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  1. Article ; Online: The Driver of Extreme Human-Specific Olduvai Repeat Expansion Remains Highly Active in the Human Genome.

    Heft, Ilea E / Mostovoy, Yulia / Levy-Sakin, Michal / Ma, Walfred / Stevens, Aaron J / Pastor, Steven / McCaffrey, Jennifer / Boffelli, Dario / Martin, David I / Xiao, Ming / Kennedy, Martin A / Kwok, Pui-Yan / Sikela, James M

    Genetics

    2019  Volume 214, Issue 1, Page(s) 179–191

    Abstract: Sequences encoding Olduvai protein domains (formerly DUF1220) show the greatest human lineage-specific increase in copy number of any coding region in the genome and have been associated, in a dosage-dependent manner, with brain size, cognitive aptitude, ...

    Abstract Sequences encoding Olduvai protein domains (formerly DUF1220) show the greatest human lineage-specific increase in copy number of any coding region in the genome and have been associated, in a dosage-dependent manner, with brain size, cognitive aptitude, autism, and schizophrenia. Tandem intragenic duplications of a three-domain block, termed the Olduvai triplet, in four
    MeSH term(s) Animals ; Base Sequence ; Carrier Proteins/genetics ; DNA Copy Number Variations ; Evolution, Molecular ; G-Quadruplexes ; Gene Amplification ; Gene Dosage ; Genome, Human ; Genomic Instability ; Homologous Recombination ; Humans ; Primates ; Protein Domains ; Sequence Homology ; Trinucleotide Repeat Expansion
    Chemical Substances Carrier Proteins ; NBPF1 protein, human
    Language English
    Publishing date 2019-11-21
    Publishing country United States
    Document type Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
    ZDB-ID 2167-2
    ISSN 1943-2631 ; 0016-6731
    ISSN (online) 1943-2631
    ISSN 0016-6731
    DOI 10.1534/genetics.119.302782
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  2. Article ; Online: Three patients with homozygous familial hypercholesterolemia: Genomic sequencing and kindred analysis.

    Wong, Karen H Y / Levy-Sakin, Michal / Ma, Walfred / Gonzaludo, Nina / Mak, Angel C Y / Vaka, Dedeepya / Poon, Annie / Chu, Catherine / Lao, Richard / Balamir, Melek / Grenville, Zoe / Wong, Nicolas / Kane, John P / Kwok, Pui-Yan / Malloy, Mary J / Pullinger, Clive R

    Molecular genetics & genomic medicine

    2019  Volume 7, Issue 12, Page(s) e1007

    Abstract: Background: Homozygous Familial Hypercholesterolemia (HoFH) is an inherited recessive condition associated with extremely high levels of low-density lipoprotein (LDL) cholesterol in affected individuals. It is usually caused by homozygous or compound ... ...

    Abstract Background: Homozygous Familial Hypercholesterolemia (HoFH) is an inherited recessive condition associated with extremely high levels of low-density lipoprotein (LDL) cholesterol in affected individuals. It is usually caused by homozygous or compound heterozygous functional mutations in the LDL receptor (LDLR). A number of mutations causing FH have been reported in literature and such genetic heterogeneity presents great challenges for disease diagnosis.
    Objective: We aim to determine the likely genetic defects responsible for three cases of pediatric HoFH in two kindreds.
    Methods: We applied whole exome sequencing (WES) on the two probands to determine the likely functional variants among candidate FH genes. We additionally applied 10x Genomics (10xG) Linked-Reads whole genome sequencing (WGS) on one of the kindreds to identify potentially deleterious structural variants (SVs) underlying HoFH. A PCR-based screening assay was also established to detect the LDLR structural variant in a cohort of 641 patients with elevated LDL.
    Results: In the Caucasian kindred, the FH homozygosity can be attributed to two compound heterozygous LDLR damaging variants, an exon 12 p.G592E missense mutation and a novel 3kb exon 1 deletion. By analyzing the 10xG phased data, we ascertained that this deletion allele was most likely to have originated from a Russian ancestor. In the Mexican kindred, the strikingly elevated LDL cholesterol level can be attributed to a homozygous frameshift LDLR variant p.E113fs.
    Conclusions: While the application of WES can provide a cost-effective way of identifying the genetic causes of FH, it often lacks sensitivity for detecting structural variants. Our finding of the LDLR exon 1 deletion highlights the broader utility of Linked-Read WGS in detecting SVs in the clinical setting, especially when HoFH patients remain undiagnosed after WES.
    MeSH term(s) Base Sequence/genetics ; Child, Preschool ; Cholesterol, LDL/genetics ; Chromosome Mapping/methods ; Cohort Studies ; Frameshift Mutation/genetics ; Genetic Variation/genetics ; Genome, Human/genetics ; Heterozygote ; Homozygote ; Humans ; Hyperlipoproteinemia Type II/genetics ; Infant ; Lipoproteins, LDL/genetics ; Pedigree ; Phenotype ; Receptors, LDL/genetics ; Sequence Analysis, DNA/methods ; Whole Exome Sequencing/methods
    Chemical Substances Cholesterol, LDL ; LDLR protein, human ; Lipoproteins, LDL ; Receptors, LDL
    Language English
    Publishing date 2019-10-16
    Publishing country United States
    Document type Case Reports ; Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
    ZDB-ID 2734884-2
    ISSN 2324-9269 ; 2324-9269
    ISSN (online) 2324-9269
    ISSN 2324-9269
    DOI 10.1002/mgg3.1007
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  3. Article ; Online: Towards a reference genome that captures global genetic diversity.

    Wong, Karen H Y / Ma, Walfred / Wei, Chun-Yu / Yeh, Erh-Chan / Lin, Wan-Jia / Wang, Elin H F / Su, Jen-Ping / Hsieh, Feng-Jen / Kao, Hsiao-Jung / Chen, Hsiao-Huei / Chow, Stephen K / Young, Eleanor / Chu, Catherine / Poon, Annie / Yang, Chi-Fan / Lin, Dar-Shong / Hu, Yu-Feng / Wu, Jer-Yuarn / Lee, Ni-Chung /
    Hwu, Wuh-Liang / Boffelli, Dario / Martin, David / Xiao, Ming / Kwok, Pui-Yan

    Nature communications

    2020  Volume 11, Issue 1, Page(s) 5482

    Abstract: The current human reference genome is predominantly derived from a single individual and it does not adequately reflect human genetic diversity. Here, we analyze 338 high-quality human assemblies of genetically divergent human populations to identify ... ...

    Abstract The current human reference genome is predominantly derived from a single individual and it does not adequately reflect human genetic diversity. Here, we analyze 338 high-quality human assemblies of genetically divergent human populations to identify missing sequences in the human reference genome with breakpoint resolution. We identify 127,727 recurrent non-reference unique insertions spanning 18,048,877 bp, some of which disrupt exons and known regulatory elements. To improve genome annotations, we linearly integrate these sequences into the chromosomal assemblies and construct a Human Diversity Reference. Leveraging this reference, an average of 402,573 previously unmapped reads can be recovered for a given genome sequenced to ~40X coverage. Transcriptomic diversity among these non-reference sequences can also be directly assessed. We successfully map tens of thousands of previously discarded RNA-Seq reads to this reference and identify transcription evidence in 4781 gene loci, underlining the importance of these non-reference sequences in functional genomics. Our extensive datasets are important advances toward a comprehensive reference representation of global human genetic diversity.
    MeSH term(s) Chromosome Mapping ; Computational Biology ; Gene Expression ; Genetic Variation ; Genome, Human ; Genomics ; Genotyping Techniques ; Humans ; Molecular Sequence Annotation ; Population/genetics ; RNA-Seq ; Sequence Analysis, DNA ; Transcriptome ; Whole Genome Sequencing
    Language English
    Publishing date 2020-10-30
    Publishing country England
    Document type Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
    ZDB-ID 2553671-0
    ISSN 2041-1723 ; 2041-1723
    ISSN (online) 2041-1723
    ISSN 2041-1723
    DOI 10.1038/s41467-020-19311-w
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  4. Article ; Online: Genome maps across 26 human populations reveal population-specific patterns of structural variation.

    Levy-Sakin, Michal / Pastor, Steven / Mostovoy, Yulia / Li, Le / Leung, Alden K Y / McCaffrey, Jennifer / Young, Eleanor / Lam, Ernest T / Hastie, Alex R / Wong, Karen H Y / Chung, Claire Y L / Ma, Walfred / Sibert, Justin / Rajagopalan, Ramakrishnan / Jin, Nana / Chow, Eugene Y C / Chu, Catherine / Poon, Annie / Lin, Chin /
    Naguib, Ahmed / Wang, Wei-Ping / Cao, Han / Chan, Ting-Fung / Yip, Kevin Y / Xiao, Ming / Kwok, Pui-Yan

    Nature communications

    2019  Volume 10, Issue 1, Page(s) 1025

    Abstract: Large structural variants (SVs) in the human genome are difficult to detect and study by conventional sequencing technologies. With long-range genome analysis platforms, such as optical mapping, one can identify large SVs (>2 kb) across the genome in one ...

    Abstract Large structural variants (SVs) in the human genome are difficult to detect and study by conventional sequencing technologies. With long-range genome analysis platforms, such as optical mapping, one can identify large SVs (>2 kb) across the genome in one experiment. Analyzing optical genome maps of 154 individuals from the 26 populations sequenced in the 1000 Genomes Project, we find that phylogenetic population patterns of large SVs are similar to those of single nucleotide variations in 86% of the human genome, while ~2% of the genome has high structural complexity. We are able to characterize SVs in many intractable regions of the genome, including segmental duplications and subtelomeric, pericentromeric, and acrocentric areas. In addition, we discover ~60 Mb of non-redundant genome content missing in the reference genome sequence assembly. Our results highlight the need for a comprehensive set of alternate haplotypes from different populations to represent SV patterns in the genome.
    MeSH term(s) Algorithms ; Base Sequence ; Chromosome Mapping/methods ; Chromosomes, Human, Y ; Computational Biology ; Female ; Gene Dosage ; Genetic Linkage ; Genome, Human ; Genomic Structural Variation ; Genomics ; Humans ; Male ; Mutation ; Phylogeny ; Segmental Duplications, Genomic/genetics ; Sequence Analysis, DNA
    Language English
    Publishing date 2019-03-04
    Publishing country England
    Document type Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
    ZDB-ID 2553671-0
    ISSN 2041-1723 ; 2041-1723
    ISSN (online) 2041-1723
    ISSN 2041-1723
    DOI 10.1038/s41467-019-08992-7
    Database MEDical Literature Analysis and Retrieval System OnLINE

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