MAY 09, 2019 9:00 AM PDT

Completing the Human Genome: The Progress and Challenge of Satellite DNA Assembly

C.E. Credits: P.A.C.E. CE Florida CE
Speaker
  • Assistant Research Scientist, Department of Biomolecular Engineering, University of California, Santa Cruz
    Biography
      Dr. Miga is a satellite DNA biologist based out of UC Santa Cruz. As an Assistant Research Scientist at the UCSC Genomics Institute and the co-lead of the Telomere-to-Telomere (T2T) Consortium, she works on the forefront of long-read sequencing technologies to generate telomere-to-telomere reference quality assemblies of human chromosomes. Her research program combines innovative computational and experimental approaches to produce the high-resolution sequence maps of human centromeric and pericentromeric DNAs. In doing so, she is uncovering a new source of genetic and epigenetic variation in the human population, which is useful to investigate novel associations between genotype and phenotype of inherited traits and disease. During her doctorate work, under the mentorship of Huntington Willard at Duke University, she gained expertise in human alpha satellite DNA sequence structure and evolution. While a postdoctoral scholar with David Haussler at the University of California in Santa Cruz, Dr. Miga advanced long-read sequencing strategies and satellite DNA graphs to advance our understanding of human centromeric satellites.Her team presented the first linear map of a human centromere on the Y chromosome, and she is working within the T2T Consortium to ensure high-quality, experimentally validated linear assemblies are available for all human centromeric regions.

    Abstract

    Release of the first human genome assembly was a landmark achievement, and after nearly two decades of improvements, the current human reference genome (GRCh38) is the most accurate and complete vertebrate genome ever produced. However, no one chromosome has yet been finished end to end, and hundreds of gaps persist across the genome. This is a fundamental problem because these gaps vary in repeat structure and copy number between individuals, which can affect genome stability and health. 

    To address this challenge, I will present a whole-genome de novo assembly that surpasses the continuity of GRCh38, along with the first complete, telomere-to-telomere assembly of a human X chromosome. We have collected 40X coverage of ultra-long Oxford Nanopore sequencing for the CHM13hTERT cell line, including 44 Gb of sequence in reads >100 kb and a maximum read length exceeding 1 Mb.  This unprecedented coverage of ultra-long reads enabled the resolution of most repeats in the genome, including large fractions of the centromeric satellite arrays and short arms of the acrocentrics. Using this assembly as a basis, we chose to manually finish the X chromosome. These results demonstrate that it is now possible to finish entire human chromosomes without gaps, and our future work (Telomere-to-telomere, T2T Consortium) will focus on completing and validating the remainder of the genome.

    Finally, centromeric sequences are expected to vary in repeat composition and copy number between individuals in the population. To study the extent of this variation, I have performed a comprehensive study of centromere sequence structural variation using a panel of high-coverage, long read datasets from individuals from diverse populations. Efforts to increase production of UL-read sequencing – thereby dramatically increasing our ability to characterize satellite array structure – using the PromethION sequencing platform from Oxford Nanopore will be discussed.

    Learning Objectives: 

    1. Human centromere sequence structure and organization.
    2. Long-read sequencing and scaffolding assembly strategies to complete human chromosome assemblies.
     


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