Biology subjects

Leung, T. Y.

Publications and source records attributed to Leung, T. Y..

6 recordsLinked to original sources

bioRxiv2025

Population differences of chromosome 22q11.2 duplication structure predisposes differentially to microdeletion and inversion.

The most common genomic disorder, chromosome 22q11.2 microdeletion syndrome (22q11.2DS), is mediated by highly identical and polymorphic segmental duplications (SDs) known as low copy repeats (LCRs; regions A-D) that have been challenging to sequence and characterize. Here, we report the sequence-resolved genomic architecture of 135 chromosome 22q11.2 haplotypes from diverse 1000 Genomes Project samples. We find that more than 90% of the copy number variation is polarized to the most proximal LCR region A (LCRA) where 50 distinct structural configurations are observed ([~]189 kbp to [~]2.15 Mbp or 11-fold length variation). A higher-order SD cassette structure of 105 kbp in length, flanked by 25 kbp long inverted repeats, drives this variation and emerged in the human-chimpanzee ancestral lineage later expanding in humans [~]1.0 [0.8-1.2] million years ago. African LCRA haplotypes are significantly longer (p=0.0047) when compared to non-Africans yet are predicted to be more protected against recurrent microdeletions (p=0.00053) due to a preponderance of flanking SDs in an inverted orientation. Conversely, we identified nine distinct inversion polymorphisms, including five recurrent [~]2.28 Mbp inversions extending across the critical region (LCRA-D) and four smaller inversions (two LCRA-B, one LCRC-D, and one LCRB-D); 7/9 of these events were identified in haplotypes of African and admixed American ancestry. Finally, we sequence and assemble four families and show that LCRA-D deletion breakpoints map to the 105 kbp repeat unit while inversion breakpoints associate with the 25 kbp repeats adjacent to palindromic AT-rich regions. In one family, we observe evidence of more complex unequal crossover events associated with gene conversion and multiple breakpoints. Our findings suggest that specific haplotype configurations are protective and susceptible to chromosome 22q11.2DS while recurrent large-scale inversions help to explain why this syndrome is less prevalent among individuals of African descent.

genomics↗

bioRxiv2024

A familial, telomere-to-telomere reference for human de novo mutation and recombination from a four-generation pedigree

Using five complementary short- and long-read sequencing technologies, we phased and assembled >95% of each diploid human genome in a four-generation, 28-member family (CEPH 1463) allowing us to systematically assess de novo mutations (DNMs) and recombination. From this family, we estimate an average of 192 DNMs per generation, including 75.5 de novo single-nucleotide variants (SNVs), 7.4 non-tandem repeat indels, 79.6 de novo indels or structural variants (SVs) originating from tandem repeats, 7.7 centromeric de novo SVs and SNVs, and 12.4 de novo Y chromosome events per generation. STRs and VNTRs are the most mutable with 32 loci exhibiting recurrent mutation through the generations. We accurately assemble 288 centromeres and six Y chromosomes across the generations, documenting de novo SVs, and demonstrate that the DNM rate varies by an order of magnitude depending on repeat content, length, and sequence identity. We show a strong paternal bias (75-81%) for all forms of germline DNM, yet we estimate that 17% of de novo SNVs are postzygotic in origin with no paternal bias. We place all this variation in the context of a high-resolution recombination map ([~]3.5 kbp breakpoint resolution). We observe a strong maternal recombination bias (1.36 maternal:paternal ratio) with a consistent reduction in the number of crossovers with increasing paternal (r=0.85) and maternal (r=0.65) age. However, we observe no correlation between meiotic crossover locations and de novo SVs, arguing against non-allelic homologous recombination as a predominant mechanism. The use of multiple orthogonal technologies, near-telomere-to-telomere phased genome assemblies, and a multi-generation family to assess transmission has created the most comprehensive, publicly available "truth set" of all classes of genomic variants. The resource can be used to test and benchmark new algorithms and technologies to understand the most fundamental processes underlying human genetic variation.

genomics↗

bioRxiv2023

Deficits in neural encoding of speech in preterm infants

Preterm children show developmental cognitive and language deficits that can be subtle and sometimes undetectable until later in life. Studies of brain development in children who are born preterm have largely focused on vascular and gross anatomical characteristics rather than pathophysiological processes that may contribute to these developmental deficits. Neural encoding of speech as reflected in EEG recordings is predictive of future language development and could provide insights into those pathophysiological processes. We recorded EEG from 45 preterm ([≤] 34 weeks of gestation) and 45 full-term ([≥] 38 weeks) Chinese-learning infants 0 to 12 months of (corrected) age during natural sleep. Each child listened to three speech stimuli that differed in lexically meaningful pitch (2 native and 1 non-native speech categories). EEG measures associated with synchronization and gross power of the frequency following response (FFR) were examined. ANCOVAs revealed no main effect of stimulus nativeness but main effects of age, consistent with earlier studies. A main effect of prematurity also emerged, with synchronization measures showing stronger group differences than power. By detailing differences in FFR measures related to synchronization and power, this study brings us closer to identifying the pathophysiological pathway to often subtle language problems experienced by preterm children.

neuroscience↗

bioRxiv2020

Applications of genetic-epigenetic tissue mapping for plasma DNA in prenatal testing, transplantation and oncology

We developed Genetic-Epigenetic Tissue Mapping (GETMap) to determine the tissue composition of plasma DNA carrying genetic variants not present in the constitutional genome through comparing their methylation profiles with relevant tissues. We validated this approach by showing that, in pregnant women, circulating DNA carrying fetal-specific alleles was entirely placenta-derived. In lung-transplant recipients, we showed that, at 72 hours after transplantation, the lung contributed only a median of 17% to the plasma DNA carrying donor-specific alleles and hematopoietic cells contributed a median of 78%. In hepatocellular cancer patients, the liver was identified as the predominant source of plasma DNA carrying tumor-specific mutations. In a pregnant woman with lymphoma, plasma DNA molecules carrying cancer mutations and fetal-specific alleles were accurately shown to be derived from the lymphocytes and placenta, respectively. Analysis of tissue origin for plasma DNA carrying genetic variants is potentially useful for noninvasive prenatal testing, transplantation monitoring and cancer screening.

physiology↗

bioRxiv2020

Simultaneous transcriptome and methylome profiles of single mouse oocytes provide novel insights on maturation and aging

BackgroundAdvanced maternal aging has become a worldwide public health issue that contributes to female fertility decline and significant risk to embryo development. Despite transcriptional and epigenetic alterations reported in oocyte maturation and development, the dynamics of gene expression and DNA dynamics associated with aging remain elusive. Here we generated simultaneous transcriptome and methylome profiles of mouse oocytes during aging and maturation at single-cell and single-base resolution to examine key biological processes and identify the key targets for novel treatment options. ResultsWe report the dynamics in transcriptome and DNA methylome in mouse oocytes during maternal aging and oocyte maturation. Age-associated gene expression changes showed mitochondrial dysfunction in GV oocytes and defects of chromosome segregation and spindle assembly in MII oocytes. EIF2 signaling protein synthesis pathway was also impaired during aged oocyte maturation. Moreover, distinctive DNA methylation patterns were demonstrated during maternal aging in GV and MII oocytes. A positive correlation between gene expression and methylation in gene body was characterized. Furthermore, we identified several promising biomarkers, including IL-7, to assess oocyte quality, which are potential therapeutic targets for improve oocyte maturation. More importantly, we built the first mouse oocyte maturation and age prediction model using transcriptome data and validated its feasibility in published data. ConclusionsThis work provides a better understanding of molecular and cellular mechanisms during mouse oocyte aging, points a new direction of oocyte quality assessment, and paves the way for developing novel treatments to improve oocyte maturation and quality in the future.

genomics↗

bioRxiv2019

Prenatal Diagnosis of Fetuses with Increased Nuchal Translucency by Genome Sequencing Analysis

BackgroundIncreased Nuchal Translucency (NT) is an important biomarker associated with increased risk of fetal structural anomalies. It is known to be contributed by a wide range of genetic etiologies from single nucleotide variants to those affecting millions of base-pairs. Currently, prenatal diagnosis is routinely performed by karyotyping and chromosomal microarray analysis (CMA), however, both of them have limited resolution. The diversity of the genetic etiologies warrants an integrated assay such as genome sequencing (GS) for comprehensive detection of genomic variants. Herein, we aim to evaluate the feasibility of applying GS in prenatal diagnosis for the fetuses with increased NT.\n\nMethodsWe retrospectively applied GS (>30-fold) for fetuses with increased NT ([≥]3.5-mm), who underwent routine prenatal diagnosis. Detection of single-nucleotide variants, copy-number variants and structural rearrangements was performed simultaneously and the results were integrated for interpretation in accordance with the guidelines of the American College of Medical Genetics and Genomics. Pathogenic or likely pathogenic (P/LP) variants were selected for validation and parental confirmation, when available.\n\nResultsOverall, 50 fetuses were enrolled, including 34 cases with isolated increased NT and 16 cases with other fetal structural malformations. Routine CMA and karyotyping reported eight P/LP CNVs, yielding a diagnostic rate of 16.0% (8/50). In comparison, GS provided a 2-fold increase in diagnostic yield (32.0%, 16/50), including one mosaic turner syndrome, eight cases with microdeletions/microduplications and seven cases with P/LP point mutations. Moreover, GS identified two cryptic insertions and two inversions. Follow-up study further demonstrated the potential pathogenicity of an apparently balanced insertion which disrupted an OMIM autosomal dominant disease-causing gene at the inserted site.\n\nConclusionsOur study demonstrates that applying GS in fetuses with increased NT can comprehensively detect and delineate the various genomic variants that are causative to the diseases. Importantly, prenatal diagnosis by GS doubled the diagnostic yield compared with routine protocols. Given a comparable turn-around-time and less DNA required, our study provides strong evidence to facilitate GS in prenatal diagnosis, particularly in fetuses with increased NT.

genomics↗