The 3q29 locus is a genomic region associated with microdeletion and microduplication syndromic disorders, and also neurodevelopmental and psychiatric disorders such as schizophrenia, autism spectrum disorder, and attention-deficit/hyperactivity disorder (ADHD). It remains a focal point of research due to its complex nature. In an exciting recent study titled “High level of complexity and global diversity of the 3q29 locus revealed by optical mapping and long-read sequencing”(Ref 1), researchers from The Jackson Laboratory, Rutgers University, Emory University, UCSF, and University of Colorado bring to light the complexity of the 3q29 locus.

The 3q29 locus is notorious for its high sequence homology, where similar or identical sequences are scattered throughout the genome. This confounding characteristic has stymied traditional sequencing methods, rendering the region a black box for researchers. OGM steps in as a powerful ally, offering an ingenious way to overcome the challenges posed by complex genomic regions. Feyza Yilmaz, first author of this paper and associate computational scientist at The Jackson Laboratory, underscores OGM’s strength, “The strength of optical mapping is its ability to provide long-range information about genomic regions. This makes it particularly useful for studying complex loci such as the 3q29 locus.” She continues, “The OGM assembly contigs, contigs that span 3q29 segmental duplications in their entirety, used in this study were constructed using single DNA molecules with N50 > 284 kbp in size, which allowed for the accurate characterization of the 3q29 haplotypes containing highly similar segmental duplications.”

In this study, the researchers were able to characterize the locus in unaffected individuals, probands with genetic disorders, and their parents. The outcome was nothing short of remarkable:

Key Discoveries:

1). Diverse Haplotypes: 34 distinct haplotypes emerged in this study, with 19 being novel – unveiling a hidden genetic diversity previously inaccessible through traditional means.

2). Genetic Diagnosis: The ability to define breakpoints with precision enables clinicians to diagnose genetic disorders more accurately. This refined insight is invaluable for future genotype-phenotype association studies.

3). The Evolutionary Edge: This study suggests a rapid evolution of the 3q29 locus driven by mutation and recombination.

According to Feyza Yilmaz, “One of the study’s most fascinating findings was that, despite a small sample size (n<150), 36 haplotypes have been identified at 3q29 locus. This implies that the true number of haplotypes at this locus is probably substantially higher. This finding suggests that this locus is undergoing rapid evolution due to its high rate of mutation and recombination. This makes studying genomic disorders like del3q29S more difficult, but also more intriguing, because it shows that there is still a lot to learn about this locus. In addition, I’d like to investigate other complex loci using a similar approach to define haplotype structures and structural variants within haplotypes.”

This study not only showcases the potential of optical genome mapping in unraveling the mysteries of complex genetic regions, but its implications also extend beyond the 3q29 locus. Optical genome mapping, with its ability to decipher complex regions, opens the door to investigating other genetic regions and diseases that influence human health.

References:

1. Yilmaz, F., Gurusamy, U., Mosley, T. J., Hallast, P., Kim, K., Mostovoy, Y., Purcell, R. H., Shaikh, T. H., Zwick, M. E., Kwok, P. Y., Lee, C., & Mulle, J. G. (2023). High level of complexity and global diversity of the 3q29 locus revealed by optical mapping and long-read sequencing. Genome medicine, 15(1), 35. https://doi.org/10.1186/s13073-023-01184-5