Repeat Alleles Research Articles

The Similarity Measurement of Human DNA Profile Using Fuzzy Similarity

This research investigated the similarity of human DNA profile using fuzzy similarity measure. The similarity measurement of DNA profile had been done by measuring the similarity between query’s DNA profile and its biological family such as father, mother, brother, sister, grandmother and grandfather. The similarity measurement had been done to the short tandem repeat (STR) alleles in sixteen loci. The result of the experiment showed that each simulation gave matching result. This research is useful for Indonesian National Police (POLRI) in identifying process of disaster victim, terrorism victim and other criminal conduct.

The gray matter volume of the temporoparietal junction varies across cultures: a moderating role of the dopamine D4 receptor gene (DRD4).

Prior work shows that compared to European Americans, East Asians show an enhanced propensity to take the perspective of another person. In the current work, we tested whether this cultural difference might be reflected in the gray matter (GM) volume of the temporoparietal junction (TPJ), a brain region selectively implicated in perspective taking and mentalizing. We also explored whether the cultural difference in the TPJ GM volume might be moderated by dopamine D4 receptor gene (DRD4) exon 3 variable-number tandem repeat polymorphism. Structural magnetic resonance imaging of 66 European Americans and 66 East Asian-born Asians were subjected to voxel-based morphometry. It was observed that the GM volume of the right TPJ was greater among East Asians than among European Americans. Moreover, this cultural difference was significantly more pronounced among carriers of the 7- or 2-repeat allele of DRD4 than among the non-carriers of these alleles. Our findings contribute to the growing evidence that culture can shape the brain.

The SLC6A3 gene polymorphism is related to the development of attentional functions but not to ADHD

Neuropharmacological and human clinical studies have suggested that the brain dopaminergic system is substantively involved in normal and pathological phenotypes of attention. Dopamine transporter gene (SLC6A3) was proposed as a candidate gene for Attention-Deficit/Hyperactivity Disorder (ADHD). We investigated the effect of the SLC6A3 variants on cognitive performance in ADHD and healthy children and teenagers. Participants completed cognitive tasks measuring attentional switching, selective and sustained attention, and effectiveness of alerting, orienting and executive attention. We estimated the effects of 40 bp variable number of tandem repeat (VNTR) polymorphism located in the 3′ untranslated region (3′ UTR) (9-repeat vs 10-repeat allele) of the SLC6A3 gene, ADHD diagnosis, age, and their interactions as predictors of cognitive performance. ADHD children demonstrated deficits in most of the examined attention processes, persistent within the examined age range (9–16 years). No significant effects were observed for the interaction of ADHD and the SLC6A3 polymorphism, but the results revealed a significant main effect of SLC6A3 genotype in the entire research sample. Subjects carrying 9R allele performed the switching task significantly worse in comparison to children with 10R/10R or 10R/11R genotype. SLC6A3 polymorphism moderated age-related improvements in orienting and attentional switching. Results suggest that SLC6A3 genotype influence these attentional/cognitive functions which deficits are not the key symptoms in ADHD.

Parental repeat length instability in myotonic dystrophy type 1 pre- and protomutations.

Myotonic dystrophy type 1 (DM1) is caused by a CTG trinucleotide repeat expansion on chromosome 19q13.3. While DM1 premutation (36-50 repeats) and protomutation (51-80 repeats) allele carriers are mostly asymptomatic, offspring is at risk of inheriting expanded, symptom-associated, (CTG)n repeats of n > 80. In this study we aimed to evaluate the intergenerational instability of DM1 pre- and protomutation alleles, focussing on the influence of parental gender. One hundred and forty-six parent-child pairs (34 parental premutations, 112 protomutations) were retrospectively selected from the DM1 patient cohort of the Maastricht University Medical Center+. CTG repeat size of parents and children was determined by (triplet-primed) PCR followed by fragment length analysis and Southern blot analysis. Fifty-eight out of eighty-one (71.6%) paternal transmissions led to a (CTG)n repeat of n > 80 in offspring, compared with 15 out of 65 (23.1%) maternal transmissions (p < 0.001). Repeat length instability occurred for paternal (CTG)n repeats of n ≥ 45, while maternal instability did not occur until (CTG)n repeats reached a length of n ≥ 71. Transmission of premutations caused (CTG)n repeats of n > 80 in offspring only when paternally transmitted (two cases), while protomutations caused (CTG)n repeats of n > 80 in offspring in 71 cases, of which 56 (78.9%) were paternally transmitted. In conclusion, our data show that paternally transmitted pre- and protomutations were more unstable than maternally transmitted pre- and protomutations. For genetic counseling, this implies that males with a small DMPK mutation have a higher risk of symptomatic offspring compared with females. Consequently, we suggest addressing sex-dependent factors in genetic counseling of small-sized CTG repeat carriers.

Chinese women with 29–30 FMR1 CGG repeats have an earlier menopause

Purpose: A strong, well-established non-linear relationship exists between fragile X mental retardation (FMR1) premutation and menopausal age. The aim of this study is to evaluate whether this relationship continues into the normal CGG repeat range.Methods: FMR1 CGG repeats of 111 Chinese postmenopausal women from a prospective cohort and the relationship with age at menopause were analyzed. Associations of FMR1 genotypes with annually measured estradiol and follicle stimulating hormone (FSH) levels were also assessed.Results: One premutation and two intermediate carriers were identified, with a prevalence of 0.90% and 1.80%, respectively. The age at menopause differed with statistical significance (p = 0.007) between women carrying bi-allelic 29–30 repeats (49.66 ± 3.26 years) and those carrying a different number of repeats (51.26 ± 2.74 years). Age at menopause among subgroups (≤28, 29–30, and ≥31 repeats) of alleles 1 and 2 were also different (p = 0.014, p = 0.044). FSH trajectories to final menstrual period differed between women with the bi-allelic 29–30 repeats and others (p = 0.019).Conclusions: Women with 29–30 FMR1 CGG repeats may experience menopause approximately 2 years earlier than those carrying ≤28 or ≥31 CGG repeats, and have a longer FSH fluctuant period.

Dopamine-Related Genes Moderate the Association Between Family Environment and Executive Function Following Pediatric Traumatic Brain Injury: An Exploratory Study.

This study examined whether carrying dopamine-related "risk" genes-either the dopamine transporter (DAT1) 10-repeat allele or dopamine receptor-4 (DRD4) 7-repeat allele-moderated the association of family environment and executive function (EF) following traumatic brain injury (TBI) in early childhood. Caregivers of children with TBI or orthopedic injury (OI) completed the Behavior Rating Inventory of Executive Function (BRIEF) at postinjury visits. General linear models examined gene by environment interactions as moderators of the effects of TBI on EF at 12 months and 7 years postinjury. At 12 months, we did not find any significant gene by environment interactions. At 7 years, we found a significant 3-way interaction among combined carrier status, level of permissive parenting, and injury type. For children exposed to more optimal parenting, carriers of DAT1 and/or DRD4 risk alleles with TBI showed significantly worse parent-reported EF than carriers with OI. In those with less optimal parenting, carriers and noncarriers with TBI, as well as carriers with OI, showed significantly worse parent-reported EF than noncarriers with OI, with medium to large effect sizes. The findings highlight the importance of considering polygenetic and environmental factors in future studies of recovery following TBI and other injuries in childhood.

Combining feature selection and shape analysis uncovers precise rules for miRNA regulation in Huntington\u2019s disease mice

BackgroundMicroRNA (miRNA) regulation is associated with several diseases, including neurodegenerative diseases. Several approaches can be used for modeling miRNA regulation. However, their precision may be limited for analyzing multidimensional data. Here, we addressed this question by integrating shape analysis and feature selection into miRAMINT, a methodology that we used for analyzing multidimensional RNA-seq and proteomic data from a knock-in mouse model (Hdh mice) of Huntington’s disease (HD), a disease caused by CAG repeat expansion in huntingtin (htt). This dataset covers 6 CAG repeat alleles and 3 age points in the striatum and cortex of Hdh mice.ResultsRemarkably, compared to previous analyzes of this multidimensional dataset, the miRAMINT approach retained only 31 explanatory striatal miRNA-mRNA pairs that are precisely associated with the shape of CAG repeat dependence over time, among which 5 pairs with a strong change of target expression levels. Several of these pairs were previously associated with neuronal homeostasis or HD pathogenesis, or both. Such miRNA-mRNA pairs were not detected in cortex.ConclusionsThese data suggest that miRNA regulation has a limited global role in HD while providing accurately-selected miRNA-target pairs to study how the brain may compute molecular responses to HD over time. These data also provide a methodological framework for researchers to explore how shape analysis can enhance multidimensional data analytics in biology and disease.

Current Understanding of Host Genetics of Otitis Media.

The pathogenesis of otitis media (OM), an inflammatory disease of the middle ear (ME), involves interplay between many different factors, including the pathogenicity of infectious pathogens, host immunological status, environmental factors, and genetic predisposition, which is known to be a key determinant of OM susceptibility. Animal models and human genetics studies have identified many genes and gene variants associated with OM susceptibility: genes that encode components of multiple signaling pathways involved in host immunity and inflammatory responses of the ME mucosa; genes involved in cellular function, such as mucociliary transport, mucin production, and mucous cell metaplasia; and genes that are essential for Eustachian tube (ET) development, ME cavitation, and homeostasis. Since our last review, several new mouse models with mutations in genes such as CCL3, IL-17A, and Nisch have been reported. Moreover, genetic variants and polymorphisms in several genes, including FNDC1, FUT2, A2ML1, TGIF1, CD44, and IL1-RA variable number tandem repeat (VNTR) allele 2, have been identified as being significantly associated with OM. In this review, we focus on the current understanding of the role of host genetics in OM, including recent discoveries and future research prospects. Further studies on the genes identified thus far and the discovery of new genes using advanced technologies such as gene editing, next generation sequencing, and genome-wide association studies, will advance our understanding of the molecular mechanism underlying the pathogenesis of OM and provide new avenues for early screening and developing effective preventative and therapeutic strategies to treat OM.

The Association of IL-1 and HRAS Gene Polymorphisms with Breast Cancer Susceptibility in a Jordanian Population of Arab Descent: A Genotype-Phenotype Study.

Breast cancer (BC) pathogenesis is poorly understood and not yet completely determined. BC susceptibility genes are responsible for 20% to 25% of breast cancer risk. The main objective of this study is to identify the genetic polymorphisms within the Harvey rat sarcoma viral oncogene homolog (HRAS1) and interleukin-1 receptor antagonist (IL1-Ra) genes in Jordanian BC female patients and to investigate the genetic association of these polymorphisms with BC. Samples were collected from 150 Jordanian BC patients and 187 healthy age-matched controls. PCR and PCR-RFLP techniques were used to identify genetic polymorphisms within these candidate genes. The single nucleotide polymorphism single nucleotide polymorphism (SNP) association web tool SNPStats (v. 3.6) was used to investigate the allelic and genotypic association with BC. Different statistical analyses were used to study the correlation between the investigated genetic variants and several prognosis factors of BC. A genetic association between BC susceptibility and Il-1β rs1143634 was found specifically at the allelic level of E1 as a risk allele (72% in the cases vs. 64.2% in the controls). Another genetic association was found in the IL-Ra gene (86-VNTR (variable number tandem repeat)), which presented one repeat allele (24.1% in cases vs. 15.59% in controls) and could be considered as a risk allele in Jordanian women. In contrast, this study found that there is no genetic association between Il-1β SNP rs16944 and BC. In addition, a significant association was found between the allelic level of the HRAS1 gene and BC susceptibility. Since this study is the first to be conducted on the genetic susceptibility of these genes to BC in the Jordanian population, more investigations on the link between BC and these variants are recommended to determine the impact of these polymorphisms on other ethnic groups.

Frequency and distribution of polyQ disease intermediate-length repeat alleles in healthy Italian population

Huntington disease (HD) and spinocerebellar ataxia type 1-2-17 (SCA1-2-17) are adult-onset autosomal dominant diseases, caused by triplet repeat expansions in the HTT, ATXN1, ATXN2, and TBP genes. Alleles with a repeat number just below the pathological threshold are associated with reduced penetrance and meiotic instability and are defined as intermediate alleles (IAs). We aimed to determine the frequencies of IAs in healthy Italian subjects and to compare the proportion of the IAs with the prevalence of the respective diseases. We analyzed the triplet repeat size in HTT, ATXN1, ATXN2, and TBP genes in the DNA samples from 729 consecutive adult healthy Italian subjects. IAs associated with reduced penetrance were found in ATXN2 gene (1 subject, 0.1%) and TBP gene (0.82%). IAs at risk for meiotic instability were found in HTT (5.3%) and ATXN2 genes (2.7%). In ATXN1, we found a low percentage of IAs (0.4%). Alleles lacking the common CAT interruption within the CAG sequence were also rare (0.3%). The high frequencies of IAs in HTT and ATXN2 genes suggest a correlation with the prevalence of the diseases in our population and support the hypothesis that IAs could represent a reservoir of new pathological expansions. On the opposite, ATXN1-IA were very rare in respect to the prevalence of SCA1 in our country, and TBP- IA were more frequent than expected, suggesting that other mechanisms could influence the occurrence of novel pathological expansions.

MAOA-uVNTR polymorphism in male recidivist violent offenders in the Indian population.

An association of MAOA-uVNTR polymorphism with aggression and violence has been demonstrated in many studies; however, this association is inconclusive due to the allelic variation in different populations. Allelic variants and the frequency of this polymorphism among recidivist violent offenders could provide more information about this complex behaviour. Hence, the association between violence and the polymorphism of variable numbers of tandem repeats located upstream of the MAOA gene needs to be ruled out. Identified recidivist violent offenders by various laws of 'Offences against Human Body and Property' of the Indian Penal Code and natives of the southern state of India, Kerala, were the cases. Individuals without ahistory of any offences, from the same locality, were taken as controls. DNA extracted from the buccal epithelial cells from the subjects was genotyped using PCR methods for identifying MAOA-uVNTR polymorphism. In the subjects (n = 67), polymorphism in the promoter region of the MAOA gene, which comprises of 30bp repeats, 3.5 and 4.5 repeat alleles were observed statistically significantly (p = 0.015). Both 3.5 and 4.5 repeat alleles were present in the participants belonging to the control group. All the participants belonging to experiment group had 3.5 repeats only. This candidate gene-environment interaction (cGxE) may be one of the reasons for the development of psychopathology in violent offenders. This is the first study among offenders in this regard in India, and data generated will be asignificant contribution to the aetiology of various psychiatric disorders and population-specific genome database.

Determination of the Relationship Between Craving and 4-repeat Allele of DRD4 Gene Polymorphism in the Early Withdrawal Period of Alcohol Use Disorders.

Alcohol use disorder (AUD) is a disease with chronic relapses. Risk factors of craving, which is thought to be one of the predictors of relapse, have been studied for a long time. The DRD4 gene is located on chromosome 11p and has a 48-base pair variable number of tandem repeat (VNTR) polymorphisms in the 3rd exon. This study aimed to investigate if a relationship existed between craving and DRD4 VNTR polymorphism and to determine the predictors of craving. A total of 125 patients with AUD were included in the study. The sociodemographic data form, the Michigan Alcoholism Screening Test (MAST), the Obsessive Compulsive Drinking Scale (OCDS), and the Penn Alcohol Craving Scale (PACS) were applied to the patients. Polymerase chain reaction (PCR) was used to determine the DRD4 VNTR variant of all participants in the peripheral blood sample. In the 4R/4R homozygous group, it was found that the age at first alcohol use was higher and the scores of the OCDS on the seventh day were lower, but this relationship could not be demonstrated in further statistical analyses. In the stepwise linear regression model, the age at first alcohol use, MAST score, duration of AUD, and delirium tremens history were found to be the predictors of craving. DRD4 VNTR polymorphism does not play a role as a predictor of craving. A decrease in age at first alcohol use, an increase in the MAST score, and the presence of delirium tremens were found to be the predictors of craving among the participants of this study.

Critical assessment of bioinformatics methods for the characterization of pathological repeat expansions with single-molecule sequencing data.

A number of studies have reported the successful application of single-molecule sequencing technologies to the determination of the size and sequence of pathological expanded microsatellite repeats over the last 5years. However, different custom bioinformatics pipelines were employed in each study, preventing meaningful comparisons and somewhat limiting the reproducibility of the results. In this review, we provide a brief summary of state-of-the-art methods for the characterization of expanded repeats alleles, along with a detailed comparison of bioinformatics tools for the determination of repeat length and sequence, using both real and simulated data. Our reanalysis of publicly available human genome sequencing data suggests a modest, but statistically significant, increase of the error rate of single-molecule sequencing technologies at genomic regions containing short tandem repeats. However, we observe that all the methods herein tested, irrespective of the strategy used for the analysis of the data (either based on the alignment or assembly of the reads), show high levels of sensitivity in both the detection of expanded tandem repeats and the estimation of the expansion size, suggesting that approaches based on single-molecule sequencing technologies are highly effective for the detection and quantification of tandem repeat expansions and contractions.

Genotyping Two Promoter Polymorphisms in the MIF Gene: A -794 CATT5-8 Microsatellite Repeat and a -173 G/C SNP.

Macrophage migration inhibitory factor (MIF) is an upstream proinflammatory cytokine encoded by a functionally polymorphic locus. The promoter region of the human MIF gene contains two polymorphisms. A variable nucleotide tandem repeat at position -794 comprises five to eight CATT repeats (referred to henceforth by numbers from 5 to 8, rs5844572). Gene reporter assays show a proportional increase in transcription with CATT repeat number; the 5-repeat allele leads to low expression, and the 6-, 7-, and 8-repeat alleles lead to correspondingly higher expression of MIF. A second MIF promoter polymorphism comprises a G-to-C single nucleotide polymorphism (SNP) at position -173 (rs755622), which is in strong linkage disequilibrium with -794 7-CATT and is associated with arthritis clinical severity and higher serum and synovial fluid MIF levels. This allele also has been reported to confer improved survival in patients with outpatient pneumonia. In this chapter, we will introduce the methods of genotyping CATT5-8 repeats and the MIF -173 G/C from human samples.

Limits of using oligonucleotides for allele-selective inhibition at trinucleotide repeat sequences – targeting the CAG repeat within ataxin-1

Trinucleotide repeats are responsible for many genetic diseases. Previous studies have shown that duplex RNAs (dsRNAs) can be used to target expression of a mutant repeat allele while leaving expression of the wild-type allele untouched, creating opportunities for allele-selective inhibition and better therapeutic outcomes. In contrast to successes with other genes, we report here that we cannot achieve allele-selective inhibition when targeting the expanded CAG repeat within Ataxin-1 (ATXN1), the cause of spinal cerebellar ataxia-1 (SCA1). The most likely explanation for this unfavorable outcome is that the mean CAG repeat number within wild-type ATXN1 is relatively high compared to other trinucleotide repeat diseases. Because the wild-type repeat number is high, it is likely that there is poor discrimination between the mutant and wild-type repeat and less opportunity for allele-selective inhibition across the entire spectrum of mutations found in SCA1 patients. Our data support the conclusion that the potential for multiple cooperative binding interactions is a critical factor governing allele-selective recognition of trinucleotide repeat genes by duplex RNAs. These results should be helpful in predicting which diseases and which patients are most likely to benefit from allele-selective targeting of expanded repeats.

STRNaming: Standardised STR sequence allele naming to simplify MPS data analysis and interpretation

With the introduction of Massively Parallel Sequencing, the need for comprehensive nomenclature of sequenced Short Tandem Repeat alleles became apparent. We propose an independently functioning solution for standardised, automatic, human-readable, sequence-informative naming.

Fast Assays to Detect Interruptions in CTG.CAG Repeat Expansions.

Different interrupted repeat expansions have been found in several trinucleotide repeat (TNR) diseases such as fragile X syndrome (FXS), spinocerebellar ataxias (SCAs), and myotonic dystrophies (DMs). Their origins and roles remain poorly understood, especially in myotonic dystrophy type 1 (DM1). We present here the triplet repeat primed polymerase chain reaction (TP-PCR) and restriction enzyme-digested PCR to detect and identify interrupted triplet repeat alleles in DM1. TP-PCR consists of a PCR amplification using a fluoresceinated (FAM) primer flanking the repeat region and a primer pair in CTG.CAG repeats. A detailed analysis of interrupted triplet repeat tracts is essential to fully understand the role of interruptions in the pathogenesis and molecular mechanisms observed in TNR diseases.

Relationship between executive functions, body mass index and the DRD4 VNTR 7-repeat allele

Introduction and aim: Earlier results in the literature suggest that overweight subjects show weaker performance in executive function tasks as compared to normal weight people. Dopaminergic system is strongly linked to executive functions, body mass regulation and ingestion. The aim of the present study was to examine the possible relationship between DRD4 VNTR 7-repeat allele, body mass index and Stroop performance in a healthy adult population, and to draw psychogenetic conclusions. Method: 152 subjects without diabetic or psychiatric history participated in the study. Along with non-invasive DNA sampling, demographic, weight and height data were collected. The participants also solved the computerized Stroop task. 11 subjects belonged to the underweight (mean body mass index = 17.9 kg/m2), 98 subjects to the normal (mean body mass index = 21.8 kg/m2), and 43 subjects to the overweight (mean body mass index = 28.9 kg/m2) category. After grouping participants according to their body mass index and DRD4 VNTR genotype, we compared their mean performance to investigate the possible psychogenetic associations. Results: Body mass index and stimuli type showed significant interaction on error number (p = 0.045): subjects with normal body mass index made significantly less error as compared to under- and overweight subjects in incongruent trials. The 7-repeat allele carriers made tendentiously more errors than non-carriers. Normal weight people made less error - independently from their genotype -, while subjects with either low or high BMI carrying the 7-repeat allele made more errors compared to non-carriers. Conclusion: Under- and overweight subjects perform weaker where inhibition is necessary in the task. This may reflect their reactions to food-related situations. Orv Hetil. 2019; 160(39): 1554-1562.

The role of AGG interruptions in the FMR1 gene stability: A survey in ethnic groups with low and high rate of consanguinity.

BackgroundThe prevalence and the role of AGG interruptions within the FMR1 gene in the normal population is unknown. In this study, we investigated the frequent of AGG loss, in one or two alleles within the normal population. The role of AGG in the FMR1 stability has been assessed by correlating AGG loss to the prevalence of premutation/full mutation in two ethnic groups differing in their consanguinity rate: high versus low consanguinity rate (HCR vs. LCR).MethodsThe CGG repeat allele size and AGG presence were measured in 6,865 and 6,204 females belonging to the LCR (5%) and HCR (>45%) groups, respectively, by Tripled‐Primed‐PCR technique.ResultsA lower prevalence of the premutation was observed in the HCR (1:158) as compared to the LCR group (1:128). No full mutation was found in the HCR females while in the LCR group the prevalence found was 1:1,149. Homozygosity rate was higher in the HCR population compared to the LCR group.The overall AGG loss was higher in the HCR population than in the LCR and increased with increased CGG repeat number in both ethnic groups.ConclusionsAlthough we observed a significantly higher rate of homozygosity and AGG loss in the HCR group, this did not affect the prevalence of the premutation and full mutation in this population. Their prevalence was significantly lower than in the LCR population. Finally, we discuss whether the loss of AGG could be also a polymorphic event but not only a stabilizing factor.

Determination of association between the polymorphism in exon 3 of dopamine receptor gene type 4 with attention deficit-hyperactivity disorder

IntroductionEvidences suggest that attention deficit-hyperactivity disorder (ADHD) is a hereditary disorder and at least 20 potential genes associated with ADHD have been identified. Dopamine receptor gene type 4 (DRD4) has been more considered due to a stronger relationship with ADHD. However, no study has yet been conducted on the Iranian population to assess the association. ObjectiveIn this study, the association between polymorphism of DRD4 gene with ADHD has been studied among capital of Iran population. Materials and methodsThis study is a case-control study conducted on children aged 6–12 years with ADHD referred to child and adolescent psychiatric clinic Imam Hussein (AS) and normal subjects in 2011. Diagnosis was done based on the DSM-IV-TR criteria and interviewing by two child and adolescent psychiatrists. If parental were consent, then saliva samples of subjects were prepared and DRD4 gene and related allele were evaluated using PCR method. The K-SADS questionnaire was also used to assess comorbid disorders. ResultsIn this study, 114 patients in ADHD group and 109 patients in the control group were studied. The most frequency was obtained for allele 4 allele that has been observed in about 90% of both case and control groups. However, frequency of allele 6 in the case group was 8.8% where the frequency was 5% in the control group (p = 0.02). The presence of repeat of allele 6 increased chance of suffering from ADHD to 1.809 (95% equal to 3.871–0.845). ConclusionFor the first time this study showed that in Iranian population repeat of DRD4 gene allele 6 unlike the other geographic areas is relatively common and it will increase the chances of suffering from ADHD. However, additional studies are required.