Publication from the lab in Nucleic Acids Research

posted Feb 18, 2019, 10:33 AM by Alexej Abyzov   [ updated Feb 18, 2019, 10:33 AM ]

https://doi.org/10.1093/nar/gkz103

Chromatin organization modulates the origin of heritable structural variations in human genome 

Structural variations (SVs) in the human genome originate from different mechanisms related to DNA repair, replication errors, and retrotransposition. Our analyses of 26 927 SVs from the 1000 Genomes Project revealed differential distributions and consequences of SVs of different origin, e.g. deletions from non-allelic homologous recombination (NAHR) are more prone to disrupt chromatin organization while processed pseudogenes can create accessible chromatin. Spontaneous double stranded breaks (DSBs) are the best predictor of enrichment of NAHR deletions in open chromatin. This evidence, along with strong physical interaction of NAHR breakpoints belonging to the same deletion suggests that majority of NAHR deletions are non-meiotic i.e. originate from errors during homology directed repair (HDR) of spontaneous DSBs. In turn, the origin of the spontaneous DSBs is associated with transcription factor binding in accessible chromatin revealing the vulnerability of functional, open chromatin. The chromatin itself is enriched with repeats, particularly fixed Alu elements that provide the homology required to maintain stability via HDR. Through co-localization of fixed Alus and NAHR deletions in open chromatin we hypothesize that old Alu expansion had a stabilizing role on the human genome.

Publication from the lab in Science

posted Dec 13, 2018, 11:30 AM by Alexej Abyzov

http://doi.org/10.1126/science.aat6720

Transcriptome and epigenome landscape of human cortical development modeled in organoids

Genes implicated in neuropsychiatric disorders are active in human fetal brain, yet difficult to study in a longitudinal fashion. We demonstrate that organoids from human pluripotent cells model cerebral cortical development on the molecular level before 16 weeks postconception. A multiomics analysis revealed differentially active genes and enhancers, with the greatest changes occurring at the transition from stem cells to progenitors. Networks of converging gene and enhancer modules were as sembled into six and four global patterns of expression and activity across time. A pattern with progressive down-regulation was enriched with human-gained enhancers, suggesting their importance in early human brain development. A few convergent gene and enhancer modules were enriched in autism-associated genes and genomic variants in autistic children. The organoid model helps identify functional elements that may drive disease onset.

New lab member!!!

posted Oct 16, 2018, 10:15 AM by Alexej Abyzov

Postdoctoral fellow Shobana Sekar, Ph.D. joined the lab on October 8, 2018. Welcome!

New lab member!!!

posted Oct 7, 2018, 9:40 PM by Alexej Abyzov   [ updated Oct 7, 2018, 9:40 PM ]

Postdoctoral fellow Milovan Suvakov, Ph.D. joined the lab on September 4, 2018. Welcome!

Publication from the lab in Science

posted Dec 7, 2017, 6:32 PM by Alexej Abyzov   [ updated Dec 7, 2017, 6:33 PM ]

http://doi.org/10.1126/science.aan8690


Different mutational rates and mechanisms in human cells at pregastrulation and neurogenesis

Somatic mosaicism in the human brain may alter function of individual neurons. We analyzed genomes of single cells from the forebrains of three human fetuses (15 to 21 weeks post-conception) using clonal cell populations. We detected 200-400 single nucleotide variations (SNVs) per cell. SNV patterns resembled those found in cancer cell genomes, indicating a role of background mutagenesis in cancer. SNVs with a frequency of >2% in brain were shared with the spleen, revealing a pregastrulation origin. We reconstructed cell lineages for the first five post-zygotic cleavages and calculated a mutation rate of ~1.3 per division per cell. Later in development, during neurogenesis, the mutation spectrum shifted toward oxidative damage and the mutation rate increased. Both neurogenesis and early embryogenesis exhibit drastically more mutagenesis than adulthood.

Publication from the lab in Science

posted Apr 27, 2017, 11:57 AM by Alexej Abyzov

http://science.sciencemag.org/content/356/6336/eaal1641.full


Intersection of diverse neuronal genomes and neuropsychiatric disease: The Brain Somatic Mosaicism Network
Neuropsychiatric disorders have a complex genetic architecture. Human genetic population-based studies have identified numerous heritable sequence and structural genomic variants associated with susceptibility to neuropsychiatric disease. However, these germline variants do not fully account for disease risk. During brain development, progenitor cells undergo billions of cell divisions to generate the ~80 billion neurons in the brain. The failure to accurately repair DNA damage arising during replication, transcription, and cellular metabolism amid this dramatic cellular expansion can lead to somatic mutations. Somatic mutations that alter subsets of neuronal transcriptomes and proteomes can, in turn, affect cell proliferation and survival and lead to neurodevelopmental disorders. The long life span of individual neurons and the direct relationship between neural circuits and behavior suggest that somatic mutations in small populations of neurons can significantly affect individual neurodevelopment. The Brain Somatic Mosaicism Network has been founded to study somatic mosaicism both in neurotypical human brains and in the context of complex neuropsychiatric disorders.

Publication from the lab in Genome Research

posted Mar 7, 2017, 9:40 AM by Alexej Abyzov   [ updated Mar 7, 2017, 9:42 AM ]


One thousand somatic SNVs per skin fibroblast cell set baseline of mosaic mutational load with patterns that suggest proliferative origin
Few studies have been conducted to understand post-zygotic accumulation of mutations in cells of the healthy human body. We reprogrammed 32 skin fibroblast cells from families of donors into human induced pluripotent stem cell (hiPSC) lines. The clonal nature of hiPSC lines allows a high-resolution analysis of the genomes of the founder fibroblast cells without being confounded by the artifacts of single cell whole genome amplification. We estimate that on average a fibroblast cell in children has 1,035 mostly benign mosaic SNVs. On average, 235 SNVs could be directly confirmed in the original fibroblast population by ultra-deep sequencing, down to an allele frequency (AF) of 0.1%. More sensitive droplet digital PCR experiments confirmed more SNVs as mosaic with AF as low as 0.01%, suggesting that 1,035 mosaic SNVs per fibroblast cell is the true average. Similar analyses in adults revealed no significant increase in the number of SNVs per cell, suggesting that a major fraction of mosaic SNVs in fibroblasts arises during development. Mosaic SNVs were distributed uniformly across the genome and were enriched in a mutational signature previously observed in cancers and in de novo variants and which, we hypothesize, is a hallmark of normal cell proliferation. Finally, AF distribution of mosaic SNVs had distinct narrow peaks, which could be a characteristic of clonal cell selection, clonal expansion, or both. These findings reveal a large degree of somatic mosaicism in healthy human tissues, link de novo and cancer mutations to somatic mosaicism and couple somatic mosaicism with cell proliferation.

Publication from the lab in Genome Research

posted May 29, 2016, 5:47 PM by Taejeong Bae   [ updated May 29, 2016, 5:47 PM ]


Elevated variant density around SVs breakpoints in germline lineage lends support to error prone replication hypothesis.
Copy number variants (CNVs) are a class of structural variants that may involve complex genomic rearrangements (CGRs) and that are hypothesized to have additional mutations around their breakpoints. Understanding the mechanisms underlying CNV formation is fundamental for understanding the repair and mutation mechanisms in cells, thereby shedding light on evolution, genomic disorders, cancer, and complex human traits. In this study, we employ data from the 1000 Genomes Project, to analyze hundreds of loci harboring heterozygous germline deletions in the subjects NA12878 and NA19240. By utilizing synthetic long-read data (longer than 2 kbp) in combination with high coverage short-read data and, in parallel, by comparing with parental genomes, we interrogated the phasing of these deletions with the flanking tens of thousands of heterozygous SNPs and indels. We found, that the density of SNPs/indels flanking the breakpoints of deletions (in-phase variants) is approximately twice as high as the corresponding density for the variants on the haplotype without deletion (out-of-phase variants). This fold-change was even larger, for the subset of deletions with signatures of replication-based mechanism of formation. The allele frequency (AF) spectrum for deletions is enriched for rare events; and the AF spectrum for in-phase SNPs is shifted towards this deletion spectrum, thus offering evidence consistent with the concomitance of the in-phase SNPs/indels with the deletion events. These findings, therefore, lend support to the hypothesis that the mutational mechanisms underlying CNV formation are error prone. Our results could also be relevant for resolving mutation rate discrepancies in human and to explain kataegis.

New lab member!!!

posted Feb 17, 2016, 11:09 PM by Alexej Abyzov   [ updated Feb 17, 2016, 11:10 PM ]

Postdoctoral fellow Tanmoy Roychowdhury, Ph.D. joined the lab on February 8, 2016. Welcome!

Publication from the lab in Nature

posted Oct 1, 2015, 10:51 PM by Alexej Abyzov   [ updated Oct 1, 2015, 10:52 PM ]

Our collaborative work within the framework of the 1000 Genomes Project on discovery and analysis of genome structural variants has been published in Nature.


An integrated map of structural variation in 2,504 human genomes
Structural variants are implicated in numerous diseases and make up the majority of varying nucleotides among human genomes. Here we describe an integrated set of eight structural variant classes comprising both balanced and unbalanced variants, which we constructed using short-read DNA sequencing data and statistically phased onto haplotype blocks in 26 human populations. Analysing this set, we identify numerous gene-intersecting structural variants exhibiting population stratification and describe naturally occurring homozygous gene knockouts that suggest the dispensability of a variety of human genes. We demonstrate that structural variants are enriched on haplotypes identified by genome-wide association studies and exhibit enrichment for expression quantitative trait loci. Additionally, we uncover appreciable levels of structural variant complexity at different scales, including genic loci subject to clusters of repeated rearrangement and complex structural variants with multiple breakpoints likely to have formed through individual mutational events. Our catalogue will enhance future studies into structural variant demography, functional impact and disease association.

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