EichlerLab

EichlerLab

@eichlerlab.bsky.social

https://eichler.gs.washington.edu/

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EichlerLab reposted

The American Journal of Human Genetics
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🧬New from @eichlerlab.bsky.social 📄Complete chromosome 21 centromere sequencing of families with Down syndrome 🧑‍🤝‍🧑 @glennislogsdon.bsky.social @fkma.bsky.social & co

cell.comComplete chromosome 21 centromere sequencing of families with Down syndromeThis article describes the genetic and epigenetic landscapes of chromosome 21 centromeres in families with trisomy 21 and the general population. It reveals an extreme size asymmetry of the two matern...
EichlerLab
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Noyes et al. apply long-read sequencing to autism families identifying increased numbers of germline & postzygotic mutations. Repetitive sequences like segmental duplications are hypermutable, especially in early embryo. @uwgenome.bsky.social @hhmi-science.bsky.social www.nature.com/articles/s41...

nature.comLong-read sequencing of families reveals increased germline and postzygotic mutation rates in repetitive DNA - Nature CommunicationsShort‑read sequencing misses many early and repeat‑driven mutations. Here, the authors show that long‑read sequencing in autism families increases detection of germline and postzygotic mutations and r...
EichlerLab
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Real et al. find human-specific NOTCH2NL duplications linked to cortical expansion. Analysis of 82 long-read ape & human genomes shows independent duplications, major structural variation, & gene conversion, with rapid gene & regulatory divergence. @uwgenome.bsky.social www.cell.com/cell-genomic...

cell.comGenetic diversity and regulatory features of human-specific NOTCH2NL duplicationsHuman-specific NOTCH2NL segmental duplications are implicated in brain cortical expansion. Analysis of 82 long-read assemblies from apes and humans shows independent duplications. Human-specific NOTCH...
EichlerLab
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Check out new AoU collaboration paper: Long-read sequencing of 1027 All of Us participants self-identified as African American discovers new structural variant disease associations: www.medrxiv.org/content/10.1... @uwgenome.bsky.social

medrxiv.orgPopulation-scale Long-read Sequencing in the All of Us Research ProgramThe All of Us Research Program (AoU) is a national biobank seeking to enroll one million individuals in the United States to link genomic and biomedical data, including short- and long-read whole-geno...
EichlerLab
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www.biorxiv.org/content/10.1...

biorxiv.orgPopulation differences of chromosome 22q11.2 duplication structure predispose differentially to microdeletion and inversion.The most common genomic disorder, chromosome 22q11.2 microdeletion syndrome (22q11.2DS), is mediated by highly identical and polymorphic segmental duplications (SDs) known as low copy repeats (LCRs; regions A-D) that have been challenging to sequence and characterize. Here, we report the sequence-resolved genomic architecture of 135 chromosome 22q11.2 haplotypes from diverse 1000 Genomes Project samples. We find that more than 90% of the copy number variation is polarized to the most proximal LCR region A (LCRA) where 50 distinct structural configurations are observed (~189 kbp to ~2.15 Mbp or 11-fold length variation). A higher-order SD cassette structure of 105 kbp in length, flanked by 25 kbp long inverted repeats, drives this variation and emerged in the human-chimpanzee ancestral lineage later expanding in humans ~1.0 [0.8-1.2] million years ago. African LCRA haplotypes are significantly longer (p=0.0047) when compared to non-Africans yet are predicted to be more protected against recurrent microdeletions (p=0.00053) due to a preponderance of flanking SDs in an inverted orientation. Conversely, we identified nine distinct inversion polymorphisms, including five recurrent ~2.28 Mbp inversions extending across the critical region (LCRA-D) and four smaller inversions (two LCRA-B, one LCRC-D, and one LCRB-D); 7/9 of these events were identified in haplotypes of African and admixed American ancestry. Finally, we sequence and assemble four families and show that LCRA-D deletion breakpoints map to the 105 kbp repeat unit while inversion breakpoints associate with the 25 kbp repeats adjacent to palindromic AT-rich regions. In one family, we observe evidence of more complex unequal crossover events associated with gene conversion and multiple breakpoints. Our findings suggest that specific haplotype configurations are protective and susceptible to chromosome 22q11.2DS while recurrent large-scale inversions help to explain why this syndrome is less prevalent among individuals of African descent. ### Competing Interest Statement E.E.E. is a scientific advisory board (SAB) member of Variant Bio, Inc. D.P. and J.O.K. have previously disclosed a patent application (no. EP19169090) relevant to Strand-seq. P.M.L. is a founding shareholder of Repeat Diagnostic, Inc. and in Evident Genomics, Inc. He is listed as an inventor in US patent US-20250146052-A1. All other authors declare no competing interests.
EichlerLab
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Our Nature paper (rdcu.be/ei1NM) deep sequencing a 4-generation, 28-member family using multiple sequencing technologies to study transmission of all classes of genetic variation is out! @uwgenome.bsky.social @hhmi.org @pacbio.bsky.social @utah.edu

rdcu.beHuman de novo mutation rates from a four-generation pedigree referenceNature - Analysis of more than 95% of each diploid human genome of a four-generation, twenty-eight-member family using five complementary short-read and long-read sequencing technologies provides a...
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Advanced genomic analysis of 4 generation family offers new knowledge about genetic mutations & their transmission, including inherited variants & those that arise anew @nature.com @uwgenome.bsky.social @eichlerlab.bsky.social @uwmedicine.bsky.social @utah.edu @pacbio.bsky.social

bit.ly4 generations help science explore genome mutation rate - UW Medicine | Newsroom

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