Biology subjects

Morton, C. C.

Publications and source records attributed to Morton, C. C..

5 recordsLinked to original sources

bioRxiv2023

Resolution of ring chromosomes, Robertsonian translocations, and complex structural variants from long-read sequencing and telomere-to-telomere assembly

The capacity to resolve structural variants (SVs) at sequence resolution in highly repetitive genomic regions has long been intractable. Consequently, the properties, origins, and functional effects of multiple classes of complex rearrangement are unknown. To resolve these challenges, we leveraged recent technical milestones: 1) Oxford-Nanopore (ONT) sequencing; 2) the gapless Telomere-to-Telomere (T2T) genome assembly; and 3) a novel tool to discover large-scale rearrangements from long-reads. We applied these technologies across 13 patients with ring chromosomes, Robertsonian translocations, and complex balanced SVs that were unresolved by short-read sequencing. We resolved 10 of 13 events, including ring chromosomes, the complex SVs, and a Robertsonian translocation. Multiple breakpoints were localized to highly repetitive regions inaccessible to short-read alignment, such as acrocentric p-arms, ribosomal DNA arrays, and telomeric repeats, and involved complex structures such as a deletion-inversion and interchromosomal dispersed duplications. We also leveraged ONT native methylation detection to discover phased differential methylation in a gene promoter proximal to a ring fusion site, suggesting a long-range positional effect with heterochromatin spreading. Breakpoint sequences were consistent with common mechanisms of SV formation, including microhomology-mediated mechanisms, non-homologous end-joining, and non-allelic homologous recombination. These methods provide some of the first glimpses into the sequence resolution of ring chromosomes and Robertsonian translocations and illuminate the structural diversity of chromosomal rearrangements with implications for molecular diagnosis and genome biology. HighlightsO_LICryptic rearrangements revealed in repetitive and previously inaccessible regions C_LIO_LIAligning long-reads to telomere-to-telomere assembly enabled breakpoint discovery C_LIO_LIFirst sequence resolution of a Robertsonian translocation breakpoint C_LIO_LIHaplotype-specific methylation changes associated with ring formation C_LI Graphical abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=200 SRC="FIGDIR/small/555775v1_ufig1.gif" ALT="Figure 1"> View larger version (57K): org.highwire.dtl.DTLVardef@188cef8org.highwire.dtl.DTLVardef@cc2ed5org.highwire.dtl.DTLVardef@116b7e6org.highwire.dtl.DTLVardef@837f73_HPS_FORMAT_FIGEXP M_FIG C_FIG

genomics↗

bioRxiv2019

SYCP2 translocation-mediated dysregulation and frameshift variants cause human male infertility

Infertility is one of the most common disorders for men of reproductive age. To identify novel genetic etiologies, we studied a male with severe oligozoospermia and 46, XY,t(20;22)(q13.3;q11.2). We identified exclusive overexpression of SYCP2 from the der(20) allele that is hypothesized to result from enhancer adoption. Modeling the dysregulation in budding yeast resulted in disruption of the synaptonemal complex, a common cause of defective spermatogenesis in mammals. Exome sequencing of infertile males revealed three novel heterozygous SYCP2 frameshift variants in additional subjects with cryptozoospermia and azoospermia. This study provides the first evidence of SYCP2-mediated male infertility in humans.

genetics↗

bioRxiv2019

Genome-wide association study identifies 44 independent genomic loci for self-reported adult hearing difficulty in the UK Biobank cohort

Age-related hearing impairment (ARHI) is the most common sensory impairment in the aging population; a third of individuals are affected by disabling hearing loss by the age of 651. ARHI is a multifactorial condition caused by both genetic and environmental factors, with estimates of heritability between 35% and 55%2-4. The genetic risk factors and underlying biological pathology of ARHI are largely unknown, meaning that targets for new therapies remain elusive. We performed genome-wide association studies (GWAS) for two self-reported hearing phenotypes, hearing difficulty (HDiff) and hearing aid use (HAid), using over 250,000 UK Biobank5 volunteers aged between 40-69 years. We identified 44 independent genome-wide significant loci (P<5E-08), 33 of which have not previously been associated with any form of hearing loss. Gene sets from these loci are enriched in auditory processes such as synaptic activities, nervous system processes, inner ear morphology and cognition. Immunohistochemistry for protein localisation in adult mouse cochlea indicate metabolic, sensory and neuronal functions for NID2, CLRN2 and ARHGEF28 identified in the GWAS. These results provide new insight into the genetic landscape underlying susceptibility to ARHI.

genetics↗

bioRxiv2018

Nationwide population genetic screening improves outcomes of newborn screening for hearing loss in China

PurposeConcurrent newborn hearing and genetic screening has been reported, but its benefits have not been statistically proven due to limited sample sizes and outcome data. To fill this gap, we analyzed outcomes of a large number of newborns with genetic screening results.\n\nMethodsNewborns in China were screened for 20 hearing-loss-related genetic variants from 2012-2017. Genetic results were categorized as positive, at-risk, inconclusive, or negative. Hearing screening results, risk factors, and up-to-date hearing status were followed-up via phone interviews.\n\nResultsWe completed genetic screening on one million newborns and followed up 12,778. We found that a positive genetic result significantly indicated a higher positive predictive value of the initial hearing screening (60% vs. 5.0%, P<0.001) and a lower rate of loss-to-follow-up (5% vs. 22%, P<0.001) than an inconclusive one. Importantly, 42% of subjects in the positive group with reported or presymptomatic hearing loss were \"missed\" by conventional hearing screening. Furthermore, genetic screening identified 0.23% of subjects predisposed to preventable ototoxicity.\n\nConclusionOur results demonstrate that limited genetic screening identified additional cases, reduced loss-to-follow-up, and informed families of ototoxicity risks, providing convincing evidence to support integrating genetic screening into universal newborn hearing screening programs.

genetics↗

bioRxiv2018

Genome-wide association analysis identifies 27 novel loci associated with uterine leiomyomata revealing common genetic origins with endometriosis

Uterine leiomyomata (UL), also known as uterine fibroids, are the most common neoplasms of the reproductive tract and the primary cause for hysterectomy, leading to considerable impact on womens lives as well as high economic burden1,2. Genetic epidemiologic studies indicate that heritable risk factors contribute to UL pathogenesis3. Previous genome-wide association studies (GWAS) identified five loci associated with UL at genome-wide significance (P < 5 x 10-8)4-6. We conducted GWAS meta-analysis in 20,406 cases and 223,918 female controls of white European ancestry, identifying 24 genome-wide significant independent loci; 17 replicated in an unrelated cohort of 15,068 additional cases and 43,587 female controls. Aggregation of discovery and replication studies (35,474 cases and 267,505 female controls) revealed six additional significant loci. Interestingly, four of the 17 loci identified and replicated in these analyses have also been associated with risk for endometriosis - another common gynecologic disorder. These findings increase our understanding of the biological mechanisms underlying UL development, and suggest overlapping genetic origins with endometriosis.

genomics↗