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/lp/springer-journals/correlation-of-cag-repeat-length-between-the-maternal-and-paternal-XVR7zQXjuj
- Publisher
- Springer Journals
- Copyright
- Copyright © 2011 by Nopoulos et al; licensee BioMed Central Ltd.
- Subject
- Biomedicine; Neurosciences; Neurology; Behavioral Therapy; Psychiatry
- eISSN
- 1744-9081
- DOI
- 10.1186/1744-9081-7-45
- pmid
- 22008211
- Publisher site
- See Article on Publisher Site
Abstract
Triplet repeats contribute to normal variation in behavioral traits and when expanded, cause brain disorders. While Huntington’s Disease is known to be caused by a CAG triplet repeat in the gene Huntingtin, the effect of CAG repeats on brain function below disease threshold has not been studied. The current study shows a significant correlation between the CAG repeat length of the maternal and paternal allele in the Huntingtin gene among healthy subjects, suggesting assortative mating. correlations for characteristics such as intelligence [10,11], Introduction Huntington’s Disease (HD) is a neurodegenerative disorder body size [12-15] education [16], personality characteris- caused by a triplet repeat expansion of the gene Huntingtin tics [17-19] and mental disorders [20,21]. A recent review (HTT, OMIM 613004). Triplet repeats are an example of outlined a number of human behaviors that are associated simple sequence repeats (SSRs) which are scattered with SSRs including anxiety related traits, novelty seeking throughout the genome and can increase or decrease in behavior, cognitive function, and altruism [3]. Therefore, length between generations. Triplet repeats can be referred behaviors modified by SSRs may undergo assortative mat- to as ‘dynamic mutations’ andtheymakeupalarge class of ing, as shown for the allelic variation of the dopamine genomic variants that contribute to a wide variety of disor- receptor D4 (DRD4) gene, an SSR associated with novelty ders, mostly affecting the brain [1]. More importantly, seeking behavior [22]. there is increasing evidence that dynamic mutations serve A better understanding of the function of HTT below important functions (namely regulation of gene expression) disease threshold may be important for understanding and may play a substantial role in modulating brain devel- the disease process of HD. For instance, if there is pheno- opment and brain function [1-9]. For instance, SSRs are typic variation in brain structure or function associated particularly abundant in genes involved in brain develop- with HTT CAG length below disease threshold, it may ment and have been shown to contribute to normal varia- help to define a possible spectrum of phenotype ranging tion in behavioral traits in animals and humans [3]. These from normal to pathologic. This phenotypic spectrum SSRs therefore may have provided the variability needed extends the concept of disease pathology beyond the clas- for the changes of brain development and function in the sic dichotomous categorization between normal and dis- primate lineage leading to human evolution [4]. eased brain. Furthermore, some literature supports the notion of important relationships between the normal In sexually reproducing populations, mating does not occur randomly, but in relationship to certain characteris- HTT allele and the expanded allele, manifesting as differ- tics - either with a positive correlation (a male pairs with a ences in disease expression [23]. similar female) or a negative correlation (a male pairs with Although HTT has not directly been associated with a dissimilar female). This phenomenon, termed assortative variance in behavior, it is critical for brain development mating, has been widely reported in humans with positive [24,25] and therefore may be associated with variance in brain structure and function. We sought to evaluate the * Correspondence: peggy-nopoulos@uiowa.edu possibility of assortative mating in a group of subjects Department of Psychiatry, University of Iowa Carver College of Medicine, recruited from the community and with no family history Iowa City, Iowa, USA of Huntington’s. Full list of author information is available at the end of the article © 2011 Nopoulos et al; licensee BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. Nopoulos et al. Behavioral and Brain Functions 2011, 7:45 Page 2 of 4 http://www.behavioralandbrainfunctions.com/content/7/1/45 as Allele1 and the shorter allele as Allele2. Parent DNA Methods was not available to determine maternal or paternal trans- As a control group for a study on children at risk for mission of each allele. Huntington’s Disease, healthy children are recruited from the surrounding community of our hospital via Statistical analysis advertising. Through a screening interview with parents, Normality of distribution of CAG lengths of both alleles children are excluded if they have a history of significant was tested using the Shapiro-Wilk test. If either allele medical neurologic, or psychiatric history. All partici- was found to be non-normally distributed, then non- pants signed informed consent prior to enrolling in the protocol, which was approved by the local Investiga- parametric analysis was used (Spearman Correlation) to assess the association between length of Allele1 and tional Review Board (IRB). Participants ages 6-12 years length of Allele2. signed both an assent form (language geared toward children) and the consent form. Results Several children who participated were siblings and to Distribution of CAG repeat lengths were not normally avoid the confound of genetic relatedness, in the cases in distributed. For Allele1, the range was from 15 to 30 with which there were 1 or more siblings, the participants were mean of 20.20, s.d. of 3.88. Shapiro-Wilk statistic was sig- randomly deleted and only 1 child from each family was nificant (0.873, p < 0.0001) indicating non-normality of included. The demographics of the group included 47 distribution. For Allele2, the range was 4 to 29, mean of healthy children, including 31 girls and 16 boys, ranging 17.29 and s.d. of 3.67. Shapiro-Wilk statistic was signifi- from 6-18 years of age. A total of 40 of the 47 children cant (0.848, p < 0.0001) again indicating a non-normal were Caucasian (85% of the sample), 4 were African distribution. American (8.6%) and 3 were multiracial (6.4%). The Spearman correlation between Allele1 and Allele2 Each child provided either blood or saliva for genetic was highly significant at r = 0.511, p = 0.0002. This analysis. All analyses were done through the University of observation confirms that longer Allele1 lengths are posi- Iowa Molecular Diagnostics Laboratory. Size of the CAG tively associated with longer Allele2 lengths. Figure 1 repeat region of HTT on chromosome 4p16.3 was deter- shows the scatter plot of the data with regression line mined with PCR analysis of genomic DNA. PCR primers displayed. that exclude the adjacent polymorphic CCG tract were used to amplify the CAG region. A second set of primers Discussion that includes the CCG polymorphism is routinely used to This simple analysis of a unique data set shows evidence assist in differentiating two alleles with an identical CAG that there is assortative mating in regard to CAG length repeat number. The CAG repeat length for each subject is of HTT. That is, the length of CAG repeat in the mater- determined by comparing the PCR products to sizing nal allele of HTT strongly correlates with the length of standards. By convention, the longest allele is designated Figure 1 Relationship between CAG repeat length of Allele1 and CAG repeat length of Allele2. Nopoulos et al. Behavioral and Brain Functions 2011, 7:45 Page 3 of 4 http://www.behavioralandbrainfunctions.com/content/7/1/45 the CAG repeat of the paternal allele of HTT, suggesting ethnic group. Yet, recent reports of distribution of normal that the male and female pair mated based on the com- HTT allele sizes suggest that the prevalence of modifier mon feature of having a similar genotype (length of genes may be different even among sub-groups of Cauca- CAG repeat). sians [40]. Again, this explanation requires multiple sub- One interpretation of these findings would be that varia- jects within several discreet sub-groups within this sample bility of CAG length is manifest by variation in phenotype of 40 Caucasians which, although possible, seems less likely. Thus, assortative mating based not on ethnic group of brain structure and function. This notion supports a but on some other human feature remains a viable expla- report in which measures of mitochondrial energy meta- nation for the findings reported here. Nevertheless, given bolism (ATP/ADP) directly correlated to HTT CAG repeat lengths below disease threshold [26]. Although in the preliminary nature of the findings, follow-up in larger that study the genetic variation was associated with meta- samples and further exploration of the functions of the bolic phenotypic variation, brain structure/function phe- variance of normal CAG length in HTT are warranted. notypic variation also may be associated with CAG repeat length in HTT. As is seen with other SSRs, variation in Acknowledgements multiple types of behavior and cognitive functions have This work supported by a grant from the National Institutes for Neurologic been shown to be associated with variations in repeat sizes Disorders and Stroke (NINDS), 5R01NS055903-03, and the CHDI Foundation. of these genetic elements. With expansion of HTT CAG Author details repeat length beyond 36 repeats, disease is manifested and 1 Department of Psychiatry, University of Iowa Carver College of Medicine, the brain region most heavily affected is that of the basal Iowa City, Iowa, USA. Department of Pediatrics, University of Iowa Carver College of Medicine, Iowa City, Iowa, USA. Department of Neurology, ganglia. Basal ganglia circuits include widespread connec- University of Iowa Carver College of Medicine, Iowa City, Iowa, USA. tions from and to multiple cortical regions, including fron- 4 Department of Radiology, Washington University School of Medicine, St. tal lobes. These frontal circuits influence numerous Louis, MO, USA. Department of Pediatrics, Washington University School of Medicine, St. Louis, MO, USA. Department of Anatomy & Neurobiology, complex functions including cognitive and personality Washington University School of Medicine, St. Louis, MO, USA. Department traits [27-32]. Potential influence of CAG repeat length on of Neurology, Washington University School of Medicine, St. Louis, MO, USA. these basal ganglia frontal circuits could influence beha- Department of Occupational Therapy, Washington University School of Medicine, St. Louis, MO, USA. viors that provide the basis for assortative mating. An alternative explanation for the current findings Authors’ contributions could be that a post-meiotic recombination between PN secured funding, completed the analysis, and drafted the manuscript. EA provided feedback and revisions to manuscript. TW provided feedback and CAG repeat domains of the two HTT alleles ‘equilibrate’ revisions to manuscript. BS provided feedback and revisions to manuscript. the 2 allele sizes, thereby producing a correlation JP provided feedback and revisions to manuscript. All authors read and between the sizes of the HTT alleles [33]. To distinguish approved the final manuscript. whether the mechanism responsible for the reported cor- Competing interests relation is assortative mating or post-meiotic recombina- The authors declare that they have no competing interests. tion, future studies will need to analyze parental DNA Received: 27 July 2011 Accepted: 18 October 2011 along with the proband’s DNA. Published: 18 October 2011 Racial or ethnic relationships within the sample is an important consideration in the current study since there References are differences in the distribution of normal HTT allele 1. Richards RI, Sutherland GR: Dynamic mutations: a new class of mutations causing human disease. Cell 1992, 70(5):709-12. sizes in different ethnic groups [34-38]. Furthermore, dif- 2. Fondon JW, Garner HR: Molecular origins of rapid and continuous ferent haplotypes associated with different distribution of morphological evolution. 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Journal
Behavioral and Brain Functions – Springer Journals
Published: Oct 18, 2011