DOCSLIB.ORG

Segmental Duplications 73 5 Segmental Duplications

Total Page：16

File Type：pdf, Size：1020Kb

Download full-text PDF Read full-text
Segmental Duplications 73 5 Segmental Duplications Chapter 5 / Segmental Duplications 73 5 Segmental Duplications Andrew J. Sharp, PhD and Evan E. Eichler, PhD CONTENTS INTRODUCTION FEATURES OF SEGMENTAL DUPLICATIONS DISTRIBUTION OF SEGMENTAL DUPLICATIONS SEGMENTAL DUPLICATIONS AND EVOLUTION SEGMENTAL DUPLICATIONS AND GENOMIC VARIATION SUMMARY REFERENCES INTRODUCTION Until recent times, the identification and characterization of segmental duplications has often been based purely on anecdotal reports. However, the completion of the Human Genome Project has now made possible the systematic analysis of the extent and distribution of dupli- cated sequences in humans. Both in situ hybridization and in silico approaches have shown that approx 5% of our genome is composed of highly homologous duplicated sequence (1,2), with enrichments of six- to sevenfold in pericentromeric (3), and two- to threefold in subtelomeric regions (4), respectively. Not only does the presence of these paralogous segments represent a significant challenge to the correct assembly of the human genome, but there is also an increasing awareness of their role in human evolution, variation, and disease. We present a review of segmental duplications in the mammalian genome. We describe their basic characteristics, distribution, and dynamic nature during recent evolutionary history. Based on these features, we discuss models to account for the proliferation of these sequences in the mammalian lineage, and also their contribution towards karyotypic evolution and phe- notypic differences between primates. Finally, we highlight the role of segmental duplications as mediators of human variation at the genomic level. FEATURES OF SEGMENTAL DUPLICATIONS Human segmental duplications (also termed low-copy repeats) are blocks of DNA ranging from 1 to 200 kb in length that occur at more than one site within the genome and share a high level (often >90%) of sequence identity. They can include both genic sequences and high-copy repeats, such as long interspersed elements and short interspersed elements, and, unlike tan- dem duplications, are interspersed throughout the genome. This unique distribution pattern From: Genomic Disorders: The Genomic Basis of Disease Edited by: J. R. Lupski and P. Stankiewicz © Humana Press, Totowa, NJ 73 74 Part II / Genomic Structure suggests that segmental duplications arise through a process termed duplicative transposition, whereby whole blocks of sequence are first duplicated and then transposed from one genomic location to another. Although they have been identified on every human chromosome, their distribution is nonuniform with some chromosomes and chromosomal regions showing pecu- liar enrichment. Segmental duplications tend to cluster within pericentromeric and, to a lesser extent, subtelomeric regions. Many human pericentromeric regions in particular contain high concentrations of duplicated sequence, often arranged in large blocks composed of complex modular structures of individual duplications (3). Segmental duplications may be further classified based on their chromosomal distribution. Although some blocks of sequence may be duplicated to multiple locations within a single chromosome (termed intrachromosomal duplication), others may be located on non-homologous chromosomes (inter- or transchromosomal duplication). Intriguingly, the distribution of these two types of duplication appears to be largely exclusive of one another (2), suggesting mecha- nistic differences in their mode of propagation. Intrachromosomal Duplications Initial identification of chromosome-specific duplications often came about through the study of common microdeletion/micoduplication syndromes, such as Prader-Willi/Angelman syndromes, Williams-Beuren syndrome, Smith-Magenis syndrome, Charcot-Marie-Tooth disease type 1A, and DiGeorge/Velocardiofacial syndrome (5). As more of these syndromes were analyzed, it became apparent that the presence of large and highly homologous segmental duplications flanking these sites of rearrangement was a recurring theme. Available evidence suggests that homology between these duplicated sequences acts as a substrate for unequal meiotic recombination, leading to the deletion, duplication, or inversion of the intervening sequence (Fig. 1). Review of known genomic disorders caused by chromosome-specific duplications shows that these usually involve duplications that are more than 95% similar and 10–500 kb in length, separated by 50 kb to 4 Mb of DNA (5). Although intrachromosomal duplications are found throughout the euchromatic portions of virtually every human chromosome, some chromosomes, such as 1, 9, 16, 17, and 22, show particularly high concentrations within their most proximal regions (2). In these cases the density of duplication can be such that little or no unique sequence occurs across relatively large stretches (300 kb to 4 Mb) of DNA. The organization of these regions can be complex, with large duplication blocks often composed of smaller modules, which have been derived from different genomic locations. This feature has often led to difficulties in characterizing these regions, necessitating the development of specialized methods to allow these regions to be successfully mapped and sequenced. Many intrachromosomal duplications also share very high levels of sequence identity, with the majority having more than 95% identity between paralogous copies. In extreme cases, this level of nucleotide identity approaches the frequency of allelic variation found in the genome as a whole (approx 1 base per kilobase) (6). This property further confounds the mapping and identification of individual duplicated segments within the genome, and may also represent a significant impediment in the ability to distinguish true allelic polymorphism from paralogous genomic copies (7–9). Indeed, both gene and single nucleotide polymorphism annotation show significant improvements in accuracy when duplicated sequences are correctly defined within a genome assembly (10). Thus, the correct definition of segmental duplications is an important aspect of achieving high-quality genomic sequence (11). Chapter 5 / Segmental Duplications 75 Fig. 1. Segmental duplications mediate structural rearrangement. Misalignment of paralogous blocks of sequence during meiosis leads to unequal recombination and the deletion or duplication of the interven- ing sequence. These events may create structural polymorphisms or, if the genes (A,B,C) flanked by the duplications are dosage sensitive, genomic disease. ᭺, centromere; TEL, telomere. (Reproduced with permission from ref. 95.) Based on the neutral mutation rate in primates of approx 1.5 × 10–9 substitutions per site per year (12), the high levels of homology observed between many chromosome-specific dupli- cations suggests they have emerged only recently during evolutionary history. Indeed, com- parative analysis of different primate lineages has demonstrated that some are species-specific, confirming their dynamic nature (13). In other cases, analysis of the levels of sequence diver- gence between pairs of duplication in different primates, such as those flanking the common Williams-Beuren syndrome deletion region in 7q11.23 and the large palindromic repeats on long arm of the Y chromosome, has provided evidence that they may also act as substrates for gene conversion (14–16). Although fluorescence in situ hybridization analysis shows the presence of these duplications in multiple primate species, thus, suggesting they originated before the separation of these lin- eages, estimates of their evolutionary age based on the rate of nucleotide divergence because of random mutation suggest a much more recent origin (17,18). One explanation for this apparent contradiction is that the homology between pairs of repeats acts as a substrate for gene conversion events, thus, homogenizing their sequence and maintaining unexpectedly high levels of identity. Although less likely, an alternative explanation is that some segments of DNA have duplicated to the same genomic location independently in different primate lineages. 76 Part II / Genomic Structure Interchromosomal Duplications The most striking property of duplications that map to nonhomologous chromosomes is their propensity to accumulate adjacent to certain regions of the genome, particularly in pericentromeric and subtelomeric regions and in the short arms of the acrocentric chromo- somes. In silico analysis has shown a six- to sevenfold enrichment of duplicated segments within 100 kb and 1 Mb of telomeres and centromeres, respectively (3), and more than one- third of all interchromosomal duplications have a pericentromeric localization. Indeed, inter- chromosomal duplication has been one of the major forces involved in remodeling these chromosomal regions in recent primate evolution (3). As with chromosome-specific duplications, many of which have been implicated as media- tors of recurrent microdeletion/microduplication syndromes, certain interchromosomal dupli- cations have also been associated with recurrent chromosomal rearrangement (19–21), albeit at much lower frequencies. In addition, certain pericentromeric and subtelomeric regions have been found to exhibit polymorphic variation within the human population, indicating that the process of interchromosomal duplication is ongoing (22,23). DISTRIBUTION OF SEGMENTAL DUPLICATIONS One of the most remarkable features of segmental duplications is their tendency to often cluster in close proximity to one another, particularly within peri- and subtelomeric regions
Load more

Recommended publications
  • Adaptive Tuning of Mutation Rates Allows Fast Response to Lethal Stress In
    Manuscript 1 Adaptive tuning of mutation rates allows fast response to lethal stress in 2 Escherichia coli 3 4 a a a a a,b 5 Toon Swings , Bram Van den Bergh , Sander Wuyts , Eline Oeyen , Karin Voordeckers , Kevin J. a,b a,c a a,* 6 Verstrepen , Maarten Fauvart , Natalie Verstraeten , Jan Michiels 7 8 a 9 Centre of Microbial and Plant Genetics, KU Leuven - University of Leuven, Kasteelpark Arenberg 20, 10 3001 Leuven, Belgium b 11 VIB Laboratory for Genetics and Genomics, Vlaams Instituut voor Biotechnologie (VIB) Bioincubator 12 Leuven, Gaston Geenslaan 1, 3001 Leuven, Belgium c 13 Smart Systems and Emerging Technologies Unit, imec, Kapeldreef 75, 3001 Leuven, Belgium * 14 To whom correspondence should be addressed: Jan Michiels, Department of Microbial and 2 15 Molecular Systems (M S), Centre of Microbial and Plant Genetics, Kasteelpark Arenberg 20, box 16 2460, 3001 Leuven, Belgium, [email protected], Tel: +32 16 32 96 84 1 Manuscript 17 Abstract 18 19 While specific mutations allow organisms to adapt to stressful environments, most changes in an 20 organism's DNA negatively impact fitness. The mutation rate is therefore strictly regulated and often 21 considered a slowly-evolving parameter. In contrast, we demonstrate an unexpected flexibility in 22 cellular mutation rates as a response to changes in selective pressure. We show that hypermutation 23 independently evolves when different Escherichia coli cultures adapt to high ethanol stress. 24 Furthermore, hypermutator states are transitory and repeatedly alternate with decreases in mutation 25 rate. Specifically, population mutation rates rise when cells experience higher stress and decline again 26 once cells are adapted.
    [Show full text]
  • Dynamic Mutations on the Move
    9789 Mled Genet 1993; 30: 978-981 REVIEW ARTICLE J Med Genet: first published as 10.1136/jmg.30.12.978 on 1 December 1993. Downloaded from Dynamic mutations on the move Grant R Sutherland, Robert I Richards It is only a short time since the isolation and quences is rapidly increasing (table). These characterisation of the fragile X syndrome mu- include another fragile site (FRAXE) that may tation'-3 uncovered a new genetic element and be associated with mild mental retardation.'2 mechanism of mutation. The genetic element This fragile site has turned out to be similar in was an unstable DNA sequence resulting from structure to the fragile X (FRAXA), involving amplification of a naturally occurring poly- the same trinucleotide p(CCG)n and being morphic trinucleotide repeat, p(CCG)n. The close to a CpG island which is hypermethy- mechanism of mutation, which we have lated when the copy number exceeds approx- termed dynamic mutation,4 is the change (in- imately 200.* crease or decrease) in copy number of the The dynamic mutations characterised to trinucleotide repeat with the rate of change date fall into two categories probably deter- related to the number of copies present at any mined by whether the trinucleotide repeat is in time. This process, in which an initial change a translated or untranslated region of a gene. to a DNA sequence alters the chance of further The mutations in known or presumed changes to it, contrasts with classical or static untranslated regions, FRAXA, FRAXE, and mutation in which the product of a mutation is DM, appear to have little constraint on the no more likely to undergo further changes than number of repeats, which can range up to was the initial DNA sequence.
    [Show full text]
  • General Contribution
    24 Abstracts of 37th Annual Meeting A1 A SCREENING METHOD FOR FRAGILE X MUTATION: DETECTION OF THE CGG REPEAT IN FMR-1 GENE BY PCR WITH BIOTIN-LABELED PRIMER. ..Eiji NANBA, Kousaku OHNO and Kenzo TAKESHITA Division of Child Neurology, Institute of Neurological Sciences, Tot- tori University School of Medicine. Yonago We have developed a new polymerase chain reaction(PCR)-based method for detection of the CGG repeat in FMR-1 gene. No specific product from PCR was detected on the gel with ethidium bromide staining, because 7-deaza-2'-dGTP is necessary for amplification of this repeat. Biotin-labeled primer was used for PCR and the product was transferred to a nylon membrane followed the detection of biotin by Smilight kit. The size of PCR product from normal control were slightly various and around 300bp. No PCR product was detected from 3 fragile X male patients in 2 families diagnosed by cytogenetic examination. This method is useful for genetic screen- ing of male mental retardation patients to exclude the fragile X mutation. A2 DNA ANALYSISFOR FRAGILE X SYNDROME Osamu KOSUDA,Utak00GASA, ~.ideynki INH, a~ji K/NAGIJCltI, and Kazumasa ]tIKIJI (SILL Inc., Tokyo) Fragile X syndrome is X-linked disease having the amplification of (CG6)n repeat sequence in the chromsomeXq27.3. We performed Southern blot analysis using three probes recognized repetitive sequence resion. Normal controle showed 5.2Kb with Eco RI digest and 2.7Kb with Eco RI/Bss ttII digest as the germ tines by the Southern blot analysis. However, three cell lines established fro~ unrelated the patients with fragile X showed the abnormal bands between 5.2 and 7.7Kb with Eco RI digest, and between 2.7 and 7.7Kb with Eco aI/Bss HII digest.
    [Show full text]
  • Test ID: NGMEM
    NEW TEST NOTIFICATION DATE: April 25, 2017 EFFECTIVE DATE: May 15, 2017 RED BLOOD CELL MEMBRANE SEQUENCING, VARIES Test ID: NGMEM USEFUL FOR: Providing a comprehensive genetic evaluation for patients with a personal or family history suggestive of an RBC membrane disorder Second-tier testing for patients in whom previous targeted gene mutation analyses were negative for a specific RBC membrane disorder Establishing a diagnosis of a hereditary RBC membrane disorder, allowing for appropriate management and surveillance of disease features based on the gene involved Identifying mutations within genes associated with phenotypic severity, allowing for predictive testing and further genetic counseling METHOD: Hereditary Mutation Detection by Next-Generation Sequencing (NGS) REFERENCE VALUES: An interpretive report will be provided. This next-generation sequencing assay is performed to test for the presence of a mutation in targeted regions of the following 15 genes and intronic regions: ANK1, EPB41, EPB42, GYPC, HBB, HBD, PIEZO1, RHAG, SLC2A1, SLC4A1, SPTA1, SPTB, STOM, UGT1A1, and XK. SPECIMEN REQUIREMENTS: Submit only 1 of the following specimens: Specimen Type: Peripheral blood (preferred) Container/Tube: Preferred: Lavender top (EDTA) or yellow top (ACD) Acceptable: Green top (heparin) Specimen Volume: 3 mL Specimen Stability: Ambient < or =14 days Collection Instructions: 1. Invert several times to mix blood. 2. Send specimen in original tube. 3. Label specimen as blood. Specimen Type: Extracted DNA Container/Tube: 1.5- to 2-mL tube with indication of volume and concentration of the DNA. Specimen Volume: Entire specimen Specimen Stability: Frozen/Refrigerated/Ambient < or =30 days Collection Instructions: Label specimen as extracted DNA and source of specimen.
    [Show full text]
  • Genome Mapping Resolves Structural Variation Within Segmental Duplications Associated
    bioRxiv preprint doi: https://doi.org/10.1101/2020.04.30.071449; this version posted May 2, 2020. The copyright holder for this preprint (which was not certified by peer review) is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under aCC-BY-ND 4.0 International license. 1 Genome mapping resolves structural variation within segmental duplications associated 2 with microdeletion/microduplication syndromes 3 4 Authors 5 Yulia Mostovoy1,*, Feyza Yilmaz2,3,*, Stephen K. Chow1, Catherine Chu1, Chin Lin1, Elizabeth A. 6 Geiger3, Naomi J. L. Meeks3, Kathryn. C. Chatfield3,4, Curtis R. Coughlin II3, Pui-Yan Kwok1,5,6,#, 7 Tamim H. Shaikh3,# 8 9 Affiliations 10 1Cardiovascular Research Institute, UCSF School of Medicine, San Francisco, California 94143, 11 USA 12 2Department of Integrative Biology, University of Colorado Denver, Denver, Colorado 80204, 13 USA 14 3Department of Pediatrics, Section of Clinical Genetics and Metabolism, University of Colorado 15 School of Medicine, Aurora, Colorado 80045, USA 16 4Department of Pediatrics, Section of Cardiology, University of Colorado School of Medicine, 17 Aurora, Colorado 80045, USA 18 5Department of Dermatology, and 6Institute for Human Genetics, UCSF School of Medicine, San 19 Francisco, California 94143, USA 20 21 * These two authors contributed equally to the work presented 22 # Address correspondence to: [email protected]; [email protected] 23 24 Running Title 25 Resolving structures within segmental duplications 26 27 Keywords 28 Segmental duplications, genome mapping, structural variation, genomic disorders 29 1 bioRxiv preprint doi: https://doi.org/10.1101/2020.04.30.071449; this version posted May 2, 2020.
    [Show full text]
  • Integrative Networks in Intellectual Disabilities
    Conference 1st International Integrative Networks in Intellectual Disabilities 14-17 April, 2013 Coral Beach Hotel Paphos Cyprus Gene Networks Conference book 1st INTERNATIONAL GENCODYS CONFERENCE “Integrative Networks in Intellectual Disabilities” 14‐17 April, 2013 Coral Beach Hotel, Paphos, Cyprus MAIN SPONSOR AND ORGANISERS: EU project: GENCODYS Genetic and Epigenetic Networks in Cognitive Dysfunction EU 7th Framework Program Grant agreement no.: 241995 www.Gencodys.EU CO SPONSORS: WELCOME WELCOME We bid you a very warm welcome at the first International GENCODYS Conference. We hope that you will enjoy the scientific contents of this conference as well as its lovely settings, provided by the beautiful island of Cyprus and the hospitality of its people! The increasing power of sequencing allows the elucidation of causative genetic defects and risk factors in cognitive disorders (CD) by analysis of entire exomes and even complete genomes. A wide variety of chromosomal aberrations and a bewildering number of single gene mutations underlie intellectual disability (ID), and in a growing number of examples share a common etiology with other cognitive defects such as autism and schizophrenia. Elucidation of the complete landscape of all CD‐associated genes will allow us to recognize the underlying common pathological mechanisms. Already now, extensive functional interactions are seen between ID‐associated proteins and intricate networks are becoming apparent. Examples include protein networks driving synaptic morphology and plasticity and the epigenetic orchestration of neuronal gene expression. The European funded research consortium GENCODYS exploits a multilevel approach to resolve the integrative networks in intellectual disabilities. We are bringing together top researchers with complementary expertise and patient representatives to apply a systems biology approach to reveal the common molecular and cellular mechanisms leading to cognitive impairment and translational research possibilities.
    [Show full text]
  • Gene Mutation and DNA Polymorphism Outline of This Chapter
    Gene mutation and DNA polymorphism Outline of this chapter Gene Mutation DNA Polymorphism GeneGene MutationMutation Definition Major Types DefinitionDefinition A gene mutation is a change in the nucleotide sequence that composes a gene. Somatic mutations Germline mutations SomaticSomatic mutationsmutations are mutations that occur in cells of the body excluding the germline. Affects subsequent somatic cell descendants Limited to impact on the individual and not transmitted to offspring Germline mutations are mutations that occur in the germline cells Possibility of transmission to offspring Major Types Point mutations Insertion or deletion Fusion gene Dynamic mutation Point mutation substitution of one base with another Point mutation Transition purine replaces purine A G or pyrimidine replaces pyrimidine C T Transversion purine replaces pyrimidine A G or pyrimidine replaces purine C T What are the consequences? Within coding region: Silent mutation (same sense mutation) Missense mutation Nonsense mutation Stop codon mutation Within noncoding region: Splicing mutation Regulatory sequence mutation SilentSilent MutationMutation changes one codon for an amino acid to another codon for that amino acid no change in amino acid MissenseMissense mutationmutation A point mutation that exchanges one codon for another causing substitution of an amino acid Missense mutations may affect protein function severely, mildly or not at all. CGT AGT Hemoglobin Four globular proteins surrounding heme group with iron atom: two beta chains and two alpha chains Function is to carry oxygen in red blood cells from lungs to body and carbon dioxide from cells to lungs SingleSingle basebase changechange inin hemoglobinhemoglobin genegene causescauses sicklesickle cellcell anemiaanemia Wild-type mutant allele allele Wild-type mutant phenotype phenotype NonsenseNonsense mutationmutation A point mutation changing a codon for an amino acid into a stop codon (UAA, UAG or UGA).
    [Show full text]
  • Idiopathic Infertility As a Feature of Genome Instability
    life Review Idiopathic Infertility as a Feature of Genome Instability Agrita Puzuka 1,2, Baiba Alksere 1,3, Linda Gailite 1 and Juris Erenpreiss 1,3,* 1 Scientific Laboratory of Molecular Genetics, Riga Stradins University, LV-1007 Riga, Latvia; [email protected] (A.P.); [email protected] (B.A.); [email protected] (L.G.) 2 Department of Biology and Microbiology, Riga Stradins University, LV-1007 Riga, Latvia 3 EAA Andrology Centre, Clinic IVF-Riga, LV-1010 Riga, Latvia * Correspondence: [email protected] Abstract: Genome instability may play a role in severe cases of male infertility, with disrupted sper- matogenesis being just one manifestation of decreased general health and increased morbidity. Here, we review the data on the association of male infertility with genetic, epigenetic, and environmental alterations, the causes and consequences, and the methods for assessment of genome instability. Male infertility research has provided evidence that spermatogenic defects are often not limited to testicular dysfunction. An increased incidence of urogenital disorders and several types of cancer, as well as overall reduced health (manifested by decreased life expectancy and increased morbidity) have been reported in infertile men. The pathophysiological link between decreased life expectancy and male infertility supports the notion of male infertility being a systemic rather than an isolated condition. It is driven by the accumulation of DNA strand breaks and premature cellular senescence. We have presented extensive data supporting the notion that genome instability can lead to severe male infertility termed “idiopathic oligo-astheno-teratozoospermia.” We have detailed that genome instability in men with oligo-astheno-teratozoospermia (OAT) might depend on several genetic Citation: Puzuka, A.; Alksere, B.; and epigenetic factors such as chromosomal heterogeneity, aneuploidy, micronucleation, dynamic Gailite, L.; Erenpreiss, J.
    [Show full text]
  • By Duplicons Among Patients with Developmental Delay And/Or Congenital Malformations; Detection of Reciprocal and Partial Williams-Beuren Duplications
    The human genome; you gain some, you lose some Kriek, M. Citation Kriek, M. (2007, December 6). The human genome; you gain some, you lose some. Retrieved from https://hdl.handle.net/1887/12479 Version: Corrected Publisher’s Version Licence agreement concerning inclusion of doctoral License: thesis in the Institutional Repository of the University of Leiden Downloaded from: https://hdl.handle.net/1887/12479 Note: To cite this publication please use the final published version (if applicable). Chapter II-2 Copy number variation in regions flanked (or unflanked) by duplicons among patients with developmental delay and/or congenital malformations; detection of reciprocal and partial Williams-Beuren duplications Marjolein Kriek1, Stefan J White1, Karoly Szuhai2, Jeroen Knijnenburg2, Gert-Jan B van Ommen1, Johan T den Dunnen1 and Martijn H Breuning1 1Center for Human and Clinical Genetics, Leiden University Medical Center, The Netherlands; 2Department of Molecular Cell Biology, Leiden University Medical Center, The Netherlands Eur J Hum Genet. 2006 Feb;14(2):180-9 63 Chapter 2 Summary Duplicons, that is, DNA sequences with minimum length 10 kb and a high sequence similarity, are known to cause unequal homologous recombination, leading to deletions and the reciprocal duplications. In this study, we designed a Multiplex Amplifiable Probe Hybridisation (MAPH) assay containing 63 exon-specific single-copy sequences from within a selection of the 169 regions flanked by duplicons that were identified, at a first pass, in 2001. Subsequently, we determined the frequency of chromosomal rear- rangements among patients with developmental delay (DD) and/or congenital mal- formations (CM). In addition, we tried to identify new regions involved in DD/CM using the same assay.
    [Show full text]
  • Genomic Rearrangements of the 7Q11-21 Region
    GENOMIC REARRANGEMENTS IN HUMAN AND MOUSE AND THEIR CONTRIBUTION TO THE WILLIAMS-BEUREN SYNDROME PHENOTYPE. by Edwin James Young A thesis submitted in conformity with the requirements for the degree of Doctor of Philosophy, Institute of Medical Science University of Toronto © Copyright by Edwin James Young (2010) Genomic rearrangements in human and mouse and their contribution to the Williams- Beuren Syndrome phenotype. Doctor of Philosophy (2010) Edwin James Young Institute of Medical Science University of Toronto Abstract: Genomic rearrangements, particularly deletions and duplications, are known to cause many genetic disorders. The chromosome 7q11.23 region in humans is prone to recurrent chromosomal rearrangement, due to the presence of low copy repeats that promote non-allelic homologous recombination. The most well characterized rearrangement of 7q11.23 is a hemizygous 1.5 million base pair (Mb) deletion spanning more than 25 genes. This deletion causes Williams-Beuren Syndrome (WBS; OMIM 194050), a multisystem developmental disorder with distinctive physical and behavioural features. Other rearrangements of the region lead to phenotypes distinct from that of WBS. Here we describe the first individual identified with duplication of the same 1.5 Mb region, resulting in severe impairment of expressive language, in striking contrast to people with WBS who have relatively well preserved language skills. We also describe the identification of a new gene for a severe form of childhood epilepsy through the analysis of individuals with deletions on ii chromosome 7 that extend beyond the boundaries typical for WBS. This gene, MAGI2, is part of the large protein scaffold at the post-synaptic membrane and provides a new avenue of research into both the molecular basis of infantile spasms and the development of effective therapies.
    [Show full text]
  • Properties and Rates of Germline Mutations in Humans
    Review Feature Review Properties and rates of germline mutations in humans 1 1,2 Catarina D. Campbell and Evan E. Eichler 1 Department of Genome Sciences, University of Washington, Seattle, WA 98195, USA 2 Howard Hughes Medical Institute, Seattle, WA 98195, USA All genetic variation arises via new mutations; therefore, (often linked to dominant genetic disorders; for example, determining the rate and biases for different classes of see [3]). Over the past few years, it has become feasible to mutation is essential for understanding the genetics of generate large amounts of sequence data (including the human disease and evolution. Decades of mutation rate genomes of parents and their offspring), and it is now analyses have focused on a relatively small number of possible to calculate empirically a genome-wide mutation loci because of technical limitations. However, advances rate. In addition, much interest has focused on under- in sequencing technology have allowed for empirical standing the role of de novo mutations in human disease. assessments of genome-wide rates of mutation. Recent Therefore, in this review, we synthesize the recent anal- studies have shown that 76% of new mutations originate yses of mutation rate for multiple forms of genetic varia- in the paternal lineage and provide unequivocal evidence tion and discuss their implications with respect to human for an increase in mutation with paternal age. Although disease and evolution. most analyses have focused on single nucleotide var- iants (SNVs), studies have begun to provide insight into SNV mutation rate the mutation rate for other classes of variation, including It is now feasible to perform whole-genome sequencing on copy number variants (CNVs), microsatellites, and mo- all individuals from a nuclear family; from these data, one bile element insertions (MEIs).
    [Show full text]
  • Living Organisms Author Their Read-Write Genomes in Evolution
    biology Review Living Organisms Author Their Read-Write Genomes in Evolution James A. Shapiro ID Department of Biochemistry and Molecular Biology, University of Chicago GCIS W123B, 979 E. 57th Street, Chicago, IL 60637, USA; [email protected]; Tel.: +1-773-702-1625 Academic Editor: Andrés Moya Received: 23 August 2017; Accepted: 28 November 2017; Published: 6 December 2017 Abstract: Evolutionary variations generating phenotypic adaptations and novel taxa resulted from complex cellular activities altering genome content and expression: (i) Symbiogenetic cell mergers producing the mitochondrion-bearing ancestor of eukaryotes and chloroplast-bearing ancestors of photosynthetic eukaryotes; (ii) interspecific hybridizations and genome doublings generating new species and adaptive radiations of higher plants and animals; and, (iii) interspecific horizontal DNA transfer encoding virtually all of the cellular functions between organisms and their viruses in all domains of life. Consequently, assuming that evolutionary processes occur in isolated genomes of individual species has become an unrealistic abstraction. Adaptive variations also involved natural genetic engineering of mobile DNA elements to rewire regulatory networks. In the most highly evolved organisms, biological complexity scales with “non-coding” DNA content more closely than with protein-coding capacity. Coincidentally, we have learned how so-called “non-coding” RNAs that are rich in repetitive mobile DNA sequences are key regulators of complex phenotypes. Both biotic and abiotic ecological challenges serve as triggers for episodes of elevated genome change. The intersections of cell activities, biosphere interactions, horizontal DNA transfers, and non-random Read-Write genome modifications by natural genetic engineering provide a rich molecular and biological foundation for understanding how ecological disruptions can stimulate productive, often abrupt, evolutionary transformations.
    [Show full text]