Publications by authors named "Kirill Grigorev"

10 Publications

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Cell-free DNA (cfDNA) and Exosome Profiling from a Year-Long Human Spaceflight Reveals Circulating Biomarkers.

iScience 2020 Dec 25;23(12):101844. Epub 2020 Nov 25.

Department of Physiology and Biophysics, Weill Cornell Medicine, 1305 York Avenue, Y13-05, New York, NY 10021, USA.

Liquid biopsies based on cell-free DNA (cfDNA) or exosomes provide a noninvasive approach to monitor human health and disease but have not been utilized for astronauts. Here, we profile cfDNA characteristics, including fragment size, cellular deconvolution, and nucleosome positioning, in an astronaut during a year-long mission on the International Space Station, compared to his identical twin on Earth and healthy donors. We observed a significant increase in the proportion of cell-free mitochondrial DNA (cf-mtDNA) inflight, and analysis of post-flight exosomes in plasma revealed a 30-fold increase in circulating exosomes and patient-specific protein cargo (including brain-derived peptides) after the year-long mission. This longitudinal analysis of astronaut cfDNA during spaceflight and the exosome profiles highlights their utility for astronaut health monitoring, as well as cf-mtDNA levels as a potential biomarker for physiological stress or immune system responses related to microgravity, radiation exposure, and the other unique environmental conditions of spaceflight.
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http://dx.doi.org/10.1016/j.isci.2020.101844DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7756145PMC
December 2020

Temporal Telomere and DNA Damage Responses in the Space Radiation Environment.

Cell Rep 2020 Dec 25;33(10):108435. Epub 2020 Nov 25.

Department of Environmental and Radiological Health Sciences, Colorado State University, Fort Collins, CO, USA; Cell and Molecular Biology Program, Colorado State University, Fort Collins, CO, USA. Electronic address:

Telomeres, repetitive terminal features of chromosomes essential for maintaining genome integrity, shorten with cell division, lifestyle factors and stresses, and environmental exposures, and so they provide a robust biomarker of health, aging, and age-related diseases. We assessed telomere length dynamics (changes over time) in three unrelated astronauts before, during, and after 1-year or 6-month missions aboard the International Space Station (ISS). Similar to our results for National Aeronautics and Space Administration's (NASA's) One-Year Mission twin astronaut (Garrett-Bakelman et al., 2019), significantly longer telomeres were observed during spaceflight for two 6-month mission astronauts. Furthermore, telomere length shortened rapidly after return to Earth for all three crewmembers and, overall, telomere length tended to be shorter after spaceflight than before spaceflight. Consistent with chronic exposure to the space radiation environment, signatures of persistent DNA damage responses were also detected, including mitochondrial and oxidative stress, inflammation, and telomeric and chromosomal aberrations, which together provide potential mechanistic insight into spaceflight-specific telomere elongation.
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http://dx.doi.org/10.1016/j.celrep.2020.108435DOI Listing
December 2020

Advancing the Integration of Biosciences Data Sharing to Further Enable Space Exploration.

Cell Rep 2020 Dec 25;33(10):108441. Epub 2020 Nov 25.

Space Biosciences Division, NASA Ames Research Center, Moffett Field, CA 94035, USA. Electronic address:

Understanding the impact of space exploration remains biologically elusive. Cell Press is dedicating this month to spaceflight (Afshinnekoo et al., 2020), with the open science NASA GeneLab database enabling the study revealing mitochondria as a key biological feature from spaceflight (da Silveira et al., 2020).
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http://dx.doi.org/10.1016/j.celrep.2020.108441DOI Listing
December 2020

NASA GeneLab: interfaces for the exploration of space omics data.

Nucleic Acids Res 2021 01;49(D1):D1515-D1522

NASA Ames Research Center, Moffett Field, CA 94035, USA.

The mission of NASA's GeneLab database (https://genelab.nasa.gov/) is to collect, curate, and provide access to the genomic, transcriptomic, proteomic and metabolomic (so-called 'omics') data from biospecimens flown in space or exposed to simulated space stressors, maximizing their utilization. This large collection of data enables the exploration of molecular network responses to space environments using a systems biology approach. We review here the various components of the GeneLab platform, including the new data repository web interface, and the GeneLab Online Data Entry (GEODE) web portal, which will support the expansion of the database in the future to include companion non-omics assay data. We discuss our design for GEODE, particularly how it promotes investigators providing more accurate metadata, reducing the curation effort required of GeneLab staff. We also introduce here a new GeneLab Application Programming Interface (API) specifically designed to support tools for the visualization of processed omics data. We review the outreach efforts by GeneLab to utilize the spaceflight data in the repository to generate novel discoveries and develop new hypotheses, including spearheading data analysis working groups, and a high school student training program. All these efforts are aimed ultimately at supporting precision risk management for human space exploration.
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http://dx.doi.org/10.1093/nar/gkaa887DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7778922PMC
January 2021

Epigenetic evolution and lineage histories of chronic lymphocytic leukaemia.

Nature 2019 05 15;569(7757):576-580. Epub 2019 May 15.

New York Genome Center, New York, NY, USA.

Genetic and epigenetic intra-tumoral heterogeneity cooperate to shape the evolutionary course of cancer. Chronic lymphocytic leukaemia (CLL) is a highly informative model for cancer evolution as it undergoes substantial genetic diversification and evolution after therapy. The CLL epigenome is also an important disease-defining feature, and growing populations of cells in CLL diversify by stochastic changes in DNA methylation known as epimutations. However, previous studies using bulk sequencing methods to analyse the patterns of DNA methylation were unable to determine whether epimutations affect CLL populations homogeneously. Here, to measure the epimutation rate at single-cell resolution, we applied multiplexed single-cell reduced-representation bisulfite sequencing to B cells from healthy donors and patients with CLL. We observed that the common clonal origin of CLL results in a consistently increased epimutation rate, with low variability in the cell-to-cell epimutation rate. By contrast, variable epimutation rates across healthy B cells reflect diverse evolutionary ages across the trajectory of B cell differentiation, consistent with epimutations serving as a molecular clock. Heritable epimutation information allowed us to reconstruct lineages at high-resolution with single-cell data, and to apply this directly to patient samples. The CLL lineage tree shape revealed earlier branching and longer branch lengths than in normal B cells, reflecting rapid drift after the initial malignant transformation and a greater proliferative history. Integration of single-cell bisulfite sequencing analysis with single-cell transcriptomes and genotyping confirmed that genetic subclones mapped to distinct clades, as inferred solely on the basis of epimutation information. Finally, to examine potential lineage biases during therapy, we profiled serial samples during ibrutinib-associated lymphocytosis, and identified clades of cells that were preferentially expelled from the lymph node after treatment, marked by distinct transcriptional profiles. The single-cell integration of genetic, epigenetic and transcriptional information thus charts the lineage history of CLL and its evolution with therapy.
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http://dx.doi.org/10.1038/s41586-019-1198-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6533116PMC
May 2019

Single-molecule sequencing detection of N6-methyladenine in microbial reference materials.

Nat Commun 2019 02 4;10(1):579. Epub 2019 Feb 4.

Department of Physiology and Biophysics, Weill Cornell Medicine, New York, 10065, NY, USA.

The DNA base modification N6-methyladenine (mA) is involved in many pathways related to the survival of bacteria and their interactions with hosts. Nanopore sequencing offers a new, portable method to detect base modifications. Here, we show that a neural network can improve mA detection at trained sequence contexts compared to previously published methods using deviations between measured and expected current values as each adenine travels through a pore. The model, implemented as the mCaller software package, can be extended to detect known or confirm suspected methyltransferase target motifs based on predictions of methylation at untrained contexts. We use PacBio, Oxford Nanopore, methylated DNA immunoprecipitation sequencing (MeDIP-seq), and whole-genome bisulfite sequencing data to generate and orthogonally validate methylomes for eight microbial reference species. These well-characterized microbial references can serve as controls in the development and evaluation of future methods for the identification of base modifications from single-molecule sequencing data.
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http://dx.doi.org/10.1038/s41467-019-08289-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6362088PMC
February 2019

Genomes of Three Closely Related Caribbean Amazons Provide Insight for Species History and Conservation.

Genes (Basel) 2019 01 16;10(1). Epub 2019 Jan 16.

Department of Biology, University of Puerto Rico at Mayaguez, Mayaguez, PR 00680, USA.

Islands have been used as model systems for studies of speciation and extinction since Darwin published his observations about finches found on the Galapagos. Amazon parrots inhabiting the Greater Antillean Islands represent a fascinating model of species diversification. Unfortunately, many of these birds are threatened as a result of human activity and some, like the Puerto Rican parrot, are now critically endangered. In this study we used a combination of de novo and reference-assisted assembly methods, integrating it with information obtained from related genomes to perform genome reconstruction of three amazon species. First, we used whole genome sequencing data to generate a new de novo genome assembly for the Puerto Rican parrot (). We then improved the obtained assembly using transcriptome data from used the resulting sequences as a reference to assemble the genomes Hispaniolan () and Cuban () parrots. Finally, we, annotated genes and repetitive elements, estimated genome sizes and current levels of heterozygosity, built models of demographic history and provided interpretation of our findings in the context of parrot evolution in the Caribbean.
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http://dx.doi.org/10.3390/genes10010054DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6356210PMC
January 2019

Innovative assembly strategy contributes to understanding the evolution and conservation genetics of the endangered Solenodon paradoxus from the island of Hispaniola.

Gigascience 2018 06;7(6)

Department of Biology, University of Puerto Rico at Mayagüez, Mayagüez, Puerto Rico.

Solenodons are insectivores that live in Hispaniola and Cuba. They form an isolated branch in the tree of placental mammals that are highly divergent from other eulipothyplan insectivores The history, unique biology, and adaptations of these enigmatic venomous species could be illuminated by the availability of genome data. However, a whole genome assembly for solenodons has not been previously performed, partially due to the difficulty in obtaining samples from the field. Island isolation and reduced numbers have likely resulted in high homozygosity within the Hispaniolan solenodon (Solenodon paradoxus). Thus, we tested the performance of several assembly strategies on the genome of this genetically impoverished species. The string graph-based assembly strategy seemed a better choice compared to the conventional de Bruijn graph approach due to the high levels of homozygosity, which is often a hallmark of endemic or endangered species. A consensus reference genome was assembled from sequences of 5 individuals from the southern subspecies (S. p. woodi). In addition, we obtained an additional sequence from 1 sample of the northern subspecies (S. p. paradoxus). The resulting genome assemblies were compared to each other and annotated for genes, with an emphasis on venom genes, repeats, variable microsatellite loci, and other genomic variants. Phylogenetic positioning and selection signatures were inferred based on 4,416 single-copy orthologs from 10 other mammals. We estimated that solenodons diverged from other extant mammals 73.6 million years ago. Patterns of single-nucleotide polymorphism variation allowed us to infer population demography, which supported a subspecies split within the Hispaniolan solenodon at least 300 thousand years ago.
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http://dx.doi.org/10.1093/gigascience/giy025DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6009670PMC
June 2018

Developmental dynamics of the epigenome: A longitudinal study of three toddlers.

Neurotoxicol Teratol 2018 Mar - Apr;66:125-131. Epub 2017 Dec 13.

Dept. of Psychology, University of Houston, Houston, TX, USA; Dept. of Psychology, Saint Petersburg State University, St. Petersburg, Russia; Child Study Center, Yale University, New Haven, CT, USA; Office of the Rector, Moscow State University of Psychology and Education, Moscow, Russia. Electronic address:

Epigenetic regulation plays an important role in development, at the embryonic stages and later during the lifespan. Some epigenetic marks are highly conserved throughout the lifespan whereas others are closely associated with specific age periods and/or particular environmental factors. Little is known about the dynamics of epigenetic regulation during childhood, especially during the period of rapid early development. Our study was aimed to determine whether the developmental program at the early stages of human development is accompanied by significant changes in the systems of genome regulation, specifically, by genome-wide changes in DNA methylation. Using a sequencing approach (MBD-seq) we investigated genome-wide DNA methylation patterns in the T-lymphocytes of three healthy toddlers at two timepoints within the second year of life. Pairwise comparison of the methylation patterns across the individuals and time points was conducted to determine common longitudinal changes in the DNA methylation patterns. Despite relatively high interindividual variability in their epigenetic profiles and the dynamics of these profiles during the second year of life, all children showed consistent changes in the DNA methylation patterns of genes involved in the control of the immune system and genes related to the development of the CNS. Thereby, we provide evidence that early development might be accompanied by epigenetic changes in specific functional groups of genes; many such epigenetic changes appear to be related to the rapid development of the CNS.
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http://dx.doi.org/10.1016/j.ntt.2017.12.006DOI Listing
January 2020

Mitogenomic sequences support a north-south subspecies subdivision within Solenodon paradoxus.

Mitochondrial DNA A DNA Mapp Seq Anal 2017 09 20;28(5):662-670. Epub 2016 Apr 20.

a Department of Animal Sciences , University of Illinois at Urbana-Champaign , Urbana , IL , USA.

Solenodons are insectivores found only in Hispaniola and Cuba, with a Mesozoic divergence date versus extant mainland mammals. Solenodons are the oldest lineage of living eutherian mammal for which a mitogenome sequence has not been reported. We determined complete mitogenome sequences for six Hispaniolan solenodons (Solenodon paradoxus) using next-generation sequencing. The solenodon mitogenomes were 16,454-16,457 bp long and carried the expected repertoire of genes. A mitogenomic phylogeny confirmed the basal position of solenodons relative to shrews and moles, with solenodon mitogenomes estimated to have diverged from those of other mammals ca. 78 Mya. Control region sequences of solenodons from the northern (n = 3) and southern (n = 5) Dominican Republic grouped separately in a network, with F = 0.72 (p = 0.036) between north and south. This regional genetic divergence supports previous morphological and genetic reports recognizing northern (S. p. paradoxus) and southern (S. p. woodi) subspecies in need of separate conservation plans.
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http://dx.doi.org/10.3109/24701394.2016.1167891DOI Listing
September 2017