%0 Journal Article %J Hum Genet %D 2019 %T Leveraging linkage evidence to identify low-frequency and rare variants on 16p13 associated with blood pressure using TOPMed whole genome sequencing data. %A He, Karen Y %A Li, Xiaoyin %A Kelly, Tanika N %A Liang, Jingjing %A Cade, Brian E %A Assimes, Themistocles L %A Becker, Lewis C %A Beitelshees, Amber L %A Bress, Adam P %A Chang, Yen-Pei Christy %A Chen, Yii-Der Ida %A de Vries, Paul S %A Fox, Ervin R %A Franceschini, Nora %A Furniss, Anna %A Gao, Yan %A Guo, Xiuqing %A Haessler, Jeffrey %A Hwang, Shih-Jen %A Irvin, Marguerite Ryan %A Kalyani, Rita R %A Liu, Ching-Ti %A Liu, Chunyu %A Martin, Lisa Warsinger %A Montasser, May E %A Muntner, Paul M %A Mwasongwe, Stanford %A Palmas, Walter %A Reiner, Alex P %A Shimbo, Daichi %A Smith, Jennifer A %A Snively, Beverly M %A Yanek, Lisa R %A Eric Boerwinkle %A Correa, Adolfo %A Cupples, L Adrienne %A He, Jiang %A Kardia, Sharon L R %A Kooperberg, Charles %A Mathias, Rasika A %A Mitchell, Braxton D %A Psaty, Bruce M %A Vasan, Ramachandran S %A Rao, D C %A Rich, Stephen S %A Rotter, Jerome I %A Wilson, James G %A Chakravarti, Aravinda %A Morrison, Alanna C %A Levy, Daniel %A Arnett, Donna K %A Redline, Susan %A Zhu, Xiaofeng %K Alternative Splicing %K Blood Pressure %K Chromosomes, Human, Pair 16 %K Exome %K Female %K Follow-Up Studies %K Genetic Linkage %K Genetic Variation %K Genome, Human %K Genome-Wide Association Study %K High-Throughput Nucleotide Sequencing %K Humans %K Male %K Recombinases %K RNA Splicing Factors %X

In this study, we investigated low-frequency and rare variants associated with blood pressure (BP) by focusing on a linkage region on chromosome 16p13. We used whole genome sequencing (WGS) data obtained through the NHLBI Trans-Omics for Precision Medicine (TOPMed) program on 395 Cleveland Family Study (CFS) European Americans (CFS-EA). By analyzing functional coding variants and non-coding rare variants with CADD score > 10 residing within the chromosomal region in families with linkage evidence, we observed 25 genes with nominal statistical evidence (burden or SKAT p < 0.05). One of the genes is RBFOX1, an evolutionarily conserved RNA-binding protein that regulates tissue-specific alternative splicing that we previously reported to be associated with BP using exome array data in CFS. After follow-up analysis of the 25 genes in ten independent TOPMed studies with individuals of European, African, and East Asian ancestry, and Hispanics (N = 29,988), we identified variants in SLX4 (p = 2.19 × 10) to be significantly associated with BP traits when accounting for multiple testing. We also replicated the associations previously reported for RBFOX1 (p = 0.007). Follow-up analysis with GTEx eQTL data shows SLX4 variants are associated with gene expression in coronary artery, multiple brain tissues, and right atrial appendage of the heart. Our study demonstrates that linkage analysis of family data can provide an efficient approach for detecting rare variants associated with complex traits in WGS data.

%B Hum Genet %V 138 %P 199-210 %8 2019 Feb %G eng %N 2 %1 https://www.ncbi.nlm.nih.gov/pubmed/30671673?dopt=Abstract %R 10.1007/s00439-019-01975-0 %0 Journal Article %J Hum Genet %D 2016 %T Pathogenetics of alveolar capillary dysplasia with misalignment of pulmonary veins. %A Szafranski, Przemyslaw %A Gambin, Tomasz %A Dharmadhikari, Avinash V %A Akdemir, Kadir Caner %A Jhangiani, Shalini N %A Schuette, Jennifer %A Godiwala, Nihal %A Yatsenko, Svetlana A %A Sebastian, Jessica %A Madan-Khetarpal, Suneeta %A Surti, Urvashi %A Abellar, Rosanna G %A Bateman, David A %A Wilson, Ashley L %A Markham, Melinda H %A Slamon, Jill %A Santos-Simarro, Fernando %A Palomares, María %A Nevado, Julián %A Lapunzina, Pablo %A Chung, Brian Hon-Yin %A Wong, Wai-Lap %A Chu, Yoyo Wing Yiu %A Mok, Gary Tsz Kin %A Kerem, Eitan %A Reiter, Joel %A Ambalavanan, Namasivayam %A Anderson, Scott A %A Kelly, David R %A Shieh, Joseph %A Rosenthal, Taryn C %A Scheible, Kristin %A Steiner, Laurie %A Iqbal, M Anwar %A McKinnon, Margaret L %A Hamilton, Sara Jane %A Schlade-Bartusiak, Kamilla %A English, Dawn %A Hendson, Glenda %A Roeder, Elizabeth R %A DeNapoli, Thomas S %A Littlejohn, Rebecca Okashah %A Wolff, Daynna J %A Wagner, Carol L %A Yeung, Alison %A Francis, David %A Fiorino, Elizabeth K %A Edelman, Morris %A Fox, Joyce %A Hayes, Denise A %A Janssens, Sandra %A De Baere, Elfride %A Menten, Björn %A Loccufier, Anne %A Vanwalleghem, Lieve %A Moerman, Philippe %A Sznajer, Yves %A Lay, Amy S %A Kussmann, Jennifer L %A Chawla, Jasneek %A Payton, Diane J %A Phillips, Gael E %A Brosens, Erwin %A Tibboel, Dick %A de Klein, Annelies %A Maystadt, Isabelle %A Fisher, Richard %A Sebire, Neil %A Male, Alison %A Chopra, Maya %A Pinner, Jason %A Malcolm, Girvan %A Peters, Gregory %A Arbuckle, Susan %A Lees, Melissa %A Mead, Zoe %A Quarrell, Oliver %A Sayers, Richard %A Owens, Martina %A Shaw-Smith, Charles %A Lioy, Janet %A McKay, Eileen %A de Leeuw, Nicole %A Feenstra, Ilse %A Spruijt, Liesbeth %A Elmslie, Frances %A Thiruchelvam, Timothy %A Bacino, Carlos A %A Langston, Claire %A Lupski, James R %A Sen, Partha %A Popek, Edwina %A Stankiewicz, Paweł %K Chromosomes, Human, Pair 16 %K Comparative Genomic Hybridization %K Female %K Forkhead Transcription Factors %K Genes, Lethal %K Genome, Human %K Genomic Imprinting %K High-Throughput Nucleotide Sequencing %K Humans %K Infant, Newborn %K Male %K Pedigree %K Persistent Fetal Circulation Syndrome %K Pulmonary Alveoli %K Pulmonary Veins %K Sequence Deletion %X

Alveolar capillary dysplasia with misalignment of pulmonary veins (ACDMPV) is a lethal lung developmental disorder caused by heterozygous point mutations or genomic deletion copy-number variants (CNVs) of FOXF1 or its upstream enhancer involving fetal lung-expressed long noncoding RNA genes LINC01081 and LINC01082. Using custom-designed array comparative genomic hybridization, Sanger sequencing, whole exome sequencing (WES), and bioinformatic analyses, we studied 22 new unrelated families (20 postnatal and two prenatal) with clinically diagnosed ACDMPV. We describe novel deletion CNVs at the FOXF1 locus in 13 unrelated ACDMPV patients. Together with the previously reported cases, all 31 genomic deletions in 16q24.1, pathogenic for ACDMPV, for which parental origin was determined, arose de novo with 30 of them occurring on the maternally inherited chromosome 16, strongly implicating genomic imprinting of the FOXF1 locus in human lungs. Surprisingly, we have also identified four ACDMPV families with the pathogenic variants in the FOXF1 locus that arose on paternal chromosome 16. Interestingly, a combination of the severe cardiac defects, including hypoplastic left heart, and single umbilical artery were observed only in children with deletion CNVs involving FOXF1 and its upstream enhancer. Our data demonstrate that genomic imprinting at 16q24.1 plays an important role in variable ACDMPV manifestation likely through long-range regulation of FOXF1 expression, and may be also responsible for key phenotypic features of maternal uniparental disomy 16. Moreover, in one family, WES revealed a de novo missense variant in ESRP1, potentially implicating FGF signaling in the etiology of ACDMPV.

%B Hum Genet %V 135 %P 569-586 %8 2016 May %G eng %N 5 %1 https://www.ncbi.nlm.nih.gov/pubmed/27071622?dopt=Abstract %R 10.1007/s00439-016-1655-9 %0 Journal Article %J Am J Med Genet A %D 2016 %T Phenotypic expansion of TBX4 mutations to include acinar dysplasia of the lungs. %A Szafranski, Przemyslaw %A Coban-Akdemir, Zeynep H %A Rupps, Rosemarie %A Grazioli, Serge %A Wensley, David %A Jhangiani, Shalini N %A Popek, Edwina %A Lee, Anna F %A Lupski, James R %A Boerkoel, Cornelius F %A Stankiewicz, Paweł %K Alleles %K Autopsy %K Chromosomes, Human, Pair 16 %K DNA Copy Number Variations %K DNA Mutational Analysis %K Fatal Outcome %K Female %K Genetic Association Studies %K Genotype %K Heterozygote %K Humans %K Infant, Newborn %K Karyotype %K Lung %K Mutation %K Pedigree %K Phenotype %K Radiography, Thoracic %K T-Box Domain Proteins %X

Mutations in the T-box transcription factor TBX4 gene have been reported in patients with Ischiocoxopodopatellar syndrome (MIM# 147891) and childhood-onset pulmonary arterial hypertension. Whole exome sequencing of DNA from a 1 day old deceased newborn, with severe diffuse developmental lung disorder exhibiting features of acinar dysplasia, and her unaffected parents identified a de novo TBX4 missense mutation p.E86Q (c.256G>C) in the DNA-binding T-box domain. We propose phenotypic expansion of the TBX4-related clinical disease spectrum to include acinar dysplasia of the lungs. The reported mutation is the first identified genetic variant causative for acinar dysplasia. © 2016 Wiley Periodicals, Inc.

%B Am J Med Genet A %V 170 %P 2440-4 %8 2016 Sep %G eng %N 9 %1 https://www.ncbi.nlm.nih.gov/pubmed/27374786?dopt=Abstract %R 10.1002/ajmg.a.37822 %0 Journal Article %J PLoS Genet %D 2011 %T Recurrent chromosome 16p13.1 duplications are a risk factor for aortic dissections. %A Kuang, Shao-Qing %A Guo, Dong-chuan %A Prakash, Siddharth K %A McDonald, Merry-Lynn N %A Johnson, Ralph J %A Wang, Min %A Regalado, Ellen S %A Russell, Ludivine %A Cao, Jiu-Mei %A Kwartler, Callie %A Fraivillig, Kurt %A Coselli, Joseph S %A Safi, Hazim J %A Estrera, Anthony L %A Leal, Suzanne M %A LeMaire, Scott A %A Belmont, John W %A Milewicz, Dianna M %K Adult %K Aged %K Aorta %K Aortic Aneurysm, Thoracic %K Aortic Dissection %K Case-Control Studies %K Chromosome Duplication %K Chromosomes, Human, Pair 16 %K Female %K Gene Expression Regulation %K Genetic Predisposition to Disease %K Humans %K Male %K Middle Aged %K Myosin Heavy Chains %K Pedigree %K Phenotype %K Risk Factors %X

Chromosomal deletions or reciprocal duplications of the 16p13.1 region have been implicated in a variety of neuropsychiatric disorders such as autism, schizophrenia, epilepsies, and attention-deficit hyperactivity disorder (ADHD). In this study, we investigated the association of recurrent genomic copy number variants (CNVs) with thoracic aortic aneurysms and dissections (TAAD). By using SNP arrays to screen and comparative genomic hybridization microarrays to validate, we identified 16p13.1 duplications in 8 out of 765 patients of European descent with adult-onset TAAD compared with 4 of 4,569 controls matched for ethnicity (P = 5.0 × 10⁻⁵, OR = 12.2). The findings were replicated in an independent cohort of 467 patients of European descent with TAAD (P = 0.005, OR = 14.7). Patients with 16p13.1 duplications were more likely to harbor a second rare CNV (P = 0.012) and to present with aortic dissections (P = 0.010) than patients without duplications. Duplications of 16p13.1 were identified in 2 of 130 patients with familial TAAD, but the duplications did not segregate with TAAD in the families. MYH11, a gene known to predispose to TAAD, lies in the duplicated region of 16p13.1, and increased MYH11 expression was found in aortic tissues from TAAD patients with 16p13.1 duplications compared with control aortas. These data suggest chromosome 16p13.1 duplications confer a risk for TAAD in addition to the established risk for neuropsychiatric disorders. It also indicates that recurrent CNVs may predispose to disorders involving more than one organ system, an observation critical to the understanding of the role of recurrent CNVs in human disease and a finding that may be common to other recurrent CNVs involving multiple genes.

%B PLoS Genet %V 7 %P e1002118 %8 2011 Jun %G eng %N 6 %1 https://www.ncbi.nlm.nih.gov/pubmed/21698135?dopt=Abstract %R 10.1371/journal.pgen.1002118 %0 Journal Article %J Proc Natl Acad Sci U S A %D 2006 %T Recurrent duplication-driven transposition of DNA during hominoid evolution. %A Johnson, Matthew E %A Cheng, Ze %A Morrison, V Anne %A Scherer, Steven %A Ventura, Mario %A Gibbs, Richard A %A Green, Eric D %A Eichler, Evan E %K Animals %K Base Sequence %K Biological Evolution %K Chromosomes, Human, Pair 16 %K DNA %K DNA Transposable Elements %K Evolution, Molecular %K Gene Duplication %K Hominidae %K Humans %K Molecular Sequence Data %K Phylogeny %K Sequence Alignment %K Sequence Analysis, DNA %X

The underlying mechanism by which the interspersed pattern of human segmental duplications has evolved is unknown. Based on a comparative analysis of primate genomes, we show that a particular segmental duplication (LCR16a) has been the source locus for the formation of the majority of intrachromosomal duplications blocks on human chromosome 16. We provide evidence that this particular segment has been active independently in each great ape and human lineage at different points during evolution. Euchromatic sequence that flanks sites of LCR16a integration are frequently lineage-specific duplications. This process has mobilized duplication blocks (15-200 kb in size) to new genomic locations in each species. Breakpoint analysis of lineage-specific insertions suggests coordinated deletion of repeat-rich DNA at the target site, in some cases deleting genes in that species. Our data support a model of duplication where the probability that a segment of DNA becomes duplicated is determined by its proximity to core duplicons, such as LCR16a.

%B Proc Natl Acad Sci U S A %V 103 %P 17626-31 %8 2006 Nov 21 %G eng %N 47 %1 https://www.ncbi.nlm.nih.gov/pubmed/17101969?dopt=Abstract %R 10.1073/pnas.0605426103 %0 Journal Article %J Stroke %D 2003 %T Evaluating the context-dependent effect of family history of stroke in a genome scan for hypertension. %A Morrison, Alanna C %A Brown, Andrew %A Kardia, Sharon L R %A Turner, Stephen T %A Eric Boerwinkle %K Adult %K Aged %K Black People %K Body Mass Index %K Chromosomes, Human, Pair 13 %K Chromosomes, Human, Pair 16 %K Chromosomes, Human, Pair 19 %K Chromosomes, Human, Pair 2 %K Ethnicity %K Family Health %K Female %K Genes %K Genetic Heterogeneity %K Genetic Linkage %K Genetic Predisposition to Disease %K Genetic Testing %K Genome, Human %K Humans %K Hypercholesterolemia %K Hypertension %K Male %K Middle Aged %K Minnesota %K Mississippi %K Risk Factors %K Sample Size %K Siblings %K Stroke %K Texas %K White People %X

BACKGROUND AND PURPOSE: Hypertension is an important risk factor for stroke, and the 2 diseases may share susceptibility genes in common. We sought to identify genomic regions influencing susceptibility to both hypertension and stroke.

SUBJECTS AND METHODS: Genome-wide linkage scans were performed in samples of 338 white and 265 black hypertensive sibships recruited by the Genetic Epidemiology Network of Arteriopathy Study of the NHLBI Family Blood Pressure Program (FBPP). The hypertensive sibships were stratified by positive (+FH) or negative (-FH) family history of stroke. Genome-wide scans were repeated in each stratum, and the results were compared within each ethnic group by a regression-based analysis of heterogeneity.

RESULTS: In whites, the best evidence for linkage was found on chromosome 16 in the unstratified sample of hypertensive sibpairs (logarithm of odds [LOD]=1.85 at 71 cM). In blacks, the best evidence for linkage was found on chromosome 2 in the unstratified sample of hypertensive sibpairs (LOD=1.95 at 230 cM). Additional evidence for linkage (LOD >or=1.5) was observed among white hypertensive sibpairs with a -FH on chromosome 13 and among black hypertensive sibpairs with a +FH of stroke on chromosome 19.

CONCLUSIONS: Significant evidence for linkage heterogeneity among hypertensive sibpairs stratified by family history of stroke suggests the presence of genes influencing susceptibility to both hypertension and stroke on chromosomes 13 (whites) and 19 (blacks). Although no significant evidence of heterogeneity was observed on chromosome 16 in whites and chromosome 2 in blacks, these chromosomes do provide evidence of linkage to hypertension.

%B Stroke %V 34 %P 1170-5 %8 2003 May %G eng %N 5 %1 https://www.ncbi.nlm.nih.gov/pubmed/12714704?dopt=Abstract %R 10.1161/01.STR.0000068780.47411.16 %0 Journal Article %J Eur J Hum Genet %D 2003 %T Genetic linkage and imprinting effects on body mass index in children and young adults. %A Gorlova, Olga Y %A Amos, Christopher I %A Wang, Nancy W %A Shete, Sanjay %A Turner, Stephen T %A Eric Boerwinkle %K Adolescent %K Adult %K Age Factors %K Body Mass Index %K Child %K Child, Preschool %K Chromosomes, Human, Pair 16 %K Chromosomes, Human, Pair 20 %K Genetic Linkage %K Genomic Imprinting %K Humans %K Models, Genetic %X

Body mass index (BMI) is used as a measure of fatness. Here we performed a genome-wide scan for genes related to BMI, while allowing for the possible effects of imprinting. We applied a sib pair linkage analysis to a sample of primarily children and young adults by using the Haseman-Elston method, which we modified to model the separate effects of paternally and maternally derived genetic factors. After stratification of sib pairs according to age, a number of regions showing linkage with BMI were identified. Most linkage and imprinting effects were found in children 5-11 years of age. Strongest evidences for linkage in children were found on chromosome 20 at 20p11.2-pter near the marker D20S851 (LOD(Total)=4.08, P=0.000046) and near the marker D20S482 (LOD(Total) =3.55, P=0.00016), and Chromosome 16 at 16p13 near the marker ATA41E04 (LOD(Total) =3.12, P=0.00025), and those loci did not show significant evidence for imprinting. Six regions showing evidence of imprinting were 3p23-p24 (paternal expression), 4q31.1-q32 (maternal expression), 10p14-q11 (paternal expression), and 12p12-pter (paternal expression) in children, and 4q31-qter (paternal expression) and 8p (paternal expression) in adults.

%B Eur J Hum Genet %V 11 %P 425-32 %8 2003 Jun %G eng %N 6 %1 https://www.ncbi.nlm.nih.gov/pubmed/12774034?dopt=Abstract %R 10.1038/sj.ejhg.5200979 %0 Journal Article %J Oncogene %D 2001 %T Genetic mapping and DNA sequence-based analysis of deleted regions on chromosome 16 involved in progression of bladder cancer from occult preneoplastic conditions to invasive disease. %A Yoon, D S %A Li, L %A Zhang, R D %A Kram, A %A Ro, J Y %A Johnston, D %A Grossman, H B %A Scherer, S %A Czerniak, B %K Aged %K Chromosome Mapping %K Chromosomes, Human, Pair 16 %K Disease Progression %K DNA, Neoplasm %K Genes, Tumor Suppressor %K Genetic Markers %K Humans %K Loss of Heterozygosity %K Male %K Middle Aged %K Neoplasm Invasiveness %K Precancerous Conditions %K Sequence Deletion %K Tissue Distribution %K Urinary Bladder Neoplasms %K Urine %X

Histologic and genetic mapping with 30 hypervariable markers mapped to chromosome 16 were performed on 234 DNA samples of five cystectomy specimens from patients with invasive bladder cancer. Allelic losses of individual markers were related to microscopically identified precursor conditions in the entire bladder mucosa and invasive cancer. Their significance for the development and progression of neoplasia from in situ preneoplastic conditions to invasive disease was analysed by the nearest neighbor algorithm and binomial maximum likelihood analysis. Using this approach we identified five distinct regions of allelic losses defined by their flanking markers and predicted size as follows. p13.3(D16S418-D16S406, 1.2 cM), p13.1(D16S748-D16S287, 12.9 cM), q12 1(D16S409-D16S514, 24.0 cM), q22.1 (D16S496-D16S515, 5.4 cM), and q24 (D16S507-D16S511, 5.9 cM and D16S402-D16S413, 17.4 cM). The regions mapping to p13.1 and q24 were involved in early intraurothelial phases of bladder neoplasia such as mild to moderate dysplasia. On the other hand the deleted region mapping to p13.3 was involved in progression of severe dysplasia/carcinoma in situ to invasive bladder cancer. Testing of markers that exhibited statistically significant LOH in relation to progression of neoplasia from precursor conditions to invasive cancer on 28 tumors and voided urine samples from 25 patients with bladder cancer revealed that q12.1 showed LOH in 46.4% of tumor and 32.0% of voided urine samples. The LOH of a single marker D16S541 could be detected in approximately 28% of tumors and 20% of voided urine samples of patients with bladder cancer. These data imply that the deleted region centered around marker D16S541 spanning approximately 10 cM and flanked by D16S409 and D16S415 contains a novel putative tumor suppressor gene or genes playing an important role in the development of human bladder cancer. To facilitate more precise positional mapping and identification of pathogenetically relevant genes, we analysed of human genome contig and sequence databases spanning the deleted regions. Multiple known candidate genes and several smaller gene-rich areas mapping to the target regions of chromosome 16 were identified.

%B Oncogene %V 20 %P 5005-14 %8 2001 Aug 16 %G eng %N 36 %1 https://www.ncbi.nlm.nih.gov/pubmed/11526485?dopt=Abstract %R 10.1038/sj.onc.1204612 %0 Journal Article %J Genome Res %D 1999 %T Identification of three novel Ca(2+) channel gamma subunit genes reveals molecular diversification by tandem and chromosome duplication. %A Burgess, D L %A Davis, C F %A Gefrides, L A %A Noebels, J L %K Amino Acid Sequence %K Calcium Channels %K Chromosomes, Human, Pair 16 %K Chromosomes, Human, Pair 17 %K Evolution, Molecular %K Expressed Sequence Tags %K Gene Duplication %K Genetic Variation %K Humans %K Molecular Sequence Data %K Multigene Family %K Peptides %K Phylogeny %K Physical Chromosome Mapping %K Sequence Alignment %X

Gene duplication is believed to be an important evolutionary mechanism for generating functional diversity within genomes. The accumulated products of ancient duplication events can be readily observed among the genes encoding voltage-dependent Ca(2+) ion channels. Ten paralogous genes have been identified that encode isoforms of the alpha(1) subunit, four that encode beta subunits, and three that encode alpha(2)delta subunits. Until recently, only a single gene encoding a muscle-specific isoform of the Ca(2+) channel gamma subunit (CACNG1) was known. Expression of a distantly related gene in the brain was subsequently demonstrated upon isolation of the Cacng2 gene, which is mutated in the mouse neurological mutant stargazer (stg). In this study, we sought to identify additional genes that encoded gamma subunits. Because gene duplication often generates paralogs that remain in close syntenic proximity (tandem duplication) or are copied onto related daughter chromosomes (chromosome or whole-genome duplication), we hypothesized that the known positions of CACNG1 and CACNG2 could be used to predict the likely locations of additional gamma subunit genes. Low-stringency genomic sequence analysis of targeted regions led to the identification of three novel Ca(2+) channel gamma subunit genes, CACNG3, CACNG4, and CACNG5, on chromosomes 16 and 17. These results demonstrate the value of genome evolution models for the identification of distantly related members of gene families.

%B Genome Res %V 9 %P 1204-13 %8 1999 Dec %G eng %N 12 %1 https://www.ncbi.nlm.nih.gov/pubmed/10613843?dopt=Abstract %R 10.1101/gr.9.12.1204 %0 Journal Article %J Hum Mol Genet %D 1996 %T Duplication of a gene-rich cluster between 16p11.1 and Xq28: a novel pericentromeric-directed mechanism for paralogous genome evolution. %A Eichler, E E %A Lu, F %A Shen, Y %A Antonacci, R %A Jurecic, V %A Doggett, N A %A Moyzis, R K %A Baldini, A %A Richard A Gibbs %A Nelson, D L %K Animals %K Base Sequence %K Carrier Proteins %K Centromere %K Chromosome Mapping %K Chromosomes, Human, Pair 16 %K Cosmids %K Creatine %K Evolution, Molecular %K Exons %K Hominidae %K Humans %K Hylobates %K Membrane Proteins %K Membrane Transport Proteins %K Models, Genetic %K Molecular Sequence Data %K Multigene Family %K Proteins %K Repetitive Sequences, Nucleic Acid %K Sequence Analysis, DNA %K Sequence Homology, Nucleic Acid %K X Chromosome %X

We have identified a 26.5 kb gene-rich duplication shared by human Xq28 and 16p11.1. Complete comparative sequence analysis of cosmids from both loci has revealed identical Xq28 and 16p11.1 genomic structures for both the human creatine transporter gene (SLC6A8) and five exons of the CDM gene (DXS1357E). Overall nucleotide similarity within the duplication was found to be 94.6%, suggesting that this interchromosomal duplication occurred within recent evolutionary time (7-10 mya). Based on comparisons between genomic and cDNA sequence, both the Xq28 creatine transporter and DXS1357E genes are transcriptionally active. Predicted translation of exons and RT-PCR analysis reveal that chromosome 16 paralogs likely represent pseudogenes. Comparative fluorescent in situ hybridization (FISH) analyses of chromosomes from various primates indicate that this gene-rich segment has undergone several duplications. In gorilla and chimpanzee, multiple pericentromeric localizations on a variety of chromosomes were found using probes from the duplicated region. In other species, such as the orangutan and gibbon, FISH signals were only identified at the distal end of the X chromosome, suggesting that the Xq28 locus represents the ancestral copy. Sequencing of the 16p 11.1/Xq28 duplication breakpoints has revealed the presence of repetitive immunoglobulin-like CAGGG pentamer sequences at or near the paralogy boundaries. The mobilization and dispersal of this gene-rich 27 kb element to the pericentromeric regions of primate chromosomes defines an unprecedented form of recent genome evolution and a novel mechanism for the generation of genetic diversity among closely related species.

%B Hum Mol Genet %V 5 %P 899-912 %8 1996 Jul %G eng %N 7 %1 https://www.ncbi.nlm.nih.gov/pubmed/8817324?dopt=Abstract %R 10.1093/hmg/5.7.899