Project 8p - Research Newsletter August 2023
💬 Research Question of the Month
How do the unique breakpoints and genetic variation of each 8p hero shape their disorder? New sequencing and DNA assembly technologies are enabling unprecedented resolution of genome sequences. With this information, we can start to better understand the genotype-phenotype relationship in chromosome 8p disorders.
Let us know what you think in the comments section below!
🔬Research Highlight
Chromosome 8p inversions, duplications, and deletions arise due to the presence of a gene cluster called the beta-defensin locus (Floridia et al. AJHG 1996). This locus is flanked by repetitive sequences on both ends, which have the potential to misalign and undergo recombination during meiosis I, causing the chromosome to break. Where the chromosome breaks can be different each time, resulting in breakpoints that are unique to each 8p hero.
Most of the genetic information that we have on 8p heroes comes from microarray assays, which lack the resolution to determine chromosomal breakpoints at the single-nucleotide level. Even most whole-genome sequencing methods cannot resolve complex or repetitive stretches of DNA. In Dr. Evan Eichler’s lab at the University of Washington, Dr. Glennis Logsdon and her colleagues have been working on new computational methods to assemble complete chromosome sequences from telomere-to-telomere (end-to-end) (Rautiainen et al. Nat Biotechnol 2023)
Now, Dr. Logsdon has applied these approaches to the sequencing and assembly of a chromosome with an 8p inverted duplication and deletion, allowing the accurate identification of the breakpoints for the first time. An additional, somewhat surprising, finding was that the chromosome has a normal length telomere. When the chromosome is broken during meiosis I, the telomere is lost, but the cells have apparently added a new one. Telomere defects can lead to a number of diseases, so this is good news for 8p heroes!
Next, Dr. Logsdon will look at gene expression and DNA methylation, a mechanism that cells use to alter gene expression, across chromosome 8 to better understand how the cells adjust to changes in gene dosage brought on by the inverted duplication and deletion. Understanding these changes will also help inform targets for therapeutic development. Soon, this work will be expanded to additional 8p variants, allowing for more comparative analysis.
Dr. Logsdon is also using these findings to inform the engineering of artificial chromosomes that could be used to study the effects of CNVs in cells or animal models. It’s possible that, one day, artificial chromosomes could even be used to replace the deleted genes in 8p heroes.
Featured image: Confirmation of 8p breakpoints by fluorescence in-situ hybridization (FISH). Top: A diagram of the 8p hero’s maternal chromosome 8 with the inverted duplication and deletion. The left and right facing arrows indicate the duplicated region, and the beta-defensin locus is highlighted in blue. The small blue, green, and red bars indicate the binding sites of the fluorescent probes. Bottom left: The complete set of metaphase chromosomes isolated from the 8p hero. Bottom right: The paternal (left) and maternal (right) copies of chromosome 8 with FISH probes bound. On the maternal chromosomes, the blue probe and the green probe that correspond to the duplication are seen to bind in two places, whereas on the paternal chromosomes, they only bind in one location. Image from Dr. Glennis Logsdon.
You can watch Dr. Logsdon’s recent Research Roundtable on the Project 8p YouTube Channel.
📄 Articles and Publications
Gene copy number variation and pediatric mental health/neurodevelopment in a general population. Zarrei, M. et al. August 2023. Hum Mol Genet. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10360394/. Open Access.
Of the 7,100 unrelated children sampled in this study, 807 individuals had a rare CNV on chromosome 8 and 222 had a loss-of-function variant (SNV or Indel) on chromosome 8. The study identified CSMD1, MCPH1, and COPS5 as novel loci on chromosome 8 that are associated with ADHD and/or inattention traits.
Aneuploidy effects on human gene expression across three cell types. Liu, S. et al. May 2023. PNAS. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10214149/. Open Access.
In this study, Liu et al. examined the effects of chromosome X, Y, and 21 dosage on gene expression in lymphoblastoid cell lines, fibroblasts, and induced pluripotent stem cell-derived excitatory neurons. They found that changes in gene expression on the affected chromosomes are generalizable across cell types, but that changes in gene expression beyond the affected chromosomes are not.
Mechanisms of copy number variants in neuropsychiatric disorders: From genes to therapeutics. Forrest, MP and Penzes, P. July 2023. Curr Opin Neurobiol. https://pubmed.ncbi.nlm.nih.gov/37515924/.
This review describes models of gene interactions within CNVs, approaches to rodent and stem cell disease models, recent successes in genetic and pharmacological approaches to rescuing CNV-mediated pathophysiology, and proposes using a ‘rescue approach’ for more precise mechanistic understanding and to inform therapeutic development.
Assortative mating and parental genetic relatedness drive the pathogenicity of variably expressive variants. Smolen, C. et al. May 2023. medRxiv 2023.05.18.23290169 https://www.medrxiv.org/content/10.1101/2023.05.18.23290169v1. Open Access. This article is a pre-print and has not been peer reviewed.
Smolen et al. studied 38,000 spouse pairs from four neurodevelopmental disease cohorts and the UK Biobank to identify associations with neurodevelopmental disease risk in children. Based on their analysis, they propose that spousal assortment on neuropsychiatric features drives disease risk by increasing genome-wide homozygosity in children.
Let us know if you’ve read or published a paper or article recently that you think the 8p community should know about!
💜 Family Corner
No one understands 8p heroes better than themselves and the ones who love them most. The My Hero Initiative invites families to share their 8p hero’s journey and add their piece to the Chromosome 8p Puzzle.
This puzzle of 8p reflects many questions such as:
What does this diagnosis mean?
What symptoms do I look out for?
What can I do to improve these symptoms?
What treatments have worked and what did not work?
What should I expect in the next 1 year, 3 years, 10 years, and future?
Who is experiencing the same challenges I am?
Is there an 8p expert to help me?
Is there a path to a cure?
By participating consistently, we can work as a community to answer these questions for you.
📆 Upcoming Events
No Research Roundtable for the month of August. We’ll see you again in September!
I think all of the research is so exciting. To think 25 years ago when Shelby was diagnosed, nobody knew anything. From 1998 to 2019 we had to educate any doctor or facility we saw because they had never heard anything about Chromosome 8 abnormalities. Even though most of our doctors have been pretty well "trained" now (haha) it is always nice to have new information to pass on to them! I am super excited that our very young and future heroes will not have to feel like they are on a solo journey without a map!