[Zoom] Efficient, high-resolution bioinformatic approaches for integrative sequencing analyses of complex diseases

Presenter

Shilpa Garg, Ph. D.

Shilpa is a tenure-track assistant professor at the University of Copenhagen, Denmark. Before this, she was a K99/R00 research fellow at Harvard Medical School and finished her Ph.D. in Computer Science at Max Planck Institute for Informatics. She is passionate to apply the power of computers to understand the biology of complex disease analyses. She has published in ISMB, ESA, and prestigious journals like Bioinformatics, Nature Communications, and Nature Biotechnology.

Abstract

Reconstructing the complete phased sequences of every chromosome copy in human and non-human species is important for medical genetics. The unprecedented advancements in sequencing technologies have opened up new avenues to reconstruct these phased sequences that would enable a deeper understanding of molecular, cellular, and developmental processes underlying complex diseases. Despite these interesting sequencing innovations, the highly polymorphic and gene-dense human leukocyte antigen (HLA) are not yet fully phased in the reference genome. The reference genome still contains gaps in multi-megabase repetitive regions, and thus annotating novel expression and methylation results are incomplete and inaccurate, which affect the interpretation of molecular genetics and epigenetics of diseases. There is a pressing need for streamlined, production-level, easy-to-use computational approaches that can reconstruct high-quality chromosome-scale phased sequences and that can be applied to hundreds of human genomes.

In this talk, first, I will present an efficient combinatorial phasing model that leverages new long-range strand-specific technology and long reads to generate chromosome-scale phasing. Second, I present an efficient algorithm to perform an accurate haplotype-resolved assembly of human individuals. This method takes advantage of the new long accurate data type (PacBio HiFi) and long-range Hi-C data. We, for the first time, can generate accurate chromosome-scale phased assemblies with base-level accuracy of Q50 and continuity of 25Mb within 24 hours per sample, therefore, setting up a milestone in the genomic community. Third, I will present the generalized graph-based method for phased assembly of related individuals. This graph framework provides a compact representation to encode various data types and can be applied to genomes of any complexity having varying heterozygous rates and repeat content. Finally, I will present the importance of haplotype-resolved assemblies to various medical applications.

In summary, my works efficiently and robustly combine data from a variety of sequencing technologies to produce high-quality diploid assemblies. These computational methods will enable high-quality precision medicine and facilitate new and unbiased studies of human (and non-human) haplotype variation in various populations, which are currently the goals of many large-scale human and cancer-related projects.

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