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Research Programs

Long-read Sequencing

A visual of a long string of DNA shaped like a brain going into a nanopore to depict nanopore sequencing.

CARD is pioneering large-scale long-read genetic sequencing efforts for Alzheimer's disease and Alzheimer’s disease related dementias (AD/ADRD). Our publicly available long-read datasets are designed to accelerate understanding of the genetic architecture of AD/ADRD.

To help screen, diagnose, and develop treatments for dementia, scientists need to understand the genetic architecture of AD/ADRD. This means identifying which genetic variants or alterations in the genome put people at risk or cause disease. It also includes looking at how variants influence cellular pathways and interact with each other and the environment.

Most large-scale sequencing efforts for AD/ADRD use short-read technology, where computers stitch together short reads (50-200 base pairs long) from a genome. But this stitching is imperfect and leaves gaps. Short-read sequencing can miss large structural variants and alterations in repetitive regions such as centromeres, telomeres, and highly homologous regions. It’s like assembling a large puzzle from very small pieces, with several missing pieces.

In comparison, long-read DNA sequencing reads pieces of the genome that are up to one million base pairs long. It can also read changes in DNA methylation, which are linked to aging and disease risk. With long-read sequencing, we are finding new and rare AD/ADRD-related variants in challenging genomic regions.

Harness CARD’s Long-Read Sequencing Data

At CARD, we are creating and publishing long-read data from people with Alzheimer's and related dementias as well as healthy individuals. Data from this effort is publicly available to the community, along with our analysis pipelines, algorithms, and optimized DNA isolation protocols. Explore code repositories and research protocols from this effort.

Meet the Long-Read Team

Long-read sequencing efforts are led by scientists in CARD’s Advanced Analytics Expert Group. Meet our team and learn more about CARD Expert Groups.

CARD researchers pose in front of the long-read sequencing machine at CARD.
CARD researchers Pilar Alvarez Jerez and Laksh Malik pose in front of CARD's long-read sequencing machine to celebrate the sequencing of a strand of DNA 100,000 base pairs long. Pilar says, "We used a special library prep and ultra-long DNA extraction protocol for this sample, to avoid unwanted DNA shearing. Ultra-long sequencing runs allow us to better build custom genome assemblies for a more accurate analysis."

Related Publications and News:

  • Scalable Nanopore sequencing of human genomes provides a comprehensive view of haplotype-resolved variation and methylation. Kolmogorov M, et al. Preprint. bioRxiv. 2023. doi:10.1101/2023.01.12.523790
  • Genome-Wide Analysis of Structural Variants in Parkinson Disease. Billingsley KJ, et al. Ann Neurol. 2023. doi:10.1002/ana.26608