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      Distribution of fragile X mental retardation 1 CGG repeat and flanking haplotypes in a large Chinese population

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          Abstract

          Fragile X syndrome is mainly caused by a CGG repeat expansion within the 5′ UTR of the fragile X mental retardation 1 ( FMR1) gene. Previous analyses of the FMR1 CGG repeat patterns and flanking haplotypes in Caucasians and African Americans have identified several factors that may influence repeat instability. However, the CGG repeat patterns and distribution for FRAXAC2 have not yet been investigated in mainland Chinese. We surveyed the CGG repeat lengths in 1113 Han Chinese (534 males and 579 females), and the CGG repeat patterns of 534 males were determined by sequence analysis. We also explored the flanking haplotypes (DXS548-FRAXAC1-FRAXAC2) in 566 unaffected and 28 unrelated fragile X Chinese males. The most frequent alleles for DXS548 and FRAXAC1 were identical between our Chinese population and other Asian populations. We identified several low-abundance alleles for DXS548 and FRAXAC1 not found in previous studies in mainland Chinese and Taiwanese cohorts. The most frequent allele was (CGG) 29 followed by (CGG) 30, and the most frequent patterns were 9 + 9 + 9, 10 + 9 + 9, and 9 + 9 + 6 + 9, similar to those in Singaporeans. We identified only one premutation female carrier with 89 CGG repeats in the 1113 Han Chinese. A few associations between the CGG repeat patterns and flanking haplotypes were determined in this study. In general, the Chinese population had a smaller number of alleles and lower expected heterozygosity for all three STR markers and FRAXA locus when compared with Caucasians and African Americans. We identified a novel haplotype 7-3-5 + that is significantly associated with the full mutation.

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          Most cited references34

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          Identification of a gene (FMR-1) containing a CGG repeat coincident with a breakpoint cluster region exhibiting length variation in fragile X syndrome.

          Fragile X syndrome is the most frequent form of inherited mental retardation and is associated with a fragile site at Xq27.3. We identified human YAC clones that span fragile X site-induced translocation breakpoints coincident with the fragile X site. A gene (FMR-1) was identified within a four cosmid contig of YAC DNA that expresses a 4.8 kb message in human brain. Within a 7.4 kb EcoRI genomic fragment, containing FMR-1 exonic sequences distal to a CpG island previously shown to be hypermethylated in fragile X patients, is a fragile X site-induced breakpoint cluster region that exhibits length variation in fragile X chromosomes. This fragment contains a lengthy CGG repeat that is 250 bp distal of the CpG island and maps within a FMR-1 exon. Localization of the brain-expressed FMR-1 gene to this EcoRI fragment suggests the involvement of this gene in the phenotypic expression of the fragile X syndrome.
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            Mapping of DNA instability at the fragile X to a trinucleotide repeat sequence p(CCG)n.

            The sequence of a Pst I restriction fragment was determined that demonstrate instability in fragile X syndrome pedigrees. The region of instability was localized to a trinucleotide repeat p(CCG)n. The sequence flanking this repeat were identical in normal and affected individuals. The breakpoints in two somatic cell hybrids constructed to break at the fragile site also mapped to this repeat sequence. The repeat exhibits instability both when cloned in a nonhomologous host and after amplification by the polymerase chain reaction. These results suggest variation in the trinucleotide repeat copy number as the molecular basis for the instability and possibly the fragile site. This would account for the observed properties of this region in vivo and in vitro.
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              Genetic evidence supports demic diffusion of Han culture.

              The spread of culture and language in human populations is explained by two alternative models: the demic diffusion model, which involves mass movement of people; and the cultural diffusion model, which refers to cultural impact between populations and involves limited genetic exchange between them. The mechanism of the peopling of Europe has long been debated, a key issue being whether the diffusion of agriculture and language from the Near East was concomitant with a large movement of farmers. Here we show, by systematically analysing Y-chromosome and mitochondrial DNA variation in Han populations, that the pattern of the southward expansion of Han culture is consistent with the demic diffusion model, and that males played a larger role than females in this expansion. The Han people, who all share the same culture and language, exceed 1.16 billion (2000 census), and are by far the largest ethnic group in the world. The expansion process of Han culture is thus of great interest to researchers in many fields.
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                Author and article information

                Journal
                Mol Genet Genomic Med
                Mol Genet Genomic Med
                mgg3
                Molecular Genetics & Genomic Medicine
                BlackWell Publishing Ltd (Oxford, UK )
                2324-9269
                2324-9269
                May 2015
                15 December 2014
                : 3
                : 3
                : 172-181
                Affiliations
                The State Key Laboratory of Medical Genetics & School of Life Sciences, Central South University Changsha, 410078, Hunan, China
                Author notes
                Correspondence Ranhui Duan, The State Key Lab of Medical Genetics, Central South University, Changsha 410078, Hunan, China. Tel: +8673184805349; Fax: +8673184805349; E-mail: duanranhui@ 123456sklmg.edu.cn

                Funding Information This work was funded in part by grants from the National Key Basic Research Program of China (grant number: 2012CB944600), National Natural Science Foundation of China (grant numbers: 81071028, 81172513), Program for New Century Excellent Talents in University (grant number: NCET-10-0832).

                [a]

                These authors contributed equally to the work.

                Article
                10.1002/mgg3.128
                4444158
                26029703
                2732cd7a-fda8-4e29-9ac9-0d1664cf0219
                © 2014 The Authors. Molecular Genetics & Genomic Medicine published by Wiley Periodicals, Inc.

                This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.

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                Original Articles

                fmr1,cgg repeat pattern,haplotype,chinese population
                fmr1, cgg repeat pattern, haplotype, chinese population

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