextual anxiety, even independent of 5-HTT gene variation. In contrast to our earlier findings, there was an additional interaction effect of CRHR1 rs878886 and the triallelic 5-HTTLPR/rs25531 variant on cued fear acquisition. In summary, this study replicated the initially reported association of the CRHR1 rs878886 G-allele with cued fear acquisition deficits, albeit with a different pattern of results regarding the interaction with 5-HTT variation. This further supports the notion that the human corticotropin-releasing hormone plays a role in the acquisition of fears.

  5. Allele-specific DNA methylation: beyond imprinting.

    PubMed

    Tycko, Benjamin

    2010-10-15

    Allele-specific DNA methylation (ASM) and allele-specific gene expression (ASE) have long been studied in genomic imprinting and X chromosome inactivation. But these types of allelic asymmetries, along with allele-specific transcription factor binding (ASTF), have turned out to be far more pervasive-affecting many non-imprinted autosomal genes in normal human tissues. ASM, ASE and ASTF have now been mapped genome-wide by microarray-based methods and NextGen sequencing. Multiple studies agree that all three types of allelic asymmetries, as well as the related phenomena of expression and methylation quantitative trait loci, are mostly accounted for by cis-acting regulatory polymorphisms. The precise mechanisms by which this occurs are not yet understood, but there are some testable hypotheses and already a few direct clues. Future challenges include achieving higher resolution maps to locate the epicenters of cis-regulated ASM, using this information to test mechanistic models, and applying genome-wide maps of ASE/ASM/ASTF to pinpoint functional regulatory polymorphisms influencing disease susceptibility.

  6. Serotonin transporter polymorphism modifies the association between depressive symptoms and sleep onset latency complaint in elderly people: results from the 'InveCe.Ab' study.

    PubMed

    Polito, Letizia; Davin, Annalisa; Vaccaro, Roberta; Abbondanza, Simona; Govoni, Stefano; Racchi, Marco; Guaita, Antonio

    2015-04-01

    Previous studies have documented the involvement of the central nervous system serotonin in promoting wakefulness. There are few and conflicting results over whether there is an actual association between bearing the short allele of serotonin transporter promoter polymorphism (5-HTTLPR) and worse sleep quality. This study examined whether sleep onset latency complaint is associated with the 5-HTTLPR triallelic polymorphism in the SLC6A4 gene promoter and whether this polymorphism influences the relationship between sleep onset latency complaint and depressive symptoms in elderly people. A total of 1321 community-dwelling individuals aged 70-74 years were interviewed for sleep onset latency complaint and for sleep medication consumption. Participants' genomic DNA was typed for 5-HTTLPR and rs25531 polymorphisms. Depressive symptoms were evaluated with the Geriatric Depression Scale Short form and general medical comorbidity was assessed by the Cumulative Illness Rating Scale. The presence of a past history of depression was recorded. The S' allele of the 5-HTTLPR triallelic polymorphism was associated with sleep onset latency complaint. This association was maintained after adjusting for depressive symptoms, sex, age, history of depression and medical comorbidity. After stratification for 5-HTTLPR/rs25531, only in S'S' individuals high depressive symptoms were actually associated with sleep onset latency complaint. These data indicate that the low-expressing 5-HTTLPR triallelic polymorphism is an independent risk factor for sleep onset latency disturbance. Furthermore, the 5-HTTLPR genotype influences the association between depressive symptoms and sleep onset latency complaint.

  7. AlleleSeq: analysis of allele-specific expression and binding in a network framework.

    PubMed

    Rozowsky, Joel; Abyzov, Alexej; Wang, Jing; Alves, Pedro; Raha, Debasish; Harmanci, Arif; Leng, Jing; Bjornson, Robert; Kong, Yong; Kitabayashi, Naoki; Bhardwaj, Nitin; Rubin, Mark; Snyder, Michael; Gerstein, Mark

    2011-08-02

    To study allele-specific expression (ASE) and binding (ASB), that is, differences between the maternally and paternally derived alleles, we have developed a computational pipeline (AlleleSeq). Our pipeline initially constructs a diploid personal genome sequence (and corresponding personalized gene annotation) using genomic sequence variants (SNPs, indels, and structural variants), and then identifies allele-specific events with significant differences in the number of mapped reads between maternal and paternal alleles. There are many technical challenges in the construction and alignment of reads to a personal diploid genome sequence that we address, for example, bias of reads mapping to the reference allele. We have applied AlleleSeq to variation data for NA12878 from the 1000 Genomes Project as well as matched, deeply sequenced RNA-Seq and ChIP-Seq data sets generated for this purpose. In addition to observing fairly widespread allele-specific behavior within individual functional genomic data sets (including results consistent with X-chromosome inactivation), we can study the interaction between ASE and ASB. Furthermore, we investigate the coordination between ASE and ASB from multiple transcription factors events using a regulatory network framework. Correlation analyses and network motifs show mostly coordinated ASB and ASE.

  8. Forensic Loci Allele Database (FLAD): Automatically generated, permanent identifiers for sequenced forensic alleles.

    PubMed

    Van Neste, Christophe; Van Criekinge, Wim; Deforce, Dieter; Van Nieuwerburgh, Filip

    2016-01-01

    It is difficult to predict if and when massively parallel sequencing of forensic STR loci will replace capillary electrophoresis as the new standard technology in forensic genetics. The main benefits of sequencing are increased multiplexing scales and SNP detection. There is not yet a consensus on how sequenced profiles should be reported. We present the Forensic Loci Allele Database (FLAD) service, made freely available on http://forensic.ugent.be/FLAD/. It offers permanent identifiers for sequenced forensic alleles (STR or SNP) and their microvariants for use in forensic allele nomenclature. Analogous to Genbank, its aim is to provide permanent identifiers for forensically relevant allele sequences. Researchers that are developing forensic sequencing kits or are performing population studies, can register on http://forensic.ugent.be/FLAD/ and add loci and allele sequences with a short and simple application interface (API).

  9. TT Mutant Homozygote of Kruppel-like Factor 5 Is a Key Factor for Increasing Basal Metabolic Rate and Resting Metabolic Rate in Korean Elementary School Children.

    PubMed

    Choi, Jung Ran; Kwon, In-Su; Kwon, Dae Young; Kim, Myung-Sunny; Lee, Myoungsook

    2013-12-01

    We investigated the contribution of genetic variations of KLF5 to basal metabolic rate (BMR) and resting metabolic rate (RMR) and the inhibition of obesity in Korean children. A variation of KLF5 (rs3782933) was genotyped in 62 Korean children. Using multiple linear regression analysis, we developed a model to predict BMR in children. We divided them into several groups; normal versus overweight by body mass index (BMI) and low BMR versus high BMR by BMR. There were no differences in the distributions of alleles and genotypes between each group. The genetic variation of KLF5 gene showed a significant correlation with several clinical factors, such as BMR, muscle, low-density lipoprotein cholesterol, and insulin. Children with the TT had significantly higher BMR than those with CC (p = 0.030). The highest muscle was observed in the children with TT compared with CC (p = 0.032). The insulin and C-peptide values were higher in children with TT than those with CC (p= 0.029 vs. p = 0.004, respectively). In linear regression analysis, BMI and muscle mass were correlated with BMR, whereas insulin and C-peptide were not associated with BMR. In the high-BMR group, we observed that higher muscle, fat mass, and C-peptide affect the increase of BMR in children with TT (p < 0.001, p < 0.001, and p = 0.018, respectively), while Rohrer's index could explain the usual decrease in BMR (adjust r(2) = 1.000, p < 0.001, respectively). We identified a novel association between TT of KLF5 rs3782933 and BMR in Korean children. We could make better use of the variation within KLF5 in a future clinical intervention study of obesity.

  10. Transformation of QTL genotypic effects to allelic effects

    PubMed Central

    Nagamine, Yoshitaka

    2005-01-01

    The genotypic and allelic effect models are equivalent in terms of QTL detection in a simple additive model, but the QTL allelic model has the advantage of providing direct information for marker-assisted selection. However, the allelic matrix is four times as large as the genotypic IBD matrix, causing computational problems, especially in genome scans examining multiple positions. Transformation from genotypic to allelic effects, after estimating the genotypic effects with a smaller IBD matrix, can solve this problem. Although the validity of transformation from genotypic to allelic effects has been disputed, this work proves that transformation can successfully yield unique allelic effects when genotypic and allelic IBD matrixes exist. PMID:16093016

  11. Effect of metallothionein 2A gene polymorphism on allele-specific gene expression and metal content in prostate cancer

    SciTech Connect

    Krześlak, Anna; Forma, Ewa; Jóźwiak, Paweł; Szymczyk, Agnieszka; Bryś, Magdalena

    2013-05-01

    Metallothioneins (MTs) are highly conserved, small molecular weight, cysteine rich proteins. The major physiological functions of metallothioneins include homeostasis of essential metals Zn and Cu and protection against cytotoxicity of heavy metals. The aim of this study was to determine whether there is an association between the − 5 A/G single nucleotide polymorphism (SNP; rs28366003) in core promoter region and expression of metallothionein 2A (MT2A) gene and metal concentration in prostate cancer tissues. MT2A polymorphism was determined by the polymerase chain reaction–restriction fragment length polymorphism technique (PCR–RFLP) using 412 prostate cancer tissue samples. MT2A gene expression analysis was performed by real-time RT-PCR method. A significant association between rs28366003 genotype and MT2A expression level was found. The average mRNA level was found to be lower among minor allele carriers (the risk allele) than average expression among homozygotes for the major allele. Metal levels were analyzed by flamed atomic absorption spectrometer system. Highly statistically significant associations were detected between the SNP and Cd, Zn, Cu and Pb levels. The results of Spearman's rank correlation showed that the expressions of MT2A and Cu, Pb and Ni concentrations were negatively correlated. On the basis of the results obtained in this study, we suggest that SNP polymorphism may affect the MT2A gene expression in prostate and this is associated with some metal accumulation. - Highlights: • MT2A gene expression and metal content in prostate cancer tissues • Association between SNP (rs28366003) and expression of MT2A • Significant associations between the SNP and Cd, Zn, Cu and Pb levels • Negative correlation between MT2A gene expression and Cu, Pb and Ni levels.

  12. Intragenic allele pyramiding combines different specificities of wheat Pm3 resistance alleles.

    PubMed

    Brunner, Susanne; Hurni, Severine; Streckeisen, Philipp; Mayr, Gabriele; Albrecht, Mario; Yahiaoui, Nabila; Keller, Beat

    2010-11-01

    Some plant resistance genes occur as allelic series, with each member conferring specific resistance against a subset of pathogen races. In wheat, there are 17 alleles of the Pm3 gene. They encode nucleotide-binding (NB-ARC) and leucine-rich-repeat (LRR) domain proteins, which mediate resistance to distinct race spectra of powdery mildew. It is not known if specificities from different alleles can be combined to create resistance genes with broader specificity. Here, we used an approach based on avirulence analysis of pathogen populations to characterize the molecular basis of Pm3 recognition spectra. A large survey of mildew races for avirulence on the Pm3 alleles revealed that Pm3a has a resistance spectrum that completely contains that of Pm3f, but also extends towards additional races. The same is true for the Pm3b and Pm3c gene pair. The molecular analysis of these allelic pairs revealed a role of the NB-ARC protein domain in the efficiency of effector-dependent resistance. Analysis of the wild-type and chimeric Pm3 alleles identified single residues in the C-terminal LRR motifs as the main determinant of allele specificity. Variable residues of the N-terminal LRRs are necessary, but not sufficient, to confer resistance specificity. Based on these data, we constructed a chimeric Pm3 gene by intragenic allele pyramiding of Pm3d and Pm3e that showed the combined resistance specificity and, thus, a broader recognition spectrum compared with the parental alleles. Our findings support a model of stepwise evolution of Pm3 recognition specificities.

  13. Estimating the probability of allelic drop-out of STR alleles in forensic genetics.

    PubMed

    Tvedebrink, Torben; Eriksen, Poul Svante; Mogensen, Helle Smidt; Morling, Niels

    2009-09-01

    In crime cases with available DNA evidence, the amount of DNA is often sparse due to the setting of the crime. In such cases, allelic drop-out of one or more true alleles in STR typing is possible. We present a statistical model for estimating the per locus and overall probability of allelic drop-out using the results of all STR loci in the case sample as reference. The methodology of logistic regression is appropriate for this analysis, and we demonstrate how to incorporate this in a forensic genetic framework.

  14. High-Throughput Genotyping with TaqMan Allelic Discrimination and Allele-Specific Genotyping Assays.

    PubMed

    Heissl, Angelika; Arbeithuber, Barbara; Tiemann-Boege, Irene

    2017-01-01

    Real-time PCR-based genotyping methods, such as TaqMan allelic discrimination assays and allele-specific genotyping, are particularly useful when screening a handful of single nucleotide polymorphisms in hundreds of samples; either derived from different individuals, tissues, or pre-amplified DNA. Although real-time PCR-based methods such as TaqMan are well-established, alternative methods, like allele-specific genotyping, are powerful alternatives, especially for genotyping short tandem repeat (STR) length polymorphisms. Here, we describe all relevant aspects when developing an assay for a new SNP or STR using either TaqMan or allele-specific genotyping, respectively, such as primer and probe design, optimization of reaction conditions, the experimental procedure for typing hundreds of samples, and finally the data evaluation. Our goal is to provide a guideline for developing genotyping assays using these two approaches that render reliable and reproducible genotype calls involving minimal optimization.

  15. HLA-B alleles of the Cayapa of Ecuador: new B39 and B15 alleles.

    PubMed

    Garber, T L; Butler, L M; Trachtenberg, E A; Erlich, H A; Rickards, O; De Stefano, G; Watkins, D I

    1995-01-01

    Recent data suggest that HLA-B locus alleles can evolve quickly in native South American populations. To investigate further this phenomenon of new HLA-B variants among Amerindians, we studied samples from another South American tribe, the Cayapa from Ecuador. We selected individuals for HLA-B molecular typing based upon their HLA class II typing results. Three new variants of HLA-B39 and one new variant of HLA-B15 were found in the Cayapa: HLA-B*3905, HLA-B*3906, HLA-B*3907, and HLA-B*1522. A total of thirteen new HLA-B alleles have now been found in the four South American tribes studied. Each of these four tribes studied, including the Cayapa, had novel alleles that were not found in any of the other tribes, suggesting that many of these new HLA-B alleles may have evolved since the Paleo-Indians originally populated South America. Each of these 13 new alleles contained predicted amino acid replacements that were located in the peptide binding site. These amino acid replacements may affect the sequence motif of the bound peptides, suggesting that these new alleles have been maintained by selection. New allelic variants have been found for all common HLA-B locus antigenic groups present in South American tribes with the exception of B48. In spite of its high frequency in South American tribes, no evidence for variants of B48 has been found in all the Amerindians studied, suggesting that B48 may have unique characteristics among the B locus alleles.

  16. Serotonin transporter genotype modulates the association between depressive symptoms and amygdala activity among psychiatrically healthy adults.

    PubMed

    Gillihan, Seth J; Rao, Hengyi; Brennan, Lauretta; Wang, Danny J J; Detre, John A; Sankoorikal, Geena Mary V; Brodkin, Edward S; Farah, Martha J

    2011-09-30

    Recent attempts to understand the biological bases of depression vulnerability have revealed that both the short allele of the serotonin transporter-linked polymorphic region (5-HTTLPR) and activity in the amygdala are associated with depression. Other studies have reported amygdala hyperactivity associated with the 5-HTTLPR short allele, linking the genetic and neuroimaging lines of research and suggesting a mechanism whereby the short allele confers depression risk. However, fewer investigations have examined the associations among depression, 5-HTTLPR variability, and amygdala activation in a single study. The current study thus investigated whether 5-HTTLPR genotype modulates the association between depressive symptoms and amygdala activity among psychiatrically healthy adults. Regional cerebral blood flow was measured with perfusion fMRI during a task-free scan. We hypothesized differential associations between depressive symptoms and amygdala activity among individuals homozygous for the short allele and individuals homozygous for the long allele. Both whole brain analyses and region-of-interest analyses confirmed this prediction, revealing a significant negative association among the long allele group and a trend of positive association among the short allele group. These results complement existing reports of short allele related amygdala hyperactivity and suggest an additional neurobiological mechanism whereby the 5-HTTLPR is associated with psychiatric outcomes.

  17. Serotonin transporter genotype modulates the association between depressive symptoms and amygdala activity among psychiatrically healthy adults

    PubMed Central

    Gillihan, Seth J.; Rao, Hengyi; Brennan, Lauretta; Wang, Danny JJ; Detre, John A.; Sankoorikal, Geena Mary V.; Brodkin, Edward S.; Farah, Martha J.

    2011-01-01

    Recent attempts to understand the biological bases of depression vulnerability have revealed that both the short allele of the serotonin transporter-linked polymorphic region (5-HTTLPR) and activity in the amygdala are associated with depression. Other studies have reported amygdala hyperactivity associated with the 5-HTTLPR short allele, linking the genetic and neuroimaging lines of research and suggesting a mechanism whereby the short allele confers depression risk. However, fewer investigations have examined the associations between depression, 5-HTTLPR variability, and amygdala activation in a single study. The current study thus investigated whether 5-HTTLPR genotype modulates the association between depressive symptoms and amygdala activity among psychiatrically healthy adults. Regional cerebral blood flow was measured with perfusion fMRI during a task-free scan. We hypothesized differential associations between depressive symptoms and amygdala activity among individuals homozygous for the short allele and individuals homozygous for the long allele. Both whole brain analyses and region-of-interest analyses confirmed this prediction, revealing a significant negative association among the long allele group and a trend of positive association among the short allele group. These results complement existing reports of short allele related amygdala hyperactivity and suggest an additional neurobiological mechanism whereby the 5-HTTLPR is associated with psychiatric outcomes. PMID:21764567

  18. Initial invasion of gametophytic self-incompatibility alleles in the absence of tight linkage between pollen and pistil S alleles.

    PubMed

    Sakai, Satoki; Wakoh, Haluka

    2014-08-01

    In homomorphic self-incompatibility (SI) systems of plants, the loci controlling the pollen and pistil types are tightly linked, and this prevents the generation of compatible combinations of alleles expressing pollen and pistil types, which would result in self-fertilization. We modeled the initial invasion of the first pollen and pistil alleles in gametophytic SI to determine whether these alleles can stably coexist in a population without tight linkage. We assume pollen and pistil loci each carry an incompatibility allele S and an allele without an incompatibility function N. We assume that pollen with an S allele are incompatible with pistils carrying S alleles, whereas other crosses are compatible. Ovules in pistils carrying an S allele suffer viability costs because recognition consumes resources. We found that the cost of carrying a pistil S allele allows pollen and pistil S alleles to coexist in a stable equilibrium if linkage is partial. This occurs because parents that carry pistil S alleles but are homozygous for pollen N alleles cannot avoid self-fertilization; however, they suffer viability costs. Hence, pollen N alleles are selected again. When pollen and pistil S alleles can coexist in a polymorphic equilibrium, selection will favor tighter linkage.

  19. Do Heliconius butterfly species exchange mimicry alleles?

    PubMed Central

    Smith, Joel; Kronforst, Marcus R.

    2013-01-01

    Hybridization has the potential to transfer beneficial alleles across species boundaries, and there are a growing number of examples in which this has apparently occurred. Recent studies suggest that Heliconius butterflies have transferred wing pattern mimicry alleles between species via hybridization, but ancestral polymorphism could also produce a signature of shared ancestry around mimicry genes. To distinguish between these alternative hypotheses, we measured DNA sequence divergence around putatively introgressed mimicry loci and compared this with the rest of the genome. Our results reveal that putatively introgressed regions show strongly reduced sequence divergence between co-mimetic species, suggesting that their divergence times are younger than the rest of the genome. This is consistent with introgression and not ancestral variation. We further show that this signature of introgression occurs at sites throughout the genome, not just around mimicry genes. PMID:23864282

  20. [The normotensive carriers of the MTHFR 677T allele, displaying the increased risk of development of the abdominal aortic aneurysm (AAA), occur at the highest frequency among the smoking patients].

    PubMed

    Strauss, Ewa; Waliszewski, Krzysztof; Pawlak, Andrzej L

    2004-01-01

    Abdominal aortic aneurysm (AAA) presents itself as a progressive dilation of the abdominal aorta, leading--if untreated--to rupture. It is a common disease of the elderly, with a complex etiology. Smoking, hypertension and several genetic factors are recognized as relevant for the pathogenesis of AAA. We studied association between the polymorphism of the MTHFR (methylenetetrahydrofolate reductase) gene within the fourth exon (677C>T) and the occurrence of hypertension and smoking status in the group of 74 male patients with AAA. In the patients group, the smoking hypertensive persons represented the largest subgroup (43%). We determined the the MTHFR 677C>T polymorphism in AAA patients and compared it to that in 71 healthy normotensive males. The frequencies of the 677T allele and MTHFR 677C>T genotypes were similar in both groups, but the subgroup of normotensive AAA patients (n=29) displayed significantly increased frequencies of 677T allele (0.4) and of 677CT and TT genotypes (69%), as compared to those in the control group (0.28 and 46%, respectively). This corresponds to the 3.3-fold greater risk of AAA in normotensive subjects with the 677T allele of MTHFR, as compared to the homo-zygotes 677CC (p<0.03; 95% CI=1.2-9.2). The highest frequencies of MTHFR 677T allele (0.43) and 677CT and TT genotypes (73%) were found in the subgroup of normotensive smoking patients (n=22).

  1. Genetic analysis of viable Hsp90 alleles reveals a critical role in Drosophila spermatogenesis.

    PubMed Central

    Yue, L; Karr, T L; Nathan, D F; Swift, H; Srinivasan, S; Lindquist, S

    1999-01-01

    The Hsp90 chaperone protein maintains the activities of a remarkable variety of signal transducers, but its most critical functions in the context of the whole organism are unknown. Point mutations of Hsp83 (the Drosophila Hsp90 gene) obtained in two different screens are lethal as homozygotes. We report that eight transheterozygous mutant combinations produce viable adults. All exhibit the same developmental defects: sterile males and sterile or weakly fertile females. We also report that scratch, a previously identified male-sterile mutation, is an allele of Hsp82 with a P-element insertion in the intron that reduces expression. Thus, it is a simple reduction in Hsp90 function, rather than possible altered functions in the point mutants, that leads to male sterility. As shown by light and electron microscopy, all stages of spermatogenesis involving microtubule function are affected, from early mitotic divisions to later stages of sperm maturation, individualization, and motility. Aberrant microtubules are prominent in yeast cells carrying mutations in HSP82 (the yeast Hsp90 gene), confirming that Hsp90 function is connected to microtubule dynamics and that this connection is highly conserved. A small fraction of Hsp90 copurifies with taxol-stabilized microtubule proteins in Drosophila embryo extracts, but Hsp90 does not remain associated with microtubules through repeated temperature-induced assembly and disassembly reactions. If the spermatogenesis phenotypes are due to defects in microtubule dynamics, we suggest these are indirect, reflecting a role for Hsp90 in maintaining critical signal transduction pathways and microtubule effectors, rather than a direct role in the assembly and disassembly of microtubules themselves. PMID:10049923

  2. Allelic variation contributes to bacterial host specificity

    SciTech Connect

    Yue, Min; Han, Xiangan; Masi, Leon De; Zhu, Chunhong; Ma, Xun; Zhang, Junjie; Wu, Renwei; Schmieder, Robert; Kaushik, Radhey S.; Fraser, George P.; Zhao, Shaohua; McDermott, Patrick F.; Weill, François-Xavier; Mainil, Jacques G.; Arze, Cesar; Fricke, W. Florian; Edwards, Robert A.; Brisson, Dustin; Zhang, Nancy R.; Rankin, Shelley C.; Schifferli, Dieter M.

    2015-10-30

    Understanding the molecular parameters that regulate cross-species transmission and host adaptation of potential pathogens is crucial to control emerging infectious disease. Although microbial pathotype diversity is conventionally associated with gene gain or loss, the role of pathoadaptive nonsynonymous single-nucleotide polymorphisms (nsSNPs) has not been systematically evaluated. Here, our genome-wide analysis of core genes within Salmonella enterica serovar Typhimurium genomes reveals a high degree of allelic variation in surface-exposed molecules, including adhesins that promote host colonization. Subsequent multinomial logistic regression, MultiPhen and Random Forest analyses of known/suspected adhesins from 580 independent Typhimurium isolates identifies distinct host-specific nsSNP signatures. Moreover, population and functional analyses of host-associated nsSNPs for FimH, the type 1 fimbrial adhesin, highlights the role of key allelic residues in host-specific adherence in vitro. In conclusion, together, our data provide the first concrete evidence that functional differences between allelic variants of bacterial proteins likely contribute to pathoadaption to diverse hosts.

  3. Allelic variation contributes to bacterial host specificity

    DOE PAGES

    Yue, Min; Han, Xiangan; Masi, Leon De; ...

    2015-10-30

    Understanding the molecular parameters that regulate cross-species transmission and host adaptation of potential pathogens is crucial to control emerging infectious disease. Although microbial pathotype diversity is conventionally associated with gene gain or loss, the role of pathoadaptive nonsynonymous single-nucleotide polymorphisms (nsSNPs) has not been systematically evaluated. Here, our genome-wide analysis of core genes within Salmonella enterica serovar Typhimurium genomes reveals a high degree of allelic variation in surface-exposed molecules, including adhesins that promote host colonization. Subsequent multinomial logistic regression, MultiPhen and Random Forest analyses of known/suspected adhesins from 580 independent Typhimurium isolates identifies distinct host-specific nsSNP signatures. Moreover, population andmore » functional analyses of host-associated nsSNPs for FimH, the type 1 fimbrial adhesin, highlights the role of key allelic residues in host-specific adherence in vitro. In conclusion, together, our data provide the first concrete evidence that functional differences between allelic variants of bacterial proteins likely contribute to pathoadaption to diverse hosts.« less

  4. Association of a serotonin transporter gene promoter polymorphism with harm avoidance behaviour in an elderly population.

    PubMed

    Ricketts, M H; Hamer, R M; Sage, J I; Manowitz, P; Feng, F; Menza, M A

    1998-01-01

    A polymorphic 44-nucleotide insertion/deletion in the promoter region of the serotonin transporter gene (5-HTTLPR) has been shown to affect the level of expression of the serotonin transporter protein. An association between anxiety-related behavioural traits and the short form of the 5-HTTLPR has been reported. We determined the 5-HTTLPR genotype in genomic DNA samples from 84 subjects (47 Parkinson's disease patients and 37 controls) with a mean age of 67.4 years. The TPQ of Cloninger was used to obtain values for harm avoidance (HA), reward dependence and novelty seeking for all subjects. Analysis of variance showed a significant influence of the s-allele of the 5-HTTLPR on HA in both subject groups, with no significant interaction between diagnosis and genotype. Subjects with the l/l-genotype had significantly lower mean HA scores than the l/s subjects (P < 0.04) and s/s subjects (P < 0.003). A linear change in HA with genotype was observed, indicating a gene dose effect of the 5-HTTLPR s-allele on this personality dimension. Based on these findings it is suggested that there may be increased influence of the 5-HTTLPR short allele on anxiety-related traits during aging.

  5. The serotonin transporter promoter polymorphism and childhood positive and negative emotionality.

    PubMed

    Hayden, Elizabeth P; Klein, Daniel N; Sheikh, Haroon I; Olino, Thomas M; Dougherty, Lea R; Dyson, Margaret W; Durbin, C Emily; Singh, Shiva M

    2010-10-01

    Association studies of the serotonin transporter promoter polymorphism (5-HTTLPR) and negative emotionality (NE) are inconclusive. However, emerging evidence suggests that the association between this polymorphism and NE may be influenced by levels of another temperament trait, positive emotionality (PE). Therefore, this study examined whether the association between the 5-HTTLPR and NE was moderated by PE. A community sample of 413 three-year-old children completed a standardized battery of laboratory tasks designed to tap temperamental emotionality. Children were also genotyped for the 5-HTTLPR. No direct association between 5-HTTLPR genotype and NE was found. However, the interaction of child PE and NE predicted 5-HTTLPR genotype. Furthermore, children with a short allele who were also low in PE had significantly greater NE than children without a short allele or children with high PE. Our findings suggest that the short allele of the 5-HTTLPR is associated with NE only in the context of low PE. Inconsistent links between NE and this gene in previous research may stem from the failure to consider other temperament traits that moderate associations.

  6. Prevalence of bovine dermatophilosis and disease-associated alleles in zebu Goudali cattle and their Italian Simmental crosses ranching in the western highland plateau savannah of Cameroon.

    PubMed

    Ojong, Bessong Willington; Saccà, Elena; Bessong, Pascal; Piasentier, Edi

    2016-10-01

    Abundance of native pastures makes Cameroon's western highland savannah (WHS) a hotspot for low-input beef-type cattle. Dumbo Ranch is central to cattle seed stock multiplication in WHS and holds that Dermatophilus congolensis infection undermines production. The bovine BoLA-DRB3 has been variously demonstrated as the principal gene of the major histocompatibility locus associated with immunity and resistance to dermatophilosis in cattle. We studied the profile of dermatophilosis prevalence in zebu Goudali (G) and its Simmental composite, SimGoud (SG), at Dumbo Ranch and determined the distribution of a dermatophilosis-associated susceptibility allele of the BoLA-DRB3 gene by allele-specific polymerase chain reaction (PCR). We recorded a 42 % prevalence of dermatophilosis in the studied cohort (337 animals). Dermatophilosis was more common in older cattle than in cattle ≤36 months (p ≤ 0.05). G was more affected compared to SG, because of the prevalence of the disease in the oldest animals and the age distribution of the experimental subjects. No susceptible homozygote was observed. About 85 and 15 % of the cohort carried the homozygous resistant and heterozygous condition, respectively. This genotype distribution was not affected by cattle type. The study confirms the presence of dermatophilosis among G and SG cattle in WHS. However, there was no correlation between the presence of the disease-associated susceptible allele considered and clinical manifestation. Screening for this dermatophilosis resistance-associated allele of BoLA-DRB3 gene appeared not useful for selection of G and SG in WHS.

  7. Increasing long term response by selecting for favorable minor alleles

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Long-term response of genomic selection can be improved by considering allele frequencies of selected markers or quantitative trait loci (QTLs). A previous formula to weight allele frequency of favorable minor alleles was tested, and 2 new formulas were developed. The previous formula used nonlinear...

  8. Mutant maize variety containing the glt1-1 allele

    DOEpatents

    Nelson, O.E.; Pan, D.

    1994-07-19

    A maize plant has in its genome a non-mutable form of a mutant allele designated vitX-8132. The allele is located at a locus designated as glt which conditions kernels having an altered starch characteristic. Maize plants including such a mutant allele produce a starch that does not increase in viscosity on cooling, after heating. 2 figs.

  9. Mutant maize variety containing the glt1-1 allele

    DOEpatents

    Nelson, Oliver E.; Pan, David

    1994-01-01

    A maize plant has in its genome a non-mutable form of a mutant allele designated vitX-8132. The allele is located at a locus designated as glt which conditions kernels having an altered starch characteristic. Maize plants including such a mutant allele produce a starch that does not increase in viscosity on cooling, after heating.

  10. Alleles versus mutations: Understanding the evolution of genetic architecture requires a molecular perspective on allelic origins.

    PubMed

    Remington, David L

    2015-12-01

    Perspectives on the role of large-effect quantitative trait loci (QTL) in the evolution of complex traits have shifted back and forth over the past few decades. Different sets of studies have produced contradictory insights on the evolution of genetic architecture. I argue that much of the confusion results from a failure to distinguish mutational and allelic effects, a limitation of using the Fisherian model of adaptive evolution as the lens through which the evolution of adaptive variation is examined. A molecular-based perspective reveals that allelic differences can involve the cumulative effects of many mutations plus intragenic recombination, a model that is supported by extensive empirical evidence. I discuss how different selection regimes could produce very different architectures of allelic effects under a molecular-based model, which may explain conflicting insights on genetic architecture from studies of variation within populations versus between divergently selected populations. I address shortcomings of genome-wide association study (GWAS) practices in light of more suitable models of allelic evolution, and suggest alternate GWAS strategies to generate more valid inferences about genetic architecture. Finally, I discuss how adopting more suitable models of allelic evolution could help redirect research on complex trait evolution toward addressing more meaningful questions in evolutionary biology.

  11. DRD4 long allele carriers show heightened attention to high-priority items relative to low-priority items.

    PubMed

    Gorlick, Marissa A; Worthy, Darrell A; Knopik, Valerie S; McGeary, John E; Beevers, Christopher G; Maddox, W Todd

    2015-03-01

    Humans with seven or more repeats in exon III of the DRD4 gene (long DRD4 carriers) sometimes demonstrate impaired attention, as seen in attention-deficit hyperactivity disorder, and at other times demonstrate heightened attention, as seen in addictive behavior. Although the clinical effects of DRD4 are the focus of much work, this gene may not necessarily serve as a "risk" gene for attentional deficits, but as a plasticity gene where attention is heightened for priority items in the environment and impaired for minor items. Here we examine the role of DRD4 in two tasks that benefit from selective attention to high-priority information. We examine a category learning task where performance is supported by focusing on features and updating verbal rules. Here, selective attention to the most salient features is associated with good performance. In addition, we examine the Operation Span (OSPAN) task, a working memory capacity task that relies on selective attention to update and maintain items in memory while also performing a secondary task. Long DRD4 carriers show superior performance relative to short DRD4 homozygotes (six or less tandem repeats) in both the category learning and OSPAN tasks. These results suggest that DRD4 may serve as a "plasticity" gene where individuals with the long allele show heightened selective attention to high-priority items in the environment, which can be beneficial in the appropriate context.

  12. Identification of the third/extra allele for forensic application in cases with TPOX tri-allelic pattern.

    PubMed

    Picanço, Juliane Bentes; Raimann, Paulo Eduardo; da Motta, Carlos Henrique Ares Silveira; Rodenbusch, Rodrigo; Gusmão, Leonor; Alho, Clarice Sampaio

    2015-05-01

    Genotyping of polymorphic short tandem repeats (STRs) loci is widely used in forensic DNA analysis. STR loci eventually present tri-allelic pattern as a genotyping irregularity and, in that situation, the doubt about the tri-allele locus frequency calculation can reduce the analysis strength. In the TPOX human STR locus, tri-allelic genotypes have been reported with a widely varied frequency among human populations. We investigate whether there is a single extra allele (the third allele) in the TPOX tri-allelic pattern, what it is, and where it is, aiming to understand its genomic anatomy and to propose the knowledge of this TPOX extra allele from genetic profile, thus preserving the two standard TPOX alleles in forensic analyses. We looked for TPOX tri-allelic subjects in 75,113 Brazilian families. Considering only the parental generation (mother+father) we had 150,226 unrelated subjects evaluated. From this total, we found 88 unrelated subjects with tri-allelic pattern in the TPOX locus (0.06%; 88/150,226). Seventy three of these 88 subjects (73/88; 83%) had the Clayton's original Type 2 tri-allelic pattern (three peaks of even intensity). The remaining 17% (15/88) show a new Type 2 derived category with heterozygote peak imbalance (one double dose peak plus one regular sized peak). In this paper we present detailed data from 66 trios (mother+father+child) with true biological relationships. In 39 of these families (39/66; 59%) the extra TPOX allele was transmitted either from the mother or from the father to the child. Evidences indicated the allele 10 as the extra TPOX allele, and it is on the X chromosome. The present data, which support the previous Lane hypothesis, improve the knowledge about tri-allelic pattern of TPOX CODIS' locus allowing the use of TPOX profile in forensic analyses even when with tri-allelic pattern. This evaluation is now available for different forensic applications.

  13. Update on allele nomenclature for human cytochromes P450 and the Human Cytochrome P450 Allele (CYP-allele) Nomenclature Database.

    PubMed

    Sim, Sarah C; Ingelman-Sundberg, Magnus

    2013-01-01

    Interindividual variability in xenobiotic metabolism and drug response is extensive and genetic factors play an important role in this variation. A majority of clinically used drugs are substrates for the cytochrome P450 (CYP) enzyme system and interindividual variability in expression and function of these enzymes is a major factor for explaining individual susceptibility for adverse drug reactions and drug response. Because of the existence of many polymorphic CYP genes, for many of which the number of allelic variants is continually increasing, a universal and official nomenclature system is important. Since 1999, all functionally relevant polymorphic CYP alleles are named and published on the Human Cytochrome P450 Allele (CYP-allele) Nomenclature Web site (http://www.cypalleles.ki.se). Currently, the database covers nomenclature of more than 660 alleles in a total of 30 genes that includes 29 CYPs as well as the cytochrome P450 oxidoreductase (POR) gene. On the CYP-allele Web site, each gene has its own Webpage, which lists the alleles with their nucleotide changes, their functional consequences, and links to publications identifying or characterizing the alleles. CYP2D6, CYP2C9, CYP2C19, and CYP3A4 are the most important CYPs in terms of drug metabolism, which is also reflected in their corresponding highest number of Webpage hits at the CYP-allele Web site.The main advantage of the CYP-allele database is that it offers a rapid online publication of CYP-alleles and their effects and provides an overview of peer-reviewed data to the scientific community. Here, we provide an update of the CYP-allele database and the associated nomenclature.

  14. Borrowed alleles and convergence in serpentine adaptation

    PubMed Central

    Arnold, Brian J.; Lahner, Brett; DaCosta, Jeffrey M.; Weisman, Caroline M.; Hollister, Jesse D.; Salt, David E.; Bomblies, Kirsten; Yant, Levi

    2016-01-01

    Serpentine barrens represent extreme hazards for plant colonists. These sites are characterized by high porosity leading to drought, lack of essential mineral nutrients, and phytotoxic levels of metals. Nevertheless, nature forged populations adapted to these challenges. Here, we use a population-based evolutionary genomic approach coupled with elemental profiling to assess how autotetraploid Arabidopsis arenosa adapted to a multichallenge serpentine habitat in the Austrian Alps. We first demonstrate that serpentine-adapted plants exhibit dramatically altered elemental accumulation levels in common conditions, and then resequence 24 autotetraploid individuals from three populations to perform a genome scan. We find evidence for highly localized selective sweeps that point to a polygenic, multitrait basis for serpentine adaptation. Comparing our results to a previous study of independent serpentine colonizations in the closely related diploid Arabidopsis lyrata in the United Kingdom and United States, we find the highest levels of differentiation in 11 of the same loci, providing candidate alleles for mediating convergent evolution. This overlap between independent colonizations in different species suggests that a limited number of evolutionary strategies are suited to overcome the multiple challenges of serpentine adaptation. Interestingly, we detect footprints of selection in A. arenosa in the context of substantial gene flow from nearby off-serpentine populations of A. arenosa, as well as from A. lyrata. In several cases, quantitative tests of introgression indicate that some alleles exhibiting strong selective sweep signatures appear to have been introgressed from A. lyrata. This finding suggests that migrant alleles may have facilitated adaptation of A. arenosa to this multihazard environment. PMID:27357660

  15. Biased gene conversion skews allele frequencies in human populations, increasing the disease burden of recessive alleles.

    PubMed

    Lachance, Joseph; Tishkoff, Sarah A

    2014-10-02

    Gene conversion results in the nonreciprocal transfer of genetic information between two recombining sequences, and there is evidence that this process is biased toward G and C alleles. However, the strength of GC-biased gene conversion (gBGC) in human populations and its effects on hereditary disease have yet to be assessed on a genomic scale. Using high-coverage whole-genome sequences of African hunter-gatherers, agricultural populations, and primate outgroups, we quantified the effects of GC-biased gene conversion on population genomic data sets. We find that genetic distances (FST and population branch statistics) are modified by gBGC. In addition, the site frequency spectrum is left-shifted when ancestral alleles are favored by gBGC and right-shifted when derived alleles are favored by gBGC. Allele frequency shifts due to gBGC mimic the effects of natural selection. As expected, these effects are strongest in high-recombination regions of the human genome. By comparing the relative rates of fixation of unbiased and biased sites, the strength of gene conversion was estimated to be on the order of Nb ≈ 0.05 to 0.09. We also find that derived alleles favored by gBGC are much more likely to be homozygous than derived alleles at unbiased SNPs (+42.2% to 62.8%). This results in a curse of the converted, whereby gBGC causes substantial increases in hereditary disease risks. Taken together, our findings reveal that GC-biased gene conversion has important population genetic and public health implications.

  16. Allelic genealogies in sporophytic self-incompatibility systems in plants.

    PubMed Central

    Schierup, M H; Vekemans, X; Christiansen, F B

    1998-01-01

    Expectations for the time scale and structure of allelic genealogies in finite populations are formed under three models of sporophytic self-incompatibility. The models differ in the dominance interactions among the alleles that determine the self-incompatibility phenotype: In the SSIcod model, alleles act codominantly in both pollen and style, in the SSIdom model, alleles form a dominance hierarchy, and in SSIdomcod, alleles are codominant in the style and show a dominance hierarchy in the pollen. Coalescence times of alleles rarely differ more than threefold from those under gametophytic self-incompatibility, and transspecific polymorphism is therefore expected to be equally common. The previously reported directional turnover process of alleles in the SSIdomcod model results in coalescence times lower and substitution rates higher than those in the other models. The SSIdom model assumes strong asymmetries in allelic action, and the most recessive extant allele is likely to be the most recent common ancestor. Despite these asymmetries, the expected shape of the allele genealogies does not deviate markedly from the shape of a neutral gene genealogy. The application of the results to sequence surveys of alleles, including interspecific comparisons, is discussed. PMID:9799270

  17. Variation in the Serotonin Transporter Gene and Alcoholism: Risk and Response to Pharmacotherapy

    PubMed Central

    Thompson, Miles D.; Kenna, George A.

    2016-01-01

    SLC6A4, the gene encoding the serotonin transporter protein (5-HTT), has been extensively examined as a risk factor for alcohol dependence (AD). More recently, variability in the transporter gene was identified to be a potential moderator of treatment response to serotonergic medications such as ondansetron and sertraline. There is an insertion-deletion polymorphism in the promoter region (5-HTTLPR) of the SLC6A4, with the most common alleles being a 14-repeat short (S) allele and a 16-repeat long (L) allele. The S allele has often been associated with AD. By contrast, the L allele has been associated with pharmacological responsiveness in some individuals with AD. Differences in clinical phenotype may determine the utility of the 5-HTTLPR polymorphism as a moderator of pharmacological interventions for AD. We review the AD typology and disease onset in the context of pharmacogenetic and genomic studies that examine the utility of 5-HTTLPR in improving treatment outcomes. PMID:26311211

  18. Exquisite allele discrimination by toehold hairpin primers

    PubMed Central

    Byrom, Michelle; Bhadra, Sanchita; Jiang, Yu Sherry; Ellington, Andrew D.

    2014-01-01

    The ability to detect and monitor single nucleotide polymorphisms (SNPs) in biological samples is an enabling research and clinical tool. We have developed a surprising, inexpensive primer design method that provides exquisite discrimination between SNPs. The field of DNA computation is largely reliant on using so-called toeholds to initiate strand displacement reactions, leading to the execution of kinetically trapped circuits. We have now similarly found that the short toehold sequence to a target of interest can initiate both strand displacement within the hairpin and extension of the primer by a polymerase, both of which will further stabilize the primer:template complex. However, if the short toehold does not bind, neither of these events can readily occur and thus amplification should not occur. Toehold hairpin primers were used to detect drug resistance alleles in two genes, rpoB and katG, in the Mycobacterium tuberculosis genome, and ten alleles in the Escherichia coli genome. During real-time PCR, the primers discriminate between mismatched templates with Cq delays that are frequently so large that the presence or absence of mismatches is essentially a ‘yes/no’ answer. PMID:24990378

  19. The serotonin transporter 5-HTTLPR polymorphism and treatment response to nicotine patch: follow-up of a randomized controlled trial.

    PubMed

    David, Sean P; Munafò, Marcus R; Murphy, Michael F G; Walton, Robert T; Johnstone, Elaine C

    2007-02-01

    In this follow-up of a randomized placebo-controlled clinical trial of nicotine replacement transdermal patch for smoking cessation, 741 smokers of European ancestry who were randomized to receive active patch or placebo patch were genotyped for the serotonin transporter gene-linked polymorphic region. The study setting was a primary care research network in Oxfordshire, United Kingdom. The primary outcome measures were biochemically verified sustained abstinence from cigarette smoking at end of treatment and 24-week follow-up. The main effect of genotype was not associated with sustained abstinence from smoking at either end of treatment (SL: p=.33; SS: p=.81) or 24-week follow-up (SL: p=.05; SS: p=.21), and we found no evidence for a genotypextreatment interaction effect. In summary, despite the theoretically important contribution of serotonin neurotransmission to smoking cessation, the serotonin transporter gene was not associated with treatment response to nicotine patch for smoking cessation in this primary care-based trial.

  20. Deleterious alleles in the human genome are on average younger than neutral alleles of the same frequency.

    PubMed

    Kiezun, Adam; Pulit, Sara L; Francioli, Laurent C; van Dijk, Freerk; Swertz, Morris; Boomsma, Dorret I; van Duijn, Cornelia M; Slagboom, P Eline; van Ommen, G J B; Wijmenga, Cisca; de Bakker, Paul I W; Sunyaev, Shamil R

    2013-01-01

    Large-scale population sequencing studies provide a complete picture of human genetic variation within the studied populations. A key challenge is to identify, among the myriad alleles, those variants that have an effect on molecular function, phenotypes, and reproductive fitness. Most non-neutral variation consists of deleterious alleles segregating at low population frequency due to incessant mutation. To date, studies characterizing selection against deleterious alleles have been based on allele frequency (testing for a relative excess of rare alleles) or ratio of polymorphism to divergence (testing for a relative increase in the number of polymorphic alleles). Here, starting from Maruyama's theoretical prediction (Maruyama T (1974), Am J Hum Genet USA 6:669-673) that a (slightly) deleterious allele is, on average, younger than a neutral allele segregating at the same frequency, we devised an approach to characterize selection based on allelic age. Unlike existing methods, it compares sets of neutral and deleterious sequence variants at the same allele frequency. When applied to human sequence data from the Genome of the Netherlands Project, our approach distinguishes low-frequency coding non-synonymous variants from synonymous and non-coding variants at the same allele frequency and discriminates between sets of variants independently predicted to be benign or damaging for protein structure and function. The results confirm the abundance of slightly deleterious coding variation in humans.

  1. Microarrays for high-throughput genotyping of MICA alleles using allele-specific primer extension.

    PubMed

    Baek, I C; Jang, J-P; Choi, H-B; Choi, E-J; Ko, W-Y; Kim, T-G

    2013-10-01

    The role of major histocompatibility complex (MHC) class I chain-related gene A (MICA), a ligand of NKG2D, has been defined in human diseases by its allele associations with various autoimmune diseases, hematopoietic stem cell transplantation (HSCT) and cancer. This study describes a practical system to develop MICA genotyping by allele-specific primer extension (ASPE) on microarrays. From the results of 20 control primers, strict and reliable cut-off values of more than 30,000 mean fluorescence intensity (MFI) as positive and less than 3000 MFI as negative, were applied to select high-quality specific extension primers. Among 55 allele-specific primers, 44 primers could be initially selected as optimal primer. Through adjusting the length, six primers were improved. The other failed five primers were corrected by refractory modification. MICA genotypes by ASPE on microarrays showed the same results as those by nucleotide sequencing. On the basis of these results, ASPE on microarrays may provide high-throughput genotyping for MICA alleles for population studies, disease-gene associations and HSCT.

  2. Evaluation de la tolérance et de l'efficacité du traitement de l'hépatite virale chronique C chez les patients drépanocytaires homozygotes

    PubMed Central

    El Agheb, Mohamed Ould Mohamed; Grange, Jean-Didier

    2015-01-01

    La drépanocytose est une maladie génétique à transmission autosomale codominante. Les patients homozygotes ont des crises hémolytiques qui génèrent les symptômes cliniques. Il s'agit d'une maladie fréquente. En France, la plupart des cas hospitalisés sont observés en Ile de France et aux Antilles. Le pronostic des patients s'est beaucoup amélioré ces dernières années. L’âge médian au décès a doublé en 20 ans. Il est passé de 18 à 36 ans, témoignant d'une meilleure prise en charge des malades. De ce fait, les complications hépatiques de la maladie, et notamment celles liées à l'hépatite virale chronique C, sont de plus en plus fréquentes. La Ribavirine étant contre indiquée dans le traitement de l'hépatite C chez les malades atteints d'anémie hémolytique (talassémie, drépanocytose), il n'existe que très peu de cas publiés dans les littératures et aucun cas traité par trithérapie antivirale incluant un inhibiteur de protéase. Le but de ce travail était d’évaluer la tolérance, l'efficacité du traitement de l'hépatite virale chronique C chez des patients drépanocytaires homozygotes. Dans la cohorte de patients drépanocytaires homozygotes adultes de l'hôpital Tenon (n = 560), la prévalence de l'hépatite C chez les derepanocytaires était de 7% (n = 38) en 2012. Il s'agissait de 15 hommes et 23 femmes âgés de 20 à 59 ans. Vingt-cinq patients avaient reçu plus de 10 transfusions et 13 patients avaient reçu moins de 10 transfusions au cours des années précédant le bilan. La répartition des génotypes était: G1 (n = 7); G2 (n = 2); G3 (n = 1); G4 (n = 6); G inconnu (n = 22). Neuf patients ont été traités dont 8 par bithérapie (Peg/Rbv) et 1 par trithérapie (télaprevir). La posologie de ribavirine était supérieure ou égale à 800mg/jour chez 7 patients et inférieure à cette dose chez les deux autres patients. Le score METAVIR de fibrose était: F1 (n = 3), F2 (n = 4) et F 3 (n = 1);un patient n'a pas

  3. Use of allele scores as instrumental variables for Mendelian randomization

    PubMed Central

    Burgess, Stephen; Thompson, Simon G

    2013-01-01

    Background An allele score is a single variable summarizing multiple genetic variants associated with a risk factor. It is calculated as the total number of risk factor-increasing alleles for an individual (unweighted score), or the sum of weights for each allele corresponding to estimated genetic effect sizes (weighted score). An allele score can be used in a Mendelian randomization analysis to estimate the causal effect of the risk factor on an outcome. Methods Data were simulated to investigate the use of allele scores in Mendelian randomization where conventional instrumental variable techniques using multiple genetic variants demonstrate ‘weak instrument’ bias. The robustness of estimates using the allele score to misspecification (for example non-linearity, effect modification) and to violations of the instrumental variable assumptions was assessed. Results Causal estimates using a correctly specified allele score were unbiased with appropriate coverage levels. The estimates were generally robust to misspecification of the allele score, but not to instrumental variable violations, even if the majority of variants in the allele score were valid instruments. Using a weighted rather than an unweighted allele score increased power, but the increase was small when genetic variants had similar effect sizes. Naive use of the data under analysis to choose which variants to include in an allele score, or for deriving weights, resulted in substantial biases. Conclusions Allele scores enable valid causal estimates with large numbers of genetic variants. The stringency of criteria for genetic variants in Mendelian randomization should be maintained for all variants in an allele score. PMID:24062299

  4. Allele-specific disparity in breast cancer

    PubMed Central

    2011-01-01

    Background In a cancer cell the number of copies of a locus may vary due to amplification and deletion and these variations are denoted as copy number alterations (CNAs). We focus on the disparity of CNAs in tumour samples, which were compared to those in blood in order to identify the directional loss of heterozygosity. Methods We propose a numerical algorithm and apply it to data from the Illumina 109K-SNP array on 112 samples from breast cancer patients. B-allele frequency (BAF) and log R ratio (LRR) of Illumina were used to estimate Euclidian distances. For each locus, we compared genotypes in blood and tumour for subset of samples being heterozygous in blood. We identified loci showing preferential disparity from heterozygous toward either the A/B-allele homozygous (allelic disparity). The chi-squared and Cochran-Armitage trend tests were used to examine whether there is an association between high levels of disparity in single nucleotide polymorphisms (SNPs) and molecular, clinical and tumour-related parameters. To identify pathways and network functions over-represented within the resulting gene sets, we used Ingenuity Pathway Analysis (IPA). Results To identify loci with a high level of disparity, we selected SNPs 1) with a substantial degree of disparity and 2) with substantial frequency (at least 50% of the samples heterozygous for the respective locus). We report the overall difference in disparity in high-grade tumours compared to low-grade tumours (p-value < 0.001) and significant associations between disparity in multiple single loci and clinical parameters. The most significantly associated network functions within the genes represented in the loci of disparity were identified, including lipid metabolism, small-molecule biochemistry, and nervous system development and function. No evidence for over-representation of directional disparity in a list of stem cell genes was obtained, however genes appeared to be more often altered by deletion than by

  5. Serotonin Transporter Gene Moderates Associations between Mood, Memory and Hippocampal Volume

    PubMed Central

    Price, Jenessa S.; Strong, Judith; Eliassen, James; McQueeny, Tim; Miller, Megan; Padula, Claudia B.; Shear, Paula K.; Lisdahl, Krista M.

    2015-01-01

    Background The short (S) allele of the serotonin transporter gene (5-HTTLPR) is associated with reduced serotonin turnover compared to the long (L) allele in Caucasians. Few studies have examined its impact on memory and brain structure in healthy young adults. Methods Participants included 51 healthy young adults (25 female; ages 18-25). Multiple regressions examined the independent contribution of 5-HTTLPR biomarker genotype and its interactions with gender and sub-clinical depressive symptoms on hippocampal volumes and memory. Results The 5-HTTLPR genotype significantly interacted with gender in predicting larger left hippocampal volumes in S-carrying females and smaller hippocampal volumes in males (p<.03). Gender also moderated the impact of the 5-HTTLPR on neurocognition. In females, S allele carriers had poorer visual recall compared to L carriers (p<.05). A three-way interaction between 5-HTTLPR, gender, and depressive symptoms was also observed (p<.04). In females, larger left hippocampal volumes were associated with increased depressive symptoms while the opposite was seen in males. Finally, in male and female S carriers, increased depressive symptoms were marginally associated with poorer verbal memory (p<.09). Conclusions In females, the 5-HTTLPR S allele was associated with poorer memory performance, increased depressive symptoms and larger hippocampal volumes. In males, the S allele predicted smaller hippocampal volumes and increased depressive symptoms. The opposite morphometric patterns likely reflect gender differences in adolescent hippocampal development. Larger longitudinal studies are needed to examine whether the impact of 5-HTTLPR genotype on neurocognition across development differs according to extent of mood symptoms and gender. PMID:23266326

  6. Neuroticism-related personality traits are related to symptom severity in patients with premenstrual dysphoric disorder and to the serotonin transporter gene-linked polymorphism 5-HTTPLPR.

    PubMed

    Gingnell, Malin; Comasco, Erika; Oreland, Lars; Fredrikson, Mats; Sundström-Poromaa, Inger

    2010-10-01

    Neuroticism has been linked to a functional polymorphism in the serotonin transporter gene (5-HTTLPR), with short-allele carriers being overrepresented among high-scorers on neuroticism. Studies evaluating neuroticism-related personality traits in relation to the 5-HTTLPR polymorphism among patients with premenstrual dysphoric disorder (PMDD) and are lacking. The primary aim of this study was to evaluate the relationship between PMDD and neuroticism-related personality traits, and secondly, to relate the personality trait scores of PMDD patients to experienced symptom severity and to the 5-HTTLPR short allele. Thirty PMDD patients and 55 asymptomatic healthy controls were included in the study. The Swedish Universities Scale of Personality was used to evaluate personality traits. Genotype analyses were available in 27 PMDD patients and 18 healthy controls. Women with PMDD displayed higher levels of neuroticism-related personality traits (psychic trait anxiety, somatic trait anxiety, embitterment, stress susceptibility and mistrust) than healthy controls, and these effects were most prominent in women with more severe luteal phase symptoms. Furthermore, PMDD patients with at least one copy of the short allele of the 5-HTTLPR polymorphism scored higher on psychic trait anxiety and lack of assertiveness than PMDD patients who were homozygous for the long allele. PMDD patients who suffer from more severe luteal phase symptoms also display increased scores of neuroticism-related personality traits in comparison with healthy controls. Within the group of PMDD patients, differences in certain personality trait scores are associated with the short allele of the 5-HTTLPR polymorphism.

  7. Identification of a novel HLA-A allele, A*3120.

    PubMed

    Chang, Y; Pascual, C J; Alonzo, P; Chamizo, A

    2009-03-01

    A novel human leukocyte antigen (HLA)-A allele, HLA-A*3120, was first identified in a National Marrow Donor Program (NMDP) donor. The A*3120 allele resulted from a single nucleotide substitution (T to G) at codon 92 of exon 3 of A*310102. The substitution caused an amino acid change (serine to alanine). This novel allele was also seen in two other unrelated NMDP donors.

  8. Reduced carriership of 4G allele of plasminogen activator inhibitor-1 4G/5G polymorphism in very young survivors of myocardial infarction.

    PubMed

    Rallidis, Loukianos S; Gialeraki, Argyri; Merkouri, Efrosyni; Liakos, George; Dagres, Nikolaos; Sionis, Dimitrios; Travlou, Anthi; Lekakis, John; Kremastinos, Dimitrios T

    2010-05-01

    There are limited and controversial data regarding the impact of 4G/5G polymorphism of the plasminogen activator inhibitor-1 (PAI-1) gene in the pathogenesis of premature myocardial infarction (MI). We explored whether 4G/5G polymorphism of the PAI-1 gene is associated with the development of MI allele carriers (4G/4G and 4G/5G genotypes) of PAI-1 were less frequent in patients than in controls (69.6 vs. 83.6%, P = 0.007). 4G carriership of the polymorphism of PAI-1 was associated with lower risk for acute MI (odds ratio 0.45, 95% confidence interval 0.23-0.88, P = 0.02) after adjusting for major cardiovascular risk factors. Patients possessing the 4G allele had higher PAI-1 plasma levels (32.2 +/- 25 vs. 22.2 +/- 11.3 ng/ml, P = 0.006) but lower lipoprotein(a) levels (10.1 [2.1-29.9] vs. 15.3 [8.2-57.1] mg/dl, P = 0.03) compared to 5G/5G homozygotes. Our data indicate that the 4G allele of the PAI-1 4G/5G polymorphism is less frequent among survivors of MI at very young age compared with matched controls.

  9. Stressful life events increase aggression and alcohol use in young carriers of the GABRA2 rs279826/rs279858 A-allele.

    PubMed

    Kiive, Evelyn; Laas, Kariina; Vaht, Mariliis; Veidebaum, Toomas; Harro, Jaanus

    2017-02-23

    Research of GABRA2 gene in alcohol use and impulse control suggests its role in aggressive behaviour. The purpose of the present study was to examine the effects of GABRA2 genotype and stressful life events on aggressive behaviour, alcohol use frequency and occurrence of alcohol use disorder in a population representative sample of adolescents followed up from third grade to 25 years of age. The sample consisted of the younger cohort of the longitudinal Estonian Children Personality, Behaviour and Health Study. Aggressive behaviour was rated with the activity scale of af Klinteberg, Illinois Bully Scale and Buss-Perry Aggression Questionnaire. Stressful life events and alcohol use were self-reported. Life history of aggression and lifetime occurrence of psychiatric disorders were estimated in a structured interview. The sample was genotyped for GABRA2 rs279826 and rs279858 polymorphisms that are in strong linkage disequilibrium and yielded very similar findings: Higher number of stressful life events reported at age 15 was associated with increased fighting in A-allele carriers, but not in GG homozygotes. At age 25, A-allele carriers with more stressful life events scored higher on physical aggression than those with less stress, and this was also observed regarding life history of aggression. A-allele carriers exposed to higher stress had consumed alcoholic beverages more frequently at age 15, and by age 25, they had alcohol use disorder with higher prevalence. The results of the present study suggest that the GABRA2 genotype interacts with stress in young people with impact on the development of alcohol use and aggressive behaviour.

  10. Novel HLA-A and HLA-B alleles.

    PubMed

    Hurley, C K; Steiner, N; Kosman, C; Mitton, W; Koester, R; Bei, M; Bush, J; McCormack, J; Hahn, A; Henson, V; Hoyer, R; Wade, J A; Hartzman, R J; Ng, J

    1998-07-01

    Nine novel HLA-A and HLA-B alleles are described: A*2609, A*6803, A*6806, B*1539, B*1540, B*2712, B*4103, B*5109, and B*5603. Most appear to have arisen by gene conversion events. B*5603 appears to have arisen by a reciprocal recombination event joining exon 2 of a B*55/ *56 allele with exon 3 of a B*15 allele. Serologically, the antigen encoded by this allele types with broad B22- and Bw6-specific alloantisera. Also unique, the antigen encoded by B*2712 does not react with B27-specific alloantisera but does react with Bw6-specific alloantisera.

  11. Mutated tumor alleles are expressed according to their DNA frequency.

    PubMed

    Castle, John C; Loewer, Martin; Boegel, Sebastian; Tadmor, Arbel D; Boisguerin, Valesca; de Graaf, Jos; Paret, Claudia; Diken, Mustafa; Kreiter, Sebastian; Türeci, Özlem; Sahin, Ugur

    2014-04-22

    The transcription of tumor mutations from DNA into RNA has implications for biology, epigenetics and clinical practice. It is not clear if mutations are in general transcribed and, if so, at what proportion to the wild-type allele. Here, we examined the correlation between DNA mutation allele frequency and RNA mutation allele frequency. We sequenced the exome and transcriptome of tumor cell lines with large copy number variations, identified heterozygous single nucleotide mutations and absolute DNA copy number, and determined the corresponding DNA and RNA mutation allele fraction. We found that 99% of the DNA mutations in expressed genes are expressed as RNA. Moreover, we found a high correlation between the DNA and RNA mutation allele frequency. Exceptions are mutations that cause premature termination codons and therefore activate nonsense-mediated decay. Beyond this, we did not find evidence of any wide-scale mechanism, such as allele-specific epigenetic silencing, preferentially promoting mutated or wild-type alleles. In conclusion, our data strongly suggest that genes are equally transcribed from all alleles, mutated and wild-type, and thus transcribed in proportion to their DNA allele frequency.

  12. Analyses of Allele-Specific Gene Expression in Highly Divergent Mouse Crosses Identifies Pervasive Allelic Imbalance

    PubMed Central

    Crowley, James J; Zhabotynsky, Vasyl; Sun, Wei; Huang, Shunping; Pakatci, Isa Kemal; Kim, Yunjung; Wang, Jeremy R; Morgan, Andrew P; Calaway, John D; Aylor, David L; Yun, Zaining; Bell, Timothy A; Buus, Ryan J; Calaway, Mark E; Didion, John P; Gooch, Terry J; Hansen, Stephanie D; Robinson, Nashiya N; Shaw, Ginger D; Spence, Jason S; Quackenbush, Corey R; Barrick, Cordelia J; Nonneman, Randal J.; Kim, Kyungsu; Xenakis, James; Xie, Yuying; Valdar, William; Lenarcic, Alan B; Wang, Wei; Welsh, Catherine E; Fu, Chen-Ping; Zhang, Zhaojun; Holt, James; Guo, Zhishan; Threadgill, David W; Tarantino, Lisa M; Miller, Darla R; Zou, Fei; McMillan, Leonard; Sullivan, Patrick F; de Villena, Fernando Pardo-Manuel

    2015-01-01

    Complex human traits are influenced by variation in regulatory DNA through mechanisms that are not fully understood. Since regulatory elements are conserved between humans and mice, a thorough annotation of cis regulatory variants in mice could aid in this process. Here we provide a detailed portrait of mouse gene expression across multiple tissues in a three-way diallel. Greater than 80% of mouse genes have cis regulatory variation. These effects influence complex traits and usually extend to the human ortholog. Further, we estimate that at least one in every thousand SNPs creates a cis regulatory effect. We also observe two types of parent-of-origin effects, including classical imprinting and a novel, global allelic imbalance in favor of the paternal allele. We conclude that, as with humans, pervasive regulatory variation influences complex genetic traits in mice and provide a new resource toward understanding the genetic control of transcription in mammals. PMID:25730764

  13. Multimer Formation Explains Allelic Suppression of PRDM9 Recombination Hotspots

    PubMed Central

    Baker, Christopher L.; Petkova, Pavlina; Walker, Michael; Flachs, Petr; Mihola, Ondrej; Trachtulec, Zdenek; Petkov, Petko M.; Paigen, Kenneth

    2015-01-01

    Genetic recombination during meiosis functions to increase genetic diversity, promotes elimination of deleterious alleles, and helps assure proper segregation of chromatids. Mammalian recombination events are concentrated at specialized sites, termed hotspots, whose locations are determined by PRDM9, a zinc finger DNA-binding histone methyltransferase. Prdm9 is highly polymorphic with most alleles activating their own set of hotspots. In populations exhibiting high frequencies of heterozygosity, questions remain about the influences different alleles have in heterozygous individuals where the two variant forms of PRDM9 typically do not activate equivalent populations of hotspots. We now find that, in addition to activating its own hotspots, the presence of one Prdm9 allele can modify the activity of hotspots activated by the other allele. PRDM9 function is also dosage sensitive; Prdm9 +/- heterozygous null mice have reduced numbers and less active hotspots and increased numbers of aberrant germ cells. In mice carrying two Prdm9 alleles, there is allelic competition; the stronger Prdm9 allele can partially or entirely suppress chromatin modification and recombination at hotspots of the weaker allele. In cell cultures, PRDM9 protein variants form functional heteromeric complexes which can bind hotspots sequences. When a heteromeric complex binds at a hotspot of one PRDM9 variant, the other PRDM9 variant, which would otherwise not bind, can still methylate hotspot nucleosomes. We propose that in heterozygous individuals the underlying molecular mechanism of allelic suppression results from formation of PRDM9 heteromers, where the DNA binding activity of one protein variant dominantly directs recombination initiation towards its own hotspots, effectively titrating down recombination by the other protein variant. In natural populations with many heterozygous individuals, allelic competition will influence the recombination landscape. PMID:26368021

  14. Multimer Formation Explains Allelic Suppression of PRDM9 Recombination Hotspots.

    PubMed

    Baker, Christopher L; Petkova, Pavlina; Walker, Michael; Flachs, Petr; Mihola, Ondrej; Trachtulec, Zdenek; Petkov, Petko M; Paigen, Kenneth

    2015-09-01

    Genetic recombination during meiosis functions to increase genetic diversity, promotes elimination of deleterious alleles, and helps assure proper segregation of chromatids. Mammalian recombination events are concentrated at specialized sites, termed hotspots, whose locations are determined by PRDM9, a zinc finger DNA-binding histone methyltransferase. Prdm9 is highly polymorphic with most alleles activating their own set of hotspots. In populations exhibiting high frequencies of heterozygosity, questions remain about the influences different alleles have in heterozygous individuals where the two variant forms of PRDM9 typically do not activate equivalent populations of hotspots. We now find that, in addition to activating its own hotspots, the presence of one Prdm9 allele can modify the activity of hotspots activated by the other allele. PRDM9 function is also dosage sensitive; Prdm9+/- heterozygous null mice have reduced numbers and less active hotspots and increased numbers of aberrant germ cells. In mice carrying two Prdm9 alleles, there is allelic competition; the stronger Prdm9 allele can partially or entirely suppress chromatin modification and recombination at hotspots of the weaker allele. In cell cultures, PRDM9 protein variants form functional heteromeric complexes which can bind hotspots sequences. When a heteromeric complex binds at a hotspot of one PRDM9 variant, the other PRDM9 variant, which would otherwise not bind, can still methylate hotspot nucleosomes. We propose that in heterozygous individuals the underlying molecular mechanism of allelic suppression results from formation of PRDM9 heteromers, where the DNA binding activity of one protein variant dominantly directs recombination initiation towards its own hotspots, effectively titrating down recombination by the other protein variant. In natural populations with many heterozygous individuals, allelic competition will influence the recombination landscape.

  15. Observations Suggesting Allelism of the Achondroplasia and Hypochondroplasia Genes

    PubMed Central

    McKusick, Victor A.; Kelly, Thaddeus E.; Dorst, John P.

    1973-01-01

    It is argued that there are at least two alleles at the achondroplasia locus: one responsible for classic achondroplasia and one responsible for hypochondroplasia. Homozygosity for the achondroplasia gene produces a lethal skeletal dysplasia; homozygosity for hypochondroplasia has not been described. We report here a child considered to be a genetic compound for the achondroplasia and hypochondroplasia alleles. Images PMID:4697848

  16. "Viable motheaten," a new allele at the motheaten locus. I. Pathology.

    PubMed Central

    Shultz, L. D.; Coman, D. R.; Bailey, C. L.; Beamer, W. G.; Sidman, C. L.

    1984-01-01

    A new spontaneous autosomal recessive mutation has recently occurred at the motheaten (me) locus on Chromosome 6 in strain C57BL/6J mice. Homozygotes for the new allele, designated "viable motheaten" (mev), have a mean life span of 61 +/- 2.4 days, compared with only 22 +/- 1.3 days for C57BL/6J-me/me mice. Like the original motheaten mutation, the immediate cause of death in mev/mev mice appears to be severe pneumonitis associated with accumulations of macrophages, granulocytes, and lymphocytes in the lungs. However, because of its longer life span, progression of the disease in mev/mev mice is more amenable to investigation. Eosinophilic crystalline material in alveolar macrophages from mev/mev mice is associated with extravasation of erythrocytes into alveoli. These crystals are morphologically indistinguishable from hematoidin, which results from hemoglobin breakdown following uptake of erythrocytes by macrophages. Severe macrocytic hypochromic anemia with abnormalities in size and shape of erythrocytes develops by 7 weeks. A two-fold increase in peripheral leukocyte count and a five-fold increase in the percentage of neutrophils is seen by 10 weeks. Viable motheaten mice develop focal granulocytic skin lesions by 4 days of age, show depletion of cells from the thymus cortex by 4 weeks, and lack lymphoid follicles in the lymph nodes, spleen, and Peyer's patches. Excessive erythropoiesis and myelopoiesis in the spleen result in marked splenomegaly. Lymph nodes and spleens from mev/mev mice contain increased numbers of plasma cells by 3 weeks; and by 6 weeks, large numbers of atypical plasma cells with Russell bodies are evident. Development of glomerulonephritis by 10 weeks is characterized by granular depositis of immunoglobulin and complement within glomeruli. A twofold increase of blood urea nitrogen levels is present by 15 weeks. Sterility of male mev/mev mice is associated with Leydig cell depletion in the testes, lowered testosterone levels, and impaired

  17. Assortative mating can impede or facilitate fixation of underdominant alleles.

    PubMed

    Newberry, Mitchell G; McCandlish, David M; Plotkin, Joshua B

    2016-12-01

    Underdominant mutations have fixed between divergent species, yet classical models suggest that rare underdominant alleles are purged quickly except in small or subdivided populations. We predict that underdominant alleles that also influence mate choice, such as those affecting coloration patterns visible to mates and predators alike, can fix more readily. We analyze a mechanistic model of positive assortative mating in which individuals have n chances to sample compatible mates. This one-parameter model naturally spans random mating (n=1) and complete assortment (n→∞), yet it produces sexual selection whose strength depends non-monotonically on n. This sexual selection interacts with viability selection to either inhibit or facilitate fixation. As mating opportunities increase, underdominant alleles fix as frequently as neutral mutations, even though sexual selection and underdominance independently each suppress rare alleles. This mechanism allows underdominant alleles to fix in large populations and illustrates how life history can affect evolutionary change.

  18. Estimating Relatedness in the Presence of Null Alleles.

    PubMed

    Huang, Kang; Ritland, Kermit; Dunn, Derek W; Qi, Xiaoguang; Guo, Songtao; Li, Baoguo

    2016-01-01

    Studies of genetics and ecology often require estimates of relatedness coefficients based on genetic marker data. However, with the presence of null alleles, an observed genotype can represent one of several possible true genotypes. This results in biased estimates of relatedness. As the numbers of marker loci are often limited, loci with null alleles cannot be abandoned without substantial loss of statistical power. Here, we show how loci with null alleles can be incorporated into six estimators of relatedness (two novel). We evaluate the performance of various estimators before and after correction for null alleles. If the frequency of a null allele is <0.1, some estimators can be used directly without adjustment; if it is >0.5, the potency of estimation is too low and such a locus should be excluded. We make available a software package entitled PolyRelatedness v1.6, which enables researchers to optimize these estimators to best fit a particular data set.

  19. A gene feature enumeration approach for describing HLA allele polymorphism.

    PubMed

    Mack, Steven J

    2015-12-01

    HLA genotyping via next generation sequencing (NGS) poses challenges for the use of HLA allele names to analyze and discuss sequence polymorphism. NGS will identify many new synonymous and non-coding HLA sequence variants. Allele names identify the types of nucleotide polymorphism that define an allele (non-synonymous, synonymous and non-coding changes), but do not describe how polymorphism is distributed among the individual features (the flanking untranslated regions, exons and introns) of a gene. Further, HLA alleles cannot be named in the absence of antigen-recognition domain (ARD) encoding exons. Here, a system for describing HLA polymorphism in terms of HLA gene features (GFs) is proposed. This system enumerates the unique nucleotide sequences for each GF in an HLA gene, and records these in a GF enumeration notation that allows both more granular dissection of allele-level HLA polymorphism and the discussion and analysis of GFs in the absence of ARD-encoding exon sequences.

  20. Frequency of FCGR3B Alleles in Thai Blood Donors

    PubMed Central

    Kaset, Chollanot; Leetrakool, Nipapan; Intharanut, Kamphon

    2013-01-01

    Background Human neutrophil antigens (HNAs) are involved in autoimmune and alloimmune neutropenia and transfusion-related acute lung injury. The HNA-1 system is important in immunogenetics, and allele frequencies have been described in different populations. This study investigated the frequency of FCGR3B alleles encoding HNA-1a, HNA-1b, and HNA-1c among Thai blood donors and compared these frequencies with those previously reported for other populations. Methods Eight hundred DNA samples obtained from unrelated healthy blood donors at the National Blood Centre, Thai Red Cross Society, Bangkok, and the Blood Bank, Faculty of Medicine, Chiang Mai University, Chiang Mai, Thailand, were included. Samples were simultaneously typed for each FCGR3B allele using an in-house polymerase chain reaction with sequence-specific primer (PCR-SSP) technique. Results The frequencies of FCGR3B*1, FCGR3B*2, and FCGR3B*3 alleles in central Thai blood donors were 0.548, 0.452, and 0.004, respectively; only FCGR3B*1 and FCGR3B*2 alleles were found in northern Thai blood donors (0.68 and 0.32, respectively). Compared with other Asian populations, central Thais had higher frequencies of the FCGR3B*2 allele (P<0.001), while the frequencies of the FCGR3B*1 and FCGR3B*2 alleles in northern Thais were similar to those previously reported in Taiwanese and Japanese populations. In contrast, the frequencies of the FCGR3B*1 and FCGR3B*2 alleles in the northern Thai population were statistically different from those observed in central Thai, Korean, German, and Turkish populations. Conclusions FCGR3B allele frequencies were significantly different between central and northern Thai blood donors. Our in-house PCR-SSP method is a simple, cost-effective, and convenient method for FCGR3B allele detection. PMID:24205492

  1. Microsatellite null alleles and estimation of population differentiation.

    PubMed

    Chapuis, Marie-Pierre; Estoup, Arnaud

    2007-03-01

    Microsatellite null alleles are commonly encountered in population genetics studies, yet little is known about their impact on the estimation of population differentiation. Computer simulations based on the coalescent were used to investigate the evolutionary dynamics of null alleles, their impact on F(ST) and genetic distances, and the efficiency of estimators of null allele frequency. Further, we explored how the existing method for correcting genotype data for null alleles performed in estimating F(ST) and genetic distances, and we compared this method with a new method proposed here (for F(ST) only). Null alleles were likely to be encountered in populations with a large effective size, with an unusually high mutation rate in the flanking regions, and that have diverged from the population from which the cloned allele state was drawn and the primers designed. When populations were significantly differentiated, F(ST) and genetic distances were overestimated in the presence of null alleles. Frequency of null alleles was estimated precisely with the algorithm presented in Dempster et al. (1977). The conventional method for correcting genotype data for null alleles did not provide an accurate estimate of F(ST) and genetic distances. However, the use of the genetic distance of Cavalli-Sforza and Edwards (1967) corrected by the conventional method gave better estimates than those obtained without correction. F(ST) estimation from corrected genotype frequencies performed well when restricted to visible allele sizes. Both the proposed method and the traditional correction method have been implemented in a program that is available free of charge at http://www.montpellier.inra.fr/URLB/. We used 2 published microsatellite data sets based on original and redesigned pairs of primers to empirically confirm our simulation results.

  2. Allele-Specific Reduction of the Mutant Huntingtin Allele Using Transcription Activator-Like Effectors in Human Huntington's Disease Fibroblasts.

    PubMed

    Fink, Kyle D; Deng, Peter; Gutierrez, Josh; Anderson, Joseph S; Torrest, Audrey; Komarla, Anvita; Kalomoiris, Stefanos; Cary, Whitney; Anderson, Johnathon D; Gruenloh, William; Duffy, Alexandra; Tempkin, Teresa; Annett, Geralyn; Wheelock, Vicki; Segal, David J; Nolta, Jan A

    2016-01-01

    Huntington's disease (HD) is an autosomal dominant neurodegenerative disorder caused by an abnormal expansion of CAG repeats. Although pathogenesis has been attributed to this polyglutamine expansion, the underlying mechanisms through which the huntingtin protein functions have yet to be elucidated. It has been suggested that postnatal reduction of mutant huntingtin through protein interference or conditional gene knockout could prove to be an effective therapy for patients suffering from HD. For allele-specific targeting, transcription activator-like effectors (TALE) were designed to target single-nucleotide polymorphisms (SNP) in the mutant allele and packaged into a vector backbone containing KRAB to promote transcriptional repression of the disease-associated allele. Additional TALEs were packaged into a vector backbone containing heterodimeric FokI and were designed to be used as nucleases (TALEN) to cause a CAG-collapse in the mutant allele. Human HD fibroblasts were treated with each TALE-SNP or TALEN. Allele-expression was measured using a SNP-genotyping assay and mutant protein aggregation was quantified with Western blots for anti-ubiquitin. The TALE-SNP and TALEN significantly reduced mutant allele expression (p < 0.05) when compared to control transfections while not affecting expression of the nondisease allele. This study demonstrates the potential of allele-specific gene modification using TALE proteins, and provides a foundation for targeted treatment for individuals suffering from Huntington's or other genetically linked diseases.

  3. Allele-specific H3K79 Di- versus trimethylation distinguishes opposite parental alleles at imprinted regions.

    PubMed

    Singh, Purnima; Han, Li; Rivas, Guillermo E; Lee, Dong-Hoon; Nicholson, Thomas B; Larson, Garrett P; Chen, Taiping; Szabó, Piroska E

    2010-06-01

    Imprinted gene expression corresponds to parental allele-specific DNA CpG methylation and chromatin composition. Histone tail covalent modifications have been extensively studied, but it is not known whether modifications in the histone globular domains can also discriminate between the parental alleles. Using multiplex chromatin immunoprecipitation-single nucleotide primer extension (ChIP-SNuPE) assays, we measured the allele-specific enrichment of H3K79 methylation and H4K91 acetylation along the H19/Igf2 imprinted domain. Whereas H3K79me1, H3K79me2, and H4K91ac displayed a paternal-specific enrichment at the paternally expressed Igf2 locus, H3K79me3 was paternally biased at the maternally expressed H19 locus, including the paternally methylated imprinting control region (ICR). We found that these allele-specific differences depended on CTCF binding in the maternal ICR allele. We analyzed an additional 11 differentially methylated regions (DMRs) and found that, in general, H3K79me3 was associated with the CpG-methylated alleles, whereas H3K79me1, H3K79me2, and H4K91ac enrichment was specific to the unmethylated alleles. Our data suggest that allele-specific differences in the globular histone domains may constitute a layer of the "histone code" at imprinted genes.

  4. Cooperation of Adhesin Alleles in Salmonella-Host Tropism

    PubMed Central

    De Masi, Leon; Yue, Min; Hu, Changmin; Rakov, Alexey V.; Rankin, Shelley C.

    2017-01-01

    ABSTRACT Allelic combinations and host specificities for three fimbrial adhesins, FimH, BcfD, and StfH, were compared for 262 strains of Salmonella enterica serovar Newport, a frequent human and livestock pathogen. Like FimH, BcfD had two major alleles (designated A and B), whereas StfH had two allelic groups, each with two alleles (subgroup A1 and A2 and subgroup B1 and B2). The most prevalent combinations of FimH/BcfD/StfH alleles in S. Newport were A/A/A1 and B/B/B1. The former set was most frequently found in bovine and porcine strains, whereas the latter combination was most frequently found in environmental and human isolates. Bacteria genetically engineered to express Fim, Bcf, or Stf fimbriae on their surface were tested with the different alleles for binding to human, porcine, and bovine intestinal epithelial cells. The major allelic combinations with bovine and porcine strains (A/A/A1) or with human isolates (B/B/B1) provided at least two alleles capable of binding significantly better than the other alleles to an intestinal epithelial cell line from the respective host(s). However, each combination of alleles kept at least one allele mediating binding to an intestinal epithelial cell from another host. These findings indicated that allelic variation in multiple adhesins of S. Newport contributes to bacterial adaptation to certain preferential hosts without losing the capacity to maintain a broad host range. IMPORTANCE Salmonella enterica remains a leading foodborne bacterial pathogen in the United States; infected livestock serve often as the source of contaminated food products. A study estimated that over a billion Salmonella gastroenteritis cases and up to 33 million typhoid cases occur annually worldwide, with 3.5 million deaths. Although many Salmonella strains with a broad host range present preferential associations with certain host species, it is not clear what determines the various levels of host adaptation. Here, causal properties of host

  5. Assignment of SNP allelic configuration in polyploids using competitive allele-specific PCR: application to citrus triploid progeny

    PubMed Central

    Cuenca, José; Aleza, Pablo; Navarro, Luis; Ollitrault, Patrick

    2013-01-01

    Background Polyploidy is a major component of eukaryote evolution. Estimation of allele copy numbers for molecular markers has long been considered a challenge for polyploid species, while this process is essential for most genetic research. With the increasing availability and whole-genome coverage of single nucleotide polymorphism (SNP) markers, it is essential to implement a versatile SNP genotyping method to assign allelic configuration efficiently in polyploids. Scope This work evaluates the usefulness of the KASPar method, based on competitive allele-specific PCR, for the assignment of SNP allelic configuration. Citrus was chosen as a model because of its economic importance, the ongoing worldwide polyploidy manipulation projects for cultivar and rootstock breeding, and the increasing availability of SNP markers. Conclusions Fifteen SNP markers were successfully designed that produced clear allele signals that were in agreement with previous genotyping results at the diploid level. The analysis of DNA mixes between two haploid lines (Clementine and pummelo) at 13 different ratios revealed a very high correlation (average = 0·9796; s.d. = 0·0094) between the allele ratio and two parameters [θ angle = tan−1 (y/x) and y′ = y/(x + y)] derived from the two normalized allele signals (x and y) provided by KASPar. Separated cluster analysis and analysis of variance (ANOVA) from mixed DNA simulating triploid and tetraploid hybrids provided 99·71 % correct allelic configuration. Moreover, triploid populations arising from 2n gametes and interploid crosses were easily genotyped and provided useful genetic information. This work demonstrates that the KASPar SNP genotyping technique is an efficient way to assign heterozygous allelic configurations within polyploid populations. This method is accurate, simple and cost-effective. Moreover, it may be useful for quantitative studies, such as relative allele-specific expression analysis and bulk segregant analysis

  6. Characterization of the dwg mutations: dwg and dwg(Bayer) are new mutant alleles of the Ggt1 gene.

    PubMed

    Tsuji, Takehito; Yamada, Kaoru; Kunieda, Tetsuo

    2009-01-01

    The dwg and dwg (Bayer) are allelic mutations of the mouse that are characterized by dwarfism, cataracts, and coat color change in homozygotes. The Ggt1 gene encodes gamma-glutamyltransferase 1 (GGT1), an extracellular membrane-bound enzyme that is critical for glutathione homeostasis. Both the dwg locus and Ggt1 gene are localized on mouse chromosome 10, and the phenotypes of GGT1-deficient mice with targeted disruption of the Ggt1 gene show remarkable similarities with those of dwg/dwg and dwg (Bayer)/dwg (Bayer) mice. This evidence led us to hypothesize that the Ggt1 gene is responsible for dwg and dwg (Bayer) mutations. In this study we characterized dwg mutations by investigating their association with the Ggt1 gene. Histological analysis revealed reduced numbers of proliferative and hypertrophic chondrocytes in the growth plate of dwg/dwg mice, which are characteristic abnormalities observed in GGT1-deficient mice. To identify the causative mutations of dwg mutations, we analyzed the Ggt1 gene in dwg/dwg and dwg (Bayer)/dwg (Bayer) mice. In dwg/dwg mice, 13 nucleotides on exon 7 of the Ggt1 gene were deleted, resulting in the generation of aberrant transcripts due to disrupted pre-mRNA splicing. Furthermore, dwg (Bayer)/dwg (Bayer) mice had a 46.7-kb deletion containing complete coding sequences of Ggt1 and AI646023 genes and the first exon of the Ggt5 gene, which is closely related to the Ggt1 gene as a member of the GGT gene family. These results indicate that both dwg and dwg (Bayer) have defective mutations of the Ggt1 gene. Thus, we concluded that mutations in the Ggt1 gene are responsible for the phenotypes of dwg/dwg and dwg (Bayer)/dwg (Bayer) mice.

  7. Generation of a Conditional Null Allele of Jumonji

    PubMed Central

    Mysliwiec, Matthew R.; Chen, Junqin; Powers, Patricia A.; Bartley, Christopher R.; Schneider, Michael D.; Lee, Youngsook

    2007-01-01

    Summary: The jumonji (jmj) gene plays important roles in multiple organ development in mouse, including cardiovascular development. Since JMJ is expressed widely during mouse development, it is essential that conditional knockout approaches be employed to ablate JMJ in a tissue-specific manner to identify the cell lineage specific roles of JMJ. In this report, we describe the establishment of a jmj conditional null allele in mice by generating a loxP-flanked (floxed) jmj allele, which allows the in vivo ablation of jmj via Cre recombinase-mediated deletion. Gene targeting was used to introduce loxP sites flanking exon 3 of the jmj allele to mouse embryonic stem cells. Our results indicate that the jmj floxed allele converts to a null allele in a heart-specific manner when embryos homozygous for the floxed jmj allele and carrying the α-myosin heavy chain promoter-Cre transgene were analyzed by Southern and Northern blot analyses. Therefore, this mouse line harboring the conditional jmj null allele will provide a valuable tool for deciphering the tissue and cell lineage specific roles of JMJ. PMID:16900512

  8. Allele Frequencies at Microsatellite Loci: The Stepwise Mutation Model Revisited

    PubMed Central

    Valdes, A. M.; Slatkin, M.; Freimer, N. B.

    1993-01-01

    We summarize available data on the frequencies of alleles at microsatellite loci in human populations and compare observed distributions of allele frequencies to those generated by a simulation of the stepwise mutation model. We show that observed frequency distributions at 108 loci are consistent with the results of the model under the assumption that mutations cause an increase or decrease in repeat number by one and under the condition that the product Nu, where N is the effective population size and u is the mutation rate, is larger than one. We show that the variance of the distribution of allele sizes is a useful estimator of Nu and performs much better than previously suggested estimators for the stepwise mutation model. In the data, there is no correlation between the mean and variance in allele size at a locus or between the number of alleles and mean allele size, which suggests that the mutation rate at these loci is independent of allele size. PMID:8454213

  9. Estimating relatedness and relationships using microsatellite loci with null alleles.

    PubMed

    Wagner, A P; Creel, S; Kalinowski, S T

    2006-11-01

    Relatedness is often estimated from microsatellite genotypes that include null alleles. When null alleles are present, observed genotypes represent one of several possible true genotypes. If null alleles are detected, but analyses do not adjust for their presence (ie, observed genotypes are treated as true genotypes), then estimates of relatedness and relationship can be incorrect. The number of loci available in many wildlife studies is limited, and loci with null alleles are commonly a large proportion of data that cannot be discarded without substantial loss of power. To resolve this problem, we present a new approach for estimating relatedness and relationships from data sets that include null alleles. Once it is recognized that the probability of the observed genotypes is dependent on the probabilities of a limited number of possible true genotypes, the required adjustments are straightforward. The concept can be applied to any existing estimators of relatedness and relationships. We review established maximum likelihood estimators and apply the correction in that setting. In an application of the corrected method to data from striped hyenas, we demonstrate that correcting for the presence of null alleles affect results substantially. Finally, we use simulated data to confirm that this method works better than two common approaches, namely ignoring the presence of null alleles or discarding affected loci.

  10. Quantifying RNA allelic ratios by microfluidic multiplex PCR and sequencing.

    PubMed

    Zhang, Rui; Li, Xin; Ramaswami, Gokul; Smith, Kevin S; Turecki, Gustavo; Montgomery, Stephen B; Li, Jin Billy

    2014-01-01

    We developed a targeted RNA sequencing method that couples microfluidics-based multiplex PCR and deep sequencing (mmPCR-seq) to uniformly and simultaneously amplify up to 960 loci in 48 samples independently of their gene expression levels and to accurately and cost-effectively measure allelic ratios even for low-quantity or low-quality RNA samples. We applied mmPCR-seq to RNA editing and allele-specific expression studies. mmPCR-seq complements RNA-seq for studying allelic variations in the transcriptome.

  11. A New Electrophoresis Technique to Seperate Microsatellite Alleles

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Traditional agarose and polyacrylamide gel electrophoresis have been used commonly for microsatellite (simple sequence repeats, SSRs) analysis, but they are labor- intensive and not always able to provide accurate sizes for different alleles. Capillary sequencers provide automated analysis and accur...

  12. Robust identification of local adaptation from allele frequencies.

    PubMed

    Günther, Torsten; Coop, Graham

    2013-09-01

    Comparing allele frequencies among populations that differ in environment has long been a tool for detecting loci involved in local adaptation. However, such analyses are complicated by an imperfect knowledge of population allele frequencies and neutral correlations of allele frequencies among populations due to shared population history and gene flow. Here we develop a set of methods to robustly test for unusual allele frequency patterns and correlations between environmental variables and allele frequencies while accounting for these complications based on a Bayesian model previously implemented in the software Bayenv. Using this model, we calculate a set of "standardized allele frequencies" that allows investigators to apply tests of their choice to multiple populations while accounting for sampling and covariance due to population history. We illustrate this first by showing that these standardized frequencies can be used to detect nonparametric correlations with environmental variables; these correlations are also less prone to spurious results due to outlier populations. We then demonstrate how these standardized allele frequencies can be used to construct a test to detect SNPs that deviate strongly from neutral population structure. This test is conceptually related to FST and is shown to be more powerful, as we account for population history. We also extend the model to next-generation sequencing of population pools-a cost-efficient way to estimate population allele frequencies, but one that introduces an additional level of sampling noise. The utility of these methods is demonstrated in simulations and by reanalyzing human SNP data from the Human Genome Diversity Panel populations and pooled next-generation sequencing data from Atlantic herring. An implementation of our method is available from http://gcbias.org.

  13. Sequencing of 15 new BoLA-DRB3 alleles.

    PubMed

    Wang, K; Sun, D; Zhang, Y

    2008-08-01

    The class II DR of bovine major histocompatibility complex of cattle (BoLA) plays a central role in the regulation of the immune response through their ability to present those peptides to T-cell receptors. In this work, we sequenced the exon2 of DRB3 to identify new alleles in Chinese yellow cattle, a total of 15 new BoLA-DRB3 alleles were found.

  14. DRD4 dopamine receptor allelic diversity in various primate species

    SciTech Connect

    Adamson, M.; Higley, D.; O`Brien, S.

    1994-09-01

    The DRD4 dopamine receptor is uniquely characterized by a 48 bp repeating segment within the coding region, located in exon III. Different DRD4 alleles are produced by the presence of additional 48 bp repeats, each of which adds 16 amino acids to the length of the 3rd intracytoplasmic loop of the receptor. The DRD4 receptor is therefore an intriguing candidate gene for behaviors which are influenced by dopamine function. In several human populations, DRD4 alleles with 2-8 and 10 repeats have previously been identified, and the 4 and 7 repeat alleles are the most abundant. We have determined DRD4 genotypes in the following nonhuman primate species: chimpanzee N=2, pygmy chimpanzee N=2, gorilla N=4, siamang N=2, Gelada baboon N=1, gibbon N=1, orangutan (Bornean and Sumatran) N=62, spider monkey N=4, owl monkey N=1, Colobus monkey N=1, Patas monkey N=1, ruffed lemur N=1, rhesus macaque N=8, and vervet monkey N=28. The degree of DRD4 polymorphism and which DRD4 alleles were present both showed considerable variation across primate species. In contrast to the human, rhesus macaque monkeys were monomorphic. The 4 and 7 repeat allels, highly abundant in the human, may not be present in certain other primates. For example, the four spider monkeys we studied showed the 7, 8 and 9 repeat length alleles and the only gibbon we analyzed was homozygous for the 9 repeat allele (thus far not observed in the human). Genotyping of other primate species and sequencing of the individual DRD4 repeat alleles in different species may help us determine the ancestral DRD4 repeat length and identify connections between DRD4 genotype and phenotype.

  15. [The HIV-infection outbreak in the town Lys'va (Perm region): homozygote genotype CCR5 delta32/CCR5 delta32 provides the high level of the persistence in the parenteral transmission of the virus].

    PubMed

    Riabov, G S; Kazennova, E V; Korepanova, L B; Mal'tseva, E A; Zhalnin, V V; Krasnikova, L A; Zverev, S Ia; Pokrovskiĭ, V V; Bobkov, A F; Weber, J N

    2002-01-01

    Specific features of human immunodeficiency virus type 1 (HIV-1) transmission among injecting drug users were studied on HIV infection outbreak in Lysva, the Perm region. During the period from November 1998 to March 2000, 32 injecting drug users infected with the subtype A HIV-1 variant originating from the same source, were found in this town. To understand the role of the CCR5 delta 32 mutation in parenteral transmission of HIV-1 the distribution of the mutant CCR5 delta 32 allele in HIV-infected and in non-infected but HIV-exposed drug users (n = 74) was analysed. The percentage of the homozygous CCR5 delta 32 genotype among HIV-exposed individuals (4/74, 5.4%) was significantly (p < 0.05) higher than the analogous rate for healthy blood donors in Russia (1/163, 0.6%). Thus, the homozygosity for this mutant allele confers a high resistance level to HIV even in parenteral transmission.

  16. Genetically-mediated Grey and White Matter Alteration in Normal 
Elderly Individuals with the CLU-C Allele Gene

    PubMed Central

    Qiu, Lihua; He, Yong; Tang, Hehan; Zhou, Yi; Wang, Jinhong; Zhang, Weiwei; Chen, Guangxiang; Zhao, Fei; Ouyang, Tingxue; Ju, Bin; Li, Zhengyan; Wang, Lanlan; Zou, Ling; Gong, Qiyong

    2016-01-01

    Abstract: Background Several genome-wide association studies have found that the rs11136000 polymorphism of the C allele (CLU-C) is associated with the risk for developing late-onset Alzheimer’s disease (LOAD). However, the effects of the CLU-C/C genotype on brain structure, including gray and white matter, are not adequately understood. Objectives We aimed to clarify the gray matter and white matter integrity changes in non-demented ageing individuals with the AD risk gene of the rs11136000 polymorphism of the C allele (CLU-C) and the correlation with cognitive performance. Methods Voxel-based analysis was used to compare the differences in high-resolution structural T1 and diffusion tensor imaging data between 31 CLU-C/C and 15 non-CLU-C/C carriers in non-demented older adults. Results Compared to non-CLU-C/C carriers, CLU-C homozygotes showed a reduced gray matter concentration (GMC) in the left parahippocampal gyrus, right middle frontal and temporal middle gyri, increased GMC in the left middle frontal and right fusiform gyri and increased gray matter volume (GMV) in the left middle frontal gyrus (P < 0.001). Decreased fractional anisotropy (FA) in the sub-gyral white matter of the left external capsule and left anterior cingulate and increased FA in the sub-gyral white matter of the left temporal lobe were also found in CLU-C/C genotype carriers. Moreover, the FA value in the left external capsule correlated with several cognitive measures. Conclusion Our findings provide further evidence for the CLU risk variant as a candidate gene for AD and may serve as a pre-clinical neuroimaging phenotype of late-onset AD. PMID:27396407

  17. SSR allelic variation in almond (Prunus dulcis Mill.).

    PubMed

    Xie, Hua; Sui, Yi; Chang, Feng-Qi; Xu, Yong; Ma, Rong-Cai

    2006-01-01

    Sixteen SSR markers including eight EST-SSR and eight genomic SSRs were used for genetic diversity analysis of 23 Chinese and 15 international almond cultivars. EST- and genomic SSR markers previously reported in species of Prunus, mainly peach, proved to be useful for almond genetic analysis. DNA sequences of 117 alleles of six of the 16 SSR loci were analysed to reveal sequence variation among the 38 almond accessions. For the four SSR loci with AG/CT repeats, no insertions or deletions were observed in the flanking regions of the 98 alleles sequenced. Allelic size variation of these loci resulted exclusively from differences in the structures of repeat motifs, which involved interruptions or occurrences of new motif repeats in addition to varying number of AG/CT repeats. Some alleles had a high number of uninterrupted repeat motifs, indicating that SSR mutational patterns differ among alleles at a given SSR locus within the almond species. Allelic homoplasy was observed in the SSR loci because of base substitutions, interruptions or compound repeat motifs. Substitutions in the repeat regions were found at two SSR loci, suggesting that point mutations operate on SSRs and hinder the further SSR expansion by introducing repeat interruptions to stabilize SSR loci. Furthermore, it was shown that some potential point mutations in the flanking regions are linked with new SSR repeat motif variation in almond and peach.

  18. Mutable R-Navajo Alleles of Cyclic Origin in Maize

    PubMed Central

    Brink, R. Alexander; Williams, Elizabeth

    1973-01-01

    The generation in cyclic fashion of 26 mutable R-Navajo (mRnj) alleles in maize involved transposition of a non-specific repressor of gene action, Modulator (Mp), first away from, and then back to, the R locus represented by the R-Navajo (Rnj) allele on chromosome 10. The mRnj alleles reconstituted in this way varied widely, and continuously, in mutability to Rnj—that is, in transposition of Mp away from the R locus, thus derepressing the Rnj gene. They were alike, or nearly so, however, in activating Ds chromosome breakage and in increasing the stability of variegated pericarp, another unstable compound allele comprising Mp conjoined with Prr on chromosomal 1. These latter two phenomena are based primarily on loci elsewhere in the genome. It is postulated that the 26 reconstituted mRnj alleles carry a common Mp which, however, is intercalated at a different site within each allele. Nucleotide sequence in the regions adjacent to Mp is assumed to determine the frequency with which a form of micro-nondisjunction occurs whereby Mp is released from a donor site. Transposition to a new site is interpreted in terms of a chromosome model that gives effect to nicking, or single strand breaks, occurring throughout the genome as a prerequisite to unwinding, strand separation, and replication, of the DNA double helix. PMID:17248592

  19. Allele-specific MMP-3 transcription under in vivo conditions

    SciTech Connect

    Zhu Chaoyong; Odeberg, Jacob; Hamsten, Anders; Eriksson, Per . E-mail: Per.Eriksson@ki.se

    2006-09-29

    A common matrix metalloproteinases-3 (MMP-3) -1612 5A/6A promoter polymorphism is associated with risk for cardiovascular disease, rheumatoid arthritis, and other diseases. Here we used the haplotype chromatin immunoprecipitation method to study allele-specific MMP-3 expression under in vivo conditions in heterozygous THP-1 cells. Pyrosequencing was used to analyse the ratio of 5A-allele to 6A-allele after chromatin immunoprecipitation using an antibody against phosphorylated active RNA polymerase II. There was no allele-specific difference in transcriptional activity during basal conditions, i.e., in unstimulated monocytic THP-1 cells. However, after stimulation of MMP-3 expression by monocyte differentiation or incubation with IL-1{beta}, the haplotype containing the 5A-allele was associated with higher transcriptional activity compared with the 6A-containing haplotype. Electromobility shift assay demonstrated increased binding of nuclear proteins to the 5A-allele after monocyte differentiation. In conclusion, the common MMP-3 5A/6A promoter polymorphism appears to be functional only during specific environmental conditions involving inflammation.

  20. Overdominant alleles in a population of variable size.

    PubMed Central

    Slatkin, M; Muirhead, C A

    1999-01-01

    An approximate method is developed to predict the number of strongly overdominant alleles in a population of which the size varies with time. The approximation relies on the strong-selection weak-mutation (SSWM) method introduced by J. H. Gillespie and leads to a Markov chain model that describes the number of common alleles in the population. The parameters of the transition matrix of the Markov chain depend in a simple way on the population size. For a population of constant size, the Markov chain leads to results that are nearly the same as those of N. Takahata. The Markov chain allows the prediction of the numbers of common alleles during and after a population bottleneck and the numbers of alleles surviving from before a bottleneck. This method is also adapted to modeling the case in which there are two classes of alleles, with one class causing a reduction in fitness relative to the other class. Very slight selection against one class can strongly affect the relative frequencies of the two classes and the relative ages of alleles in each class. PMID:10353917

  1. Impriniting of human H19: Allele-specific CpG methylation, loss of the active allele in Wilms tumor, and potential for somatic allele switching

    SciTech Connect

    Zhang, Y.; Shields, T.; Crenshaw, T.; Hao, Y.; Moulton, T.; Tycko, B. )

    1993-07-01

    Genomic imprinting and monoallelic gene expression appear to play a role in human genetic disease and tumorigenesis. The human H19 gene, at chromosome 11p15, has previously been shown to be monoallelically expressed. Since CpG methylation has been implicated in imprinting, the authors analyzed methylation of H19 DNA. In fetal and adult organs the transcriptionally silent H19 allele was extensively hypermethylated through the entire gene and its promoter, and, consistent with a functional role for DNA methylation, expression of an H19 promoter-reporter construct was inhibited by in vitro methylation. Gynogenetic ovarian teratomas were found to contain only hypomethylated H19 DNA, suggesting that the expressed H19 allele might be maternal. This was confirmed by analysis of 11p15 polymorphisms in a patient with Wilms tumor. The tumor had lost the maternal 11p15, and H19 expression in the normal kidney was exclusively from this allele. Imprinting of human H19 appears to be susceptible to tissue-specific modulation in somatic development; in one individual, cerebellar cells were found to express only the otherwise silent allele. Implications of these findings for the role of DNA methylation in imprinting and for H19 as a candidate imprinted tumor-suppressor gene are discussed. 57 refs., 7 figs.

  2. Distribution of BoLA-DRB3 allelic frequencies and identification of two new alleles in Iranian buffalo breed.

    PubMed

    Mosafer, J; Heydarpour, M; Manshad, E; Russell, G; Sulimova, G E

    2012-01-01

    The role of the major histocompatibility complex (MHC) in the immune response makes it an attractive candidate gene for associations with disease resistance and susceptibility. This study describes genetic variability in the BoLA-DRB3 in Iranian buffaloes. Heminested PCR-RFLP method was used to identify the frequency of BoLA-DRB3 alleles. The BoLA-DRB3 locus is highly polymorphic in the study herd (12 alleles). Almost 63.50% of the alleles were accounted for by four alleles (BoLA-DRB3.2 ∗48, ∗20, ∗21, and obe) in Iranian buffalo. The DRB3.2 ∗48 allele frequency (24.20%) was higher than the others. The frequencies of the DRB3.2 ∗20 and DRB3.2 ∗21 are 14.52 and 14.00, respectively, and obe and gbb have a new pattern. Significant distinctions have been found between Iranian buffalo and other cattle breed studied. In the Iranian buffaloes studied alleles associated with resistance to various diseases are found.

  3. Distribution of BoLA-DRB3 Allelic Frequencies and Identification of Two New Alleles in Iranian Buffalo Breed

    PubMed Central

    Mosafer, J.; Heydarpour, M.; Manshad, E.; Russell, G.; Sulimova, G. E.

    2012-01-01

    The role of the major histocompatibility complex (MHC) in the immune response makes it an attractive candidate gene for associations with disease resistance and susceptibility. This study describes genetic variability in the BoLA-DRB3 in Iranian buffaloes. Heminested PCR-RFLP method was used to identify the frequency of BoLA-DRB3 alleles. The BoLA-DRB3 locus is highly polymorphic in the study herd (12 alleles). Almost 63.50% of the alleles were accounted for by four alleles (BoLA-DRB3.2 ∗48, ∗20, ∗21, and obe) in Iranian buffalo. The DRB3.2 ∗48 allele frequency (24.20%) was higher than the others. The frequencies of the DRB3.2 ∗20 and DRB3.2 ∗21 are 14.52 and 14.00, respectively, and obe and gbb have a new pattern. Significant distinctions have been found between Iranian buffalo and other cattle breed studied. In the Iranian buffaloes studied alleles associated with resistance to various diseases are found. PMID:22454612

  4. A limit to the divergent allele advantage model supported by variable pathogen recognition across HLA-DRB1 allele lineages.

    PubMed

    Lau, Q; Yasukochi, Y; Satta, Y

    2015-11-01

    Genetic diversity in human leukocyte antigen (HLA) molecules is thought to have arisen from the co-evolution between host and pathogen and maintained by balancing selection. Heterozygote advantage is a common proposed scenario for maintaining high levels of diversity in HLA genes, and extending from this, the divergent allele advantage (DAA) model suggests that individuals with more divergent HLA alleles bind and recognize a wider array of antigens. While the DAA model seems biologically suitable for driving HLA diversity, there is likely an upper threshold to the amount of sequence divergence. We used peptide-binding and pathogen-recognition capacity of DRB1 alleles as a model to further explore the DAA model; within the DRB1 locus, we examined binding predictions based on two distinct phylogenetic groups (denoted group A and B) previously identified based on non-peptide-binding region (PBR) nucleotide sequences. Predictions in this study support that group A allele and group B allele lineages have contrasting binding/recognition capacity, with only the latter supporting the DAA model. Furthermore, computer simulations revealed an inconsistency in the DAA model alone with observed extent of polymorphisms, supporting that the DAA model could only work effectively in combination with other mechanisms. Overall, we support that the mechanisms driving HLA diversity are non-exclusive. By investigating the relationships among HLA alleles, and pathogens recognized, we can provide further insights into the mechanisms on how humans have adapted to infectious diseases over time.

  5. How the Number of Alleles Influences Gene Expression

    NASA Astrophysics Data System (ADS)

    Hat, Beata; Paszek, Pawel; Kimmel, Marek; Piechor, Kazimierz; Lipniacki, Tomasz

    2007-07-01

    The higher organisms, eukaryotes, are diploid and most of their genes have two homological copies (alleles). However, the number of alleles in a cell is not constant. In the S phase of the cell cycle all the genome is duplicated and then in the G2 phase and mitosis, which together last for several hours, most of the genes have four copies instead of two. Cancer development is, in many cases, associated with a change in allele number. Several genetic diseases are caused by haploinsufficiency: Lack of one of the alleles or its improper functioning. In the paper we consider the stochastic expression of a gene having a variable number of copies. We applied our previously developed method in which the reaction channels are split into slow (connected with change of gene state) and fast (connected with mRNA/protein synthesis/decay), the later being approximated by deterministic reaction rate equations. As a result we represent gene expression as a piecewise deterministic time-continuous Markov process, which is further related with a system of partial differential hyperbolic equations for probability density functions (pdfs) of protein distribution. The stationary pdfs are calculated analytically for haploidal gene or numerically for diploidal and tetraploidal ones. We distinguished nine classes of simultaneous activation of haploid, diploid and tetraploid genes. This allows for analysis of potential consequences of gene duplication or allele loss. We show that when gene activity is autoregulated by a positive feedback, the change in number of gene alleles may have dramatic consequences for its regulation and may not be compensated by the change of efficiency of mRNA synthesis per allele.

  6. Association between ACE D allele and elite short distance swimming.

    PubMed

    Costa, Aldo Matos; Silva, António José; Garrido, Nuno Domingos; Louro, Hugo; de Oliveira, Ricardo Jacó; Breitenfeld, Luiza

    2009-08-01

    The influence of ACE gene on athletic performance has been widely explored, and most of the published data refers to an I/D polymorphism leading to the presence (I allele) or absence (D allele) of a 287-bp sequence in intron 16, determining ACE activity in serum and tissues. A higher I allele frequency has been reported among elite endurance athletes, while the D allele was more frequent among those engaged in more power-orientated sports. However, on competitive swimming, the reproducibility of such associations is controversial. We thus compared the ACE genotype of elite swimmers with that of non-elite swimming cohort and of healthy control subjects. We thus sought an association of the ACE genotype of elite swimmers with their competitive distance. 39 Portuguese Olympic swimming candidates were classified as: short (<200 m) and middle (400-1,500 m) distance swimmers, respectively. A group of 32 non-elite swimmers were studied and classified as well, and a control group (n = 100) was selected from the Portuguese population. Chelex 100 was used for DNA extraction and genotype was determined by PCR-RFLP methods. We found that ACE genotype distribution and allelic frequency differs significantly by event distance only among elite swimmers (P < or = 0.05). Moreover, the allelic frequency of the elite short distance swimmers differed significantly from that of the controls (P = 0.021). No associations were found between middle distance swimmers and controls. Our results seem to support an association between the D allele and elite short distance swimming.

  7. Construction of a library of cloned short tandem repeat (STR) alleles as universal templates for allelic ladder preparation.

    PubMed

    Wang, Le; Zhao, Xing-Chun; Ye, Jian; Liu, Jin-Jie; Chen, Ting; Bai, Xue; Zhang, Jian; Ou, Yuan; Hu, Lan; Jiang, Bo-Wei; Wang, Feng

    2014-09-01

    Short tandem repeat (STR) genotyping methods are widely used for human identity testing applications, including forensic DNA analysis. Samples of DNA containing the length-variant STR alleles are typically separated and genotyped by comparison to an allelic ladder. Here, we describe a newly devised library of cloned STR alleles. The library covers alleles X and Y for the sex-determining locus Amelogenin and 259 other alleles for 22 autosomal STR loci (TPOX, D3S1358, FGA, D5S818, CSF1PO, D7S820, D8S1179, TH01, vWA, D13S317, D16S539, D18S51, D21S11, D2S1338, D6S1043, D12S391, Penta E, D19S433, D11S4463, D17S974, D3S4529 and D12ATA63). New primers were designed for all these loci to construct recombinant plasmids so that the library retains core repeat elements of STR as well as 5'- and 3'-flanking sequences of ∼500 base pairs. Since amplicons of commercial STR genotyping kits and systems developed in laboratories are usually distributed from 50 to <500 base pairs, this library could provide universal templates for allelic ladder preparation. We prepared three different sets of allelic ladders for this locus TH01 and an updated version of an allelic ladder for the DNATyper(®)19 multiplex system using these plasmids to confirm the suitability of the library as a good source for allelic ladder preparation. Importantly, the authenticity of each construct was confirmed by bidirectional nucleotide sequencing and we report the repeat structures of the 259 STR alleles. The sequencing results showed all repeat structures we obtained for TPOX, CSF1PO, D7S820, TH01, D16S539, D18S51 and Penta E were the same as reported. However, we identified 102 unreported repeat structures from the other 15 STR loci, supplementing our current knowledge of repeat structures and leading to further understanding of these widely used loci.

  8. Genetic influences on the acquisition and inhibition of fear.

    PubMed

    Wendt, Julia; Neubert, Jörg; Lindner, Katja; Ernst, Florian D; Homuth, Georg; Weike, Almut I; Hamm, Alfons O

    2015-12-01

    As a variant of the Pavlovian fear conditioning paradigm the conditional discrimination design allows for a detailed investigation of fear acquisition and fear inhibition. Measuring fear-potentiated startle responses, we investigated the influence of two genetic polymorphisms (5-HTTLPR and COMT Val(158)Met) on fear acquisition and fear inhibition which are considered to be critical mechanisms for the etiology and maintenance of anxiety disorders. 5-HTTLPR s-allele carriers showed a more stable potentiation of the startle response during fear acquisition. Homozygous COMT Met-allele carriers, which had demonstrated delayed extinction in previous investigations, show deficient fear inhibition in presence of a learned safety signal. Thus, our results provide further evidence that 5-HTTLPR and COMT Val(158)Met genotypes influence the vulnerability for the development of anxiety disorders via different mechanisms.

  9. Family-based association study of serotonin transporter promoter in suicidal adolescents: no association with suicidality but possible role in violence traits.

    PubMed

    Zalsman, G; Frisch, A; Bromberg, M; Gelernter, J; Michaelovsky, E; Campino, A; Erlich, Z; Tyano, S; Apter, A; Weizman, A

    2001-04-08

    The serotonin transporter-linked promoter region polymorphism (5-HTTLPR) is thought to be associated with some serotonin dysfunction-related psychopathologies such as depression and anxiety disorders. Suicide and suicide-related behaviors such as violence, aggression, and impulsivity have been reproducibly associated with serotonin dysfunction and are partially genetic. This study examined the association of 5-HTTLPR with suicidal behavior and related traits in Israeli suicidal adolescent inpatients using the haplotype relative risk (HRR) method that controls for artifacts caused by population stratification. Forty-eight inpatient adolescents who recently attempted suicide were assessed by structured interviews for detailed clinical history, diagnoses, suicide intent, suicide risk, impulsivity, violence, and depression. Blood samples were collected and DNA extracted from patients and their biological parents. The 5-HTTLPR allele frequencies were tested for association with suicidality by the HRR method. In addition, the relationship between genotypes and phenotypic severity of several clinical parameters was analyzed. No significant allelic association of the 5-HTTLPR polymorphism with suicidal behavior was found (chi square = 0.023; P = 0.88). Analysis of variance of the suicide-related trait measures for the three genotypes demonstrated a significant difference in violence measures between patients carrying the LL and LS genotypes (9.50+/-4.04 vs. 5.36+/-4.03; P = 0.029). This study suggests that the 5-HTTLPR polymorphism is unlikely to have major relevance to the pathogenesis of suicidal behavior in adolescence but may contribute to violent behavior in this population.

  10. STR allele sequence variation: Current knowledge and future issues.

    PubMed

    Gettings, Katherine Butler; Aponte, Rachel A; Vallone, Peter M; Butler, John M

    2015-09-01

    This article reviews what is currently known about short tandem repeat (STR) allelic sequence variation in and around the twenty-four loci most commonly used throughout the world to perform forensic DNA investigations. These STR loci include D1S1656, TPOX, D2S441, D2S1338, D3S1358, FGA, CSF1PO, D5S818, SE33, D6S1043, D7S820, D8S1179, D10S1248, TH01, vWA, D12S391, D13S317, Penta E, D16S539, D18S51, D19S433, D21S11, Penta D, and D22S1045. All known reported variant alleles are compiled along with genomic information available from GenBank, dbSNP, and the 1000 Genomes Project. Supplementary files are included which provide annotated reference sequences for each STR locus, characterize genomic variation around the STR repeat region, and compare alleles present in currently available STR kit allelic ladders. Looking to the future, STR allele nomenclature options are discussed as they relate to next generation sequencing efforts underway.

  11. Estimating Relatedness in the Presence of Null Alleles

    PubMed Central

    Huang, Kang; Ritland, Kermit; Dunn, Derek W.; Qi, Xiaoguang; Guo, Songtao; Li, Baoguo

    2016-01-01

    Studies of genetics and ecology often require estimates of relatedness coefficients based on genetic marker data. However, with the presence of null alleles, an observed genotype can represent one of several possible true genotypes. This results in biased estimates of relatedness. As the numbers of marker loci are often limited, loci with null alleles cannot be abandoned without substantial loss of statistical power. Here, we show how loci with null alleles can be incorporated into six estimators of relatedness (two novel). We evaluate the performance of various estimators before and after correction for null alleles. If the frequency of a null allele is <0.1, some estimators can be used directly without adjustment; if it is >0.5, the potency of estimation is too low and such a locus should be excluded. We make available a software package entitled PolyRelatedness v1.6, which enables researchers to optimize these estimators to best fit a particular data set. PMID:26500259

  12. Assessing allelic dropout and genotype reliability using maximum likelihood.

    PubMed Central

    Miller, Craig R; Joyce, Paul; Waits, Lisette P

    2002-01-01

    A growing number of population genetic studies utilize nuclear DNA microsatellite data from museum specimens and noninvasive sources. Genotyping errors are elevated in these low quantity DNA sources, potentially compromising the power and accuracy of the data. The most conservative method for addressing this problem is effective, but requires extensive replication of individual genotypes. In search of a more efficient method, we developed a maximum-likelihood approach that minimizes errors by estimating genotype reliability and strategically directing replication at loci most likely to harbor errors. The model assumes that false and contaminant alleles can be removed from the dataset and that the allelic dropout rate is even across loci. Simulations demonstrate that the proposed method marks a vast improvement in efficiency while maintaining accuracy. When allelic dropout rates are low (0-30%), the reduction in the number of PCR replicates is typically 40-50%. The model is robust to moderate violations of the even dropout rate assumption. For datasets that contain false and contaminant alleles, a replication strategy is proposed. Our current model addresses only allelic dropout, the most prevalent source of genotyping error. However, the developed likelihood framework can incorporate additional error-generating processes as they become more clearly understood. PMID:11805071

  13. Rare allelic forms of PRDM9 associated with childhood leukemogenesis

    PubMed Central

    Hussin, Julie; Sinnett, Daniel; Casals, Ferran; Idaghdour, Youssef; Bruat, Vanessa; Saillour, Virginie; Healy, Jasmine; Grenier, Jean-Christophe; de Malliard, Thibault; Busche, Stephan; Spinella, Jean-François; Larivière, Mathieu; Gibson, Greg; Andersson, Anna; Holmfeldt, Linda; Ma, Jing; Wei, Lei; Zhang, Jinghui; Andelfinger, Gregor; Downing, James R.; Mullighan, Charles G.; Awadalla, Philip

    2013-01-01

    One of the most rapidly evolving genes in humans, PRDM9, is a key determinant of the distribution of meiotic recombination events. Mutations in this meiotic-specific gene have previously been associated with male infertility in humans and recent studies suggest that PRDM9 may be involved in pathological genomic rearrangements. In studying genomes from families with children affected by B-cell precursor acute lymphoblastic leukemia (B-ALL), we characterized meiotic recombination patterns within a family with two siblings having hyperdiploid childhood B-ALL and observed unusual localization of maternal recombination events. The mother of the family carries a rare PRDM9 allele, potentially explaining the unusual patterns found. From exomes sequenced in 44 additional parents of children affected with B-ALL, we discovered a substantial and significant excess of rare allelic forms of PRDM9. The rare PRDM9 alleles are transmitted to the affected children in half the cases; nonetheless there remains a significant excess of rare alleles among patients relative to controls. We successfully replicated this latter observation in an independent cohort of 50 children with B-ALL, where we found an excess of rare PRDM9 alleles in aneuploid and infant B-ALL patients. PRDM9 variability in humans is thought to influence genomic instability, and these data support a potential role for PRDM9 variation in risk of acquiring aneuploidies or genomic rearrangements associated with childhood leukemogenesis. PMID:23222848

  14. Rare allelic forms of PRDM9 associated with childhood leukemogenesis.

    PubMed

    Hussin, Julie; Sinnett, Daniel; Casals, Ferran; Idaghdour, Youssef; Bruat, Vanessa; Saillour, Virginie; Healy, Jasmine; Grenier, Jean-Christophe; de Malliard, Thibault; Busche, Stephan; Spinella, Jean-François; Larivière, Mathieu; Gibson, Greg; Andersson, Anna; Holmfeldt, Linda; Ma, Jing; Wei, Lei; Zhang, Jinghui; Andelfinger, Gregor; Downing, James R; Mullighan, Charles G; Awadalla, Philip

    2013-03-01

    One of the most rapidly evolving genes in humans, PRDM9, is a key determinant of the distribution of meiotic recombination events. Mutations in this meiotic-specific gene have previously been associated with male infertility in humans and recent studies suggest that PRDM9 may be involved in pathological genomic rearrangements. In studying genomes from families with children affected by B-cell precursor acute lymphoblastic leukemia (B-ALL), we characterized meiotic recombination patterns within a family with two siblings having hyperdiploid childhood B-ALL and observed unusual localization of maternal recombination events. The mother of the family carries a rare PRDM9 allele, potentially explaining the unusual patterns found. From exomes sequenced in 44 additional parents of children affected with B-ALL, we discovered a substantial and significant excess of rare allelic forms of PRDM9. The rare PRDM9 alleles are transmitted to the affected children in half the cases; nonetheless there remains a significant excess of rare alleles among patients relative to controls. We successfully replicated this latter observation in an independent cohort of 50 children with B-ALL, where we found an excess of rare PRDM9 alleles in aneuploid and infant B-ALL patients. PRDM9 variability in humans is thought to influence genomic instability, and these data support a potential role for PRDM9 variation in risk of acquiring aneuploidies or genomic rearrangements associated with childhood leukemogenesis.

  15. A Platform for Interrogating Cancer-Associated p53 Alleles

    PubMed Central

    D’Brot, Alejandro; Kurtz, Paula; Regan, Erin; Jakubowski, Brandon; Abrams, John M

    2016-01-01

    p53 is the most frequently mutated gene in human cancer. Compelling evidence argues that full transformation involves loss of growth suppression encoded by wild-type p53 together with poorly understood oncogenic activity encoded by missense mutations. Furthermore, distinguishing disease alleles from natural polymorphisms is an important clinical challenge. To interrogate the genetic activity of human p53 variants, we leveraged the Drosophila model as an in vivo platform. We engineered strains that replace the fly p53 gene with human alleles, producing a collection of stocks that are, in effect, ‘humanized’ for p53 variants. Like the fly counterpart, human p53 transcriptionally activated a biosensor and induced apoptosis after DNA damage. However, all humanized strains representing common alleles found in cancer patients failed to complement in these assays. Surprisingly, stimulus-dependent activation of hp53 occurred without stabilization, demonstrating that these two processes can be uncoupled. Like its fly counterpart, hp53 formed prominent nuclear foci in germline cells but cancer-associated p53 variants did not. Moreover, these same mutant alleles disrupted hp53 foci and inhibited biosensor activity, suggesting that these properties are functionally linked. Together these findings establish a functional platform for interrogating human p53 alleles and suggest that simple phenotypes could be used to stratify disease variants. PMID:26996664

  16. Identification and characterization of variant alleles at CODIS STR loci.

    PubMed

    Allor, Catherine; Einum, David D; Scarpetta, Marco

    2005-09-01

    Short tandem repeat (STR) profiles from 32,671 individuals generated by the ABI Profiler Plus and Cofiler systems were screened for variant alleles not represented within manufacturer-provided allelic ladders. A total of 85 distinct variants were identified at 12 of the 13 CODIS loci, most of which involve a truncated tetranucleotide repeat unit. Twelve novel alleles, identified at D3S1358, FGA, D18S51, D5S818, D7S820 and TPOX, were confirmed by nucleotide sequence analysis and include both insertions and deletions involving the repeat units themselves as well as DNA flanking the repeat regions. Population genetic data were collected for all variants and frequencies range from 0.0003 (many single observations) to 0.0042 (D7S820 '10.3' in North American Hispanics). In total, the variant alleles identified in this study are carried by 1.6% of the estimated 1 million individuals tested annually in the U.S. for the purposes of parentage resolution. A paternity case involving a recombination event of paternal origin is presented and demonstrates how variant alleles can significantly strengthen the genetic evidence in troublesome cases. In such instances, increased costs and turnaround time associated with additional testing may be eliminated.

  17. Identification of two novel human CD1E alleles.

    PubMed

    Mirones, I; Oteo, M; Parra-Cuadrado, J F; Martínez-Naves, E

    2000-08-01

    CD1 is a family of proteins structurally related to major histocompatibility complex (MHC) molecules and specialized in presenting lipids or glycolipids to T cells. In humans, there are five CD1 genes (CD1A to CD1E). It has been shown that, in contrast with classical MHC genes, CD1 loci display a very limited polymorphism. In the present work we describe two novel CD1E alleles found in two healthy Caucasian individuals. One allele differs from the wild-type by a point mutation resulting in a replacement of arginine at position 154 by a tryptophan. In the second allele we found a substitution of the leucine 184 by a proline.

  18. Allele surfing promotes microbial adaptation from standing variation.

    PubMed

    Gralka, Matti; Stiewe, Fabian; Farrell, Fred; Möbius, Wolfram; Waclaw, Bartlomiej; Hallatschek, Oskar

    2016-08-01

    The coupling of ecology and evolution during range expansions enables mutations to establish at expanding range margins and reach high frequencies. This phenomenon, called allele surfing, is thought to have caused revolutions in the gene pool of many species, most evidently in microbial communities. It has remained unclear, however, under which conditions allele surfing promotes or hinders adaptation. Here, using microbial experiments and simulations, we show that, starting with standing adaptive variation, range expansions generate a larger increase in mean fitness than spatially uniform population expansions. The adaptation gain results from 'soft' selective sweeps emerging from surfing beneficial mutations. The rate of these surfing events is shown to sensitively depend on the strength of genetic drift, which varies among strains and environmental conditions. More generally, allele surfing promotes the rate of adaptation per biomass produced, which could help developing biofilms and other resource-limited populations to cope with environmental challenges.

  19. Generation and characterization of an analog-sensitive PERK allele.

    PubMed

    Maas, Nancy L; Singh, Nickpreet; Diehl, J Alan

    2014-08-01

    Restriction of nutrients and oxygen in the tumor microenvironment disrupts ER homeostasis and adaptation to such stress is mediated by the key UPR effector PERK. Given its pro-tumorigenic activity, significant efforts have been made to elucidate the molecular mechanisms that underlie PERK function. Chemical-genetic approaches have recently proven instrumental in pathway mapping and interrogating kinase function. To enable a detailed study of PERK signaling we have generated an analog-sensitive PERK allele that accepts N(6)-alkylated ATP analogs. We find that this allele can be regulated by bulky ATP-competitive inhibitors, confirming the identity of the PERK gatekeeper residue as methionine 886. Furthermore, this analog-sensitive allele can be used to specifically label substrates with thiophosphate both in vitro and in cells. These data highlight the potential for using chemical-genetic techniques to identify novel PERK substrates, thereby providing an expanded view of PERK function and further definition of its signaling networks.

  20. Extensive HLA class I allele promiscuity among viral CTL epitopes

    PubMed Central

    Frahm, Nicole; Yusim, Karina; Suscovich, Todd J.; Adams, Sharon; Sidney, John; Hraber, Peter; Hewitt, Hannah S.; Linde, Caitlyn H.; Kavanagh, Daniel G.; Woodberry, Tonia; Henry, Leah M.; Faircloth, Kellie; Listgarten, Jennifer; Kadie, Carl; Jojic, Nebojsa; Sango, Kaori; Brown, Nancy V.; Pae, Eunice; Zaman, M. Tauheed; Bihl, Florian; Khatri, Ashok; John, Mina; Mallal, Simon; Marincola, Francesco M.; Walker, Bruce D.; Sette, Alessandro; Heckerman, David; Korber, Bette T.; Brander, Christian

    2008-01-01

    Summary Promiscuous binding of T helper epitopes to MHC class II molecules has been well established, but few examples of promiscuous class I restricted epitopes exist. To address the extent of promiscuity of HLA class I peptides, responses to 242 well-defined viral epitopes were tested in 100 subjects regardless of the individuals’ HLA type. Surprisingly, half of all detected responses were seen in the absence of the originally reported restricting HLA class I allele, and only 3% of epitopes were recognized exclusively in the presence of their original allele. Functional assays confirmed the frequent recognition of HLA class I-restricted T cell epitopes on several alternative alleles across HLA class I supertypes and encoded on different class I loci. These data have significant implications for the understanding of MHC class I restricted antigen presentation and vaccine development. PMID:17705138

  1. Distribution of a pseudodeficiency allele among Tay-Sachs carriers

    SciTech Connect

    Tomczak, J.; Grebner, E.E. ); Boogen, C. )

    1993-08-01

    Recently Triggs-Raine et al. (1992) identified a new mutation in the gene coding for the [alpha]-subunit of [beta]-hexosaminidase A (hex A), the enzyme whose deficiency causes Tay-Sachs disease. This mutation, a C[sub 739]-to-T transition in exon 7, results in an altered enzyme that is active (albeit at reduced levels) in cells but that has essentially no activity in serum. This so-called pseudodeficient allele was first detected in compound heterozygotes who also carried a Tay-Sachs disease allele and therefore had no detectable hex A in their serum but who were in good health. Carriers of this apparently benign mutation are generally indistinguishable from carriers of a lethal mutation by means of routine enzyme-based screening tests, because the product of the pseudodeficient allele is not detectable in serum and has decreased activity in cells. This suggests that some individuals who have been classified as Tay-Sachs carriers are actually carriers of the pseudodeficient allele and are not at risk to have a child affected with Tay-Sachs disease. The pseudodeficient allele may also be responsible for some inconclusive diagnoses, where leukocyte values fall below the normal range but are still above the carrier range. The fact that there are now two mutant alleles (the psuedodeficient and the adult) that are indistinguishable from the lethal infantile mutations by means of enzyme assay yet that are phenotypically very different and that together may account for as much as 12% of enzyme-defined carriers on the basis of the data here suggests that DNA analysis should be part of a comprehensive screening program. It will be particularly useful to identify the mutations in couples at risk, before they undergo prenatal diagnosis. DNA analysis will also resolve some inconclusive diagnoses.

  2. Clonal Ordering of 17p and 5q Allelic Losses in Barrett Dysplasia and Adenocarcinoma

    NASA Astrophysics Data System (ADS)

    Blount, Patricia L.; Meltzer, Stephen J.; Yin, Jing; Huang, Ying; Krasna, Mark J.; Reid, Brian J.

    1993-04-01

    Both 17p and 5q allelic losses appear to be involved in the pathogenesis or progression of many human solid tumors. In colon carcinogenesis, there is strong evidence that the targets of the 17p and 5q allelic losses are TP53, the gene encoding p53, and APC, respectively. It is widely accepted that 5q allelic losses precede 17p allelic losses in the progression to colonic carcinoma. The data, however, supporting this proposed order are largely based on the prevalence of 17p and 5q allelic losses in adenomas and unrelated adenocarcinomas from different patients. We investigated the order in which 17p and 5q allelic losses developed during neoplastic progression in Barrett esophagus by evaluating multiple aneuploid cell populations from the same patient. Using DNA content flow cytometric cell sorting and polymerase chain reaction, 38 aneuploid cell populations from 14 patients with Barrett esophagus who had high grade dysplasia, cancer or both were evaluated for 17p and 5q allelic losses. 17p allelic losses preceded 5q allelic losses in 7 patients, both 17p and 5q allelic losses were present in all aneuploid populations of 4 patients, and only 17p (without 5q) allelic losses were present in the aneuploid populations of 3 patients. In no patient did we find that a 5q allelic loss preceded a 17p allelic loss. Our data suggest that 17p allelic losses typically occur before 5q allelic losses during neoplastic progression in Barrett esophagus.

  3. Tissue-specific patterns of allelically-skewed DNA methylation.

    PubMed

    Marzi, Sarah J; Meaburn, Emma L; Dempster, Emma L; Lunnon, Katie; Paya-Cano, Jose L; Smith, Rebecca G; Volta, Manuela; Troakes, Claire; Schalkwyk, Leonard C; Mill, Jonathan

    2016-01-01

    While DNA methylation is usually thought to be symmetrical across both alleles, there are some notable exceptions. Genomic imprinting and X chromosome inactivation are two well-studied sources of allele-specific methylation (ASM), but recent research has indicated a more complex pattern in which genotypic variation can be associated with allelically-skewed DNA methylation in cis. Given the known heterogeneity of DNA methylation across tissues and cell types we explored inter- and intra-individual variation in ASM across several regions of the human brain and whole blood from multiple individuals. Consistent with previous studies, we find widespread ASM with > 4% of the ∼220,000 loci interrogated showing evidence of allelically-skewed DNA methylation. We identify ASM flanking known imprinted regions, and show that ASM sites are enriched in DNase I hypersensitivity sites and often located in an extended genomic context of intermediate DNA methylation. We also detect examples of genotype-driven ASM, some of which are tissue-specific. These findings contribute to our understanding of the nature of differential DNA methylation across tissues and have important implications for genetic studies of complex disease. As a resource to the community, ASM patterns across each of the tissues studied are available in a searchable online database: http://epigenetics.essex.ac.uk/ASMBrainBlood.

  4. Distribution of forensic marker allelic frequencies in Pernambuco, Northestern Brazil.

    PubMed

    Santos, S M; Souza, C A; Rabelo, K C N; Souza, P R E; Moura, R R; Oliveira, T C; Crovella, S

    2015-04-30

    Pernambuco is one of the 27 federal units of Brazil, ranking seventh in the number of inhabitants. We examined the allele frequencies of 13 short tandem repeat loci (CFS1PO, D3S1358, D5S818, D7S820, D8S1179, D13S317, D16S539, D18S51, D21S11, FGA, TH01, vWA, and TPOX), the minimum recommended by the Federal Bureau of Investigation and commonly used in forensic genetics laboratories in Brazil, in a sample of 609 unrelated individuals from all geographic regions of Pernambuco. The allele frequencies ranged from 5 to 47.2%. No significant differences for any loci analyzed were observed compared with other publications in other various regions of Brazil. Most of the markers observed were in Hardy-Weinberg equilibrium. The occurrence of the allele 47.2 (locus FGA) and alleles 35.1 and 39 (locus D21S11), also described in a single study of the Brazilian population, was observed. The other forensic parameters analyzed (matching probability, power of discrimination, polymorphic information content, paternity exclusion, complement factor I, observed heterozygosity, expected heterozygosity) indicated that the studied markers are very informative for human forensic identification purposes in the Pernambuco population.

  5. Allelism and Molecular Mapping of Soybean Necrotic Root Mutants

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Mutability of the w4 flower color locus in soybean [Glycine max (L.) Merr.] is conditioned by an allele designated w4-m. Germinal revertants recovered among self-pollinated progeny of mutable plants have been associated with the generation of necrotic root mutations, chlorophyll-deficiency mutation...

  6. A genotype probability index for multiple alleles and haplotypes.

    PubMed

    Percy, A; Kinghorn, B P

    2005-12-01

    We use linear algebra to calculate an index of information content in genotype probabilities which has previously been calculated using trigonometry. The new method can be generalized allowing the index to be calculated for loci with more than two alleles. Applications of this index include its use in genotyping strategies, strategies to manage genetic disorders and in estimation of genotype effects.

  7. Natural allelic variations in highly polyploidy Saccharum complex

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Sugarcane (Saccharum spp.) as important sugar and biofuel crop are highly polypoid with complex genomes. A large amount of natural phenotypic variation exists in sugarcane germplasm. Understanding its allelic variance has been challenging but is a critical foundation for discovery of the genomic seq...

  8. Efficient nonmeiotic allele introgression in livestock using custom endonucleases

    PubMed Central

    Tan, Wenfang; Carlson, Daniel F.; Lancto, Cheryl A.; Garbe, John R.; Webster, Dennis A.; Hackett, Perry B.; Fahrenkrug, Scott C.

    2013-01-01

    We have expanded the livestock gene editing toolbox to include transcription activator-like (TAL) effector nuclease (TALEN)- and clustered regularly interspaced short palindromic repeats (CRISPR)/Cas9-stimulated homology-directed repair (HDR) using plasmid, rAAV, and oligonucleotide templates. Toward the genetic dehorning of dairy cattle, we introgressed a bovine POLLED allele into horned bull fibroblasts. Single nucleotide alterations or small indels were introduced into 14 additional genes in pig, goat, and cattle fibroblasts using TALEN mRNA and oligonucleotide transfection with efficiencies of 10–50% in populations. Several of the chosen edits mimic naturally occurring performance-enhancing or disease- resistance alleles, including alteration of single base pairs. Up to 70% of the fibroblast colonies propagated without selection harbored the intended edits, of which more than one-half were homozygous. Edited fibroblasts were used to generate pigs with knockout alleles in the DAZL and APC genes to model infertility and colon cancer. Our methods enable unprecedented meiosis-free intraspecific and interspecific introgression of select alleles in livestock for agricultural and biomedical applications. PMID:24014591

  9. MHC class II DR allelic diversity in bighorn sheep

    Technology Transfer Automated Retrieval System (TEKTRAN)

    We hypothesized that decreased diversity and/or unique polymorphisms in MHC class II alleles of bighorn sheep (BHS, Ovis canadensis) are responsible for lower titer of antibodies against Mannheimia haemolytica leukotoxin, in comparison to domestic sheep (DS, Ovis aries). To test this hypothesis, DRA...

  10. Tissue-specific patterns of allelically-skewed DNA methylation

    PubMed Central

    Marzi, Sarah J.; Meaburn, Emma L.; Dempster, Emma L.; Lunnon, Katie; Paya-Cano, Jose L.; Smith, Rebecca G.; Volta, Manuela; Troakes, Claire; Schalkwyk, Leonard C.; Mill, Jonathan

    2016-01-01

    ABSTRACT While DNA methylation is usually thought to be symmetrical across both alleles, there are some notable exceptions. Genomic imprinting and X chromosome inactivation are two well-studied sources of allele-specific methylation (ASM), but recent research has indicated a more complex pattern in which genotypic variation can be associated with allelically-skewed DNA methylation in cis. Given the known heterogeneity of DNA methylation across tissues and cell types we explored inter- and intra-individual variation in ASM across several regions of the human brain and whole blood from multiple individuals. Consistent with previous studies, we find widespread ASM with > 4% of the ∼220,000 loci interrogated showing evidence of allelically-skewed DNA methylation. We identify ASM flanking known imprinted regions, and show that ASM sites are enriched in DNase I hypersensitivity sites and often located in an extended genomic context of intermediate DNA methylation. We also detect examples of genotype-driven ASM, some of which are tissue-specific. These findings contribute to our understanding of the nature of differential DNA methylation across tissues and have important implications for genetic studies of complex disease. As a resource to the community, ASM patterns across each of the tissues studied are available in a searchable online database: http://epigenetics.essex.ac.uk/ASMBrainBlood. PMID:26786711

  11. Estimating the age of alleles by use of intraallelic variability

    SciTech Connect

    Slatkin, M.; Rannala, B.

    1997-02-01

    A method is presented for estimating the age of an allele by use of its frequency and the extent of variation among different copies. The method uses the joint distribution of the number of copies in a population sample and the coalescence times of the intraallelic gene genealogy conditioned on the number of copies. The linear birth-death process is used to approximate the dynamics of a rare allele in a finite population. A maximum-likelihood estimate of the age of the allele is obtained by Monte Carlo integration over the coalescence times. The method is applied to two alleles at the cystic fibrosis (CFTR) locus, {Delta}F508 and G542X, for which intraallelic variability at three intronic microsatellite loci has been examined. Our results indicate that G542X is somewhat older than {Delta}F508. Although absolute estimates depend on the mutation rates at the microsatellite loci, our results support the hypothesis that {Delta}F508 arose <500 generations ({approx}10,000 years) ago. 32 refs., 4 figs.

  12. Multifragment alleles in DNA fingerprints of the parrot, Amazona ventralis

    USGS Publications Warehouse

    Brock, M.K.; White, B.N.

    1991-01-01

    Human DNA probes that identify variable numbers of tandem repeat loci are being used to generate DNA fingerprints in many animal and plant species. In most species the majority of the sc rable autoradiographic bands of the DNA fingerprint represent alleles from numerous unlinked loci. This study was initiated to use DNA fingerprints to determine the amount of band-sharing among captive Hispaniolan parrots (Amazona ventralis) with known genetic relationships. This would form the data base to examine DNA fingerprints of the closely related and endangered Puerto Rican parrot (A. vittata) and to estimate the degree of inbreeding in the relic population. We found by segregation analysis of the bands scored in the DNA fingerprints of the Hispaniolan parrots that there may be as few as two to five loci identified by the human 33.15 probe. Furthermore, at one locus we identified seven alleles, one of which is represented by as many as 19 cosegregating bands. It is unknown how common multiband alleles might be in natural populations, and their existence will cause problems in the assessment of relatedness by band-sharing analysis. We believe, therefore, that a pedigree analysis should be included in all DNA fingerprinting studies, where possible, in order to estimate the number of loci identified by a minisatellite DNA probe and to examine the nature of their alleles.

  13. Registration of two allelic erect leaf mutants of sorghum

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Two allelic sorghum [Sorghum bicolor (L.) Moench] erect leaf (erl) mutants were isolated from an Annotated Individually-pedigreed Mutagenized Sorghum (AIMS) mutant library developed at the Plant Stress and Germplasm Development Unit, at Lubbock, Texas. The two mutants, erl1-1 and erl1-2, were isol...

  14. KIR2DL2/2DL3-E(35) alleles are functionally stronger than -Q(35) alleles.

    PubMed

    Bari, Rafijul; Thapa, Rajoo; Bao, Ju; Li, Ying; Zheng, Jie; Leung, Wing

    2016-03-31

    KIR2DL2 and KIR2DL3 segregate as alleles of a single locus in the centromeric motif of the killer cell immunoglobulin-like receptor (KIR) gene family. Although KIR2DL2/L3 polymorphism is known to be associated with many human diseases and is an important factor for donor selection in allogeneic hematopoietic stem cell transplantation, the molecular determinant of functional diversity among various alleles is unclear. In this study we found that KIR2DL2/L3 with glutamic acid at position 35 (E(35)) are functionally stronger than those with glutamine at the same position (Q(35)). Cytotoxicity assay showed that NK cells from HLA-C1 positive donors with KIR2DL2/L3-E(35) could kill more target cells lacking their ligands than NK cells with the weaker -Q(35) alleles, indicating better licensing of KIR2DL2/L3(+) NK cells with the stronger alleles. Molecular modeling analysis reveals that the glutamic acid, which is negatively charged, interacts with positively charged histidine located at position 55, thereby stabilizing KIR2DL2/L3 dimer and reducing entropy loss when KIR2DL2/3 binds to HLA-C ligand. The results of this study will be important for future studies of KIR2DL2/L3-associated diseases as well as for donor selection in allogeneic stem cell transplantation.

  15. KIR2DL2/2DL3-E35 alleles are functionally stronger than -Q35 alleles

    NASA Astrophysics Data System (ADS)

    Bari, Rafijul; Thapa, Rajoo; Bao, Ju; Li, Ying; Zheng, Jie; Leung, Wing

    2016-03-01

    KIR2DL2 and KIR2DL3 segregate as alleles of a single locus in the centromeric motif of the killer cell immunoglobulin-like receptor (KIR) gene family. Although KIR2DL2/L3 polymorphism is known to be associated with many human diseases and is an important factor for donor selection in allogeneic hematopoietic stem cell transplantation, the molecular determinant of functional diversity among various alleles is unclear. In this study we found that KIR2DL2/L3 with glutamic acid at position 35 (E35) are functionally stronger than those with glutamine at the same position (Q35). Cytotoxicity assay showed that NK cells from HLA-C1 positive donors with KIR2DL2/L3-E35 could kill more target cells lacking their ligands than NK cells with the weaker -Q35 alleles, indicating better licensing of KIR2DL2/L3+ NK cells with the stronger alleles. Molecular modeling analysis reveals that the glutamic acid, which is negatively charged, interacts with positively charged histidine located at position 55, thereby stabilizing KIR2DL2/L3 dimer and reducing entropy loss when KIR2DL2/3 binds to HLA-C ligand. The results of this study will be important for future studies of KIR2DL2/L3-associated diseases as well as for donor selection in allogeneic stem cell transplantation.

  16. Allelic divergence and cultivar-specific SSR alleles revealed by capillary electrophoresis using fluorescence-labeled SSR markers in sugarcane

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Though sugarcane cultivars (Saccharum spp. hybrids) are complex aneu-polyploid hybrids, genetic evaluation and tracking of clone- or cultivar-specific alleles become possible due to capillary electrophoregrams (CE) using fluorescence-labeled SSR primer pairs. Twenty-four sugarcane cultivars, 12 each...

  17. Tri-allelic pattern at the TPOX locus: a familial study.

    PubMed

    Picanço, Juliane Bentes; Raimann, Paulo Eduardo; Paskulin, Giorgio Adriano; Alvarez, Luís; Amorim, António; Batista Dos Santos, Sidney Emanuel; Alho, Clarice Sampaio

    2014-02-10

    Alleles at the TPOX STR locus have 6-14 different numbers of a four-nucleotide (AATG) repeat motif arranged in tandem. Although tri-allelic genotypes are generally rare, the TPOX tri-allelic pattern has a higher frequency, varying widely among populations. Despite this, there are few accurate reports to disclose the nature of the TPOX third allele. In this work we present data obtained from 45 individuals belonging to the same pedigree, in which there are cases of tri-allelic TPOX genotypes. The subjects were apparently healthy with a normal biological development. We noticed six tri-allelic cases in this family, and all of them were women. Karyotype analysis showed no occurrence of partial 2p trisomy. All the tri-allelic cases had the genotype 8-10-11, probably due to three copies of the TPOX STR sequence in all cells (Type 2 tri-allelic pattern). Based on previous data we assumed the allele 10 as the TPOX third allele. The pedigree analyses show evidences that the TPOX extra-allele was the allele10, it is placed far from the main TPOX locus, and that there is a potential linkage of the TPOX extra-allele-10 with Xq. This was the first study that included a large pedigree analysis in order to understand the nature TPOX tri-allelic pattern.

  18. Nonfrequent but well-documented, rare and very rare HLA alleles observed in the Croatian population.

    PubMed

    Grubic, Z; Burek Kamenaric, M; Maskalan, M; Stingl Jankovic, K; Zunec, R

    2014-12-01

    The aim of the study was to evaluate the presence of nonfrequent, rare and very rare alleles among Croats and to estimate whether they are associated with specific alleles at other human leukocyte antigen (HLA) loci. This retrospective study included the typing results from the last 10 years; total number of individuals included was approximately 45,000. Among 17 alleles so far observed only once in our population, 6 (A*24:41, B*07:02:28, B*35:03:03, B*39:40N, DRB1*13:23 and DRB1*14:111) belong to very rare alleles, 2 (B*44:16 and DRB1*01:31) belong to rare alleles according to the 'Rare Alleles Detector' tool ( www.allelefrequencies.net), while for the B*35:101:01 allele published data exist only in the IMGT/HLA database. The remaining eight HLA alleles observed only once among Croats are considered as frequent according to the 'Rare Alleles Detector'. Those 17 HLA alleles are not declared as common well defined (CWD) alleles in the CWD allele catalogue 2.0.0. Haplotype analysis of nonfrequent alleles detected in our sample supports the idea that different populations, although similar in some aspects regarding HLA allele and haplotype distribution, still have some unique characteristics. This is the case for A*01:02, B*39:10 and DRB1*13:32 which form haplotypes unreported to date among our subjects.

  19. An interaction between the serotonin transporter promoter region and dopamine transporter polymorphisms contributes to harm avoidance and reward dependence traits in normal healthy subjects.

    PubMed

    Kim, S J; Kim, Y S; Lee, H S; Kim, S Y; Kim, C-H

    2006-07-01

    There is evidence for an association between polymorphisms of serotonin- and dopamine-related genes and temperamental personality traits. Recent findings have shown that interactions between allelic variants of the different genes may contribute to personality traits. We examined the effects of serotonin transporter-linked promoter region (5-HTTLPR) and dopamine transporter (DAT1) gene polymorphisms for associations with the Temperament and Character Inventory (TCI) temperament subscales in 209 Koreans. We found that the variants of 5-HTTLPR interacted with the DAT1 gene polymorphism to influence the HA and RD temperament subscales of TCI. Neither of these two genes affected any subscales of TCI alone.Controlling for the effects of gender and age, we found significant interactions between 5-HTTLPR and DAT1 genes on Harm Avoidance (HA) and Reward Dependence (RD) as measured by the TCI (Hotelling's Trace = 3.0, P = 0.02). In the presence of the DAT1 10/10 genotype, subjects of group L of 5-HTTLPR had a significantly higher HA score and significantly lower RD score than those of group S (F = 5.04, df = 1, p = 0.03 and F = 8.35, df = 1, p = 0.004, respectively). These findings suggest that the variants of 5-HTTLPR interacted with the DAT1 gene polymorphism to influence the HA and RD temperament subscales of TCI.

  20. Latent Class Analysis of Antisocial Behavior: Interaction of Serotonin Transporter Genotype and Maltreatment

    PubMed Central

    Li, James J.

    2010-01-01

    To improve understanding about genetic and environmental influences on antisocial behavior (ASB), we tested the association of the 44-base pair polymorphism of the serotonin transporter gene (5-HTTLPR) and maltreatment using latent class analysis in 2,488 boys and girls from Wave 1 of the National Longitudinal Study of Adolescent Health. In boys, ASB was defined by three classes (Exclusive Covert, Mixed Covert and Overt, and No Problems) whereas in girls, ASB was defined by two classes (Exclusive Covert, No Problems). In boys, 5-HTTLPR and maltreatment were not significantly related to ASB. However, in girls, maltreatment, but not 5-HTTLPR, was significantly associated with ASB. A significant interaction between 5-HTTLPR and maltreatment was also observed, where maltreated girls homozygous for the short allele were 12 times more likely to be classified in the Exclusive Covert group than in the No Problems group. Structural differences in the latent structure of ASB at Wave 2 and Wave 3 prevented repeat LCA modeling. However, using counts of ASB, 5-HTTLPR, maltreatment, and its interaction were unrelated to overt and covert ASB at Wave 2 and only maltreatment was related to covert ASB at Wave 3. We discuss these findings within the context of sex differences in ASB and relevant models of gene-environment interplay across developmental periods. PMID:20405199

  1. Characterization of 18 new BoLA-DRB3 alleles.

    PubMed

    Maillard, J C; Renard, C; Chardon, P; Chantal, I; Bensaid, A

    1999-06-01

    The second exon of the bovine MHC class II DRB3 gene was amplified by polymerase chain reaction (PCR) from DNA samples of 568 zebu Brahman cattle (Bos indicus) from Martinique (French West Indies). Cloning of these PCR products allowed the isolation of both alleles from each animal, which were characterized by the PCR-restriction fragment length polymorphism (RFLP) technique using the restriction enzymes RsaI, BstYI and HaeIII. Four new PCR-RFLP patterns were obtained by digestion with RsaI. These patterns were named 'v', 'w', 'x' and 'y' continuing the accepted nomenclature. Sequencing of each allele allowed the identification of 18 new BoLA-DRB3 exon 2 nucleotide sequences and their deduced amino acid sequences.

  2. Early allelic selection in maize as revealed by ancient DNA.

    PubMed

    Jaenicke-Després, Viviane; Buckler, Ed S; Smith, Bruce D; Gilbert, M Thomas P; Cooper, Alan; Doebley, John; Pääbo, Svante

    2003-11-14

    Maize was domesticated from teosinte, a wild grass, by approximately 6300 years ago in Mexico. After initial domestication, early farmers continued to select for advantageous morphological and biochemical traits in this important crop. However, the timing and sequence of character selection are, thus far, known only for morphological features discernible in corn cobs. We have analyzed three genes involved in the control of plant architecture, storage protein synthesis, and starch production from archaeological maize samples from Mexico and the southwestern United States. The results reveal that the alleles typical of contemporary maize were present in Mexican maize by 4400 years ago. However, as recently as 2000 years ago, allelic selection at one of the genes may not yet have been complete.

  3. Stressful life events moderate the relationship between genes and biased attention to emotional faces in youth

    PubMed Central

    Jenness, Jessica L.; Hankin, Benjamin L.; Young, Jami F.; Smolen, Andrew

    2015-01-01

    Attention bias to emotion may be an intermediate trait for stress-reactive psychopathology associated with biologically plausible candidate genes, yet the precise direction of effects within the youth literature remains unclear. The present study investigated whether stressful life events (SLEs) moderate the link between genetic risk (5-HTTLPR and COMT) and attention bias to emotion among youth (n= 467). Analyses revealed a differential effect of gene. Among youth who had experienced more recent SLEs, those homozygous for the low expressing allele of 5-HTTLPR (S/S) demonstrated preferential attention toward negative emotional expressions, whereas youth homozygous for the high expressing COMT genotype (Val/Val) showed attentional avoidance of positive facial expressions. No interaction between 5-HTTLPR and COMT was found. These findings highlight the importance of investigating stress as a moderator within the intermediate trait literature and suggest that biologically plausible candidate genes may have a differential effect in the pathway to psychological disorders. PMID:27375963

  4. The Serotonin Transporter Promoter Variant, Stress, and Attentional Biases in Middle Childhood.

    PubMed

    Kotelnikova, Yuliya; LeMoult, Joelle; Mackrell, Sarah V M; Sheikh, Haroon I; Singh, Shiva M; Joormann, Jutta; Gotlib, Ian H; Hayden, Elizabeth P

    2016-09-01

    Although evidence suggests that 5-HTTLPR variants may shape risk for depression, the influence is likely complex, and involves effects on endophenotypes. We examined associations between 5-HTTLPR and biases in attention to affective stimuli in a sample of girls and a sample of both boys and girls. Children with at least one short (S) variant of the 5-HTTLPR polymorphism had lower positive attentional bias scores in both samples. This association was qualified by an interaction with stress in one sample, such that links between the S allele and decreased positive attentional bias was significant only when life stress was elevated. This difference in findings between the two samples was explained by sex differences in samples; the GXE interaction was significant only in boys. Findings are discussed in the context of sex differences in GXE.

  5. Allelic exchange in Mycobacterium tuberculosis with long linear recombination substrates.

    PubMed Central

    Balasubramanian, V; Pavelka, M S; Bardarov, S S; Martin, J; Weisbrod, T R; McAdam, R A; Bloom, B R; Jacobs, W R

    1996-01-01

    Genetic studies of Mycobacterium tuberculosis have been greatly hampered by the inability to introduce specific chromosomal mutations. Whereas the ability to perform allelic exchanges has provided a useful method of gene disruption in other organisms, in the clinically important species of mycobacteria, such as M. tuberculosis and Mycobacterium bovis, similar approaches have thus far been unsuccessful. In this communication, we report the development of a shuttle mutagenesis strategy that involves the use of long linear recombination substrates to reproducibly obtain recombinants by allelic exchange in M. tuberculosis. Long linear recombination substrates, approximately 40 to 50 kb in length, were generated by constructing libraries in the excisable cosmid vector pYUB328. The cosmid vector could be readily excised from the recombinant cosmids by digestion with PacI, a restriction endonuclease for which there exist few, if any, sites in mycobacterial genomes. A cosmid containing the mycobacterial leuD gene was isolated, and a selectable marker conferring resistance to kanamycin was inserted into the leuD gene in the recombinant cosmid by interplasmid recombination in Escherichia coli. A long linear recombination substrate containing the insertionally mutated leuD gene was generated by PacI digestion. Electroporation of this recombination substrate containing the insertionally mutated leuD allele resulted in the generation of leucine auxotrophic mutants by homologous recombination in 6% of the kanamycin-resistant transformants for both the Erdman and H37Rv strains of M. tuberculosis. The ability to perform allelic exchanges provides an important approach for investigating the biology of this pathogen as well as developing new live-cell M. tuberculosis-based vaccines. PMID:8550428

  6. Citrobacter spp. as a source of qnrB Alleles.

    PubMed

    Jacoby, George A; Griffin, Caitlin M; Hooper, David C

    2011-11-01

    qnrB is the most common of the five qnr families and has the greatest number of allelic variants. Almost two-thirds of the qnrB alleles have been reported in Citrobacter spp., and several were shown to be located on the chromosome. In this study, PCR was used to investigate the prevalence of plasmid-mediated quinolone resistance genes in 71 clinical isolates belonging to the Citrobacter freundii complex. Thirty-seven percent contained qnrB alleles, including 7 (qnrB32 to qnrB38) that were novel and 1 pseudogene, while none contained qnrA, qnrC, qnrD, qnrS, or aac(6')-Ib-cr. When the strains were arrayed by related 16S rRNA sequence and further separated into subspecies by biochemical criteria, clustering of qnrB-positive strains was evident. In only two strains with qnrB2 and qnrB4 was quinolone resistance transferable by conjugation, and only these strains contained the ISCR1 sequence that is often associated with qnrB on plasmids. Five of 26 qnrB-positive strains contained integrase genes, but these included the strains with qnrB2 and qnrB4 as well as two strains with other transmissible plasmids. In a fully sequenced genome of Citrobacter youngae, a member of the C. freundii complex, another novel qnrB allele, qnrB39, occurs in a sequence of genes that is 90% identical to sequence surrounding integron-associated qnrB4 incorporated into plasmids. The chromosome of Citrobacter is the likely source of plasmid-mediated qnrB.

  7. Fast spatial ancestry via flexible allele frequency surfaces

    PubMed Central

    Rañola, John Michael; Novembre, John; Lange, Kenneth

    2014-01-01

    Motivation: Unique modeling and computational challenges arise in locating the geographic origin of individuals based on their genetic backgrounds. Single-nucleotide polymorphisms (SNPs) vary widely in informativeness, allele frequencies change non-linearly with geography and reliable localization requires evidence to be integrated across a multitude of SNPs. These problems become even more acute for individuals of mixed ancestry. It is hardly surprising that matching genetic models to computational constraints has limited the development of methods for estimating geographic origins. We attack these related problems by borrowing ideas from image processing and optimization theory. Our proposed model divides the region of interest into pixels and operates SNP by SNP. We estimate allele frequencies across the landscape by maximizing a product of binomial likelihoods penalized by nearest neighbor interactions. Penalization smooths allele frequency estimates and promotes estimation at pixels with no data. Maximization is accomplished by a minorize–maximize (MM) algorithm. Once allele frequency surfaces are available, one can apply Bayes’ rule to compute the posterior probability that each pixel is the pixel of origin of a given person. Placement of admixed individuals on the landscape is more complicated and requires estimation of the fractional contribution of each pixel to a person’s genome. This estimation problem also succumbs to a penalized MM algorithm. Results: We applied the model to the Population Reference Sample (POPRES) data. The model gives better localization for both unmixed and admixed individuals than existing methods despite using just a small fraction of the available SNPs. Computing times are comparable with the best competing software. Availability and implementation: Software will be freely available as the OriGen package in R. Contact: ranolaj@uw.edu or klange@ucla.edu Supplementary information: Supplementary data are available at

  8. A novel allelic variant of the human TSG-6 gene encoding an amino acid difference in the CUB module. Chromosomal localization, frequency analysis, modeling, and expression.

    PubMed

    Nentwich, Hilke A; Mustafa, Zehra; Rugg, Marilyn S; Marsden, Brian D; Cordell, Martin R; Mahoney, David J; Jenkins, Suzanne C; Dowling, Barbara; Fries, Erik; Milner, Caroline M; Loughlin, John; Day, Anthony J

    2002-05-03

    Tumor necrosis factor-stimulated gene-6 (TSG-6) encodes a 35-kDa protein, which is comprised of contiguous Link and CUB modules. TSG-6 protein has been detected in the articular joints of osteoarthritis (OA) patients, with little or no constitutive expression in normal adult tissues. It interacts with components of cartilage matrix (e.g. hyaluronan and aggrecan) and thus may be involved in extracellular remodeling during joint disease. In addition, TSG-6 has been found to have anti-inflammatory properties in models of acute and chronic inflammation. Here we have mapped the human TSG-6 gene to 2q23.3, a region of chromosome 2 linked with OA. A single nucleotide polymorphism was identified that involves a non-synonymous G --> A transition at nucleotide 431 of the TSG-6 coding sequence, resulting in an Arg to Gln alteration in the CUB module (at residue 144 in the preprotein). Molecular modeling of the CUB domain indicated that this amino acid change might lead to functional differences. Typing of 400 OA cases and 400 controls revealed that the A(431) variant identified here is the major TSG-6 allele in Caucasians (with over 75% being A(431) homozygotes) but that this polymorphism is not a marker for OA susceptibility in the patients we have studied. Expression of the Arg(144) and Gln(144) allotypes in Drosophila Schneider 2 cells, and functional characterization, showed that there were no significant differences in the ability of these full-length proteins to bind hyaluronan or form a stable complex with inter-alpha-inhibitor.

  9. A novel dwarfism with gonadal dysfunction due to loss-of-function allele of the collagen receptor gene, Ddr2, in the mouse.

    PubMed

    Kano, Kiyoshi; Marín de Evsikova, C; Young, James; Wnek, Christopher; Maddatu, Terry P; Nishina, Patsy M; Naggert, Jürgen K

    2008-08-01

    Smallie (slie), a spontaneous, autosomal-recessive mutation causes dwarfing and infertility in mice. The purpose of this study was to determine and characterize the underlying molecular genetic basis for its phenotype. The slie locus was mapped to chromosome 1, and fine-structure mapping narrowed the slie allele within 2 Mb between genetic markers D1Mit36 and Mpz. To pinpoint the underlying mutation quantitative real-time PCR was used to measure the relative expression levels for the genes residing within this region. Expression of one gene, Ddr2, which encodes discoidin domain receptor 2 (DDR2), was absent in slie homozygote mice. Genomic sequencing analysis detected a 150-kb deletion that extended into the Ddr2 gene transcript. Detailed phenotype analysis revealed that gonadal dysregulation underlies infertility in slie mice because all females were anovulatory and most adult males lacked spermatogenesis. The pituitary gland of prepubertal slie mice was smaller than in wild-type mice. The basal levels and gene expression for pituitary and hypothalamic hormones, and gene expression for hypothalamic-releasing hormones, were not significantly different between slie and wild-type mice. Circulating levels of IGF-1 did not differ in slie mice despite lower Igf-1 mRNA expression in the liver. After exogenous gonadotropin administration, the levels of secreted steroid hormones in both male and female adult slie mice were blunted compared to adult wild-type, but was similar to prepubertal wild-type mice. Taken together, our results indicate that the absence of DDR2 leads to growth retardation and gonadal dysfunction due to peripheral defects in hormonal-responsive pathways in slie mice.

  10. A Novel Dwarfism with Gonadal Dysfunction Due to Loss-of-Function Allele of the Collagen Receptor Gene, Ddr2, in the Mouse

    PubMed Central

    Kano, Kiyoshi; Marín de Evsikova, C.; Young, James; Wnek, Christopher; Maddatu, Terry P.; Nishina, Patsy M.; Naggert, Jürgen K.

    2008-01-01

    Smallie (slie), a spontaneous, autosomal-recessive mutation causes dwarfing and infertility in mice. The purpose of this study was to determine and characterize the underlying molecular genetic basis for its phenotype. The slie locus was mapped to chromosome 1, and fine-structure mapping narrowed the slie allele within 2 Mb between genetic markers D1Mit36 and Mpz. To pinpoint the underlying mutation quantitative real-time PCR was used to measure the relative expression levels for the genes residing within this region. Expression of one gene, Ddr2, which encodes discoidin domain receptor 2 (DDR2), was absent in slie homozygote mice. Genomic sequencing analysis detected a 150-kb deletion that extended into the Ddr2 gene transcript. Detailed phenotype analysis revealed that gonadal dysregulation underlies infertility in slie mice because all females were anovulatory and most adult males lacked spermatogenesis. The pituitary gland of prepubertal slie mice was smaller than in wild-type mice. The basal levels and gene expression for pituitary and hypothalamic hormones, and gene expression for hypothalamic-releasing hormones, were not significantly different between slie and wild-type mice. Circulating levels of IGF-1 did not differ in slie mice despite lower Igf-1 mRNA expression in the liver. After exogenous gonadotropin administration, the levels of secreted steroid hormones in both male and female adult slie mice were blunted compared to adult wild-type, but was similar to prepubertal wild-type mice. Taken together, our results indicate that the absence of DDR2 leads to growth retardation and gonadal dysfunction due to peripheral defects in hormonal-responsive pathways in slie mice. PMID:18483174

  11. Pollution-tolerant allele in fingernail clams (Musculium transversum).

    PubMed

    Sloss, B L; Romano, M A; Anderson, R V

    1998-08-01

    For nearly 50 years, the fingernail clam (Musculium transversum) was believed to be virtually eliminated from the Illinois River. In 1991, workers began finding substantial populations of M. transversum in the Illinois River including several beds in and around the highly polluted Chicago Sanitary District. In order to determine if populations of M. transversum from polluted sites exhibited any genetic response to the high levels of toxins and to examine the genetic structure of several populations of M. transversum for any changes due to the population crash, starch-gel electrophoresis was performed on M. transversum from three Illinois River localities and four Mississippi River basin locations. The sampled populations produced an inbreeding coefficient (FIS) of 0.929, indicating that the populations were highly inbred. The results of a suspected founder effect due to a bottleneck was suggested by an FST = 0.442. The isozyme Glucose-6-phosphate isomerase-2 (Gpi-2) produced allelic frequency patterns that were consistent with expected patterns of a pollution-tolerant allele. Polluted sites exhibited elevated frequencies of Gpi-2(100) whereas nonpolluted sites exhibited elevated frequencies of Gpi-2(74). This frequency pattern suggested that natural selection was occurring in populations under severe toxic pressures, leading to an increase in the frequency of the allele Gpi-2(100). Therefore, Gpi-2(100) is a possible pollution-tolerant mutation in M. transversum.

  12. RNA-FISH to analyze allele-specific expression.

    PubMed

    Braidotti, G

    2001-01-01

    One of the difficulties associated with the analysis of imprinted gene expression is the need to distinguish RNA synthesis occurring at the maternal vs the paternally inherited copy of the gene. Most of the techniques used to examine allele-specific expression exploit naturally occurring polymorphisms and measure steady-state levels of RNA isolated from a pool of cells. Hence, a restriction fragment length polymorphism (RFLP) an be exploited in a heterozygote, by a reverse transcriptase polymerase chain reaction (RT-PCR)- based procedure, to analyze maternal vs paternal gene expression. The human IGF2R gene was analyzed in this way. Smrzka et al. (1) were thus able to show that the IGF2R gene possesses a hemimethylated, intronic CpG island analogous to the mouse imprinting box. However, IGF2R mRNA was detected that possessed the RFLP from both the maternal and paternal alleles in all but one of the 70 lymphoblastoid samples. (The one monoallelic sample reactivated its paternal allele with continued cell culturing.) It was concluded that monoallelic expression of the human gene is a polymorphic trait occurring in a small minority of all tested samples (reviewed in refs. 2,3). Although this is a sound conclusion, the question remains: Is the human IGF2R gene imprinted?

  13. Tracing pastoralist migrations to southern Africa with lactase persistence alleles.

    PubMed

    Macholdt, Enrico; Lede, Vera; Barbieri, Chiara; Mpoloka, Sununguko W; Chen, Hua; Slatkin, Montgomery; Pakendorf, Brigitte; Stoneking, Mark

    2014-04-14

    Although southern African Khoisan populations are often assumed to have remained largely isolated during prehistory, there is growing evidence for a migration of pastoralists from eastern Africa some 2,000 years ago, prior to the arrival of Bantu-speaking populations in southern Africa. Eastern Africa harbors distinctive lactase persistence (LP) alleles, and therefore LP alleles in southern African populations may be derived from this eastern African pastoralist migration. We sequenced the lactase enhancer region in 457 individuals from 18 Khoisan and seven Bantu-speaking groups from Botswana, Namibia, and Zambia and additionally genotyped four short tandem repeat (STR) loci that flank the lactase enhancer region. We found nine single-nucleotide polymorphisms, of which the most frequent is -14010(∗)C, which was previously found to be associated with LP in Kenya and Tanzania and to exhibit a strong signal of positive selection. This allele occurs in significantly higher frequency in pastoralist groups and in Khoe-speaking groups in our study, supporting the hypothesis of a migration of eastern African pastoralists that was primarily associated with Khoe speakers. Moreover, we find a signal of ongoing positive selection in all three pastoralist groups in our study, as well as (surprisingly) in two foraging groups.

  14. A survey of FRAXE allele sizes in three populations

    SciTech Connect

    Zhong, N.; Ju, W.; Curley, D.

    1996-08-09

    FRAXE is a fragile site located at Xq27-8, which contains polymorphic triplet GCC repeats associated with a CpG island. Similar to FRAXA, expansion of the GCC repeats results in an abnormal methylation of the CpG island and is associated with a mild mental retardation syndrome (FRAXE-MR). We surveyed the GCC repeat alleles of FRAXE from 3 populations. A total of 665 X chromosomes including 416 from a New York Euro-American sample (259 normal and 157 with FRAXA mutations), 157 from a Chinese sample (144 normal and 13 FRAXA), and 92 from a Finnish sample (56 normal and 36 FRAXA) were analyzed by polymerase chain reaction. Twenty-seven alleles, ranging from 4 to 39 GCC repeats, were observed. The modal repeat number was 16 in the New York and Finnish samples and accounted for 24% of all the chromosomes tested (162/665). The modal repeat number in the Chinese sample was 18. A founder effect for FRAXA was suggested among the Finnish FRAXA samples in that 75% had the FRAXE 16 repeat allele versus only 30% of controls. Sequencing of the FRAXE region showed no imperfections within the GCC repeat region, such as those commonly seen in FRAXA. The smaller size and limited range of repeats and the lack of imperfections suggests the molecular mechanisms underlying FRAXE triplet mutations may be different from those underlying FRAXA. 27 refs., 4 figs., 1 tab.

  15. Mutant power: using mutant allele collections for yeast functional genomics.

    PubMed

    Norman, Kaitlyn L; Kumar, Anuj

    2016-03-01

    The budding yeast has long served as a model eukaryote for the functional genomic analysis of highly conserved signaling pathways, cellular processes and mechanisms underlying human disease. The collection of reagents available for genomics in yeast is extensive, encompassing a growing diversity of mutant collections beyond gene deletion sets in the standard wild-type S288C genetic background. We review here three main types of mutant allele collections: transposon mutagen collections, essential gene collections and overexpression libraries. Each collection provides unique and identifiable alleles that can be utilized in genome-wide, high-throughput studies. These genomic reagents are particularly informative in identifying synthetic phenotypes and functions associated with essential genes, including those modeled most effectively in complex genetic backgrounds. Several examples of genomic studies in filamentous/pseudohyphal backgrounds are provided here to illustrate this point. Additionally, the limitations of each approach are examined. Collectively, these mutant allele collections in Saccharomyces cerevisiae and the related pathogenic yeast Candida albicans promise insights toward an advanced understanding of eukaryotic molecular and cellular biology.

  16. Systematic review and meta-analysis of serotonin transporter genotype and discontinuation from antidepressant treatment.

    PubMed

    Crawford, Andrew A; Lewis, Glyn; Lewis, Sarah J; Munafò, Marcus R

    2013-10-01

    There is evidence that 5-HTTLPR is associated with response following treatment from selective serotonin reuptake inhibitors (SSRIs). The short (S) allele has reduced serotonin transporter expression, compared to the long (L) allele, and has been reported to be associated with poorer response in Europeans, with the effect in other populations unclear. However the published literature is inconsistent. A systematic review and meta-analysis was performed to investigate the effect of 5-HTTLPR on discontinuation from antidepressant treatment. Data were obtained from 17 studies including 4309 participants. The principal outcome measure was the allelic odds ratio (OR) for the 5-HTTLPR S allele and discontinuation status. A random effects meta-analysis provided no evidence that the S allele was associated with increased odds of discontinuation from SSRIs in Europeans (OR 1.09, 95% CI 0.83-1.42, p=0.53; 10 studies, n=2504) but in East Asians there was evidence of a reduced odds of discontinuation (OR 0.28, 95% CI 0.12-0.64, p=0.002; 2 studies, n=136). There was a suggestion of small study bias (p=0.05). This meta-analysis provides no evidence of an association between 5-HTTLPR and discontinuation from antidepressant treatment in Europeans. The low number of studies in East Asian samples using SSRIs reduces confidence in our evidence that the S allele decreases the odds of discontinuation in this population. At present, there is no evidence of an association between 5-HTTLPR and discontinuation from SSRI treatment in a European population with further studies required to investigate its effects in different populations.

  17. Conditional Allele Mouse Planner (CAMP): software to facilitate the planning and design of breeding strategies involving mice with conditional alleles.

    PubMed

    Hoffert, Jason D; Pisitkun, Trairak; Miller, R Lance

    2012-06-01

    Transgenic and conditional knockout mouse models play an important role in biomedical research and their use has grown exponentially in the last 5-10 years. Generating conditional knockouts often requires breeding multiple alleles onto the background of a single mouse or group of mice. Breeding these mice depends on parental genotype, litter size, transmission frequency, and the number of breeding rounds. Therefore, a well planned breeding strategy is critical for keeping costs to a minimum. However, designing a viable breeding strategy can be challenging. With so many different variables this would be an ideal task for a computer program. To facilitate this process, we created a Java-based program called Conditional Allele Mouse Planner (CAMP). CAMP is designed to provide an estimate of the number of breeders, amount of time, and costs associated with generating mice of a particular genotype. We provide a description of CAMP, how to use it, and offer it freely as an application.

  18. Novel method for analysis of allele specific expression in triploid Oryzias latipes reveals consistent pattern of allele exclusion.

    PubMed

    Garcia, Tzintzuni I; Matos, Isa; Shen, Yingjia; Pabuwal, Vagmita; Coelho, Maria Manuela; Wakamatsu, Yuko; Schartl, Manfred; Walter, Ronald B

    2014-01-01

    Assessing allele-specific gene expression (ASE) on a large scale continues to be a technically challenging problem. Certain biological phenomena, such as X chromosome inactivation and parental imprinting, affect ASE most drastically by completely shutting down the expression of a whole set of alleles. Other more subtle effects on ASE are likely to be much more complex and dependent on the genetic environment and are perhaps more important to understand since they may be responsible for a significant amount of biological diversity. Tools to assess ASE in a diploid biological system are becoming more reliable. Non-diploid systems are, however, not uncommon. In humans full or partial polyploid states are regularly found in both healthy (meiotic cells, polynucleated cell types) and diseased tissues (trisomies, non-disjunction events, cancerous tissues). In this work we have studied ASE in the medaka fish model system. We have developed a method for determining ASE in polyploid organisms from RNAseq data and we have implemented this method in a software tool set. As a biological model system we have used nuclear transplantation to experimentally produce artificial triploid medaka composed of three different haplomes. We measured ASE in RNA isolated from the livers of two adult, triploid medaka fish that showed a high degree of similarity. The majority of genes examined (82%) shared expression more or less evenly among the three alleles in both triploids. The rest of the genes (18%) displayed a wide range of ASE levels. Interestingly the majority of genes (78%) displayed generally consistent ASE levels in both triploid individuals. A large contingent of these genes had the same allele entirely suppressed in both triploids. When viewed in a chromosomal context, it is revealed that these genes are from large sections of 4 chromosomes and may be indicative of some broad scale suppression of gene expression.

  19. The number of alleles at a microsatellite defines the allele frequency spectrum and facilitates fast accurate estimation of theta.

    PubMed

    Haasl, Ryan J; Payseur, Bret A

    2010-12-01

    Theoretical work focused on microsatellite variation has produced a number of important results, including the expected distribution of repeat sizes and the expected squared difference in repeat size between two randomly selected samples. However, closed-form expressions for the sampling distribution and frequency spectrum of microsatellite variation have not been identified. Here, we use coalescent simulations of the stepwise mutation model to develop gamma and exponential approximations of the microsatellite allele frequency spectrum, a distribution central to the description of microsatellite variation across the genome. For both approximations, the parameter of biological relevance is the number of alleles at a locus, which we express as a function of θ, the population-scaled mutation rate, based on simulated data. Discovered relationships between θ, the number of alleles, and the frequency spectrum support the development of three new estimators of microsatellite θ. The three estimators exhibit roughly similar mean squared errors (MSEs) and all are biased. However, across a broad range of sample sizes and θ values, the MSEs of these estimators are frequently lower than all other estimators tested. The new estimators are also reasonably robust to mutation that includes step sizes greater than one. Finally, our approximation to the microsatellite allele frequency spectrum provides a null distribution of microsatellite variation. In this context, a preliminary analysis of the effects of demographic change on the frequency spectrum is performed. We suggest that simulations of the microsatellite frequency spectrum under evolutionary scenarios of interest may guide investigators to the use of relevant and sometimes novel summary statistics.

  20. Increasing long-term response by selecting for favorable minor alleles

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Long-term response of genomic selection can be improved by considering allele frequencies of selected markers or quantitative trait loci (QTLs). A previous formula to weight allele frequency of favorable minor alleles was tested, and 2 new formulas were developed. The previous formula used nonlinear...

  1. Allele Mining Strategies: Principles and Utilisation for Blast Resistance Genes in Rice (Oryza sativa L.).

    PubMed

    Ashkani, Sadegh; Yusop, Mohd Rafii; Shabanimofrad, Mahmoodreza; Azady, Amin; Ghasemzadeh, Ali; Azizi, Parisa; Latif, Mohammad Abdul

    2015-01-01

    Allele mining is a promising way to dissect naturally occurring allelic variants of candidate genes with essential agronomic qualities. With the identification, isolation and characterisation of blast resistance genes in rice, it is now possible to dissect the actual allelic variants of these genes within an array of rice cultivars via allele mining. Multiple alleles from the complex locus serve as a reservoir of variation to generate functional genes. The routine sequence exchange is one of the main mechanisms of R gene evolution and development. Allele mining for resistance genes can be an important method to identify additional resistance alleles and new haplotypes along with the development of allele-specific markers for use in marker-assisted selection. Allele mining can be visualised as a vital link between effective utilisation of genetic and genomic resources in genomics-driven modern plant breeding. This review studies the actual concepts and potential of mining approaches for the discovery of alleles and their utilisation for blast resistance genes in rice. The details provided here will be important to provide the rice breeder with a worthwhile introduction to allele mining and its methodology for breakthrough discovery of fresh alleles hidden in hereditary diversity, which is vital for crop improvement.

  2. Genetic restriction of HIV-1 infection and progression to AIDS by a deletion allele of the CKR5 structural gene. Hemophilia Growth and Development Study, Multicenter AIDS Cohort Study, Multicenter Hemophilia Cohort Study, San Francisco City Cohort, ALIVE Study.

    PubMed

    Dean, M; Carrington, M; Winkler, C; Huttley, G A; Smith, M W; Allikmets, R; Goedert, J J; Buchbinder, S P; Vittinghoff, E; Gomperts, E; Donfield, S; Vlahov, D; Kaslow, R; Saah, A; Rinaldo, C; Detels, R; O'Brien, S J

    1996-09-27

    The chemokine receptor 5 (CKR5) protein serves as a secondary receptor on CD4(+) T lymphocytes for certain strains of human immunodeficiency virus-type 1 (HIV-1). The CKR5 structural gene was mapped to human chromosome 3p21, and a 32-base pair deletion allele (CKR5Delta32) was identified that is present at a frequency of approximately0.10 in the Caucasian population of the United States. An examination of 1955 patients included among six well-characterized acquired immunodeficiency syndrome (AIDS) cohort studies revealed that 17 deletion homozygotes occurred exclusively among 612 exposed HIV-1 antibody-negative individuals (2.8 percent) and not at all in 1343 HIV-1-infected individuals. The frequency of CKR5 deletion heterozygotes was significantly elevated in groups of individuals that had survived HIV-1 infection for more than 10 years, and, in some risk groups, twice as frequent as their occurrence in rapid progressors to AIDS. Survival analysis clearly shows that disease progression is slower in CKR5 deletion heterozygotes than in individuals homozygous for the normal CKR5 gene. The CKR5Delta32 deletion may act as a recessive restriction gene against HIV-1 infection and may exert a dominant phenotype of delaying progression to AIDS among infected individuals.

  3. Advancing allele group-specific amplification of the complete HLA-C gene--isolation of novel alleles from three allele groups (C*04, C*07 and C*08).

    PubMed

    Cisneros, E; Martínez-Pomar, N; Vilches, M; Martín, P; de Pablo, R; Nuñez Del Prado, N; Nieto, A; Matamoros, N; Moraru, M; Vilches, C

    2013-10-01

    A variety of strategies have been designed for sequence-based HLA typing (SBT) and for the isolation of new human leucocyte antigen (HLA) alleles, but unambiguous characterization of complete genomic sequences remains a challenge. We recently reported a simple method for the group-specific amplification (GSA) and sequencing of a full-length C*04 genomic sequence in isolation from the accompanying allele. Here we build on this strategy and present homologous methods that enable the isolation of HLA-C alleles belonging to another two allele groups. Using this approach, which can be applied to sequence-based typing in some clinical settings, we have successfully characterized three novel HLA-C alleles (C*04:128, C*07:01:01:02, and C*08:62).

  4. Common Kibra alleles are associated with human memory performance.

    PubMed

    Papassotiropoulos, Andreas; Stephan, Dietrich A; Huentelman, Matthew J; Hoerndli, Frederic J; Craig, David W; Pearson, John V; Huynh, Kim-Dung; Brunner, Fabienne; Corneveaux, Jason; Osborne, David; Wollmer, M Axel; Aerni, Amanda; Coluccia, Daniel; Hänggi, Jürgen; Mondadori, Christian R A; Buchmann, Andreas; Reiman, Eric M; Caselli, Richard J; Henke, Katharina; de Quervain, Dominique J-F

    2006-10-20

    Human memory is a polygenic trait. We performed a genome-wide screen to identify memory-related gene variants. A genomic locus encoding the brain protein KIBRA was significantly associated with memory performance in three independent, cognitively normal cohorts from Switzerland and the United States. Gene expression studies showed that KIBRA was expressed in memory-related brain structures. Functional magnetic resonance imaging detected KIBRA allele-dependent differences in hippocampal activations during memory retrieval. Evidence from these experiments suggests a role for KIBRA in human memory.

  5. Allelic melanism in American and British peppered moths.

    PubMed

    Grant, B S

    2004-01-01

    Parallel evolutionary changes in the incidence of melanism are well documented in widely geographically separated subspecies of the peppered moth (Biston betularia). The British melanic phenotype (f. carbonaria) and the American melanic phenotype (f. swettaria) are indistinguishable in appearance, and previous genetic analysis has established that both are inherited as autosomal dominants. This report demonstrates through hybridizations of the subspecies and Mendelian testcrosses of melanic progeny that carbonaria and swettaria are phenotypes produced by alleles (isoalleles) at a single locus. The possibility of close linkage at two loci remains, but the simpler one-locus model cannot be rejected in the absence of contrary evidence.

  6. Genetic Polymorphism in the Promoter Region of Serotonin Transporter: Implications for Ethanol Abuse in Children and Adolescents

    PubMed Central

    de Oliveira, Carlos Eduardo Coral; Oda, Julie Massayo Maeda; Ariza, Carolina Batista; Guembarovski, Roberta Losi; Hirata, Bruna Karina Banin; de Almeida, Felipe Campos; André, Nayara Delgado; Fungaro, Maria Helena Pelegrinelli; Watanabe, Maria Angelica Ehara

    2016-01-01

    Objectives: To provide a review of published literature regarding genetic polymorphism of serotonin transporter gene, named as 5-HTTLPR, and its potential role as a susceptibility marker for ethanol abuse in childhood and adolescence. Methods: A literature review of several databases was conducted with the following keywords: 5-HTTLPR, children or adolescents or teenagers, susceptibility, alcohol or ethanol, abuse or misuse. Results: Alcohol interacts with serotonergic synaptic transmission in several ways, and the reduced availability of serotonin transporters might foster brain dysfunction, driving to alcohol abuse. The initial use of ethanol in children and adolescents is determined primarily by environmental influences, whereas the establishment of drinking patterns is strongly controlled by genetic factors. Functional polymorphic variants in the promoter region of the 5-HTTLPR gene have age-dependent effects in alcohol abuse. This polymorphism, mapped to the 5′ region of the SLC6A4, is a variable number of tandem repeats (VNTR) and involves a direct repeat of 20–23 base pairs GC-rich sequences, comprising a short (S) allele, consisting of 14 repeats, and a long (L) allele, with 16 repeats. Additional variants have been described, although their influences on childhood and adolescence ethanol use are not clear. Conclusion: The influence of the 5-HTTLPR allelic variants in children and adolescent misuse of alcohol might be considered for clinical management, preventing long-term behavior problem. Identifying genetic markers associated to the potential alcohol misuse or abuse could be useful in guiding management and formulating effective coping strategies. PMID:27047556

  7. Accurate size comparison of short tandem repeat alleles amplified by PCR.

    PubMed

    Smith, R N

    1995-01-01

    A strategy is presented for classifying complex short tandem repeat (STR) alleles by size. Such alleles can differ in length by only 1 bp. The HUMACTBP2 locus was used as a model. Dye-labeled, PCR-amplified alleles were analyzed on an automated DNA sequencer with laser-induced fluorescence detection and fragment-sizing software. Between-gel allele sizes calculated against an in-lane allelic ladder or viral DNA size standard were too imprecise to distinguish a 1-bp difference. However, the size difference between a sample allele and its matching ladder allele provided a reliable criterion for size classification. The mean size difference +/- 3 SDs was 0.5 bp, and so an individual result within this interval signified a match. Statistically, 99.7% of the results should lie within +/- 3 SDs with virtually no chance of encountering the 9-SD difference from the mean necessary to misclassify an allele by 1 bp. The method was valid for sample alleles sized against the allelic ladder and for both sample and ladder alleles sized against the viral DNA standard. A correction for the effect of different dye labels on mobility was included in the calculations.

  8. Polymorphism of Mhc-DRB alleles in Cercopithecus aethiops (green monkey): generation and functionality.

    PubMed

    Rosal-Sánchez, M; Paz-Artal, E; Moreno-Pelayo, M A; Martínez-Quiles, N; Martínez-Laso, J; Martín-Villa, J M; Arnaiz-Villena, A

    1998-05-01

    DRB genes have been studied for the first time in green monkeys (Cercopithecus aethiops). Eleven new DRB alleles (exon 2, exon 3) have been obtained and sequenced from cDNA. A limited number of lineages have been identified: DRB1*03 (4 alleles), DRB1*07 (3 alleles), DRB5 (1 allele), DRB*w6 (1 allele), and DRB*w7 (2 alleles). The existence of Ceae-DRB1 duplications is supported by the finding of 3 DRB1 alleles in 3 different individuals. Ceae-DRB1*0701 may be non-functional because it bears serine at position 82, which hinders molecule surface expression in mice; the allele is only found in Ceae-DRB duplicated haplotypes. Base changes in cDNA Ceae-DRB alleles are consistent with the generation of polymorphism by point mutations or short segment exchanges between alleles. The eleven green monkey DRB alleles meet the requirements for functionality as antigen-presenting molecules (perhaps, excluding DRB1*0701), since: 1) they have been isolated from cDNA and do not present deletions, insertions or stop codons: 2) structural motifs necessary for a correct folding of the molecule, for the formation of DR/DR dimers and for CD4 interactions are conserved, and 3) the number of non-synonymous substitutions is higher than the number of synonymous substitutions in the peptide binding region (PBR), while the contrary holds true for the non-PBR region.

  9. The Influence of Family Structure, the TPH2 G-703T and the 5-HTTLPR Serotonergic Genes upon Affective Problems in Children Aged 10-14 Years

    ERIC Educational Resources Information Center

    Nobile, Maria; Rusconi, Marianna; Bellina, Monica; Marino, Cecilia; Giorda, Roberto; Carlet, Ombretta; Vanzin, Laura; Molteni, Massimo; Battaglia, Marco

    2009-01-01

    Background: Both genetic and psychosocial risk factors influence the risk for depression in development. While the impacts of family structure and of serotonergic polymorphisms upon individual differences for affective problems have been investigated separately, they have never been considered together in a gene-environment interplay perspective.…

  10. Analysis of elite variety tag SNPs reveals an important allele in upland rice.

    PubMed

    Lyu, Jun; Zhang, Shilai; Dong, Yang; He, Weiming; Zhang, Jing; Deng, Xianneng; Zhang, Yesheng; Li, Xin; Li, Baoye; Huang, Wangqi; Wan, Wenting; Yu, Yang; Li, Qiong; Li, Jun; Liu, Xin; Wang, Bo; Tao, Dayun; Zhang, Gengyun; Wang, Jun; Xu, Xun; Hu, Fengyi; Wang, Wen

    2013-01-01

    Elite crop varieties usually fix alleles that occur at low frequencies within non-elite gene pools. Dissecting these alleles for desirable agronomic traits can be accomplished by comparing the genomes of elite varieties with those from non-elite populations. Here we deep-sequence six elite rice varieties and use two large control panels to identify elite variety tag single-nucleotide polymorphism alleles (ETASs). Guided by this preliminary analysis, we comprehensively characterize one protein-altering ETAS in the 9-cis-epoxycarotenoid dioxygenase gene of the IRAT104 upland rice variety. This allele displays a drastic frequency difference between upland and irrigated rice, and a selective sweep is observed around this allele. Functional analysis indicates that in upland rice, this allele is associated with significantly higher abscisic acid levels and denser lateral roots, suggesting its association with upland rice suitability. This report provides a potential strategy to mine rare, agronomically important alleles.

  11. Cytochrome allelic variants and clopidogrel metabolism in cardiovascular diseases therapy.

    PubMed

    Jarrar, Mohammed; Behl, Shalini; Manyam, Ganiraju; Ganah, Hany; Nazir, Mohammed; Nasab, Reem; Moustafa, Khaled

    2016-06-01

    Clopidogrel and aspirin are among the most prescribed dual antiplatelet therapies to treat the acute coronary syndrome and heart attacks. However, their potential clinical impacts are a subject of intense debates. The therapeutic efficiency of clopidogrel is controlled by the actions of hepatic cytochrome P450 (CYPs) enzymes and impacted by individual genetic variations. Inter-individual polymorphisms in CYPs enzymes affect the metabolism of clopidogrel into its active metabolites and, therefore, modify its turnover and clinical outcome. So far, clinical trials fail to confirm higher or lower adverse cardiovascular effects in patients treated with combinations of clopidogrel and proton pump inhibitors, compared with clopidogrel alone. Such inconclusive findings may be due to genetic variations in the cytochromes CYP2C19 and CYP3A4/5. To investigate potential interactions/effects of these cytochromes and their allele variants on the treatment of acute coronary syndrome with clopidogrel alone or in combination with proton pump inhibitors, we analyze recent literature and discuss the potential impact of the cytochrome allelic variants on cardiovascular events and stent thrombosis treated with clopidogrel. The diversity of CYP2C19 polymorphisms and prevalence span within various ethnic groups, subpopulations and demographic areas are also debated.

  12. A bird's eye view of a deleterious recessive allele.

    PubMed

    Ekblom, Robert

    2016-07-01

    In the endangered Scottish chough (Pyrrhocorax pyrrhocorax) population, a lethal blindness syndrome is found to be caused by a deleterious recessive allele. Photo: Gordon Yates. In Focus: Trask, A.E., Bignal, E.M., McCracken, D.I., Monaghan, P., Piertney, S.B. & Reid, J.M. (2016) Evidence of the phenotypic expression of a lethal recessive allele under inbreeding in a wild population of conservation concern. Journal of Animal Ecology, 85, 879-891. In this issue of Journal of Animal Ecology, Trask et al. () report on a strange, lethal, blindness that regularly affects chicks of an endangered bird population. The authors show that the inheritance mode of this blindness disease precisely matches the expectations of a recessive deleterious mutation. Intriguingly, there is also an indication that the disease-causing variant might be maintained in the population by balancing selection, due to a selective advantage for heterozygotes. Could this finding have consequences for conservation actions implemented for the population?

  13. Allele mining and enhanced genetic recombination for rice breeding.

    PubMed

    Leung, Hei; Raghavan, Chitra; Zhou, Bo; Oliva, Ricardo; Choi, Il Ryong; Lacorte, Vanica; Jubay, Mona Liza; Cruz, Casiana Vera; Gregorio, Glenn; Singh, Rakesh Kumar; Ulat, Victor Jun; Borja, Frances Nikki; Mauleon, Ramil; Alexandrov, Nickolai N; McNally, Kenneth L; Sackville Hamilton, Ruaraidh

    2015-12-01

    Traditional rice varieties harbour a large store of genetic diversity with potential to accelerate rice improvement. For a long time, this diversity maintained in the International Rice Genebank has not been fully used because of a lack of genome information. The publication of the first reference genome of Nipponbare by the International Rice Genome Sequencing Project (IRGSP) marked the beginning of a systematic exploration and use of rice diversity for genetic research and breeding. Since then, the Nipponbare genome has served as the reference for the assembly of many additional genomes. The recently completed 3000 Rice Genomes Project together with the public database (SNP-Seek) provides a new genomic and data resource that enables the identification of useful accessions for breeding. Using disease resistance traits as case studies, we demonstrated the power of allele mining in the 3,000 genomes for extracting accessions from the GeneBank for targeted phenotyping. Although potentially useful landraces can now be identified, their use in breeding is often hindered by unfavourable linkages. Efficient breeding designs are much needed to transfer the useful diversity to breeding. Multi-parent Advanced Generation InterCross (MAGIC) is a breeding design to produce highly recombined populations. The MAGIC approach can be used to generate pre-breeding populations with increased genotypic diversity and reduced linkage drag. Allele mining combined with a multi-parent breeding design can help convert useful diversity into breeding-ready genetic resources.

  14. Characterization of ROP18 alleles in human toxoplasmosis.

    PubMed

    Sánchez, Víctor; de-la-Torre, Alejandra; Gómez-Marín, Jorge Enrique

    2014-04-01

    The role of the virulent gene ROP18 polymorphisms is not known in human toxoplasmosis. A total of 320 clinical samples were analyzed. In samples positive for ROP18 gene, we determined by an allele specific PCR, if patients got the upstream insertion positive ROP18 sequence Toxoplasma strain (mouse avirulent strain) or the upstream insertion negative ROP18 sequence Toxoplasma strain (mouse virulent strain). We designed an ELISA assay for antibodies against ROP18 derived peptides from the three major clonal lineages of Toxoplasma. 20 clinical samples were of quality for ROP18 allele analysis. In patients with ocular toxoplasmosis, a higher inflammatory reaction on eye was associated to a PCR negative result for the upstream region of ROP18. 23.3%, 33% and 16.6% of serums from individuals with ocular toxoplasmosis were positive for type I, type II and type III ROP18 derived peptides, respectively but this assay was affected by cross reaction. The absence of Toxoplasma ROP18 promoter insertion sequence in ocular toxoplasmosis was correlated with severe ocular inflammatory response. Determination of antibodies against ROP18 protein was not useful for serotyping in human toxoplasmosis.

  15. Allelic loss and linkage studies in prostate cancer

    SciTech Connect

    Johnson, D.R.; Bale, A.E.; Lytton, B.

    1994-09-01

    Prostate cancer is the most common malignancy in U.S. males. Many examples of familial aggregation have been reported, and segregration analysis suggests that an autosomal dominant gene with a penetrance of 88% by age 85 accounts for 9% of all cases. Because many dominant cancer predisposition syndromes are related to germline mutations in tumor suppressor genes, we analyzed a series of sporadic and hereditary tumors for allelic loss. High grade sporadic, paraffin-embedded, primary prostate tumors were obtained from the archival collection in the Department of Pathology at Yale and hereditary tumors from three families were obtained by an advertisement in the New York Times and from referrals by urologists. PCR analysis showed loss in 4/7 informative sporadic prostate tumors with NEFL (8p21), in 8/22 informative tumors with D10S169 (10q26-qter), in 2/8 informative tumors with D10S108 (10q) and in 4/23 informative tumors with D10S89 (10p) in agreement with previous studies. PYGM on chromosome 11 and D9S127 on chromosome 9 showed no loss. Linkage analysis with NEFL in 3 prostate cancer families gave strongly negative results for close linkage (Z=-2.1 at {theta}=0.01) but LOD scores were very dependent on parameters, e.g. gene frequency, phenocopy rate, and penetrance. Linkage analysis with chromosome 10 markers and systematic analysis of the genome for other area of allelic loss are underway.

  16. Allelic variations of glut-1 deficiency syndrome: the chinese experience.

    PubMed

    Liu, Yanyan; Bao, Xinhua; Wang, Dong; Fu, Na; Zhang, Xiaoying; Cao, Guangna; Song, Fuying; Wang, Shuang; Zhang, Yuehua; Qin, Jiong; Yang, Hong; Engelstad, Kristin; De Vivo, Darryl C; Wu, Xiru

    2012-07-01

    Glucose transporter type 1 deficiency syndrome is characterized by infantile onset seizures, development delay, movement disorders, and acquired microcephaly. The phenotype includes allelic variants such as intermittent ataxia, choreoathetosis, dystonia, and alternating hemiplegia of childhood with or without epilepsy. Dystonias involve allelic variants of glucose transporter type 1 deficiency syndrome. Three Chinese patients presented with paroxysmal behavioral disturbance, weakness, ataxia (especially after fasting), and exercise intolerance. Electroencephalogram findings did not correlate with clinical manifestations. Cranial magnetic resonance imaging produced normal results or mild hypomyelination. Hypoglycorrhachia was evident in all cases. Cerebrospinal fluid glucose ranged from 1.63-2.45 mmol/L. Erythrocyte 3-O-methyl-d-glucose uptake was decreased to 58% in patient 1. Three SLC2A1 disease-causing mutations (761delA, P383H, and R400C) were observed. No patient tolerated ketogenic diets. Two patients responded to frequent meals with snacks. Cerebrospinal fluid evaluation constitutes the diagnostic testing permitting early treatment of glucose transporter type 1 deficiency syndrome. Early diagnosis and treatment improve prognoses.

  17. A genetic model of melanoma tumorigenesis based on allelic losses

    SciTech Connect

    Hayward, N.K.; Palmer, J.M.; Walters, M.K.

    1994-09-01

    Previous karyotypic studies have indicated a possible series of non-random chromosomal events involved in the progression of melanoma. We sought to define a model of melanocyte tumorigenesis by studying allelic deletions of polymorphic simple tandem repeat markers mapping to chromosome 1, 6q, 7, 9p, 10, 11, 17, and 21 in thirty matched pairs of melanoma and constitutional DNAs. The most frequent and earliest deletions were found on 9p (57%) and 10q (32%) and with the exception of one case, no sample has loss of markers on another chromosome without concomitant loss of markers on 9p and/or 10q. Losses on 6q were also a frequent (32%) event that sometimes occurred in primary melanomas, whereas losses of loci on distal 1p (26%) or 11q (26%) occurred only in metastic melanomas. A background rate (0-17%) of allele loss was seen on chromosomes 7, 17, and 21. Homozygous deletions in a panel of 31 melanoma cell lines were only detected for markers on 9p (4 cases). These data strongly support the previous model of melanoma tumorigenesis based primarily on karyotypic findings in melanocytic lesions. However, we have been able to further augment the model by delimiting the regions of loss on 10q to a region distal to D10S254, and on 1p, to between D1S243 and D1S160.

  18. An allele of the crm gene blocks cyanobacterial circadian rhythms.

    PubMed

    Boyd, Joseph S; Bordowitz, Juliana R; Bree, Anna C; Golden, Susan S

    2013-08-20

    The SasA-RpaA two-component system constitutes a key output pathway of the cyanobacterial Kai circadian oscillator. To date, rhythm of phycobilisome associated (rpaA) is the only gene other than kaiA, kaiB, and kaiC, which encode the oscillator itself, whose mutation causes completely arrhythmic gene expression. Here we report a unique transposon insertion allele in a small ORF located immediately upstream of rpaA in Synechococcus elongatus PCC 7942 termed crm (for circadian rhythmicity modulator), which results in arrhythmic promoter activity but does not affect steady-state levels of RpaA. The crm ORF complements the defect when expressed in trans, but only if it can be translated, suggesting that crm encodes a small protein. The crm1 insertion allele phenotypes are distinct from those of an rpaA null; crm1 mutants are able to grow in a light:dark cycle and have no detectable oscillations of KaiC phosphorylation, whereas low-amplitude KaiC phosphorylation rhythms persist in the absence of RpaA. Levels of phosphorylated RpaA in vivo measured over time are significantly altered compared with WT in the crm1 mutant as well as in the absence of KaiC. Taken together, these results are consistent with the hypothesis that the Crm polypeptide modulates a circadian-specific activity of RpaA.

  19. Allele frequency of CODIS 13 in Indonesian population.

    PubMed

    Untoro, Evi; Atmadja, Djaja Surya; Pu, Chang-En; Wu, Fang-Chi

    2009-04-01

    Since the first application of DNA technology in 1985 in forensic cases, and the acceptance of this technology in 1988 at court, the DNA typing is widely used in personal identification, parentage cases and tracing the source of biological samples found in the crime scene. The FBI on 1990 had recommended the forensic labs to used 13 loci of Short Tandem Repeats (STR), known as CODIS 13, as the loci of choice for forensic use. The research on the population DNA database on these loci is extremely important for calculating the Paternity Index as well as Matching Probability for forensic application of DNA technology. As many as 402 unrelated persons, consisted of 322 from western part of Indonesia and 80 from eastern part of Indonesia, were chosen as the respondents of this research, after signing the informed consent. The peripheral blood sample was taken using sterile lancets and dropped onto FTA classic cards. The DNA was extracted by FTA purification solution (3x) and TE(-1) (2x), and amplified by PCR mix, either Cofiler or Profiler Plus (Perkin Elmers), followed by sequencing using ABI Prism type 3100 Avant Genetic Analyzer. The analysis showed that the alleles frequencies of Indonesian is specific, different with the other Asian populations with some specific alleles and microvariant were found.

  20. Characterization of Mhc-DRB allelic diversity in white-tailed deer (Odocoileus virginianus) provides insight into Mhc-DRB allelic evolution within Cervidae.

    PubMed

    Van Den Bussche, R A; Hoofer, S R; Lochmiller, R L

    1999-05-01

    Although white-tailed deer (Odocoileus virginianus) are one of North America's best studied mammals, no information is available concerning allelic diversity at any locus of the major histocompatibility complex in this taxon. Using the polymerase chain reaction, single-stranded conformation polymorphism analysis, and DNA sequencing techniques, 15 DRB exon 2 alleles were identified among 150 white-tailed deer from a single population in southeastern Oklahoma. These alleles represent a single locus and exhibit a high degree of nucleotide and amino acid polymorphism, with most amino acid variation occurring at positions forming the peptide binding sites. Furthermore, twenty-seven amino acid residues unique to white-tailed deer DRB alleles were detected, with 19 of these occurring at residues forming contact points of the peptide binding region. Significantly higher rates of nonsynonymous than synonymous substitutions were detected among these DRB alleles. In contrast to other studies of Artiodactyla DRB sequences, interallelic recombination does not appear to be playing a significant role in the generation of allelic diversity at this locus in white-tailed deer. To examine evolution of white-tailed deer (Odvi-DRB) alleles within Cervidae, we performed a phylogenetic analysis of all published red deer (Ceel-DRB), roe deer (Caca-DRB), and moose (Alal-DRB) DRB alleles. The phylogenetic tree clearly shows a trans-species persistence of DRB lineages among these taxa. Moreover, this phylogenetic tree provides insight into evolution of DRB allelic lineages within Cervidae and may aid in assignment of red deer DRB alleles to specific loci.

  1. Maize ARGOS1 (ZAR1) transgenic alleles increase hybrid maize yield

    PubMed Central

    Guo, Mei

    2014-01-01

    Crop improvement for yield and drought tolerance is challenging due to the complex genetic nature of these traits and environmental dependencies. This study reports that transgenic over-expression of Zea mays ARGOS1 (ZAR1) enhanced maize organ growth, grain yield, and drought-stress tolerance. The ZAR1 transgene exhibited environmental interactions, with yield increase under Temperate Dry and yield reduction under Temperate Humid or High Latitude environments. Native ZAR1 allele variation associated with drought-stress tolerance. Two founder alleles identified in the mid-maturity germplasm of North America now predominate in Pioneer’s modern breeding programme, and have distinct proteins, promoters and expression patterns. These two major alleles show heterotic group partitioning, with one predominant in Pioneer’s female and the other in the male heterotic groups, respectively. These two alleles also associate with favourable crop performance when heterozygous. Allele-specific transgene testing showed that, of the two alleles discussed here, each allele differed in their impact on yield and environmental interactions. Moreover, when transgenically stacked together the allelic pair showed yield and environmental performance advantages over either single allele, resembling heterosis effects. This work demonstrates differences in transgenic efficacy of native alleles and the differences reflect their association with hybrid breeding performance. PMID:24218327

  2. Effective marker alleles associated with type 2 resistance to Fusarium head blight infection in fields

    PubMed Central

    Li, Tao; Luo, Meng; Zhang, Dadong; Wu, Di; Li, Lei; Bai, Guihua

    2016-01-01

    Molecular markers associated with known quantitative trait loci (QTLs) for type 2 resistance to Fusarium head blight (FHB) in bi-parental mapping population usually have more than two alleles in breeding populations. Therefore, understanding the association of each allele with FHB response is particularly important to marker-assisted enhancement of FHB resistance. In this paper, we evaluated FHB severities of 192 wheat accessions including landraces and commercial varieties in three field growing seasons, and genotyped this panel with 364 genome-wide informative molecular markers. Among them, 11 markers showed reproducible marker-trait association (p < 0.05) in at least two experiments using a mixed model. More than two alleles were identified per significant marker locus. These alleles were classified into favorable, unfavorable and neutral alleles according to the normalized genotypic values. The distributions of effective alleles at these loci in each wheat accession were characterized. Mean FHB severities increased with decreased number of favorable alleles at the reproducible loci. Chinese wheat landraces and Japanese accessions have more favorable alleles at the majority of the reproducible marker loci. FHB resistance levels of varieties can be greatly improved by introduction of these favorable alleles and removal of unfavorable alleles simultaneously at these QTL-linked marker loci. PMID:27436944

  3. Maize ARGOS1 (ZAR1) transgenic alleles increase hybrid maize yield.

    PubMed

    Guo, Mei; Rupe, Mary A; Wei, Jun; Winkler, Chris; Goncalves-Butruille, Marymar; Weers, Ben P; Cerwick, Sharon F; Dieter, Jo Ann; Duncan, Keith E; Howard, Richard J; Hou, Zhenglin; Löffler, Carlos M; Cooper, Mark; Simmons, Carl R

    2014-01-01

    Crop improvement for yield and drought tolerance is challenging due to the complex genetic nature of these traits and environmental dependencies. This study reports that transgenic over-expression of Zea mays AR GOS1 (ZAR1) enhanced maize organ growth, grain yield, and drought-stress tolerance. The ZAR1 transgene exhibited environmental interactions, with yield increase under Temperate Dry and yield reduction under Temperate Humid or High Latitude environments. Native ZAR1 allele variation associated with drought-stress tolerance. Two founder alleles identified in the mid-maturity germplasm of North America now predominate in Pioneer's modern breeding programme, and have distinct proteins, promoters and expression patterns. These two major alleles show heterotic group partitioning, with one predominant in Pioneer's female and the other in the male heterotic groups, respectively. These two alleles also associate with favourable crop performance when heterozygous. Allele-specific transgene testing showed that, of the two alleles discussed here, each allele differed in their impact on yield and environmental interactions. Moreover, when transgenically stacked together the allelic pair showed yield and environmental performance advantages over either single allele, resembling heterosis effects. This work demonstrates differences in transgenic efficacy of native alleles and the differences reflect their association with hybrid breeding performance.

  4. SNP-Based Quantification of Allele-Specific DNA Methylation Patterns by Pyrosequencing®.

    PubMed

    Busato, Florence; Tost, Jörg

    2015-01-01

    The analysis of allele-specific DNA methylation patterns has recently attracted much interest as loci of allele-specific DNA methylation overlap with known risk loci for complex diseases and the analysis might contribute to the fine-mapping and interpretation of non-coding genetic variants associated with complex diseases and improve the understanding between genotype and phenotype. In the presented protocol, we present a method for the analysis of DNA methylation patterns on both alleles separately using heterozygous Single Nucleotide Polymorphisms (SNPs) as anchor for allele-specific PCR amplification followed by analysis of the allele-specific DNA methylation patterns by Pyrosequencing(®). Pyrosequencing is an easy-to-handle, quantitative real-time sequencing method that is frequently used for genotyping as well as for the analysis of DNA methylation patterns. The protocol consists of three major steps: (1) identification of individuals heterozygous for a SNP in a region of interest using Pyrosequencing; (2) analysis of the DNA methylation patterns surrounding the SNP on bisulfite-treated DNA to identify regions of potential allele-specific DNA methylation; and (3) the analysis of the DNA methylation patterns associated with each of the two alleles, which are individually amplified using allele-specific PCR. The enrichment of the targeted allele is re-enforced by modification of the allele-specific primers at the allele-discriminating base with Locked Nucleic Acids (LNA). For the proof-of-principle of the developed approach, we provide assay details for three imprinted genes (IGF2, IGF2R, and PEG3) within this chapter. The mean of the DNA methylation patterns derived from the individual alleles corresponds well to the overall DNA methylation patterns and the developed approach proved more reliable compared to other protocols for allele-specific DNA methylation analysis.

  5. Non-Equilibrium Allele Frequency Spectra Via Spectral Methods

    PubMed Central

    Hey, Jody; Chen, Kevin

    2011-01-01

    A major challenge in the analysis of population genomics data consists of isolating signatures of natural selection from background noise caused by random drift and gene flow. Analyses of massive amounts of data from many related populations require high-performance algorithms to determine the likelihood of different demographic scenarios that could have shaped the observed neutral single nucleotide polymorphism (SNP) allele frequency spectrum. In many areas of applied mathematics, Fourier Transforms and Spectral Methods are firmly established tools to analyze spectra of signals and model their dynamics as solutions of certain Partial Differential Equations (PDEs). When spectral methods are applicable, they have excellent error properties and are the fastest possible in high dimension; see [15]. In this paper we present an explicit numerical solution, using spectral methods, to the forward Kolmogorov equations for a Wright-Fisher process with migration of K populations, influx of mutations, and multiple population splitting events. PMID:21376069

  6. New York State TrueAllele® Casework Validation Study*

    PubMed Central

    Perlin, Mark W; Belrose, Jamie L; Duceman, Barry W

    2013-01-01

    DNA evidence can pose interpretation challenges, particularly with low-level or mixed samples. It would be desirable to make full use of the quantitative data, consider every genotype possibility, and objectively produce accurate and reproducible DNA match results. Probabilistic genotype computing is designed to achieve these goals. This validation study assessed TrueAllele® probabilistic computer interpretation on 368 evidence items in 41 test cases and compared the results with human review of the same data. Whenever there was a human result, the computer's genotype was concordant. Further, the computer produced a match statistic on 81 mixture items (for 87 inferred matching genotypes) in the test cases, while human review reported a statistic on 25 of these items (30.9%). Using match statistics to quantify information, probabilistic genotyping was shown to be sensitive, specific, and reproducible. These results demonstrate that objective probabilistic genotyping of biological evidence can reliably preserve DNA identification information. PMID:23865896

  7. Four p67 alleles identified in South African Theileria parva field samples.

    PubMed

    Sibeko, Kgomotso P; Geysen, Dirk; Oosthuizen, Marinda C; Matthee, Conrad A; Troskie, Milana; Potgieter, Frederick T; Coetzer, Jacobus A W; Collins, Nicola E

    2010-02-10

    Previous studies characterizing the Theileria parva p67 gene in East Africa revealed two alleles. Cattle-derived isolates associated with East Coast fever (ECF) have a 129bp deletion in the central region of the p67 gene (allele 1), compared to buffalo-derived isolates with no deletion (allele 2). In South Africa, Corridor disease outbreaks occur if there is contact between infected buffalo and susceptible cattle in the presence of vector ticks. Although ECF was introduced into South Africa in the early 20th century, it has been eradicated and it is thought that there has been no cattle to cattle transmission of T. parva since. The variable region of the p67 gene was amplified and the gene sequences analyzed to characterize South African T. parva parasites that occur in buffalo, in cattle from farms where Corridor disease outbreaks were diagnosed and in experimentally infected cattle. Four p67 alleles were identified, including alleles 1 and 2 previously detected in East African cattle and buffalo, respectively, as well as two novel alleles, one with a different 174bp deletion (allele 3), the other with a similar sequence to allele 3 but with no deletion (allele 4). Sequence variants of allele 1 were obtained from field samples originating from both cattle and buffalo. Allele 1 was also obtained from a bovine that tested T. parva positive from a farm near Ladysmith in the KwaZulu-Natal Province. East Coast fever was not diagnosed on this farm, but the p67 sequence was identical to that of T. parva Muguga, an isolate that causes ECF in Kenya. Variants of allele 2 were obtained from all T. parva samples from both buffalo and cattle, except Lad 10 and Zam 5. Phylogenetic analysis revealed that alleles 3 and 4 are monophyletic and diverged early from the other alleles. These novel alleles were not identified from South African field samples collected from cattle; however allele 3, with a p67 sequence identical to those obtained in South African field samples from

  8. Introgressive hybridization: brown bears as vectors for polar bear alleles.

    PubMed

    Hailer, Frank

    2015-03-01

    The dynamics and consequences of introgression can inform about numerous evolutionary processes. Biologists have therefore long been interested in hybridization. One challenge, however, lies in the identification of nonadmixed genotypes that can serve as a baseline for accurate quantification of admixture. In this issue of Molecular Ecology, Cahill et al. (2015) analyse a genomic data set of 28 polar bears, eight brown bears and one American black bear. Polar bear alleles are found to be introgressed into brown bears not only near a previously identified admixture zone on the Alaskan Admiralty, Baranof and Chichagof (ABC) Islands, but also far into the North American mainland. Elegantly contrasting admixture levels at autosomal and X chromosomal markers, Cahill and colleagues infer that male-biased dispersal has spread these introgressed alleles away from the Late Pleistocene contact zone. Compared to a previous study on the ABC Island population in which an Alaskan brown bear served as a putatively admixture-free reference, Cahill et al. (2015) utilize a newly sequenced Swedish brown bear as admixture baseline. This approach reveals that brown bears have been impacted by introgression from polar bears to a larger extent (up to 8.8% of their genome), than previously known, including the bear that had previously served as admixture baseline. No evidence for introgression of brown bear into polar bear is found, which the authors argue could be a consequence of selection. Besides adding new exciting pieces to the puzzle of polar/brown bear evolutionary history, the study by Cahill and colleagues highlights that wildlife genomics is moving from analysing single genomes towards a landscape genomics approach.

  9. The Microcephalin Ancestral Allele in a Neanderthal Individual

    PubMed Central

    Lari, Martina; Rizzi, Ermanno; Milani, Lucio; Corti, Giorgio; Balsamo, Carlotta; Vai, Stefania; Catalano, Giulio; Pilli, Elena; Longo, Laura; Condemi, Silvana; Giunti, Paolo; Hänni, Catherine; De Bellis, Gianluca; Orlando, Ludovic; Barbujani, Guido; Caramelli, David

    2010-01-01

    Background The high frequency (around 0.70 worlwide) and the relatively young age (between 14,000 and 62,000 years) of a derived group of haplotypes, haplogroup D, at the microcephalin (MCPH1) locus led to the proposal that haplogroup D originated in a human lineage that separated from modern humans >1 million years ago, evolved under strong positive selection, and passed into the human gene pool by an episode of admixture circa 37,000 years ago. The geographic distribution of haplogroup D, with marked differences between Africa and Eurasia, suggested that the archaic human form admixing with anatomically modern humans might have been Neanderthal. Methodology/Principal Findings Here we report the first PCR amplification and high- throughput sequencing of nuclear DNA at the microcephalin (MCPH1) locus from Neanderthal individual from Mezzena Rockshelter (Monti Lessini, Italy). We show that a well-preserved Neanderthal fossil dated at approximately 50,000 years B.P., was homozygous for the ancestral, non-D, allele. The high yield of Neanderthal mtDNA sequences of the studied specimen, the pattern of nucleotide misincorporation among sequences consistent with post-mortem DNA damage and an accurate control of the MCPH1 alleles in all personnel that manipulated the sample, make it extremely unlikely that this result might reflect modern DNA contamination. Conclusions/Significance The MCPH1 genotype of the Monti Lessini (MLS) Neanderthal does not prove that there was no interbreeding between anatomically archaic and modern humans in Europe, but certainly shows that speculations on a possible Neanderthal origin of what is now the most common MCPH1 haplogroup are not supported by empirical evidence from ancient DNA. PMID:20498832

  10. Generation of humoral immune responses to multi-allele PfAMA1 vaccines; effect of adjuvant and number of component alleles on the breadth of response.

    PubMed

    Kusi, Kwadwo A; Faber, Bart W; Riasat, Vanessa; Thomas, Alan W; Kocken, Clemens H M; Remarque, Edmond J

    2010-11-03

    There is increasing interest in multi-allele vaccines to overcome strain-specificity against polymorphic vaccine targets such as Apical Membrane Antigen 1 (AMA1). These have been shown to induce broad inhibitory antibodies in vitro and formed the basis for the design of three Diversity-Covering (DiCo) proteins with similar immunological effects. The antibodies produced are to epitopes that are shared between vaccine alleles and theoretically, increasing the number of component AMA1 alleles is expected to broaden the antibody response. A plateau effect could however impose a limit on the number of alleles needed to achieve the broadest specificity. Moreover, production cost and the vaccine formulation process would limit the number of component alleles. In this paper, we compare rabbit antibody responses elicited with multi-allele vaccines incorporating seven (three DiCos and four natural AMA1 alleles) and three (DiCo mix) antigens for gains in broadened specificity. We also investigate the effect of three adjuvant platforms on antigen specificity and antibody functionality. Our data confirms a broadened response after immunisation with DiCo mix in all three adjuvants. Higher antibody titres were elicited with either CoVaccine HT™ or Montanide ISA 51, resulting in similar in vitro inhibition (65-82%) of five out of six culture-adapted P. falciparum strains. The antigen binding specificities of elicited antibodies were also similar and independent of the adjuvant used or the number of vaccine component alleles. Thus neither the four extra antigens nor adjuvant had any observable benefits with respect to specificity broadening, although adjuvant choice influenced the absolute antibody levels and thus the extent of parasite inhibition. Our data confirms the feasibility and potential of multi-allele PfAMA1 formulations, and highlights the need for adjuvants with improved antibody potentiation properties for AMA1-based vaccines.

  11. An Allele Real-Coded Quantum Evolutionary Algorithm Based on Hybrid Updating Strategy.

    PubMed

    Zhang, Yu-Xian; Qian, Xiao-Yi; Peng, Hui-Deng; Wang, Jian-Hui

    2016-01-01

    For improving convergence rate and preventing prematurity in quantum evolutionary algorithm, an allele real-coded quantum evolutionary algorithm based on hybrid updating strategy is presented. The real variables are coded with probability superposition of allele. A hybrid updating strategy balancing the global search and local search is presented in which the superior allele is defined. On the basis of superior allele and inferior allele, a guided evolutionary process as well as updating allele with variable scale contraction is adopted. And H ε gate is introduced to prevent prematurity. Furthermore, the global convergence of proposed algorithm is proved by Markov chain. Finally, the proposed algorithm is compared with genetic algorithm, quantum evolutionary algorithm, and double chains quantum genetic algorithm in solving continuous optimization problem, and the experimental results verify the advantages on convergence rate and search accuracy.

  12. Molecular definition of an allelic series of mutations disrupting the mouse Lmx1a (dreher) gene.

    PubMed

    Chizhikov, Victor; Steshina, Ekaterina; Roberts, Richard; Ilkin, Yesim; Washburn, Linda; Millen, Kathleen J

    2006-10-01

    Mice homozygous for the dreher (dr) mutation are characterized by pigmentation and skeletal abnormalities and striking behavioral phenotypes, including ataxia, vestibular deficits, and hyperactivity. The ataxia is associated with a cerebellar malformation that is remarkably similar to human Dandy-Walker malformation. Previously, positional cloning identified mutations in LIM homeobox transcription factor 1 alpha gene (Lmx1a) in three dr alleles. Two of these alleles, however, are extinct and unavailable for further analysis. In this article we report a new spontaneous dr allele and describe the Lmx1a mutations in this and six additional dr alleles. Strikingly, deletion null, missense, and frameshift mutations in these alleles all cause similar cerebellar malformations, suggesting that all dr mutations analyzed to date are null alleles.

  13. Allelic diversity at the DLA-88 locus in Golden Retriever and Boxer breeds is limited

    PubMed Central

    Ross, Peter; Buntzman, Adam S.; Vincent, Benjamin G.; Grover, Elise N.; Gojanovich, Gregory S.; Collins, Edward J.; Frelinger, Jeffrey A.; Hess, Paul R.

    2012-01-01

    In the dog, previous analyses of major histocompatibility complex (MHC) class I genes suggest a single polymorphic locus, Dog Leukocyte Antigen (DLA)-88. While 51 alleles have been reported, estimates of prevalence have not been made. We hypothesized that, within a breed, DLA-88 diversity would be restricted, and one or more dominant alleles could be identified. Accordingly, we determined allele usage in 47 Golden Retrievers and 39 Boxers. In each population, 10 alleles were found; 4 were shared. Seven novel alleles were identified. DLA-88*05101 and *50801 predominated in Golden Retrievers, while most Boxers carried *03401. In these breeds DLA-88 polymorphisms are limited and largely non-overlapping. The finding of highly prevalent alleles fulfills an important prerequisite for studying canine CD8+ T-cell responses. PMID:22571293

  14. A Novel Dominant Transformer Allele of the Sex-Determining Gene Her-1 of Caenorhabditis Elegans

    PubMed Central

    Trent, C.; Wood, W. B.; Horvitz, H. R.

    1988-01-01

    We have characterized a novel dominant allele of the sex-determining gene her-1 of Caenorhabditis elegans. This allele, called n695, results in the incomplete transformation of XX animals into phenotypic males. Previously characterized recessive her-1 alleles transform XO animals into phenotypic hermaphrodites. We have identified five new recessive her-1 mutations as intragenic suppressors of n695. Three of these suppressors are weak, temperature-sensitive alleles. We show that the recessive her-1 mutations are loss-of-function alleles, and that the her-1(n695) mutation results in a gain-of-function at the her-1 locus. The existence of dominant and recessive alleles that cause opposite phenotypic transformations demonstrates that the her-1 gene acts to control sexual identity in C. elegans. PMID:3220248

  15. Identification and characterization of novel HLA alleles: Utility of next-generation sequencing methods.

    PubMed

    Brown, Nicholas K; Kheradmand, Taba; Wang, Jinguo; Marino, Susana R

    2016-04-01

    The HLA genes are the most polymorphic of the human genome, and novel HLA alleles are continuously identified, often by clinical Sanger sequencing-based typing (SBT) assays. Introduction of next-generation sequencing (NGS) technologies for clinical HLA typing may significantly improve this process. Here we compare four cases of novel HLA alleles identified and characterized by both SBT and NGS. The tested NGS system sequenced broader regions of the HLA loci, and identified novel polymorphisms undetected by SBT. Subsequent characterization of the novel alleles in isolation of coencoded alleles by SBT required custom-designed primers, while the NGS system was able to sequence both alleles in phase. However, the tested assay was unable to amplify buccal cell DNA for subsequent NGS sequencing, presumably due to the lower quality of these samples. While NGS assays will undoubtedly increase novel allele identification, more stringent DNA sample requirements may be necessary for this new technology.

  16. Two classes of deleterious recessive alleles in a natural population of zebrafish, Danio rerio.

    PubMed Central

    McCune, Amy R.; Houle, David; McMillan, Kyle; Annable, Rebecca; Kondrashov, Alexey S.

    2004-01-01

    Natural populations carry deleterious recessive alleles which cause inbreeding depression. We compared mortality and growth of inbred and outbred zebrafish, Danio rerio, between 6 and 48 days of age. Grandparents of the studied fish were caught in the wild. Inbred fish were generated by brother-sister mating. Mortality was 9% in outbred fish, and 42% in inbred fish, which implies at least 3.6 lethal equivalents of deleterious recessive alleles per zygote. There was no significant inbreeding depression in the growth, perhaps because the surviving inbred fish lived under less crowded conditions. In contrast to alleles that cause embryonic and early larval mortality in the same population, alleles responsible for late larval and early juvenile mortality did not result in any gross morphological abnormalities. Thus, deleterious recessive alleles that segregate in a wild zebrafish population belong to two sharply distinct classes: early-acting, morphologically overt, unconditional lethals; and later-acting, morphologically cryptic, and presumably milder alleles. PMID:15451692

  17. Allelic Spectra of Risk SNPs Are Different for Environment/Lifestyle Dependent versus Independent Diseases.

    PubMed

    Gorlov, Ivan P; Gorlova, Olga Y; Amos, Christopher I

    2015-07-01

    Genome-wide association studies (GWAS) have generated sufficient data to assess the role of selection in shaping allelic diversity of disease-associated SNPs. Negative selection against disease risk variants is expected to reduce their frequencies making them overrepresented in the group of minor (<50%) alleles. Indeed, we found that the overall proportion of risk alleles was higher among alleles with frequency <50% (minor alleles) compared to that in the group of major alleles. We hypothesized that negative selection may have different effects on environment (or lifestyle)-dependent versus environment (or lifestyle)-independent diseases. We used an environment/lifestyle index (ELI) to assess influence of environmental/lifestyle factors on disease etiology. ELI was defined as the number of publications mentioning "environment" or "lifestyle" AND disease per 1,000 disease-mentioning publications. We found that the frequency distributions of the risk alleles for the diseases with strong environmental/lifestyle components follow the distribution expected under a selectively neutral model, while frequency distributions of the risk alleles for the diseases with weak environmental/lifestyle influences is shifted to the lower values indicating effects of negative selection. We hypothesized that previously selectively neutral variants become risk alleles when environment changes. The hypothesis of ancestrally neutral, currently disadvantageous risk-associated alleles predicts that the distribution of risk alleles for the environment/lifestyle dependent diseases will follow a neutral model since natural selection has not had enough time to influence allele frequencies. The results of our analysis suggest that prediction of SNP functionality based on the level of evolutionary conservation may not be useful for SNPs associated with environment/lifestyle dependent diseases.

  18. Sequence of a novel HLA-B*51 allele in a volunteer haematopoietic stem cell donor.

    PubMed

    Cosentini, E; Longhi, E; Frison, S; Luongo, V; Mantovani, M; Ciardiello, G; Bruno, P; Poli, F

    2010-10-01

    We describe a novel HLA-B*51 allele detected by DNA direct sequencing. The sequence of this allele has been officially named B*51:78 as a confirmatory sequence. This new allele nucleotide sequence differs from HLA-B*51:01:01 for two point mutations in exon 2 where codons 79-80 change from CGG-ATC to CGC-ACC (p.Ile80Thr).

  19. Increased prevalence of mutant null alleles that cause hereditary fructose intolerance in the American population.

    PubMed

    Coffee, Erin M; Yerkes, Laura; Ewen, Elizabeth P; Zee, Tiffany; Tolan, Dean R

    2010-02-01

    Mutations in the aldolase B gene (ALDOB) impairing enzyme activity toward fructose-1-phosphate cleavage cause hereditary fructose intolerance (HFI). Diagnosis of the disease is possible by identifying known mutant ALDOB alleles in suspected patients; however, the frequencies of mutant alleles can differ by population. Here, 153 American HFI patients with 268 independent alleles were analyzed to identify the prevalence of seven known HFI-causing alleles (A149P, A174D, N334K, Delta4E4, R59Op, A337V, and L256P) in this population. Allele-specific oligonucleotide hybridization analysis was performed on polymerase chain reaction (PCR)-amplified genomic DNA from these patients. In the American population, the missense mutations A149P and A174D are the two most common alleles, with frequencies of 44% and 9%, respectively. In addition, the nonsense mutations Delta4E4 and R59Op are the next most common alleles, with each having a frequency of 4%. Together, the frequencies of all seven alleles make up 65% of HFI-causing alleles in this population. Worldwide, these same alleles make up 82% of HFI-causing mutations. This difference indicates that screening for common HFI alleles is more difficult in the American population. Nevertheless, a genetic screen for diagnosing HFI in America can be improved by including all seven alleles studied here. Lastly, identification of HFI patients presenting with classic symptoms and who have homozygous null genotypes indicates that aldolase B is not required for proper development or metabolic maintenance.

  20. Giant SCA8 alleles in nine children whose mother has two moderately large ones.

    PubMed

    Corral, Jordi; Genís, David; Banchs, Isabel; San Nicolás, Hector; Armstrong, Judith; Volpini, Víctor

    2005-04-01

    We report here a family in which each of nine children has inherited giant SCA8 CTG expansions from a homozygous mother who has two moderately large SCA8 CTG alleles. In contrast, three homozygous male individuals and a case of coexistence of two expansions of the FRDA gene and one of SCA8, all of them with moderately large alleles, have transmitted their respective SCA8 expanded alleles with minor changes, as usually occurs in heterozygous male transmissions.

  1. Association of apolipoprotein E allele {epsilon}4 with late-onset sporadic Alzheimer`s disease

    SciTech Connect

    Lucotte, G.; David, F.; Berriche, S.

    1994-09-15

    Apolipoprotein E, type {epsilon}4 allele (ApoE {epsilon}4), is associated with late-onset sporadic Alzheimer`s disease (AD) in French patients. The association is highly significant (0.45 AD versus 0.12 controls for {epsilon}4 allele frequencies). These data support the involvement of ApoE {epsilon}4 allele as a very important risk factor for the clinical expression of AD. 22 refs., 1 fig., 3 tabs.

  2. Allelic Spectra of Risk SNPs Are Different for Environment/Lifestyle Dependent versus Independent Diseases

    PubMed Central

    Amos, Christopher I.

    2015-01-01

    Genome-wide association studies (GWAS) have generated sufficient data to assess the role of selection in shaping allelic diversity of disease-associated SNPs. Negative selection against disease risk variants is expected to reduce their frequencies making them overrepresented in the group of minor (<50%) alleles. Indeed, we found that the overall proportion of risk alleles was higher among alleles with frequency <50% (minor alleles) compared to that in the group of major alleles. We hypothesized that negative selection may have different effects on environment (or lifestyle)-dependent versus environment (or lifestyle)-independent diseases. We used an environment/lifestyle index (ELI) to assess influence of environmental/lifestyle factors on disease etiology. ELI was defined as the number of publications mentioning “environment” or “lifestyle” AND disease per 1,000 disease-mentioning publications. We found that the frequency distributions of the risk alleles for the diseases with strong environmental/lifestyle components follow the distribution expected under a selectively neutral model, while frequency distributions of the risk alleles for the diseases with weak environmental/lifestyle influences is shifted to the lower values indicating effects of negative selection. We hypothesized that previously selectively neutral variants become risk alleles when environment changes. The hypothesis of ancestrally neutral, currently disadvantageous risk-associated alleles predicts that the distribution of risk alleles for the environment/lifestyle dependent diseases will follow a neutral model since natural selection has not had enough time to influence allele frequencies. The results of our analysis suggest that prediction of SNP functionality based on the level of evolutionary conservation may not be useful for SNPs associated with environment/lifestyle dependent diseases. PMID:26201053

  3. Increased prevalence of mutant null alleles that cause hereditary fructose intolerance in the American population

    PubMed Central

    Coffee, Erin M.; Yerkes, Laura; Ewen, Elizabeth P.; Zee, Tiffany

    2010-01-01

    Mutations in the aldolase B gene (ALDOB) impairing enzyme activity toward fructose-1-phosphate cleavage cause hereditary fructose intolerance (HFI). Diagnosis of the disease is possible by identifying known mutant ALDOB alleles in suspected patients; however, the frequencies of mutant alleles can differ by population. Here, 153 American HFI patients with 268 independent alleles were analyzed to identify the prevalence of seven known HFI-causing alleles (A149P, A174D, N334K, Δ4E4, R59Op, A337V, and L256P) in this population. Allele-specific oligonucleotide hybridization analysis was performed on polymerase chain reaction (PCR)-amplified genomic DNA from these patients. In the American population, the missense mutations A149P and A174D are the two most common alleles, with frequencies of 44% and 9%, respectively. In addition, the nonsense mutations Δ4E4 and R59Op are the next most common alleles, with each having a frequency of 4%. Together, the frequencies of all seven alleles make up 65% of HFI-causing alleles in this population. Worldwide, these same alleles make up 82% of HFI-causing mutations. This difference indicates that screening for common HFI alleles is more difficult in the American population. Nevertheless, a genetic screen for diagnosing HFI in America can be improved by including all seven alleles studied here. Lastly, identification of HFI patients presenting with classic symptoms and who have homozygous null genotypes indicates that aldolase B is not required for proper development or metabolic maintenance. PMID:20033295

  4. Serotonin transporter gene polymorphisms and hyperserotonemia in autistic disorder

    PubMed Central

    Betancur, Catalina; Corbex, Marylis; Spielewoy, Cécile; Philippe, Anne; Laplanche, Jean-Louis; Launay, Jean-Marie; Gillberg, Christopher; Mouren-Simeoni, Marie-Christine; Hamon, Michel; Giros, Bruno; Nosten-Bertrand, Marika; Leboyer, Marion

    2002-01-01

    Previous studies have provided conflicting evidence regarding the association of the serotonin transporter (5-HTT) gene with autism. Two polymorphisms have been identified in the human 5-HTT gene, a VNTR in intron 21 and a functional deletion/insertion in the promoter region (5-HTTLPR) with short and long variants.2 Positive associations of the 5-HTTLPR polymorphism with autism have been reported by two family-based studies, but one found preferential transmission of the short allele3 and the other of the long allele.4 Two subsequent studies failed to find evidence of transmission disequilibrium at the 5-HTTLPR locus.5,6 These conflicting results could be due to heterogeneity of clinical samples with regard to serotonin (5-HT) blood levels, which have been found to be elevated in some autistic subjects.7–9 Thus, we examined the association of the 5-HTTLPR and VNTR polymorphisms of the 5-HTT gene with autism, and we investigated the relationship between 5-HTT variants and whole-blood 5-HT. The transmission/disequilibrium test (TDT) revealed no linkage disequilibrium at either loci in a sample of 96 families comprising 43 trios and 53 sib pairs. Furthermore, no significant relationship between 5-HT blood levels and 5-HTT gene polymorphisms was found. Our results suggest that the 5-HTT gene is unlikely to play a major role as a susceptibility factor in autism. PMID:11803447

  5. Association between serotonin transporter genotype, brain structure and adolescent-onset major depressive disorder: a longitudinal prospective study.

    PubMed

    Little, K; Olsson, C A; Whittle, S; Youssef, G J; Byrne, M L; Simmons, J G; Yücel, M; Foley, D L; Allen, N B

    2014-09-16

    The extent to which brain structural abnormalities might serve as neurobiological endophenotypes that mediate the link between the variation in the promoter of the serotonin transporter gene (5-HTTLPR) and depression is currently unknown. We therefore investigated whether variation in hippocampus, amygdala, orbitofrontal cortex (OFC) and anterior cingulate cortex volumes at age 12 years mediated a putative association between 5-HTTLPR genotype and first onset of major depressive disorder (MDD) between age 13-19 years, in a longitudinal study of 174 adolescents (48% males). Increasing copies of S-alleles were found to predict smaller left hippocampal volume, which in turn was associated with increased risk of experiencing a first onset of MDD. Increasing copies of S-alleles also predicted both smaller left and right medial OFC volumes, although neither left nor right medial OFC volumes were prospectively associated with a first episode of MDD during adolescence. The findings therefore suggest that structural abnormalities in the left hippocampus may be present prior to the onset of depression during adolescence and may be partly responsible for an indirect association between 5-HTTLPR genotype and depressive illness. 5-HTTLPR genotype may also impact upon other regions of the brain, such as the OFC, but structural differences in these regions in early adolescence may not necessarily alter the risk for onset of depression during later adolescence.

  6. Homozygosity for the HLA-DRB1 allele selects for extraarticular manifestations in rheumatoid arthritis.

    PubMed Central

    Weyand, C M; Xie, C; Goronzy, J J

    1992-01-01

    Seropositive rheumatoid arthritis is genetically linked to a group of HLA-DRB1 alleles sharing a sequence motif within the third hypervariable region. Controversy exists over the role of the distinct allelic variants in affecting not only the risk to develop disease, but also in modifying the expression of the disease. We have stratified 81 patients according to their patterns of disease manifestations and identified the HLA-DRB1 alleles by polymerase chain reaction amplification and subsequent oligonucleotide hybridization. To identify precisely the allelic combinations at the HLA-DRB1 locus, homozygosity was confirmed by locus-specific cDNA amplification and subsequent sequencing. Our study demonstrated a high correlation of allelic combinations of disease-associated HLA-DRB1 alleles with the clinical manifestations. Characteristic genotypes were identified for patients who had progressed toward nodular disease and patients who had developed major organ involvement. Rheumatoid nodules were highly associated with a heterozygosity for two disease associated HLA-DRB1 alleles. Homozygosity for the HLA-DRB1*0401 allele was a characteristic finding for RA patients with major organ involvement. Our data suggest a role of the disease-associated sequence motif in determining severity of the disease. The finding of a codominant function of HLA-DRB1 alleles suggests that the biological function of HLA-DR molecules in thymic selection might be important in the pathogenesis of RA. Images PMID:1602009

  7. RAET1/ULBP alleles and haplotypes among Kolla South American Indians.

    PubMed

    Cox, Steven T; Arrieta-Bolaños, Esteban; Pesoa, Susanna; Vullo, Carlos; Madrigal, J Alejandro; Saudemont, Aurore

    2013-06-01

    NK cell cytolysis of infected or transformed cells can be mediated by engagement of the activating immunoreceptor NKG2D with one of eight known ligands (MICA, MICB and RAET1E-N) and is essential for innate immunity. As well as diversity of NKG2D ligands having the same function, allelic polymorphism and ethnic diversity has been reported. We previously determined HLA class I allele and haplotype frequencies in Kolla South American Indians who inhabit the northwest provinces of Argentina, and were found to have a similar restricted allelic profile to other South American Indians and novel alleles not seen in other tribes. In our current study, we characterized retinoic acid early transcription-1 (RAET1) alleles by sequencing 58 unrelated Kolla people. Only three of six RAET1 ligands were polymorphic. RAET1E was most polymorphic with five alleles in the Kolla including an allele we previously described, RAET1E*009 (allele frequency (AF) 5.2%). Four alleles of RAET1L were also found and RAET1E*002 was most frequent (AF=78%). Potential functional diversity only affected RAET1E and RAET1L, which were in linkage disequilibrium indicating a selective advantage. The results suggest that limited RAET1 polymorphism in the Kolla was not detrimental to human survival but still necessary and may affect disease susceptibility or severity.

  8. FMR1 alleles in Tasmania: a screening study of the special educational needs population.

    PubMed

    Mitchell, R J; Holden, J J A; Zhang, C; Curlis, Y; Slater, H R; Burgess, T; Kirkby, K C; Carmichael, A; Heading, K D; Loesch, D Z

    2005-01-01

    The distribution of fragile X mental retardation-1 (FMR1) allele categories, classified by the number of CGG repeats, in the population of Tasmania was investigated in 1253 males with special educational needs (SEN). The frequencies of these FMR1 categories were compared with those seen in controls as represented by 578 consecutive male births. The initial screening was based on polymerase chain reaction analysis of dried blood spots. Inconclusive results were verified by Southern analysis of a venous blood sample. The frequencies of common FMR1 alleles in both samples, and of grey zone alleles in the controls, were similar to those in other Caucasian populations. Consistent with earlier reports, we found some (although insignificant) increase of grey zone alleles in SEN subjects compared with controls. The frequencies of predisposing flanking haplotypes among grey zone males FMR1 alleles were similar to those seen in other Caucasian SEN samples. Contrary to expectation, given the normal frequency of grey zone alleles, no premutation (PM) or full mutation (FM) allele was detected in either sample, with only 15 fragile X families diagnosed through routine clinical admissions registered in Tasmania up to 2002. An explanation of this discrepancy could be that the C19th founders of Tasmania carried few PM or FM alleles. The eight to ten generations since white settlement of Tasmania has been insufficient time for susceptible grey zone alleles to evolve into the larger expansions.

  9. Rare HLA Drive Additional HIV Evolution Compared to More Frequent Alleles

    PubMed Central

    Lockhart, David W.; Listgarten, Jennifer; Maley, Stephen N.; Kadie, Carl; Learn, Gerald H.; Nickle, David C.; Heckerman, David E.; Deng, Wenjie; Brander, Christian; Ndung'u, Thumbi; Coovadia, Hoosen; Goulder, Philip J.R.; Korber, Bette T.; Walker, Bruce D.; Mullins, James I.

    2009-01-01

    Abstract HIV-1 can evolve HLA-specific escape variants in response to HLA-mediated cellular immunity. HLA alleles that are common in the host population may increase the frequency of such escape variants at the population level. When loss of viral fitness is caused by immune escape variation, these variants may revert upon infection of a new host who does not have the corresponding HLA allele. Furthermore, additional escape variants may appear in response to the nonconcordant HLA alleles. Because individuals with rare HLA alleles are less likely to be infected by a partner with concordant HLA alleles, viral populations infecting hosts with rare HLA alleles may undergo a greater amount of evolution than those infecting hosts with common alleles due to the loss of preexisting escape variants followed by new immune escape. This hypothesis was evaluated using maximum likelihood phylogenetic trees of each gene from 272 full-length HIV-1 sequences. Recent viral evolution, as measured by the external branch length, was found to be inversely associated with HLA frequency in nef (p < 0.02), env (p < 0.03), and pol (p ≤ 0.05), suggesting that rare HLA alleles provide a disproportionate force driving viral evolution compared to common alleles, likely due to the loss of preexisting escape variants during early stages postinfection. PMID:19327049

  10. Allele-specific enzymatic amplification of. beta. -globin genomic DNA for diagnosis of sickle cell anemia

    SciTech Connect

    Wu, D.Y.; Ugozzoli, L.; Pal, B.K.; Wallace, B. )

    1989-04-01

    A rapid nonradioactive approach to the diagnosis of sickle cell anemia is described based on an allele-specific polymerase chain reaction (ASPCR). This method allows direct detection of the normal or the sickle cell {beta}-globin allele in genomic DNA without additional steps of probe hybridization, ligation, or restriction enzyme cleavage. Two allele-specific oligonucleotide primers, one specific for the sickle cell allele and one specific for the normal allele, together with another primer complementary to both alleles were used in the polymerase chain reaction with genomic DNA templates. The allele-specific primers differed from each other in their terminal 3{prime} nucleotide. Under the proper annealing temperature and polymerase chain reaction conditions, these primers only directed amplification on their complementary allele. In a single blind study of DNA samples from 12 individuals, this method correctly and unambiguously allowed for the determination of the genotypes with no false negatives or positives. If ASPCR is able to discriminate all allelic variation (both transition and transversion mutations), this method has the potential to be a powerful approach for genetic disease diagnosis, carrier screening, HLA typing, human gene mapping, forensics, and paternity testing.

  11. Validation study of the TrueAllele automated data review system.

    PubMed

    Kadash, Kristy; Kozlowski, Brian E; Biega, Lisa A; Duceman, Barry W

    2004-07-01

    The New York State Convicted Offender DNA Databank is the first U.S. lab to complete an internal validation of the TrueAllele expert data review system. TrueAllele is designed to assess short tandem repeat (STR) DNA data based on several key features such as peak height, shape, area, and position relative to a standard ladder and use this information to make accurate allele calls. The software then prioritizes the allele calls based on several user-defined rules. As a result, the user need only review low-quality data. The validation of this system consisted of an extensive optimization phase and a large concordance phase. During optimization, the rule settings were tailored to minimize the amount of high-quality data viewed by the user. In the concordance phase, a large dataset was typed in parallel with the ABI software Gene Scan and Genotyper (manual review) and TrueAllele (automated review) for comparison of allele calls and sample state assignment. Only one significant difference was discovered out of 2048 samples in the concordance study. In this case, TrueAllele revealed a spike in the profile that was interpreted as a DNA peak by the analyst in Genotyper. TrueAllele was designed to focus the review on poor data and to eliminate the need for complete reanalysis technical review. This validation project proved TrueAllele to be dependable for use at the NYS Convicted Offender DNA Databank.

  12. Autism and serotonin transporter gene polymorphisms: a systematic review and meta-analysis.

    PubMed

    Huang, Christine H; Santangelo, Susan L

    2008-09-05

    The serotonin transporter gene (5-HTT) plays a crucial role in serotonergic neurotransmission and has been found to be associated, with varying degrees of significance, with many diseases, including autism. Prior association studies of autism have yielded conflicting results regarding the association between two common 5-HTT polymorphisms, the promoter insertion/deletion (5-HTTLPR) and the intron 2 VNTR (STin2 VNTR). We conducted a systematic review and meta-analysis to test the following hypotheses: (i) there is an association between autism and either or both of the 5-HTTLPR and STin2 VNTR polymorphisms, and (ii) the S allele of 5-HTTLPR and/or the STin2.12 allele of the VNTR are the specific risk alleles for autism. All published family-based and population based studies were examined to determine the overall strength of association between 5-HTT polymorphisms and autism. After exclusion of studies with overlapping samples and studies whose data did not allow for calculation of an odds ratio, 16 studies were included for final analyses, all but two of which used a family-based design. The meta-analysis failed to find a significant overall association between either of the 5-HTT polymorphisms examined and autism. Further, no allelic transmission distortion was found when studies of simplex (11 studies) and multiplex (3 studies) family samples were analyzed separately. However, there was significant heterogeneity by ethnicity; family based studies of US mixed population samples showed preferential transmission of the S allele of 5-HTTLPR (S allele:L allele = 247:183), while there was no allelic distortion among the family-based studies of European and Asian samples.

  13. Distribution of BoLA-DRB3 allelic frequencies and identification of a new allele in the iranian cattle breed sistani (Bos indicus).

    PubMed

    Mohammadi, A; Nassiry, M R; Mosafer, J; Mohammadabadi, M R; Sulimova, G E

    2009-02-01

    The distribution of the frequencies of BoLA-DRB3 gene alleles in the Iranian cattle breed Sistani was studied by the PCR-RFLP ("hemi-nested") assay using restriction endonucleases RsaI, HaeIII and BstYI. In the examined cattle breed (65 animals) 32 alleles have been identified one of which being described for the first time (6.15% frequency). The nucleotide sequence of the polymorphic region of exon 2 of this allele has been determined and submitted in the GeneBank database under accession number DQ486519. The submitted sequence has maximum homology (92%) with the previously described sequence DRB3-mRNA from Bos indicus (AccN X79346) and differs from it by 24 nucleotide substitutions which result in 16 amino acid substitutions. The peptide (on the basis of the reconstructed amino acid sequence) has 89% identity to the sequence encoded by the BIDRBF 188 locus (Bos indicus). The results obtained permit the sequence described by us to be considered as a new allele of the BoLA-DRB3 gene (DRB3.2**X). The total frequency of the main six alleles (DRB3.2*X, *10, *11, *20, *34 and *X) occurring with a frequency of over 5% is about 60% in Iranian Sistani cattle. Fifteen alleles have <1% frequency. The highest frequency was observed for DRB3.2*8 allele (21.54%) like in other previously described breeds of Bos indicus (up to 23.07%). The Iranian breed Sistani has a high level of similarity by the spectrum of BoLA-DRB3 alleles and their frequencies to other Bos indicus breeds and significantly differs by these criteria from the Bos taurus breeds. The Iranian Sistani herd under study includes alleles associated with to resistance to leukemia (DRB3.2*ll and *23) and to different forms of mastitis (DRB3.2*2, *7, *11, *23 and *24) although their frequencies are low (from 0.77 to 5.37%). On the whole, a high level of diversity of BoLA-DRB3 gene alleles and the availability of alleles associated with resistance to different diseases makes this breed of interest for breeding practice.

  14. Allele specific-PCR and melting curve analysis showed relatively high frequency of β-casein gene A1 allele in Iranian Holstein, Simmental and native cows.

    PubMed

    Gholami, M; Hafezian, S H; Rahimi, G; Farhadi, A; Rahimi, Z; Kahrizi, D; Kiani, S; Karim, H; Vaziri, S; Muhammadi, S; Veisi, F; Ghadiri, K; Shetabi, H; Zargooshi, J

    2016-10-31

    There are two allelic forms of A1 and A2 of β-casein gene in dairy cattle. Proteolytic digestion of bovine β-casein A1 type produces bioactive peptide of β-casomorphin-7 known as milk devil. β-casomorphin-7 causes many diseases, including type 1 diabetes, cardiovascular disease syndrome, sudden death and madness. The aim of the present study was to determine the different allelic forms of β-casein gene in Iranian Holstein, Simmental and native cattle in order to identify A1 and A2 variants. The blood samples were collected randomly and DNA was extracted using modified salting out method. An 854 bp fragment including part of exon 7 and part of intron 6 of β-casein gene was amplified by allele specific polymerase chain reaction (AS-PCR). Also, the accuracy of AS-PCR genotyping has been confirmed by melting temperature curve analysis using Real-time PCR machinery. The comparison of observed allele and genotype frequency among the studied breeds was performed using the Fisher exact and Chi-squared test, respectively by SAS program. Obtained results showed the A1 allele frequencies of 50, 51.57, 54.5, 49.4 and 46.6% in Holstein, Simmental, Sistani, Taleshi and Mazandarani cattle populations, respectively. The chi-square test was shown that no any populations were in Hardy-Weinberg equilibrium for studied marker locus. Comparison and analysis of the test results for allelic frequency showed no any significant differences between breeds (P>0.05). The frequency of observed genotypes only differs significantly between Holstein and Taleshi breeds but no any statistically significant differences were found for other breeds (P>0.05). A relatively high frequency of β-casein A1 allele was observed in Iranian native cattle. Therefore, determine the genotypes and preference alleles A2 in these native and commercial cattle is recommended.

  15. A "successful allele" at Campylobacter jejuni contingency locus Cj0170 regulates motility; "successful alleles" at locus Cj0045 are strongly associated with mouse colonization.

    PubMed

    Artymovich, Katherine; Kim, Joo-Sung; Linz, John E; Hall, David F; Kelley, Lauren E; Kalbach, Harrison L; Kathariou, Sophia; Gaymer, Jean; Paschke, Brenda

    2013-06-01

    Campylobacter jejuni is an important foodborne pathogen of humans and its primary reservoir is the gastrointestinal (GI) tract of chickens. Our previous studies demonstrated that phase variation to specific "successful alleles" at C. jejuni contingency loci Cj0045 (successful alleles carry 9G or 10G homopolymeric tracts) and Cj0170 (successful allele carries a 10G homopolymeric tract) in C. jejuni populations is strongly associated with colonization and enteritis in C57BL/6 IL-10 deficient mice. In the current study, we strengthened the association between locus Cj0170, Cj0045, and mouse colonization. We generated 8 independent strains derived from C. jejuni 11168 strain KanR4 that carried a Cj0170 gene disruption and these were all non motile. Two randomly chosen strains with the Cj0170 gene disruption (DM0170-2 and DM0170-6) were gavaged into mice. DM0170-2 and DM0170-6 failed to colonize mice while the control strain that carried a "successful"Cj0170 10G allele was motile and did colonize mice. In parallel studies, when we inoculated C. jejuni strain 33292 into mice, the "unsuccessful"Cj0045 11G allele experienced phase variation to "successful" 9G and 10G alleles in 2 independent experiments prior to d4 post inoculation in mice while the "successful" 9G allele in the control strain remained stable through d21 post inoculation or shifted to other successful alleles. These data confirm that locus Cj0170 regulates motility in C. jejuni strain KanR4 and is a virulence factor in the mouse model. The data also support a possible role of locus Cj0045 as a virulence factor in strain 33292 in infection of mice.

  16. Disagreement in genotyping results of drug resistance alleles of the Plasmodium falciparum dihydrofolate reductase (Pfdhfr) gene by allele-specific PCR (ASPCR) assays and Sanger sequencing.

    PubMed

    Sharma, Divya; Lather, Manila; Dykes, Cherry L; Dang, Amita S; Adak, Tridibes; Singh, Om P

    2016-01-01

    The rapid spread of antimalarial drug resistance in Plasmodium falciparum over the past few decades has necessitated intensive monitoring of such resistance for an effective malaria control strategy. P. falciparum dihydropteroate synthase (Pfdhps) and P. falciparum dihydrofolate reductase (Pfdhfr) genes act as molecular markers for resistance against the antimalarial drugs sulphadoxine and pyrimethamine, respectively. Resistance to pyrimethamine which is used as a partner drug in artemisinin combination therapy (ACT) is associated with several mutations in the Pfdhfr gene, namely A16V, N51I, C59R, S108N/T and I164L. Therefore, routine monitoring of Pfdhfr-drug-resistant alleles in a population may help in effective drug resistance management. Allele-specific PCR (ASPCR) is one of the commonly used methods for molecular genotyping of these alleles. In this study, we genotyped 55 samples of P. falciparum for allele discrimination at four codons of Pfdhfr (N51, C59, S108 and I164) by ASPCR using published methods and by Sanger's DNA sequencing method. We found that the ASPCR identified a significantly higher number of mutant alleles as compared to the DNA sequencing method. Such discrepancies arise due to the non-specificity of some of the allele-specific primer sets and due to the lack of sensitivity of Sanger's DNA sequencing method to detect minor alleles present in multiple clone infections. This study reveals the need of a highly specific and sensitive method for genotyping and detecting minor drug-resistant alleles present in multiple clonal infections.

  17. Establishment of Homozygote Mutant Human Embryonic Stem Cells by Parthenogenesis.

    PubMed

    Epsztejn-Litman, Silvina; Cohen-Hadad, Yaara; Aharoni, Shira; Altarescu, Gheona; Renbaum, Paul; Levy-Lahad, Ephrat; Schonberger, Oshrat; Eldar-Geva, Talia; Zeligson, Sharon; Eiges, Rachel

    2015-01-01

    We report on the derivation of a diploid 46(XX) human embryonic stem cell (HESC) line that is homozygous for the common deletion associated with Spinal muscular atrophy type 1 (SMA) from a pathenogenetic embryo. By characterizing the methylation status of three different imprinted loci (MEST, SNRPN and H19), monitoring the expression of two parentally imprinted genes (SNRPN and H19) and carrying out genome-wide SNP analysis, we provide evidence that this cell line was established from the activation of a mutant oocyte by diploidization of the entire genome. Therefore, our SMA parthenogenetic HESC (pHESC) line provides a proof-of-principle for the establishment of diseased HESC lines without the need for gene manipulation. As mutant oocytes are easily obtained and readily available during preimplantation genetic diagnosis (PGD) cycles, this approach should provide a powerful tool for disease modelling and is especially advantageous since it can be used to induce large or complex mutations in HESCs, including gross DNA alterations and chromosomal rearrangements, which are otherwise hard to achieve.

  18. Apolipoprotein E alleles in Alzheimer`s and Parkinson`s patients

    SciTech Connect

    Poduslo, S.E.; Schwankhaus, J.D.

    1994-09-01

    A number of investigators have found an association between the apolipoprotein E4 allele and Alzheimer`s disease. The E4 allele appears at a higher frequency in late onset familial Alzheimer`s patients. In our studies we obtained blood samples from early and late onset familial and sporadic Alzheimer`s patients and spouses, as well as from Parkinson`s patients. The patients were diagnosed as probable Alzheimer`s patients after a neurological examination, extensive blood work, and a CAT scan. The diagnosis was made according to the NINCDS-ADRDA criteria. The apolipoprotein E4 polymorphism was detected after PCR amplification of genomic DNA, restriction enzyme digestion with Hhal, and polyacrylamide gel electrophoresis. Ethidium bromide-stained bands at 91 bp were designated as allele 3, at 83 bp as allele 2, and at 72 bp as allele 4. Of the 84 probable Alzheimer`s patients (all of whom were Caucasian), 47 were heterozygous and 13 were homozygous for the E4 allele. There were 26 early onset patients; 13 were heterozygous and 7 homozygous for the E4 allele. The frequencies for the E4 allele for late onset familial patients was 0.45 and for sporadic patients was 0.37. We analyzed 77 spouses with an average age of 71.9 {plus_minus} 7.4 years as controls, and 15 were heterozygous for the E4 allele for an E4 frequency of 0.097. Of the 53 Parkinson`s patients, 11 had the E4 allele for a frequency of 0.113. Thus our findings support the association of the ApoE4 allele with Alzheimer`s disease.

  19. Allelic variation at the VRN-1 promoter region in polyploid wheat.

    PubMed

    Yan, L; Helguera, M; Kato, K; Fukuyama, S; Sherman, J; Dubcovsky, J

    2004-11-01

    Vernalization, the requirement of a long exposure to low temperatures to induce flowering, is an essential adaptation of plants to cold winters. We have shown recently that the vernalization gene VRN-1 from diploid wheat Triticum monococcum is the meristem identity gene APETALA1, and that deletions in its promoter were associated with spring growth habit. In this study, we characterized the allelic variation at the VRN-1 promoter region in polyploid wheat. The Vrn-A1a allele has a duplication including the promoter region. Each copy has similar foldback elements inserted at the same location and is flanked by identical host direct duplications (HDD). This allele was found in more than half of the hexaploid varieties but not among the tetraploid lines analyzed here. The Vrn-A1b allele has two mutations in the HDD region and a 20-bp deletion in the 5' UTR compared with the winter allele. The Vrn-A1b allele was found in both tetraploid and hexaploid accessions but at a relatively low frequency. Among the tetraploid wheat accessions, we found two additional alleles with 32 bp and 54 bp deletions that included the HDD region. We found no size polymorphisms in the promoter region among the winter wheat varieties. The dominant Vrn-A1 allele from two spring varieties from Afghanistan and Egypt ( Vrn-A1c allele) and all the dominant Vrn-B1 and Vrn-D1 alleles included in this study showed no differences from their respective recessive alleles in promoter sequences. Based on these results, we concluded that the VRN-1 genes should have additional regulatory sites outside the promoter region studied here.

  20. 5' and 3' untranslated regions contribute to the differential expression of specific HLA-A alleles.

    PubMed

    René, Céline; Lozano, Claire; Villalba, Martin; Eliaou, Jean-François

    2015-12-01

    In hematopoietic stem cell transplantation (HSCT), when no HLA full-matched donor is available, alternative donors could include one HLA-mismatched donor. Recently, the low expressed HLA-C alleles have been identified as permissive mismatches for the best donor choice. Concerning HLA-A, the degree of variability of expression is poorly understood. Here, we evaluated HLA-A expression in healthy individuals carrying HLA-A*02 allele in different genotypes using flow cytometry and allele-specific quantitative RT-PCR. While an interindividual variability of HLA-A*02 cell surface expression, not due to the allele associated, was observed, no difference of the mRNA expression level was shown, suggesting the involvement of the posttranscriptional regulation. The results of qRT-PCR analyses exhibit a differential expression of HLA-A alleles with HLA-A*02 as the strongest expressed allele independently of the second allele. The associated non-HLA-A*02 alleles were differentially expressed, particularly the HLA-A*31 and HLA-A*33 alleles (strong expression) and the HLA-A*29 (low expression). The presence of specific polymorphisms in the 5' and 3' untranslated regions of the HLA-A*31 and HLA-A*33 alleles could contribute to this high level of expression. As previously described for HLA-C, low-expressed HLA-A alleles, such as HLA-A*29, could be considered as a permissive mismatch, although this needs to be confirmed by clinical studies.

  1. Identification and DNA sequence analysis of 15 new {alpha}{sub 1}-antitrypsin variants, including two PI*QO alleles and one deficient PI*M allele

    SciTech Connect

    Faber, J.P.; Kirchgesser, M.; Schwaab, R.; Bidlingmaier, F.; Poller, W.; Weidinger, S.; Olek, K. |

    1994-12-01

    The authors have investigated the molecular basis of 15 new {alpha}{sub 1}-antitrypsin ({alpha}1AT) variants. Phenotyping by isoelectric focusing (IEF) was used as a screening method to detect {alpha}1AT variants at the protein level. Genotyping was then performed by sequence analysis of all coding exons, exon-intron junctions, and the hepatocyte-specific promotor region including exon Ic. Three of these rare variants are alleles of clinical relevance, associated with undetectable or very low serum levels of {alpha}1AT: the PI*Q0saarbruecken allele generated by a 1-bp C-nucleotide insertion within a stretch of seven cytosines spanning residues 360-362, resulting in a 3{prime} frameshift and the acquisition of a stop codon at residue 376; a point mutation in the PI*Q0lisbon allele, resulting in a single amino acid substitution Thr{sup 68}(ACC){yields}Ile(ATC); and an in-frame trinucleotide deletion {Delta}Phe{sup 51} (TTC) in the highly deficient PI*Mpalermo allele. The remaining 12 alleles are associated with normal {alpha}1AT serum levels and are characterized by point mutations causing single amino acid substitutions in all but one case. This exception is a silent mutation, which does not affect the amino acid sequence. The limitation of IEF compared with DNA sequence analysis, for identification of new variants, their generation by mutagenesis, and the clinical relevance of the three deficiency alleles are discussed.

  2. Seven novel HLA alleles reflect different mechanisms involved in the evolution of HLA diversity: description of the new alleles and review of the literature.

    PubMed

    Adamek, Martina; Klages, Cornelia; Bauer, Manuela; Kudlek, Evelina; Drechsler, Alina; Leuser, Birte; Scherer, Sabine; Opelz, Gerhard; Tran, Thuong Hien

    2015-01-01

    The human leukocyte antigen (HLA) loci are among the most polymorphic genes in the human genome. The diversity of these genes is thought to be generated by different mechanisms including point mutation, gene conversion and crossing-over. During routine HLA typing, we discovered seven novel HLA alleles which were probably generated by different evolutionary mechanisms. HLA-B*41:21, HLA-DQB1*02:10 and HLA-DQA1*01:12 likely emerged from the common alleles of their groups by point mutations, all of which caused non-synonymous amino acid substitutions. In contrast, a deletion of one nucleotide leading to a frame shift with subsequent generation of a stop codon is responsible for the appearance of a null allele, HLA-A*01:123N. Whereas HLA-B*35:231 and HLA-B*53:31 were probably products of intralocus gene conversion between HLA-B alleles, HLA-C*07:294 presumably evolved by interlocus gene conversion between an HLA-C and an HLA-B allele. Our analysis of these novel alleles illustrates the different mechanisms which may have contributed to the evolution of HLA polymorphism.

  3. Suppression among alleles encoding nucleotide-binding-leucine-rich repeat resistance proteins interferes with resistance in F1 hybrid and allele-pyramided wheat plants.

    PubMed

    Stirnweis, Daniel; Milani, Samira D; Brunner, Susanne; Herren, Gerhard; Buchmann, Gabriele; Peditto, David; Jordan, Tina; Keller, Beat

    2014-09-01

    The development of high-yielding varieties with broad-spectrum durable disease resistance is the ultimate goal of crop breeding. In plants, immune receptors of the nucleotide-binding-leucine-rich repeat (NB-LRR) class mediate race-specific resistance against pathogen attack. When employed in agriculture this type of resistance is often rapidly overcome by newly adapted pathogen races. The stacking of different resistance genes or alleles in F1 hybrids or in pyramided lines is a promising strategy for achieving more durable resistance. Here, we identify a molecular mechanism which can negatively interfere with the allele-pyramiding approach. We show that pairwise combinations of different alleles of the powdery mildew resistance gene Pm3 in F1 hybrids and stacked transgenic wheat lines can result in suppression of Pm3-based resistance. This effect is independent of the genetic background and solely dependent on the Pm3 alleles. Suppression occurs at the post-translational level, as levels of RNA and protein in the suppressed alleles are unaffected. Using a transient expression system in Nicotiana benthamiana, the LRR domain was identified as the domain conferring suppression. The results of this study suggest that the expression of closely related NB-LRR resistance genes or alleles in the same genotype can lead to dominant-negative interactions. These findings provide a molecular explanation for the frequently observed ineffectiveness of resistance genes introduced from the secondary gene pool into polyploid crop species and mark an important step in overcoming this limitation.

  4. Investigating the relationship between FMR1 allele length and cognitive ability in children: a subtle effect of the normal allele range on the normal ability range?

    PubMed

    Loat, C S; Craig, G; Plomin, R; Craig, I W

    2006-09-01

    The FMR1 gene contains a trinucleotide repeat tract which can expand from a normal size of around 30 repeats to over 200 repeats, causing mental retardation (Fragile X Syndrome). Evidence suggests that premutation males (55-200 repeats) are susceptible to a late-onset tremor/ataxia syndrome and females to premature ovarian failure, and that intermediate alleles ( approximately 41-55 repeats) and premutations may be in excess in samples with special educational needs. We explored the relationship between FMR1 allele length and cognitive ability in 621 low ability and control children assessed at 4 and 7 years, as well as 122 students with high IQ. The low and high ability and control samples showed no between-group differences in incidence of longer alleles. In males there was a significant negative correlation between allele length and non-verbal ability at 4 years (p = 0.048), academic achievement in maths (p = 0.003) and English (p = 0.011) at 7 years, and IQ in the high ability group (p = 0.018). There was a significant negative correlation between allele length and a standardised score for IQ and general cognitive ability at age 7 in the entire male sample (p = 0.002). This suggests that, within the normal spectrum of allele length, increased repeat numbers may have a limiting influence on cognitive performance.

  5. Culture-gene coevolution of individualism-collectivism and the serotonin transporter gene.

    PubMed

    Chiao, Joan Y; Blizinsky, Katherine D

    2010-02-22

    Culture-gene coevolutionary theory posits that cultural values have evolved, are adaptive and influence the social and physical environments under which genetic selection operates. Here, we examined the association between cultural values of individualism-collectivism and allelic frequency of the serotonin transporter functional polymorphism (5-HTTLPR) as well as the role this culture-gene association may play in explaining global variability in prevalence of pathogens and affective disorders. We found evidence that collectivistic cultures were significantly more likely to comprise individuals carrying the short (S) allele of the 5-HTTLPR across 29 nations. Results further show that historical pathogen prevalence predicts cultural variability in individualism-collectivism owing to genetic selection of the S allele. Additionally, cultural values and frequency of S allele carriers negatively predict global prevalence of anxiety and mood disorder. Finally, mediation analyses further indicate that increased frequency of S allele carriers predicted decreased anxiety and mood disorder prevalence owing to increased collectivistic cultural values. Taken together, our findings suggest culture-gene coevolution between allelic frequency of 5-HTTLPR and cultural values of individualism-collectivism and support the notion that cultural values buffer genetically susceptible populations from increased prevalence of affective disorders. Implications of the current findings for understanding culture-gene coevolution of human brain and behaviour as well as how this coevolutionary process may contribute to global variation in pathogen prevalence and epidemiology of affective disorders, such as anxiety and depression, are discussed.

  6. Prevalence of URAT1 allelic variants in the Roma population.

    PubMed

    Stiburkova, Blanka; Gabrikova, Dana; Čepek, Pavel; Šimek, Pavel; Kristian, Pavol; Cordoba-Lanus, Elizabeth; Claverie-Martin, Felix

    2016-12-01

    The Roma represents a transnational ethnic group, with a current European population of 8-10 million. The evolutionary process that had the greatest impact on the gene pool of the Roma population is called the founder effect. Renal hypouricemia (RHUC) is a rare heterogenous inherited disorder characterized by impaired renal urate reabsorption. The affected individuals are predisposed to recurrent episodes of exercise-induced nonmyoglobinuric acute kidney injury and nephrolithiasis. To date, more than 150 patients with a loss-of-function mutation for the SLC22A12 (URAT1) gene have been found, most of whom are Asians. However, RHUC 1 patients have been described in a variety of ethnic groups (e.g., Arab Israelis, Iraqi Jews, Caucasians, and Roma) and in geographically noncontiguous countries. This study confirms our previous findings regarding the high frequency of SLC22A12 variants observed. Frequencies of the c.1245_1253del and c.1400C>T variants were found to be 1.92% and 5.56%, respectively, in a subgroup of the Roma population from five regions in three countries: Slovakia, Czech Republic, and Spain. Our findings suggested that the common dysfunction allelic variants of URAT1 exist in the general Roma population and thus renal hypouricemia should be kept in differential diagnostic algorithm on Roma patients with defect in renal tubular urate transport. This leads to confirm that the genetic drift in the Roma have increased the prevalence of hereditary disorders caused by very rare variants in major population.

  7. Allele-specific chemical genetics: concept, strategies, and applications.

    PubMed

    Islam, Kabirul

    2015-02-20

    The relationship between DNA and protein sequences is well understood, yet because the members of a protein family/subfamily often carry out the same biochemical reaction, elucidating their individual role in cellular processes presents a challenge. Forward and reverse genetics have traditionally been employed to understand protein functions with considerable success. A fundamentally different approach that has gained widespread application is the use of small organic molecules, known as chemical genetics. However, the slow time-scale of genetics and inherent lack of specificity of small molecules used in chemical genetics have limited the applicability of these methods in deconvoluting the role of individual proteins involved in fast, dynamic biological events. Combining the advantages of both the techniques, the specificity achieved with genetics along with the reversibility and tunability of chemical genetics, has led to the development of a powerful approach to uncover protein functions in complex biological processes. This technique is known as allele-specific chemical genetics and is rapidly becoming an essential toolkit to shed light on proteins and their mechanism of action. The current review attempts to provide a comprehensive description of this approach by discussing the underlying principles, strategies, and successful case studies. Potential future implications of this technology in expanding the frontiers of modern biology are discussed.

  8. Allelic loss of chromosome 6q in gastric carcinoma.

    PubMed

    Li, Brenda C Y; Chan, Wing Y; Li, Christine Y S; Chow, Chit; Ng, Enders K W; Chung, S C Sydney

    2003-12-01

    Loss of the long arm of chromosome 6 (6q) has frequently been reported in gastric carcinoma, and most gastric cancer patients have evidence of intestinal metaplasia in the stomach. However, the relationship between loss of chromosome 6q and intestinal metaplasia has not been studied. In the first part of the study, we define the critical deletion region of chromosome 6q using loss of heterozygosity technique (LOH). Seventeen microsatellite markers were used to detect loss of heterozygosity (LOH) in 37 microdissected gastric tumors. We also examined intestinal metaplasia (IM) foci of the stomach in the same cancer patient (17 cases). Losses on chromosome 6q were detected in high frequency (51%) by LOH. Two distinct regions of common allelic loss were identified: one centered on the marker D6S300 (at 6q16.1) and the second on D6S446 (at 6q27), with LOH frequency of 36% and 31.3%, respectively. The deletions fall into 2 discrete regions, suggesting the existence of at least 2 tumor suppressor genes in 6q. The losses at 6q27 were confirmed by fluorescence in situ hybridization study (FISH). In the cases with LOH in the tumor, no LOH were detected in the autologous IM areas, but losses were detected by FISH. In some cases, these genetic changes may be acquired in the transition from normal gastric mucosa to intestinal metaplasia.

  9. Hypomorphic NOTCH3 alleles do not cause CADASIL in humans.

    PubMed

    Rutten, Julie W; Boon, Elles M J; Liem, Michael K; Dauwerse, Johannes G; Pont, Margot J; Vollebregt, Ellen; Maat-Kievit, Anneke J; Ginjaar, Hendrika B; Lakeman, Phillis; van Duinen, Sjoerd G; Terwindt, Gisela M; Lesnik Oberstein, Saskia A J

    2013-11-01

    Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is caused by stereotyped missense mutations in NOTCH3. Whether these mutations lead to the CADASIL phenotype via a neomorphic effect, or rather by a hypomorphic effect, is subject of debate. Here, we report two novel NOTCH3 mutations, both leading to a premature stop codon with predicted loss of NOTCH3 function. The first mutation, c.307C>T, p.Arg103*, was detected in two brothers aged 50 and 55 years, with a brain MRI and skin biopsy incompatible with CADASIL. The other mutation was found in a 40-year-old CADASIL patient compound heterozygous for a pathogenic NOTCH3 mutation (c.2129A>G, p.Tyr710Cys) and an intragenic frameshift deletion. The deletion was inherited from his father, who did not have the skin biopsy abnormalities seen in CADASIL patients. These individuals with rare NOTCH3 mutations indicate that hypomorphic NOTCH3 alleles do not cause CADASIL.

  10. FINDbase: a worldwide database for genetic variation allele frequencies updated

    PubMed Central

    Georgitsi, Marianthi; Viennas, Emmanouil; Antoniou, Dimitris I.; Gkantouna, Vassiliki; van Baal, Sjozef; Petricoin, Emanuel F.; Poulas, Konstantinos; Tzimas, Giannis; Patrinos, George P.

    2011-01-01

    Frequency of INherited Disorders database (FIND base; http://www.findbase.org) records frequencies of causative genetic variations worldwide. Database records include the population and ethnic group or geographical region, the disorder name and the related gene, accompanied by links to any related external resources and the genetic variation together with its frequency in that population. In addition to the regular data content updates, we report the following significant advances: (i) the systematic collection and thorough documentation of population/ethnic group-specific pharmacogenomic markers allele frequencies for 144 markers in 14 genes of pharmacogenomic interest from different classes of drug-metabolizing enzymes and transporters, representing 150 populations and ethnic groups worldwide; (ii) the development of new data querying and visualization tools in the expanded FINDbase data collection, built around Microsoft’s PivotViewer software (http://www.getpivot.com), based on Microsoft Silverlight technology (http://www.silverlight.net) that facilitates querying of large data sets and visualizing the results; and (iii) the establishment of the first database journal, by affiliating FINDbase with Human Genomics and Proteomics, a new open-access scientific journal, which would serve as a prime example of a non-profit model for sustainable database funding. PMID:21113021

  11. Naturally occurring allele diversity allows potato cultivation in northern latitudes.

    PubMed

    Kloosterman, Bjorn; Abelenda, José A; Gomez, María del Mar Carretero; Oortwijn, Marian; de Boer, Jan M; Kowitwanich, Krissana; Horvath, Beatrix M; van Eck, Herman J; Smaczniak, Cezary; Prat, Salomé; Visser, Richard G F; Bachem, Christian W B

    2013-03-14

    Potato (Solanum tuberosum L.) originates from the Andes and evolved short-day-dependent tuber formation as a vegetative propagation strategy. Here we describe the identification of a central regulator underlying a major-effect quantitative trait locus for plant maturity and initiation of tuber development. We show that this gene belongs to the family of DOF (DNA-binding with one finger) transcription factors and regulates tuberization and plant life cycle length, by acting as a mediator between the circadian clock and the StSP6A mobile tuberization signal. We also show that natural allelic variants evade post-translational light regulation, allowing cultivation outside the geographical centre of origin of potato. Potato is a member of the Solanaceae family and is one of the world's most important food crops. This annual plant originates from the Andean regions of South America. Potato develops tubers from underground stems called stolons. Its equatorial origin makes potato essentially short-day dependent for tuberization and potato will not make tubers in the long-day conditions of spring and summer in the northern latitudes. When introduced in temperate zones, wild material will form tubers in the course of the autumnal shortening of day-length. Thus, one of the first selected traits in potato leading to a European potato type is likely to have been long-day acclimation for tuberization. Potato breeders can exploit the naturally occurring variation in tuberization onset and life cycle length, allowing varietal breeding for different latitudes, harvest times and markets.

  12. Salmonella Typhi shdA: pseudogene or allelic variant?

    PubMed

    Urrutia, I M; Fuentes, J A; Valenzuela, L M; Ortega, A P; Hidalgo, A A; Mora, G C

    2014-08-01

    ShdA from Salmonella Typhimurium (ShdASTm) is a large outer membrane protein that specifically recognizes and binds to fibronectin. ShdASTm is involved in the colonization of the cecum and the Peyer's patches of terminal ileum in mice. On the other hand, shdA gene from Salmonella Typhi (shdASTy) has been considered a pseudogene (i.e. a nonfunctional sequence of genomic DNA) due to the presence of deletions and mutations that gave rise to premature stop codons. In this work we show that, despite the deletions and mutations, shdASTy is fully functional. S. Typhi ΔshdA mutants presented an impaired adherence and invasion of HEp-2 pre-treated with TGF-β1, an inducer of fibronectin production. Moreover, shdA from S. Typhi and S. Typhimurium seem to be equivalent since shdASTm restored the adherence and invasion of S. Typhi ΔshdA mutant to wild type levels. In addition, anti-FLAG mAbs interfered with the adherence and invasion of the S. Typhi shdA-3xFLAG strain. Finally, shdASTy encodes a detectable protein when heterologously expressed in Escherichia coli DH5α. The data presented here show that shdASTy is not a pseudogene, but a different functional allele compared with shdASTm.

  13. Identification of novel alleles of the rice blast resistance gene Pi54

    NASA Astrophysics Data System (ADS)

    Vasudevan, Kumar; Gruissem, Wilhelm; Bhullar, Navreet K.

    2015-10-01

    Rice blast is one of the most devastating rice diseases and continuous resistance breeding is required to control the disease. The rice blast resistance gene Pi54 initially identified in an Indian cultivar confers broad-spectrum resistance in India. We explored the allelic diversity of the Pi54 gene among 885 Indian rice genotypes that were found resistant in our screening against field mixture of naturally existing M. oryzae strains as well as against five unique strains. These genotypes are also annotated as rice blast resistant in the International Rice Genebank database. Sequence-based allele mining was used to amplify and clone the Pi54 allelic variants. Nine new alleles of Pi54 were identified based on the nucleotide sequence comparison to the Pi54 reference sequence as well as to already known Pi54 alleles. DNA sequence analysis of the newly identified Pi54 alleles revealed several single polymorphic sites, three double deletions and an eight base pair deletion. A SNP-rich region was found between a tyrosine kinase phosphorylation site and the nucleotide binding site (NBS) domain. Together, the newly identified Pi54 alleles expand the allelic series and are candidates for rice blast resistance breeding programs.

  14. Extensive allelic variation in gene expression in populus F1 hybrids.

    PubMed

    Zhuang, Yan; Adams, Keith L

    2007-12-01

    Hybridization between plant species can induce speciation as well as phenotypic novelty and heterosis. Hybrids also can show genome rearrangements and gene expression changes compared with their parents. Here we determined the allelic variation in gene expression in Populus trichocarpa x Populus deltoides F(1) hybrids. Among 30 genes analyzed in four independently formed hybrids, 17 showed >1.5-fold expression biases for one of the two alleles, and there was monoallelic expression of one gene. Expression ratios of the alleles differed between leaves and stems for 10 genes. The results suggest differential regulation of the two parental alleles in the hybrids. To determine if the allelic expression biases were caused by hybridization we compared the ratios of species-specific transcripts between an F(1) hybrid and its parents. Thirteen of 19 genes showed allelic expression ratios in the hybrid that were significantly different from the ratios of the parental species. The P. deltoides allele of one gene was silenced in the hybrid. Modes of gene regulation were inferred from the hybrid-parent comparisons. Cis-regulation was inferred for 6 genes, trans-regulation for 1 gene, and combined cis- and trans-regulation for 9 genes. The results from this study indicate that hybridization between plant species can have extensive effects on allelic expression patterns, some of which might lead to phenotypic changes.

  15. Comparison of Prion Allele Frequency found in Suffolk and Targhee Sheep

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Scrapie is a class of Transmissible Spongiform Encephalopathy that affects sheep and goats. The objective of this study was to compare genotypic and allelic frequencies among USSES Targhee and Suffolk sheep. A total of 122 sheep were genotyped for codon 171 with allele specific primers in 2 separate...

  16. An autosomal locus that controls chromosome-wide replication timing and mono-allelic expression.

    PubMed

    Stoffregen, Eric P; Donley, Nathan; Stauffer, Daniel; Smith, Leslie; Thayer, Mathew J

    2011-06-15

    Mammalian DNA replication initiates at multiple sites along chromosomes at different times, following a temporal replication program. Homologous alleles typically replicate synchronously; however, mono-allelically expressed genes such as imprinted genes, allelically excluded genes and genes on the female X chromosome replicate asynchronously. We have used a chromosome engineering strategy to identify a human autosomal locus that controls this replication timing program in cis. We show that Cre/loxP-mediated rearrangements at a discrete locus at 6q16.1 result in delayed replication of the entire chromosome. This locus displays asynchronous replication timing that is coordinated with other mono-allelically expressed genes on chromosome 6. Characterization of this locus revealed mono-allelic expression of a large intergenic non-coding RNA, which we have named asynchronous replication and autosomal RNA on chromosome 6, ASAR6. Finally, disruption of this locus results in the activation of the previously silent alleles of linked mono-allelically expressed genes. We previously found that chromosome rearrangements involving eight different autosomes display delayed replication timing, and that cells containing chromosomes with delayed replication timing have a 30-80-fold increase in the rate at which new gross chromosomal rearrangements occurred. Taken together, these observations indicate that human autosomes contain discrete cis-acting loci that control chromosome-wide replication timing, mono-allelic expression and the stability of entire chromosomes.

  17. An autosomal locus that controls chromosome-wide replication timing and mono-allelic expression

    PubMed Central

    Stoffregen, Eric P.; Donley, Nathan; Stauffer, Daniel; Smith, Leslie; Thayer, Mathew J.

    2011-01-01

    Mammalian DNA replication initiates at multiple sites along chromosomes at different times, following a temporal replication program. Homologous alleles typically replicate synchronously; however, mono-allelically expressed genes such as imprinted genes, allelically excluded genes and genes on the female X chromosome replicate asynchronously. We have used a chromosome engineering strategy to identify a human autosomal locus that controls this replication timing program in cis. We show that Cre/loxP-mediated rearrangements at a discrete locus at 6q16.1 result in delayed replication of the entire chromosome. This locus displays asynchronous replication timing that is coordinated with other mono-allelically expressed genes on chromosome 6. Characterization of this locus revealed mono-allelic expression of a large intergenic non-coding RNA, which we have named asynchronous replication and autosomal RNA on chromosome 6, ASAR6. Finally, disruption of this locus results in the activation of the previously silent alleles of linked mono-allelically expressed genes. We previously found that chromosome rearrangements involving eight different autosomes display delayed replication timing, and that cells containing chromosomes with delayed replication timing have a 30–80-fold increase in the rate at which new gross chromosomal rearrangements occurred. Taken together, these observations indicate that human autosomes contain discrete cis-acting loci that control chromosome-wide replication timing, mono-allelic expression and the stability of entire chromosomes. PMID:21459774

  18. Latent S alleles are widespread in cultivated self-compatible Brassica napus.

    PubMed

    Ekuere, U U; Parkin, I A P; Bowman, C; Marshall, D; Lydiate, D J

    2004-04-01

    The genetic control of self-incompatibility in Brassica napus was investigated using crosses between resynthesized lines of B. napus and cultivars of oilseed rape. These crosses introduced eight C-genome S alleles from Brassica oleracea (S16, S22, S23, S25, S29, S35, S60, and S63) and one A-genome S allele from Brassica rapa (SRM29) into winter oilseed rape. The inheritance of S alleles was monitored using genetic markers and S phenotypes were determined in the F1, F2, first backcross (B1), and testcross (T1) generations. Two different F1 hybrids were used to develop populations of doubled haploid lines that were subjected to genetic mapping and scored for S phenotype. These investigations identified a latent S allele in at least two oilseed rape cultivars and indicated that the S phenotype of these latent alleles was masked by a suppressor system common to oilseed rape. These latent S alleles may be widespread in oilseed rape varieties and are possibly associated with the highly conserved C-genome S locus of these crop types. Segregation for S phenotype in subpopulations uniform for S genotype suggests the existence of suppressor loci that influenced the expression of the S phenotype. These suppressor loci were not linked to the S loci and possessed suppressing alleles in oilseed rape and non-suppressing alleles in the diploid parents of resynthesized B. napus lines.

  19. An Updated Collection of Sequence Barcoded Temperature-Sensitive Alleles of Yeast Essential Genes.

    PubMed

    Kofoed, Megan; Milbury, Karissa L; Chiang, Jennifer H; Sinha, Sunita; Ben-Aroya, Shay; Giaever, Guri; Nislow, Corey; Hieter, Philip; Stirling, Peter C

    2015-07-14

    Systematic analyses of essential gene function using mutant collections in Saccharomyces cerevisiae have been conducted using collections of heterozygous diploids, promoter shut-off alleles, through alleles with destabilized mRNA, destabilized protein, or bearing mutations that lead to a temperature-sensitive (ts) phenotype. We previously described a method for construction of barcoded ts alleles in a systematic fashion. Here we report the completion of this collection of alleles covering 600 essential yeast genes. This resource covers a larger gene repertoire than previous collections and provides a complementary set of strains suitable for single gene and genomic analyses. We use deep sequencing to characterize the amino acid changes leading to the ts phenotype in half of the alleles. We also use high-throughput approaches to describe the relative ts behavior of the alleles. Finally, we demonstrate the experimental usefulness of the collection in a high-content, functional genomic screen for ts alleles that increase spontaneous P-body formation. By increasing the number of alleles and improving the annotation, this ts collection will serve as a community resource for probing new aspects of biology for essential yeast genes.

  20. Identification of novel alleles of the rice blast resistance gene Pi54.

    PubMed

    Vasudevan, Kumar; Gruissem, Wilhelm; Bhullar, Navreet K

    2015-10-26

    Rice blast is one of the most devastating rice diseases and continuous resistance breeding is required to control the disease. The rice blast resistance gene Pi54 initially identified in an Indian cultivar confers broad-spectrum resistance in India. We explored the allelic diversity of the Pi54 gene among 885 Indian rice genotypes that were found resistant in our screening against field mixture of naturally existing M. oryzae strains as well as against five unique strains. These genotypes are also annotated as rice blast resistant in the International Rice Genebank database. Sequence-based allele mining was used to amplify and clone the Pi54 allelic variants. Nine new alleles of Pi54 were identified based on the nucleotide sequence comparison to the Pi54 reference sequence as well as to already known Pi54 alleles. DNA sequence analysis of the newly identified Pi54 alleles revealed several single polymorphic sites, three double deletions and an eight base pair deletion. A SNP-rich region was found between a tyrosine kinase phosphorylation site and the nucleotide binding site (NBS) domain. Together, the newly identified Pi54 alleles expand the allelic series and are candidates for rice blast resistance breeding programs.

  1. The effect of wild card designations and rare alleles in forensic DNA database searches.

    PubMed

    Tvedebrink, Torben; Bright, Jo-Anne; Buckleton, John S; Curran, James M; Morling, Niels

    2015-05-01

    Forensic DNA databases are powerful tools used for the identification of persons of interest in criminal investigations. Typically, they consist of two parts: (1) a database containing DNA profiles of known individuals and (2) a database of DNA profiles associated with crime scenes. The risk of adventitious or chance matches between crimes and innocent people increases as the number of profiles within a database grows and more data is shared between various forensic DNA databases, e.g. from different jurisdictions. The DNA profiles obtained from crime scenes are often partial because crime samples may be compromised in quantity or quality. When an individual's profile cannot be resolved from a DNA mixture, ambiguity is introduced. A wild card, F, may be used in place of an allele that has dropped out or when an ambiguous profile is resolved from a DNA mixture. Variant alleles that do not correspond to any marker in the allelic ladder or appear above or below the extent of the allelic ladder range are assigned the allele designation R for rare allele. R alleles are position specific with respect to the observed/unambiguous allele. The F and R designations are made when the exact genotype has not been determined. The F and R designation are treated as wild cards for searching, which results in increased chance of adventitious matches. We investigated the probability of adventitious matches given these two types of wild cards.

  2. [Prevalence of VRN1 Locus Alleles among Spring Common Wheat Cultivars Cultivated in Western Siberia].

    PubMed

    Efremova, T T; Chumanova, E V; Trubacheeva, N V; Arbuzova, V S; Belan, I A; Pershina, L A

    2016-02-01

    With the use of allele-specific primers developed for the VRN1 loci, the allelic diversity of the VRN-A1, VRN-B1, and VRN-D1 genes was studied in 148 spring common wheat cultivars cultivated under the conditions of Western Siberia. It was demonstrated that modern Western Siberian cultivars have the VRN-A1a allele, which is widely distributed in the world (alone or in combination with the VRN-B1a and VRN-B1c alleles). It was established that the main contribution in acceleration of the.seedling-heading time is determined by a dominant VRN-A1a allele, while the VRN-A1b allele, on the contrary, determines later plant heading. Cultivars that have the VRN-A1b allele in the genotype are found with a frequency of 8%. It was shown that cultivars with different allele combinations of two dominant genes (VRN-A1a + VRN-B1c and VRN-A1a + VRN-B1a) are characterized by earlier heading and maturing.

  3. Fixation probability and the crossing time in the Wright-Fisher multiple alleles model

    NASA Astrophysics Data System (ADS)

    Gill, Wonpyong

    2009-08-01

    The fixation probability and crossing time in the Wright-Fisher multiple alleles model, which describes a finite haploid population, were calculated by switching on an asymmetric sharply-peaked landscape with a positive asymmetric parameter, r, such that the reversal allele of the optimal allele has higher fitness than the optimal allele. The fixation probability, which was evaluated as the ratio of the first arrival time at the reversal allele to the origination time, was double the selective advantage of the reversal allele compared with the optimal allele in the strong selection region, where the fitness parameter, k, is much larger than the critical fitness parameter, kc. The crossing time in a finite population for r>0 and kallele in the first generation should be greater than one individual in an asymmetric sharply-peaked landscape. It was also found that the crossing time in a finite population for r>0 and k≫kc scaled as a power law in the fitness parameter with a similar scaling exponent as the crossing time in an infinite population for r=0, and that the critical fitness parameter decreased with increasing sequence length with a fixed population size.

  4. Distribution of coat-color-associated alleles in the domestic horse population and Przewalski's horse.

    PubMed

    Reissmann, Monika; Musa, Lutfi; Zakizadeh, Sonia; Ludwig, Arne

    2016-11-01

    Considering the hidden mode of inheritance of some coat-color-associated alleles, we investigated the presence/absence of coat-color-associated alleles in 1093 domestic horses of 55 breeds and 20 specimens of Przewalski's horse. For coat-color genotyping, allele specific PCR, pyrosequencing and Li-Cor analyses were conducted on 12 coat-color-associated alleles of five genes. Our data provide deep insight into the distribution of coat-color-associated alleles within breeds. We found that the alleles for the basic colorations (bay, black, and chestnut) are widely distributed and occur in nearly all breeds. Alleles leading to dilutions or patterns are rare in domestic breeds and were not found in Przewalski's horse. Higher frequencies of these alleles are only found in breeds that are selected for their expressed phenotypes (e.g., Kinsky horse, Lewitzer, Tinker). Nevertheless, our study produced strong evidence that molecular testing of the coat color is necessary for well-defined phenotyping to avoid unexpected colorations of offspring that can result in legal action.

  5. An Updated Collection of Sequence Barcoded Temperature-Sensitive Alleles of Yeast Essential Genes

    PubMed Central

    Kofoed, Megan; Milbury, Karissa L.; Chiang, Jennifer H.; Sinha, Sunita; Ben-Aroya, Shay; Giaever, Guri; Nislow, Corey; Hieter, Philip; Stirling, Peter C.

    2015-01-01

    Systematic analyses of essential gene function using mutant collections in Saccharomyces cerevisiae have been conducted using collections of heterozygous diploids, promoter shut-off alleles, through alleles with destabilized mRNA, destabilized protein, or bearing mutations that lead to a temperature-sensitive (ts) phenotype. We previously described a method for construction of barcoded ts alleles in a systematic fashion. Here we report the completion of this collection of alleles covering 600 essential yeast genes. This resource covers a larger gene repertoire than previous collections and provides a complementary set of strains suitable for single gene and genomic analyses. We use deep sequencing to characterize the amino acid changes leading to the ts phenotype in half of the alleles. We also use high-throughput approaches to describe the relative ts behavior of the alleles. Finally, we demonstrate the experimental usefulness of the collection in a high-content, functional genomic screen for ts alleles that increase spontaneous P-body formation. By increasing the number of alleles and improving the annotation, this ts collection will serve as a community resource for probing new aspects of biology for essential yeast genes. PMID:26175450

  6. Retention of agronomically important variation in germplasm core collections: implications for allele mining

    Technology Transfer Automated Retrieval System (TEKTRAN)

    The primary targets of allele mining efforts are loci of agronomic importance. Agronomic loci typically exhibit patterns of allelic diversity consistent with a history of natural or artificial selection. Natural or artificial selection causes the distribution of genetic diversity at such loci to d...

  7. Detection of 549 new HLA alleles in potential stem cell donors from the United States, Poland and Germany.

    PubMed

    Hernández-Frederick, C J; Cereb, N; Giani, A S; Ruppel, J; Maraszek, A; Pingel, J; Sauter, J; Schmidt, A H; Yang, S Y

    2016-01-01

    We characterized 549 new human leukocyte antigen (HLA) class I and class II alleles found in newly registered stem cell donors as a result of high-throughput HLA typing. New alleles include 101 HLA-A, 132 HLA-B, 105 HLA-C, 2 HLA-DRB1, 89 HLA-DQB1 and 120 HLA-DPB1 alleles. Mainly, new alleles comprised single nucleotide variations when compared with homologous sequences. We identified nonsynonymous nucleotide mutations in 70.7% of all new alleles, synonymous variations in 26.4% and nonsense substitutions in 2.9% (null alleles). Some new alleles (55, 10.0%) were found multiple times, HLA-DPB1 alleles being the most frequent among these. Furthermore, as several new alleles were identified in individuals from ethnic minority groups, the relevance of recruiting donors belonging to such groups and the importance of ethnicity data collection in donor centers and registries is highlighted.

  8. Inter-allelic interactions play a major role in microsatellite evolution.

    PubMed

    Amos, William; Kosanović, Danica; Eriksson, Anders

    2015-11-07

    Microsatellite mutations identified in pedigrees confirm that most changes involve the gain or loss of single repeats. However, an unexpected pattern is revealed when the resulting data are plotted on standardized scales that range from the shortest to longest allele at a locus. Both mutation rate and mutation bias reveal a strong dependency on allele length relative to other alleles at the same locus. We show that models in which alleles mutate independently cannot explain these patterns. Instead, both mutation probability and direction appear to involve interactions between homologues in heterozygous individuals. Simple models in which the longer homologue in heterozygotes is more likely to mutate and/or biased towards contraction readily capture the observed trends. The exact model remains unclear in all its details but inter-allelic interactions are a vital component, implying a link between demographic history and the mode and tempo of microsatellite evolution.

  9. Multi-primer target PCR for rapid identification of bovine DRB3 alleles.

    PubMed

    Ledwidge, S A; Mallard, B A; Gibson, J P; Jansen, G B; Jiang, Z H

    2001-08-01

    Multi-primer target polymerase chain reaction (MPT-PCR) is a rapid method for the identification of specific BoLA-DRB3 alleles. In a single PCR reaction, the presence of two alleles associated with increased risk, DRB3.2*23 (DRB3*2701-2703, 2705-2707) and decreased risk, DRB3.2*16 (DRB3*1501, 1502), of mastitis in Canadian Holstein can be detected. Two outer primers amplify exon 2 of DRB3. Simultaneously, two inner, allele-specific primers amplify individual alleles. Initially, 40 cows previously typed by PCR-restriction fragment length polymorphism (PCR-RFLP) were genotyped using the multi-primer approach. An additional 30 cows were first genotyped by multi-primer target PCR, then by PCR-RFLP. All animals were correctly identified and there were no false positives. This technique can readily be modified to identify other BoLA alleles of interest.

  10. BaalChIP: Bayesian analysis of allele-specific transcription factor binding in cancer genomes.

    PubMed

    de Santiago, Ines; Liu, Wei; Yuan, Ke; O'Reilly, Martin; Chilamakuri, Chandra Sekhar Reddy; Ponder, Bruce A J; Meyer, Kerstin B; Markowetz, Florian

    2017-02-24

    Allele-specific measurements of transcription factor binding from ChIP-seq data are key to dissecting the allelic effects of non-coding variants and their contribution to phenotypic diversity. However, most methods of detecting an allelic imbalance assume diploid genomes. This assumption severely limits their applicability to cancer samples with frequent DNA copy-number changes. Here we present a Bayesian statistical approach called BaalChIP to correct for the effect of background allele frequency on the observed ChIP-seq read counts. BaalChIP allows the joint analysis of multiple ChIP-seq samples across a single variant and outperforms competing approaches in simulations. Using 548 ENCODE ChIP-seq and six targeted FAIRE-seq samples, we show that BaalChIP effectively corrects allele-specific analysis for copy-number variation and increases the power to detect putative cis-acting regulatory variants in cancer genomes.

  11. Lack of association between the pancreatitis risk allele CEL-HYB and pancreatic cancer.

    PubMed

    Shindo, Koji; Yu, Jun; Suenaga, Masaya; Fesharakizadeh, Shahriar; Tamura, Koji; Almario, Jose Alejandro Navarro; Brant, Aaron; Borges, Michael; Siddiqui, Abdulrehman; Datta, Lisa; Wolfgang, Christopher L; Hruban, Ralph H; Klein, Alison Patricia; Goggins, Michael

    2017-02-07

    CEL-HYB is a hybrid allele that arose from a crossover between the 3' end of the Carboxyl ester lipase (CEL) gene and the nearby CEL pseudogene (CELP) and was recently identified as a risk factor for chronic pancreatitis. Since chronic pancreatitis is a risk factor for the development of pancreatic cancer, we compared the prevalence of the CEL-HYB allele in patients with pancreatic ductal adenocarcinoma to spousal controls and disease controls. The CEL-HYB allele was detected using Sanger and next generation sequencing. There was no significant difference in the prevalence of the CEL-HYB allele between cases with pancreatic ductal adenocarcinoma compared to controls; 2.6% (22/850) vs. 1.8% (18/976) (p=0.35). CEL-HYB carriers were not more likely to report a history of pancreatitis. Patients with pancreatic cancer are not more likely than controls to be carriers of the CEL-HYB allele.

  12. Global distribution of allele frequencies at the human dopamine D4 receptor locus

    SciTech Connect

    Chang, F.M.; Kidd, J.R.; Livak, K.J.

    1994-09-01

    The dopamine D4 receptor (DRD4) is a candidate gene for schizophrenia because the dopaminergic system has been implicated in this neuropsychiatric disorder. Several research groups have reported an association between allelic variants at DRD4 and schizophrenia, while others have been unable to replicate that finding. Knowledge of the appropriate gene frequencies in the underlying populations may resolve these inconsistencies. We have determined the frequencies of 8 different alleles of the 48 bp imperfect tandem repeat of exon 3 at the DRD4 locus in samples from 33 populations around the world. The frequencies vary considerably in the different populations with the most common allele ranging from 16% to 95%. Frequencies and Fst values will be presented for the 3 most common alleles (4-, 7-, and 2- repeat) by continental groupings, but the individual populations vary significantly around the averages. The populations averaged 4.3 alleles (range 2 to 7).

  13. Inter-allelic interactions play a major role in microsatellite evolution

    PubMed Central

    Amos, William; Kosanović, Danica; Eriksson, Anders

    2015-01-01

    Microsatellite mutations identified in pedigrees confirm that most changes involve the gain or loss of single repeats. However, an unexpected pattern is revealed when the resulting data are plotted on standardized scales that range from the shortest to longest allele at a locus. Both mutation rate and mutation bias reveal a strong dependency on allele length relative to other alleles at the same locus. We show that models in which alleles mutate independently cannot explain these patterns. Instead, both mutation probability and direction appear to involve interactions between homologues in heterozygous individuals. Simple models in which the longer homologue in heterozygotes is more likely to mutate and/or biased towards contraction readily capture the observed trends. The exact model remains unclear in all its details but inter-allelic interactions are a vital component, implying a link between demographic history and the mode and tempo of microsatellite evolution. PMID:26511050

  14. Dombrock genotyping in Brazilian blood donors reveals different regional frequencies of the HY allele

    PubMed Central

    Piassi, Fabiana Chagas Camargos; Santos, Silvana Maria Eloi; de Castilho, Lilian Maria; Baleotti Júnior, Wilson; Suzuki, Rodrigo Buzinaro; da Cunha, Débora Moura

    2013-01-01

    Background Dombrock blood group system genotyping has revealed various rearrangements of the Dombrock gene and identified new variant alleles in Brazil (i.e., DO*A-SH, DO*A-WL and DO*B-WL). Because of the high heterogeneity of the Brazilian population, interregional differences are expected during the investigation of Dombrock genotypes. Objective The present study aims to determine the frequencies of Dombrock genotypes in blood donors from Minas Gerais and compare the frequencies of the HY and JO alleles to those of another population in Brazil. Methods The frequencies of the DO alleles in Minas Gerais, a southeastern state of Brazil, were determined from the genotyping of 270 blood donors. Genotyping involved polymerase chain reaction and restriction fragment length polymorphism analysis to identify the 323G>T, 350C>T, 793A>G, and 898C>G mutations, which are related to the HY, JO, DO*A/DO*B, and DO*A-WL/DO*B-WL alleles, respectively. Moreover, the frequencies of rare HY and JO alleles were statistically compared using the chi-square test with data from another Brazilian region. Results The HY allele frequency in Minas Gerais (2.4%) was almost twice that of the JO allele (1.5%). The frequency of the HY allele was significantly higher (p-value = 0.001) than that in another Brazilian population and includes a rare homozygous donor with the Hy- phenotype. In addition, the DO*A-WL and DO*B-WL alleles, which were first identified in Brazil, were found in the state of Minas Gerais. Conclusions The data confirm that the frequencies of DO alleles differ between regions in Brazil. The population of Minas Gerais could be targeted in a screening strategy to identify the Hy- phenotype in order to develop a rare blood bank. PMID:24478605

  15. Frequency of HLA-A alleles in the Syrian population genotyped by sequence-based typing.

    PubMed

    Madania, A; Ghoury, I; Al-Ashkar, W; Nweder, S; Zarzour, H

    2014-10-01

    HLA-A molecules are highly polymorphic. Their accurate typing at a high-resolution level is crucial for successful organ, bone marrow and cord blood transplantation. Furthermore, several HLA alleles have been involved in susceptibility to autoimmune diseases, allergies, cancers and inflammations. In order to determine common HLA-A alleles in Syria and their frequencies, sequence-based typing (SBT) was used to genotype HLA-A alleles at high resolution (four digit level) among one hundred and thirty randomly selected Syrian individuals. Exons 2, 3 and 4 of the HLA-A gene were amplified by PCR and sequenced. The sbt-engine software was used for allele assignment. Ambiguities were solved using group-specific sequencing primers (GSSPs). We could identify 32 different HLA-A alleles which were divided into 3 groups: high frequency (approximately 10%, A*01:01; A*24:02; A*03:01; A*02:01), moderate frequency (approximately 3%, such as A*02:05, A*31:01 and A*33:01), and low frequency (approximately 1%, such as A*02:11, A*29:01, A*02:02 and A*36:01). Homozygosity rate was higher than expected (11.5% vs. 7.15%). For high frequency alleles, our results show similarity to neighbouring countries. However, 15 alleles (such as A*02:04, A*02:06, A*02:11 and A*02:17) found in our cohort in low frequencies were never reported in some or all neighbouring countries. This is the first report on HLA-A allele frequencies in Syria. In spite of the relatively low number of tested subjects, our results revealed a high degree of diversity, with 32 different alleles, reflecting the high ethnic heterogeneity of the Syrian population. The identification of alleles rarely or never reported in neighbouring countries indicates a higher genetic diversity in Syria.

  16. Chromosome-wide analysis of parental allele-specific chromatin and DNA methylation.

    PubMed

    Singh, Purnima; Wu, Xiwei; Lee, Dong-Hoon; Li, Arthur X; Rauch, Tibor A; Pfeifer, Gerd P; Mann, Jeffrey R; Szabó, Piroska E

    2011-04-01

    To reveal the extent of domain-wide epigenetic features at imprinted gene clusters, we performed a high-resolution allele-specific chromatin analysis of over 100 megabases along the maternally or paternally duplicated distal chromosome 7 (Chr7) and Chr15 in mouse embryo fibroblasts (MEFs). We found that reciprocal allele-specific features are limited to imprinted genes and their differentially methylated regions (DMRs), whereas broad local enrichment of H3K27me3 (BLOC) is a domain-wide feature at imprinted clusters. We uncovered novel allele-specific features of BLOCs. A maternally biased BLOC was found along the H19-Igf2 domain. A paternal allele-specific gap was found along Kcnq1ot1, interrupting a biallelic BLOC in the Kcnq1-Cdkn1c domain. We report novel allele-specific chromatin marks at the Peg13 and Slc38a4 DMRs, Cdkn1c upstream region, and Inpp5f_v2 DMR and paternal allele-specific CTCF binding at the Peg13 DMR. Additionally, we derived an imprinted gene predictor algorithm based on our allele-specific chromatin mapping data. The binary predictor H3K9ac and CTCF or H3K4me3 in one allele and H3K9me3 in the reciprocal allele, using a sliding-window approach, recognized with precision the parental allele specificity of known imprinted genes, H19, Igf2, Igf2as, Cdkn1c, Kcnq1ot1, and Inpp5f_v2 on Chr7 and Peg13 and Slc38a4 on Chr15. Chromatin features, therefore, can unequivocally identify genes with imprinted expression.

  17. A hypomorphic allele of Tsc2 highlights the role of TSC1/TSC2 in signaling to AKT and models mild human TSC2 alleles.

    PubMed

    Pollizzi, Kristen; Malinowska-Kolodziej, Izabela; Doughty, Cheryl; Betz, Charles; Ma, Jian; Goto, June; Kwiatkowski, David J

    2009-07-01

    Tuberous sclerosis complex (TSC) is a tumor suppressor gene syndrome in which hamartomas develop in multiple organ systems. Knockout and conditional alleles of Tsc1 and Tsc2 have been previously reported. Here, we describe the generation of a novel hypomorphic allele of Tsc2 (del3), in which exon 3, encoding 37 amino acids near the N terminus of tuberin, is deleted. Embryos homozygous for the del3 allele survive until E13.5, 2 days longer than Tsc2 null embryos. Embryos die from underdevelopment of the liver, deficient hematopoiesis, aberrant vascular development and hemorrhage. Mice that are heterozygous for the del3 allele have a markedly reduced kidney tumor burden in comparison with conventional Tsc2(+/-) mice. Murine embryo fibroblast (MEF) cultures that are homozygous for the del3 allele express mutant tuberin at low levels, and show enhanced activation of mTORC1, similar to Tsc2 null MEFs. Furthermore, the mutant cells show prominent reduction in the activation of AKT. Similar findings were made in the analysis of homozygous del3 embryo lysates. Tsc2-del3 demonstrates GTPase activating protein activity comparable to that of wild-type Tsc2 in a functional assay. These findings indicate that the del3 allele is a hypomorphic allele of Tsc2 with partial function due to reduced expression, and highlight the consistency of AKT downregulation when Tsc1/Tsc2 function is reduced. Tsc2-del3 mice also serve as a model for hypomorphic TSC2 missense mutations reported in TSC patients.

  18. Demographic history and rare allele sharing among human populations.

    PubMed

    Gravel, Simon; Henn, Brenna M; Gutenkunst, Ryan N; Indap, Amit R; Marth, Gabor T; Clark, Andrew G; Yu, Fuli; Gibbs, Richard A; Bustamante, Carlos D

    2011-07-19

    High-throughput sequencing technology enables population-level surveys of human genomic variation. Here, we examine the joint allele frequency distributions across continental human populations and present an approach for combining complementary aspects of whole-genome, low-coverage data and targeted high-coverage data. We apply this approach to data generated by the pilot phase of the Thousand Genomes Project, including whole-genome 2-4× coverage data for 179 samples from HapMap European, Asian, and African panels as well as high-coverage target sequencing of the exons of 800 genes from 697 individuals in seven populations. We use the site frequency spectra obtained from these data to infer demographic parameters for an Out-of-Africa model for populations of African, European, and Asian descent and to predict, by a jackknife-based approach, the amount of genetic diversity that will be discovered as sample sizes are increased. We predict that the number of discovered nonsynonymous coding variants will reach 100,000 in each population after ∼1,000 sequenced chromosomes per population, whereas ∼2,500 chromosomes will be needed for the same number of synonymous variants. Beyond this point, the number of segregating sites in the European and Asian panel populations is expected to overcome that of the African panel because of faster recent population growth. Overall, we find that the majority of human genomic variable sites are rare and exhibit little sharing among diverged populations. Our results emphasize that replication of disease association for specific rare genetic variants across diverged populations must overcome both reduced statistical power because of rarity and higher population divergence.

  19. Demographic history and rare allele sharing among human populations

    PubMed Central

    Gravel, Simon; Henn, Brenna M.; Gutenkunst, Ryan N.; Indap, Amit R.; Marth, Gabor T.; Clark, Andrew G.; Yu, Fuli; Gibbs, Richard A.; Bustamante, Carlos D.; Altshuler, David L.; Durbin, Richard M.; Abecasis, Gonçalo R.; Bentley, David R.; Chakravarti, Aravinda; Clark, Andrew G.; Collins, Francis S.; De La Vega, Francisco M.; Donnelly, Peter; Egholm, Michael; Flicek, Paul; Gabriel, Stacey B.; Gibbs, Richard A.; Knoppers, Bartha M.; Lander, Eric S.; Lehrach, Hans; Mardis, Elaine R.; McVean, Gil A.; Nickerson, Debbie A.; Peltonen, Leena; Schafer, Alan J.; Sherry, Stephen T.; Wang, Jun; Wilson, Richard K.; Gibbs, Richard A.; Deiros, David; Metzker, Mike; Muzny, Donna; Reid, Jeff; Wheeler, David; Wang, Jun; Li, Jingxiang; Jian, Min; Li, Guoqing; Li, Ruiqiang; Liang, Huiqing; Tian, Geng; Wang, Bo; Wang, Jian; Wang, Wei; Yang, Huanming; Zhang, Xiuqing; Zheng, Huisong; Lander, Eric S.; Altshuler, David L.; Ambrogio, Lauren; Bloom, Toby; Cibulskis, Kristian; Fennell, Tim J.; Gabriel, Stacey B.; Jaffe, David B.; Shefler, Erica; Sougnez, Carrie L.; Bentley, David R.; Gormley, Niall; Humphray, Sean; Kingsbury, Zoya; Koko-Gonzales, Paula; Stone, Jennifer; McKernan, Kevin J.; Costa, Gina L.; Ichikawa, Jeffry K.; Lee, Clarence C.; Sudbrak, Ralf; Lehrach, Hans; Borodina, Tatiana A.; Dahl, Andreas; Davydov, Alexey N.; Marquardt, Peter; Mertes, Florian; Nietfeld, Wilfiried; Rosenstiel, Philip; Schreiber, Stefan; Soldatov, Aleksey V.; Timmermann, Bernd; Tolzmann, Marius; Egholm, Michael; Affourtit, Jason; Ashworth, Dana; Attiya, Said; Bachorski, Melissa; Buglione, Eli; Burke, Adam; Caprio, Amanda; Celone, Christopher; Clark, Shauna; Conners, David; Desany, Brian; Gu, Lisa; Guccione, Lorri; Kao, Kalvin; Kebbel, Andrew; Knowlton, Jennifer; Labrecque, Matthew; McDade, Louise; Mealmaker, Craig; Minderman, Melissa; Nawrocki, Anne; Niazi, Faheem; Pareja, Kristen; Ramenani, Ravi; Riches, David; Song, Wanmin; Turcotte, Cynthia; Wang, Shally; Mardis, Elaine R.; Wilson, Richard K.; Dooling, David; Fulton, Lucinda; Fulton, Robert; Weinstock, George; Durbin, Richard M.; Burton, John; Carter, David M.; Churcher, Carol; Coffey, Alison; Cox, Anthony; Palotie, Aarno; Quail, Michael; Skelly, Tom; Stalker, James; Swerdlow, Harold P.; Turner, Daniel; De Witte, Anniek; Giles, Shane; Gibbs, Richard A.; Wheeler, David; Bainbridge, Matthew; Challis, Danny; Sabo, Aniko; Yu, Fuli; Yu, Jin; Wang, Jun; Fang, Xiaodong; Guo, Xiaosen; Li, Ruiqiang; Li, Yingrui; Luo, Ruibang; Tai, Shuaishuai; Wu, Honglong; Zheng, Hancheng; Zheng, Xiaole; Zhou, Yan; Li, Guoqing; Wang, Jian; Yang, Huanming; Marth, Gabor T.; Garrison, Erik P.; Huang, Weichun; Indap, Amit; Kural, Deniz; Lee, Wan-Ping; Leong, Wen Fung; Quinlan, Aaron R.; Stewart, Chip; Stromberg, Michael P.; Ward, Alistair N.; Wu, Jiantao; Lee, Charles; Mills, Ryan E.; Shi, Xinghua; Daly, Mark J.; DePristo, Mark A.; Altshuler, David L.; Ball, Aaron D.; Banks, Eric; Bloom, Toby; Browning, Brian L.; Cibulskis, Kristian; Fennell, Tim J.; Garimella, Kiran V.; Grossman, Sharon R.; Handsaker, Robert E.; Hanna, Matt; Hartl, Chris; Jaffe, David B.; Kernytsky, Andrew M.; Korn, Joshua M.; Li, Heng; Maguire, Jared R.; McCarroll, Steven A.; McKenna, Aaron; Nemesh, James C.; Philippakis, Anthony A.; Poplin, Ryan E.; Price, Alkes; Rivas, Manuel A.; Sabeti, Pardis C.; Schaffner, Stephen F.; Shefler, Erica; Shlyakhter, Ilya A.; Cooper, David N.; Ball, Edward V.; Mort, Matthew; Phillips, Andrew D.; Stenson, Peter D.; Sebat, Jonathan; Makarov, Vladimir; Ye, Kenny; Yoon, Seungtai C.; Bustamante, Carlos D.; Clark, Andrew G.; Boyko, Adam; Degenhardt, Jeremiah; Gravel, Simon; Gutenkunst, Ryan N.; Kaganovich, Mark; Keinan, Alon; Lacroute, Phil; Ma, Xin; Reynolds, Andy; Clarke, Laura; Flicek, Paul; Cunningham, Fiona; Herrero, Javier; Keenen, Stephen; Kulesha, Eugene; Leinonen, Rasko; McLaren, William M.; Radhakrishnan, Rajesh; Smith, Richard E.; Zalunin, Vadim; Zheng-Bradley, Xiangqun; Korbel, Jan O.; Stütz, Adrian M.; Humphray, Sean; Bauer, Markus; Cheetham, R. Keira; Cox, Tony; Eberle, Michael; James, Terena; Kahn, Scott; Murray, Lisa; Chakravarti, Aravinda; Ye, Kai; De La Vega, Francisco M.; Fu, Yutao; Hyland, Fiona C. L.; Manning, Jonathan M.; McLaughlin, Stephen F.; Peckham, Heather E.; Sakarya, Onur; Sun, Yongming A.; Tsung, Eric F.; Batzer, Mark A.; Konkel, Miriam K.; Walker, Jerilyn A.; Sudbrak, Ralf; Albrecht, Marcus W.; Amstislavskiy, Vyacheslav S.; Herwig, Ralf; Parkhomchuk, Dimitri V.; Sherry, Stephen T.; Agarwala, Richa; Khouri, Hoda M.; Morgulis, Aleksandr O.; Paschall, Justin E.; Phan, Lon D.; Rotmistrovsky, Kirill E.; Sanders, Robert D.; Shumway, Martin F.; Xiao, Chunlin; McVean, Gil A.; Auton, Adam; Iqbal, Zamin; Lunter, Gerton; Marchini, Jonathan L.; Moutsianas, Loukas; Myers, Simon; Tumian, Afidalina; Desany, Brian; Knight, James; Winer, Roger; Craig, David W.; Beckstrom-Sternberg, Steve M.; Christoforides, Alexis; Kurdoglu, Ahmet A.; Pearson, John V.; Sinari, Shripad A.; Tembe, Waibhav D.; Haussler, David; Hinrichs, Angie S.; Katzman, Sol J.; Kern, Andrew; Kuhn, Robert M.; Przeworski, Molly; Hernandez, Ryan D.; Howie, Bryan; Kelley, Joanna L.; Melton, S. Cord; Abecasis, Gonçalo R.; Li, Yun; Anderson, Paul; Blackwell, Tom; Chen, Wei; Cookson, William O.; Ding, Jun; Kang, Hyun Min; Lathrop, Mark; Liang, Liming; Moffatt, Miriam F.; Scheet, Paul; Sidore, Carlo; Snyder, Matthew; Zhan, Xiaowei; Zöllner, Sebastian; Awadalla, Philip; Casals, Ferran; Idaghdour, Youssef; Keebler, John; Stone, Eric A.; Zilversmit, Martine; Jorde, Lynn; Xing, Jinchuan; Eichler, Evan E.; Aksay, Gozde; Alkan, Can; Hajirasouliha, Iman; Hormozdiari, Fereydoun; Kidd, Jeffrey M.; Sahinalp, S. Cenk; Sudmant, Peter H.; Mardis, Elaine R.; Chen, Ken; Chinwalla, Asif; Ding, Li; Koboldt, Daniel C.; McLellan, Mike D.; Dooling, David; Weinstock, George; Wallis, John W.; Wendl, Michael C.; Zhang, Qunyuan; Durbin, Richard M.; Albers, Cornelis A.; Ayub, Qasim; Balasubramaniam, Senduran; Barrett, Jeffrey C.; Carter, David M.; Chen, Yuan; Conrad, Donald F.; Danecek, Petr; Dermitzakis, Emmanouil T.; Hu, Min; Huang, Ni; Hurles, Matt E.; Jin, Hanjun; Jostins, Luke; Keane, Thomas M.; Le, Si Quang; Lindsay, Sarah; Long, Quan; MacArthur, Daniel G.; Montgomery, Stephen B.; Parts, Leopold; Stalker, James; Tyler-Smith, Chris; Walter, Klaudia; Zhang, Yujun; Gerstein, Mark B.; Snyder, Michael; Abyzov, Alexej; Balasubramanian, Suganthi; Bjornson, Robert; Du, Jiang; Grubert, Fabian; Habegger, Lukas; Haraksingh, Rajini; Jee, Justin; Khurana, Ekta; Lam, Hugo Y. K.; Leng, Jing; Mu, Xinmeng Jasmine; Urban, Alexander E.; Zhang, Zhengdong; Li, Yingrui; Luo, Ruibang; Marth, Gabor T.; Garrison, Erik P.; Kural, Deniz; Quinlan, Aaron R.; Stewart, Chip; Stromberg, Michael P.; Ward, Alistair N.; Wu, Jiantao; Lee, Charles; Mills, Ryan E.; Shi, Xinghua; McCarroll, Steven A.; Banks, Eric; DePristo, Mark A.; Handsaker, Robert E.; Hartl, Chris; Korn, Joshua M.; Li, Heng; Nemesh, James C.; Sebat, Jonathan; Makarov, Vladimir; Ye, Kenny; Yoon, Seungtai C.; Degenhardt, Jeremiah; Kaganovich, Mark; Clarke, Laura; Smith, Richard E.; Zheng-Bradley, Xiangqun; Korbel, Jan O.; Humphray, Sean; Cheetham, R. Keira; Eberle, Michael; Kahn, Scott; Murray, Lisa; Ye, Kai; De La Vega, Francisco M.; Fu, Yutao; Peckham, Heather E.; Sun, Yongming A.; Batzer, Mark A.; Konkel, Miriam K.; Walker, Jerilyn A.; Xiao, Chunlin; Iqbal, Zamin; Desany, Brian; Blackwell, Tom; Snyder, Matthew; Xing, Jinchuan; Eichler, Evan E.; Aksay, Gozde; Alkan, Can; Hajirasouliha, Iman; Hormozdiari, Fereydoun; Kidd, Jeffrey M.; Chen, Ken; Chinwalla, Asif; Ding, Li; McLellan, Mike D.; Wallis, John W.; Hurles, Matt E.; Conrad, Donald F.; Walter, Klaudia; Zhang, Yujun; Gerstein, Mark B.; Snyder, Michael; Abyzov, Alexej; Du, Jiang; Grubert, Fabian; Haraksingh, Rajini; Jee, Justin; Khurana, Ekta; Lam, Hugo Y. K.; Leng, Jing; Mu, Xinmeng Jasmine; Urban, Alexander E.; Zhang, Zhengdong; Gibbs, Richard A.; Bainbridge, Matthew; Challis, Danny; Coafra, Cristian; Dinh, Huyen; Kovar, Christie; Lee, Sandy; Muzny, Donna; Nazareth, Lynne; Reid, Jeff; Sabo, Aniko; Yu, Fuli; Yu, Jin; Marth, Gabor T.; Garrison, Erik P.; Indap, Amit; Leong, Wen Fung; Quinlan, Aaron R.; Stewart, Chip; Ward, Alistair N.; Wu, Jiantao; Cibulskis, Kristian; Fennell, Tim J.; Gabriel, Stacey B.; Garimella, Kiran V.; Hartl, Chris; Shefler, Erica; Sougnez, Carrie L.; Wilkinson, Jane; Clark, Andrew G.; Gravel, Simon; Grubert, Fabian; Clarke, Laura; Flicek, Paul; Smith, Richard E.; Zheng-Bradley, Xiangqun; Sherry, Stephen T.; Khouri, Hoda M.; Paschall, Justin E.; Shumway, Martin F.; Xiao, Chunlin; McVean, Gil A.; Katzman, Sol J.; Abecasis, Gonçalo R.; Blackwell, Tom; Mardis, Elaine R.; Dooling, David; Fulton, Lucinda; Fulton, Robert; Koboldt, Daniel C.; Durbin, Richard M.; Balasubramaniam, Senduran; Coffey, Allison; Keane, Thomas M.; MacArthur, Daniel G.; Palotie, Aarno; Scott, Carol; Stalker, James; Tyler-Smith, Chris; Gerstein, Mark B.; Balasubramanian, Suganthi; Chakravarti, Aravinda; Knoppers, Bartha M.; Abecasis, Gonçalo R.; Bustamante, Carlos D.; Gharani, Neda; Gibbs, Richard A.; Jorde, Lynn; Kaye, Jane S.; Kent, Alastair; Li, Taosha; McGuire, Amy L.; McVean, Gil A.; Ossorio, Pilar N.; Rotimi, Charles N.; Su, Yeyang; Toji, Lorraine H.; TylerSmith, Chris; Brooks, Lisa D.; Felsenfeld, Adam L.; McEwen, Jean E.; Abdallah, Assya; Juenger, Christopher R.; Clemm, Nicholas C.; Collins, Francis S.; Duncanson, Audrey; Green, Eric D.; Guyer, Mark S.; Peterson, Jane L.; Schafer, Alan J.; Abecasis, Gonçalo R.; Altshuler, David L.; Auton, Adam; Brooks, Lisa D.; Durbin, Richard M.; Gibbs, Richard A.; Hurles, Matt E.; McVean, Gil A.

    2011-01-01

    High-throughput sequencing technology enables population-level surveys of human genomic variation. Here, we examine the joint allele frequency distributions across continental human populations and present an approach for combining complementary aspects of whole-genome, low-coverage data and targeted high-coverage data. We apply this approach to data generated by the pilot phase of the Thousand Genomes Project, including whole-genome 2–4× coverage data for 179 samples from HapMap European, Asian, and African panels as well as high-coverage target sequencing of the exons of 800 genes from 697 individuals in seven populations. We use the site frequency spectra obtained from these data to infer demographic parameters for an Out-of-Africa model for populations of African, European, and Asian descent and to predict, by a jackknife-based approach, the amount of genetic diversity that will be discovered as sample sizes are increased. We predict that the number of discovered nonsynonymous coding variants will reach 100,000 in each population after ∼1,000 sequenced chromosomes per population, whereas ∼2,500 chromosomes will be needed for the same number of synonymous variants. Beyond this point, the number of segregating sites in the European and Asian panel populations is expected to overcome that of the African panel because of faster recent population growth. Overall, we find that the majority of human genomic variable sites are rare and exhibit little sharing among diverged populations. Our results emphasize that replication of disease association for specific rare genetic variants across diverged populations must overcome both reduced statistical power because of rarity and higher population divergence. PMID:21730125

  20. Upper bounds on FST in terms of the frequency of the most frequent allele and total homozygosity: the case of a specified number of alleles.

    PubMed

    Edge, Michael D; Rosenberg, Noah A

    2014-11-01

    FST is one of the most frequently-used indices of genetic differentiation among groups. Though FST takes values between 0 and 1, authors going back to Wright have noted that under many circumstances, FST is constrained to be less than 1. Recently, we showed that at a genetic locus with an unspecified number of alleles, FST for two subpopulations is strictly bounded from above by functions of both the frequency of the most frequent allele (M) and the homozygosity of the total population (HT). In the two-subpopulation case, FST can equal one only when the frequency of the most frequent allele and the total homozygosity are 1/2. Here, we extend this work by deriving strict bounds on FST for two subpopulations when the number of alleles at the locus is specified to be I. We show that restricting to I alleles produces the same upper bound on FST over much of the allowable domain for M and HT, and we derive more restrictive bounds in the windows M∈[1/I,1/(I-1)) and HT∈[1/I,I/(I(2)-1)). These results extend our understanding of the behavior of FST in relation to other population-genetic statistics.

  1. Carriage of One or Two FMR1 Premutation Alleles Seems to Have No Effect on Illness Severity in a FXTAS Female with an Autozygous FMR1 Premutation Allele.

    PubMed

    Rodriguez-Revenga, Laia; Pagonabarraga, Javier; Gómez-Anson, Beatriz; López-Mourelo, Olga; Izquierdo, Silvia; Alvarez-Mora, Maria Isabel; Granell, Esther; Madrigal, Irene; Milà, Montserrat

    2016-10-01

    Fragile X-associated tremor/ataxia syndrome (FXTAS) is a late-onset neurodegenerative disorder that occurs in FMR1 premutation carriers. The prevalence of FMR1 p