ORCID Profile
0000-0002-8246-4014
Current Organisations
Howard Hughes Medical Institute
,
University of Washington
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Publisher: Cold Spring Harbor Laboratory
Date: 06-03-2023
DOI: 10.1101/2023.03.04.531072
Abstract: The genetic mechanisms underlying the expansion in size and complexity of the human brain remains poorly understood. L1 retrotransposons are a source of ergent genetic information in hominoid genomes, but their importance in physiological functions and their contribution to human brain evolution is largely unknown. Using multi-omic profiling we here demonstrate that L1-promoters are dynamically active in the developing and adult human brain. L1s generate hundreds of developmentally regulated and cell-type specific transcripts, many which are co-opted as chimeric transcripts or regulatory RNAs. One L1-derived lncRNA, LINC01876, is a human-specific transcript expressed exclusively during brain development. CRISPRi-silencing of LINC01876 results in reduced size of cerebral organoids and premature differentiation of neural progenitors, implicating L1s in human-specific developmental processes. In summary, our results demonstrate that L1-derived transcripts provide a previously undescribed layer of primate- and human-specific transcriptome complexity that contributes to the functional ersification of the human brain.
Publisher: Springer Science and Business Media LLC
Date: 05-12-2017
Publisher: Cold Spring Harbor Laboratory
Date: 12-2022
DOI: 10.1101/2022.12.01.518724
Abstract: The human Y chromosome has been notoriously difficult to sequence and assemble because of its complex repeat structure including long palindromes, tandem repeats, and segmental duplications 1–3 . As a result, more than half of the Y chromosome is missing from the GRCh38 reference sequence and it remains the last human chromosome to be finished 4, 5 . Here, the Telomere-to-Telomere (T2T) consortium presents the complete 62,460,029 base pair sequence of a human Y chromosome from the HG002 genome (T2T-Y) that corrects multiple errors in GRCh38-Y and adds over 30 million base pairs of sequence to the reference, revealing the complete liconic structures of TSPY , DAZ , and RBMY gene families 41 additional protein-coding genes, mostly from the TSPY family and an alternating pattern of human satellite 1 and 3 blocks in the heterochromatic Yq12 region. We have combined T2T-Y with a prior assembly of the CHM13 genome 4 and mapped available population variation, clinical variants, and functional genomics data to produce a complete and comprehensive reference sequence for all 24 human chromosomes.
Publisher: Proceedings of the National Academy of Sciences
Date: 23-04-2018
Abstract: Genetic variation of the complement factor H ( CFH ) gene family is associated with several complex diseases. Here, we have performed both long- and short-read sequencing of multiple humans and nonhuman primates in an effort to understand its complex evolutionary history. We find that this locus has evolved predominantly through incomplete segmental duplication and identify recurrent reuse of donor and acceptor duplications leading to CFHR fusion genes with erse functions. Investigation of a large cohort of patients with age-related macular degeneration revealed multiple structural variation breakpoints and mutational burdens that cluster in specific domains of the CFH protein. These domains overlap sites showing signatures of natural selection, providing strong evidence for the shared role of selective pressure on ersity and disease.
Publisher: Springer Science and Business Media LLC
Date: 15-10-2019
DOI: 10.1038/S41467-019-12435-8
Abstract: Postsynaptic density (PSD) proteins have been implicated in the pathophysiology of neurodevelopmental and psychiatric disorders. Here, we present detailed clinical and genetic data for 20 patients with likely gene-disrupting mutations in TANC2 —whose protein product interacts with multiple PSD proteins. Pediatric patients with disruptive mutations present with autism, intellectual disability, and delayed language and motor development. In addition to a variable degree of epilepsy and facial dysmorphism, we observe a pattern of more complex psychiatric dysfunction or behavioral problems in adult probands or carrier parents. Although this observation requires replication to establish statistical significance, it also suggests that mutations in this gene are associated with a variety of neuropsychiatric disorders consistent with its postsynaptic function. We find that TANC2 is expressed broadly in the human developing brain, especially in excitatory neurons and glial cells, but shows a more restricted pattern in Drosophila glial cells where its disruption affects behavioral outcomes.
Publisher: American Association for the Advancement of Science (AAAS)
Date: 04-06-2021
Abstract: Autism-associated CHD8/CHD7/kismet deficiency in blood-brain barrier glia causes developmental hyperserotonemia and sleep defects.
Publisher: Cold Spring Harbor Laboratory
Date: 16-08-2019
DOI: 10.1101/735928
Abstract: After nearly two decades of improvements, the current human reference genome (GRCh38) is the most accurate and complete vertebrate genome ever produced. However, no one chromosome has been finished end to end, and hundreds of unresolved gaps persist 1,2 . The remaining gaps include ribosomal rDNA arrays, large near-identical segmental duplications, and satellite DNA arrays. These regions harbor largely unexplored variation of unknown consequence, and their absence from the current reference genome can lead to experimental artifacts and hide true variants when re-sequencing additional human genomes. Here we present a de novo human genome assembly that surpasses the continuity of GRCh38 2 , along with the first gapless, telomere-to-telomere assembly of a human chromosome. This was enabled by high-coverage, ultra-long-read nanopore sequencing of the complete hydatidiform mole CHM13 genome, combined with complementary technologies for quality improvement and validation. Focusing our efforts on the human X chromosome 3 , we reconstructed the ∼2.8 megabase centromeric satellite DNA array and closed all 29 remaining gaps in the current reference, including new sequence from the human pseudoautosomal regions and cancer-testis liconic gene families (CT-X and GAGE). This complete chromosome X, combined with the ultra-long nanopore data, also allowed us to map methylation patterns across complex tandem repeats and satellite arrays for the first time. These results demonstrate that finishing the human genome is now within reach and will enable ongoing efforts to complete the remaining human chromosomes.
Publisher: Springer Science and Business Media LLC
Date: 14-07-2020
DOI: 10.1038/S41586-020-2547-7
Abstract: After two decades of improvements, the current human reference genome (GRCh38) is the most accurate and complete vertebrate genome ever produced. However, no single chromosome has been finished end to end, and hundreds of unresolved gaps persist 1,2 . Here we present a human genome assembly that surpasses the continuity of GRCh38 2 , along with a gapless, telomere-to-telomere assembly of a human chromosome. This was enabled by high-coverage, ultra-long-read nanopore sequencing of the complete hydatidiform mole CHM13 genome, combined with complementary technologies for quality improvement and validation. Focusing our efforts on the human X chromosome 3 , we reconstructed the centromeric satellite DNA array (approximately 3.1 Mb) and closed the 29 remaining gaps in the current reference, including new sequences from the human pseudoautosomal regions and from cancer-testis liconic gene families (CT-X and GAGE). These sequences will be integrated into future human reference genome releases. In addition, the complete chromosome X, combined with the ultra-long nanopore data, allowed us to map methylation patterns across complex tandem repeats and satellite arrays. Our results demonstrate that finishing the entire human genome is now within reach, and the data presented here will facilitate ongoing efforts to complete the other human chromosomes.
Publisher: American Association for the Advancement of Science (AAAS)
Date: 03-08-2018
Abstract: Flores Island in Indonesia has a long history of hominin occupation, including by the extinct Homo floresiensis and a more recent settlement by modern humans. Furthermore, Flores has an extant population of pygmy humans, and H. floresiensis exhibited a diminutive adult size relative to other hominins. Tucci et al. examined genetic variation among 32 in iduals, including 10 sequenced genomes, from a population of pygmies living close to the cave where H. floresiensis remains were discovered. These in iduals exhibit signatures of polygenic selection explaining the short stature and have genomic content from both Neanderthals and Denisovans, but no additional archaic lineages. Thus, restricted height is under selection at this location and has evolved independently at least twice in hominins. Science , this issue p. 511
Publisher: American Association for the Advancement of Science (AAAS)
Date: 06-09-2929
Abstract: CSDE1 disruptive mutations are associated with autism.
No related grants have been discovered for Evan Eichler.