Category Archives: Transhuman News

Bionano Genomics, which has commercialized a genome analysis platform used in laboratories across the world, is acquiring software firm BioDiscovery in a $90 million deal intended to broaden the reach of its technology, the company announced Tuesday.

The technology of San Diego-based Bionano technology offers whats called optical genome mapping, which is an analysis of the genome that reveals structural variations in the DNA of one person compared to another. These structural variations can cause disease. Scientists and clinicians use the technology to find and identify these variations as a way of better understanding a disease, or to find targets for potential new drugs and diagnostics.

The Bionano platform, called Saphyr, is comprised of an instrument, a consumable chip that holds a sample, and software that provides structural variation analysis. The publicly traded company reported total global revenue of $8.5 million last year.

The software of El Segundo, California-based BioDiscovery collects various pieces of genetic data, providing a full picture that can be analyzed and interpreted. Like Bionano, BioDiscovery has customers across the world. According to a Bionano investor presentation, BioDiscoverys 2020 revenue was $3.6 million, and the 25-year-old company is profitable.

Bionano said in the presentation that it sees software as the key to bringing its optical genome mapping offering to more users. While Bionano specializes in optical genome mapping, clinical research labs want data analyses across platforms. BioDiscoverys software, called NxClinical, can integrate optical genome mapping with next-generation sequencing, as well as data from arrays. The plan is to integrate Bionanos optical genome mapping data into a commercially available version of NxClinical.

Integration of all genomic data types into one software solution can make [optical genome mapping] ubiquitous, Bionano said in the presentation.

The financial terms of the BioDiscovery acquisition break down to $50 million in cash and $40 million in Bionano stock. An additional $10 million cash is tied to the achievement of undisclosed commercial milestones. Vesting of a portion of the equity part of the transaction is tied to key employees of BioDiscovery staying with the company; part of the cash payment is tied to the achievement of full integration of optical genome mapping data into the BioDiscovery platform.

The companies expect the transaction to close by Oct. 22. When it does, Soheil Shams, BioDiscoverys founder and CEO, will join Bionano as chief informatics officer.

Photo: iLexx, Getty Images

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Bionano frames $90M BioDiscovery buy as way to expand genomics analysis - MedCity News

Researchers in Maryland have sequenced the genome of the blue crab, according to the Baltimore Sun. It adds that the blue crab genome could help researchers better understand diseases affecting crabs as well as uncover how to breed meatier crabs.

The University of Maryland's Sook Chung combined long Pacific Biosciences reads with short Illumina reads to piece together the blue crab, Callinectes sapidusRathbun, genome. She and her team reported in G3: Genes, Genomes, Genetics that they generated 50 chromosome-scale scaffoldsand predicted 25,249 protein-coding genes.

"Marylanders love crabs, and everybody wants to have big, fat crabs in the fall. Understanding what makes them successful is located in the chromosomes," Chung tells CBS Baltimore. "Knowing the full genome, we are several steps closer to identifying the genes responsible for growth, reproduction, and susceptibility to disease."

Chung further tells the Sun that they have already homed in on the gene encoding the molting hormone. That, she says, could help improve blue crab farming by getting crabs to all molt at the same time and pose less of a danger to one another at that vulnerable time.

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For All the Blue Crabs in Maryland - GenomeWeb

Approach using evolutionary principles identifies genes that enable plants to grow with less fertilize

A new study identifies genes that enable plants to grow with less fertilizer.

October 13, 2021

Machine learning, a type of artificial intelligence used to detect patterns in data, can pinpoint "genes of importance" that help crops grow with less fertilizer, according to a U.S. National Science Foundation-funded study published in Nature Communications. It can also predict additional traits in plants and disease outcomes in animals, illustrating its applications beyond agriculture.

"This is an excellent example of how NSF-supported scientists lead the way in using AI and cutting-edge computational approaches to accelerate translation of basic plant genomic research and discoveries to the field," said Diane Okamuro, a program director in NSF's Division of Integrative Organismal Systems.

Using genomic data to predict outcomes in agriculture and medicine is both a promise and challenge for systems biology. Researchers have been working to determine how best to use the vast amount of genomic data available to predict how organisms respond to changes in nutrition, toxins and pathogen exposure -- which in turn would inform crop improvement, disease prognosis, epidemiology and public health. But accurately predicting such complex outcomes in agriculture and medicine from genome-scale information remains a significant challenge.

"We show that focusing on genes whose expression patterns are evolutionarily conserved across species enhances our ability to learn and predict 'genes of importance' to growth performance for staple crops, as well as disease outcomes in animals," said Gloria Coruzzi, of New York University's Center for Genomics and Systems Biology and the paper's senior author.

The researchers conducted experiments that validated eight master transcription factors as genes of importance to nitrogen use efficiency. They showed that altered gene expression in Arabidopsis and in corn could increase plant growth in low nitrogen soils, which they tested in the lab at NYU and in cornfields at the University of Illinois.

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Machine learning uncovers 'genes of importance' in agriculture - National Science Foundation

Leprosy is a neglected tropical disease caused by the bacterial pathogens M.leprae and the more recently discovered Mycobacteriumlepromatosis8,9. In humans, the disease presents as a continuum of clinical manifestations with skin and nerve lesions of increasing severity, from the mildest tuberculoid form (or paucibacillary) to the most severe lepromatous type (or multibacillary)10. Symptoms develop after a long incubation period ranging from several months to 30years, averaging 5years in humans. As a result of sensory loss, leprosy can lead to permanent damage and severe deformity11. Although leprosy prevalence has markedly decreased over recent decades, approximately 210,000 new human cases are still reported every year, of which 2.3% are located in West Africa12. Transmission is thought to occur primarily between individuals with prolonged and close contact via aerosolized nasal secretions and entry through nasal or respiratory mucosae, but the exact mechanism remains unclear13,14. The role of other routes, such as skin-to-skin contact, is unknown.

Leprosy-causing bacteria were once thought to be obligate human pathogens1. However, they can circulate in other animal hosts in the wild, such as nine-banded armadillos (Dasypusnovemcinctus) in the Americas and red squirrels (Sciurusvulgaris) in the UK2,3. Although initial infection was most probably incidental and of human origin, secondary animal hosts can subsequently represent a source of infection to humans15,16,17,18. In captivity, nonhuman primates, such as chimpanzees (Pantroglodytes)4, sooty mangabeys (Cercocebusatys)5,6 and cynomolgus macaques (Macacafascicularis)7, have been known to develop leprosy without any obvious infectious source. However, due to their captive status, it is unclear how they acquired M.leprae and whether these species can also contract leprosy in the wild.

Here, we report leprosy infections and their disease course in two wild populations of western chimpanzees (P.troglodytes verus) in Cantanhez National Park (CNP), Guinea-Bissau, and in Ta National Park (TNP), Cte dIvoire, using a combination of camera trap and veterinary monitoring (Extended Data Fig. 1a and Supplementary Notes1 and 2). From analyses of faecal samples and postmortem tissues, we identified M.leprae as the causative agent of the lesions observed and determined the phylogenetic placement of the respective strains based on their complete genome sequences.

Chimpanzees at CNP are not habituated to human observers, precluding systematic behavioural observations. Longitudinal studies necessitate the use of camera traps, which we operated between 2015 and 2019. Of 624,194 data files (videos and photographs) obtained across 211 locations at CNP (Extended Data Fig. 1b, Extended Data Table 1 and Supplementary Table 1), 31,044 (5.0%) contained chimpanzees. The number of independent events (images separated by at least 60min) totalled 4,336, and of these, 241 (5.6%) contained chimpanzees with severe leprosy-like lesions, including four clearly identifiable individuals (two adult females and two adult males) across three communities (Extended Data Fig. 2 and Supplementary Note2). As with humans, paucibacillary cases in chimpanzees may be present but easily go undetected. Such minor manifestations of leprosy are not reported. All symptomatic chimpanzees showed hair loss and facial skin hypopigmentation, as well as plaques and nodules that covered different areas of their body (limbs, trunk and genitals), facial disfigurement and ulcerated and deformed hands (claw hand) and feet (Fig. 1ac), consistent with a multibacillary form of the disease. Longitudinal observations showed progression of symptoms across time with certain manifestations similar to those described in humans (such as progressive deformation of the hands) (Extended Data Fig. 2 and Supplementary Videos13). To confirm infection with M.leprae, we collected faecal samples and tested them with two nested polymerase chain reaction (PCR) assays targeting the M.leprae-specific repetitive element (RLEP) and 18kDa antigen gene. One out of 208 DNA extracts from CNP was positive in both assays and a second was positive only in the more sensitive RLEP-PCR19 (Extended Data Table 2, Supplementary Table 2 and Supplementary Note3). Microsatellite analyses of the two positive samples confirmed that they originated from two distinct female individuals (Supplementary Note4 and Supplementary Tables 3 and 4). Our results suggest that M.leprae is the most likely cause of a leprosy-like syndrome in chimpanzees from CNP.

ac, Clinical signs of leprosy in two adult female chimpanzees in CNP (images extracted from camera traps). a, Rita has large hypopigmented nodules covering the entire body; disfigurement of the face, ears, hands and feet (ulcerated lesions and swelling). b, Rita has extensive plaques covering all limbs, with hair loss. c, Brinkos has large hypopigmented nodules covering the entire face, with extreme disfigurement of the face and ears, and ulcerated plaques on the arms and the nipples. dg, Clinical signs of leprosy in an adult male chimpanzee, Woodstock, at TNP. d, Multiple hypopigmented nodules on the ears, brow ridges, eyelid margins, nostrils, lips and the area between the upper lip and the nose. e, Hypopigmentation and swelling of the hands with ulcerations and hair loss on the dorsal side of the joints. f, Claw hand with nail loss and abnormal overgrowth of fingernails. g, Scrotal reddening and ulceration with fresh blood.

At TNP, chimpanzees are habituated to the presence of researchers and have been followed daily since 1979. In addition, necropsy samples have been collected from all dead individuals recovered since 2000. In June 2018, researchers first noticed leprosy-like lesions on Woodstock, an adult male chimpanzee from one of the three habituated communities (south) (Extended Data Fig. 1c). The initial small nodules on the ears, lips and under the eye became more prominent and were followed by nodules on the eyebrows, eyelids, nostrils, ears, lips and face. The skin on facial nodules, hands, feet and testicles became hypopigmented and the loss and abnormal growth of nails was observed (Fig1dg, Extended Data Fig. 3 and Supplementary Videos4 and 5). Mycobacteriumleprae DNA was detected in all samples from June 2018 (Extended Data Table 2, Supplementary Table 2 and Supplementary Note2). Here, continuous noninvasive detection of M.leprae was associated with the onset and evolution of a leprosy-like disease.

Retrospective PCR screening of all chimpanzee spleen samples (n=38 individuals) from the TNP necropsy collection led to the identification of M.leprae DNA in two further individuals. An adult female from the same community named Zora, who had been killed by a leopard in 2009, tested positive in both PCR assays. The presence of M.leprae DNA was confirmed by PCR in various other organs (Extended Data Table 2). Retrospective analyses of photographs taken in the years before her death showed progressive skin hypopigmentation and nodule development since 2007 (Extended Data Fig. 3). Formalin-fixed skin samples (hands and feet) were prepared for histopathological examination using haematoxylin and eosin as well as Fite-Faraco stains. The skin presented typical signs of lepromatous leprosy characterized by a diffuse cutaneous cell infiltration in the dermis and the subcutis clearly separated from the basal layer of the epidermis (Extended Data Fig. 4a). We detected moderate numbers of acid-fast bacilli (single or in clumps) within histiocytes, indicative of M.leprae (Extended Data Fig. 4b). As antibodies against the M.leprae-specific antigen phenolic glycolipid-I (PGL-I) are a hallmark of M.leprae infection in humans20, we also performed a PGL-I lateral flow rapid test21 on a blood sample from this individual, which showed strong seropositivity (Extended Data Fig. 4c). Faecal samples collected in the years before Zoras death contained M.leprae DNA from 2002 onwards, implying at least 7 years of infection (Extended Data Table 2). In this case, disease manifestations, histopathological findings, serological and molecular data, as well as the overall course of the disease, all unambiguously point towards M.leprae-induced leprosy.

To ascertain whether other individuals in the south community of TNP were infected at the time of Zoras death in 2009, cross-sectional screening of contact animals (n=32) was performed by testing all available faecal samples (n=176) collected in 2009 (Supplementary Table 2). Three other chimpanzees were PCR-positive in single samples, including Woodstock. Clinical symptoms of leprosy have not been observed in other individuals, despite daily monitoring of south community members for 20 years and of neighbouring communities for 40 years22,23. Considering that, over this period, 467 individuals have been observed, it seems that leprosy is a rare disease with low transmission levels in these chimpanzee communities.

To characterize the M.leprae strains causing leprosy in wild chimpanzees and to perform phylogenomic comparisons, we selected DNA extracts that were positive in both the RLEP and the less-sensitive 18-kDa PCR, which indicates relatively high levels of M.leprae DNA. For TNP, we selected individuals that were positive in multiple samples. Following targeted enrichment using hybridization capture, samples were subjected to Illumina sequencing. Sufficient M.leprae genome coverage was obtained for sample GB-CC064 (Guinea-Bissau) and for Zora (Cte dIvoire) with mean depth of 39.3 and 25.8, respectively (Extended Data Table 2 and Supplementary Table 5). We generated 21 M.leprae genomes from human biopsies from five West African countries (Niger, Mali, Benin, Cte dIvoire and Senegal) and depth of coverage ranged from 4.7 to 170. We assembled a dataset that included the genomes generated in this study and all previously available M.leprae genomes. Of the total 286 genomes, 64 originated from six West African countries (Extended Data Fig. 5 and Supplementary Note5).

Bayesian and maximum-parsimony analyses (Extended Data Figs. 6 and 7) place the strain from Guinea-Bissau (GB-CC064) on branch 4, where it clusters outside the standard genotypes 4N, 4O and 4P, but within the so-called 4N/O genotype24,25 (Fig. 2a, c). This 4N/O genotype is rare and only comprises five M.leprae strains; one strain (Ng13-33) from a patient in Niger, two strains (2188-2007 and 2188-2014) obtained from a single patient in Brazil (of 34 strains in Brazil)26 and two strains from two captive nonhuman primates originating from West Africa (Ch4 and SM1)25. The branching order of these five strains and GB-CC064 was unresolved in our analyses, with a basal polytomy suggestive of star-like diversification within this genotype, and within the group comprising all genotype 4 strains (4N/O, 4N, 4P and 4O). Divergence from the most recent common ancestor for this group is estimated to have occurred in the sixth century ad (mean divergence time, 1,437 years ago, 95% highest posterior density (HPD) 1,1321,736 years ago). The strain that infected Zora in Cte dIvoire, designated TNP-418, belongs to branch 2F, within which, the branching order was also mostly unresolved (Fig. 2a, b). The branch is currently composed of human strains from medieval Europe (n=7) and modern Ethiopia (n=2), and this genotype has thus far never been reported to our knowledge in West Africa. Bayesian analysis estimated a divergence time during the second century ad (mean of 1,873 years ago (95% HPD 1,5642,204 years ago)), similar to previous predictions27.

a, Bayesian dated phylogenetic tree of 278 M.leprae genomes including the two new chimpanzee strains (in bold red). Hypermutated samples with mutations in the nth gene were excluded from the analysis. The tree is drawn to scale, with branch lengths representing years of age. Median estimates of node ages are shown in black above branches; 95%HPD intervals are shown in grey. Some M.leprae branches are collapsed to increase readability. b, Maximum parsimony tree of branch 2F. c, Maximum parsimony tree of the branch 4. The tree was initially constructed using 286 genomes (Supplementary Table 6), including 2 new chimpanzee strains (in bold red) and 21 new genomes from West Africa (in bold), 500 bootstrap replicates and M.lepromatosis as outgroup. Sites with missing data were partially deleted (80% genome coverage cutoff), resulting in 4,470 variable sites used for the tree calculation. Subtrees corresponding to branches were retrieved in MEGA765. Corresponding genotypes are indicated on the side of each subtree. Samples are binned according to geographical origin as given in the legend. Scale bars (b, c), number of nucleotide substitutions.Animal silhouettes are available under Public Domain licence at PhyloPic (http://PhyloPic.org/).

Samples from Woodstock did not yield enough Illumina reads to reconstruct full genomes for phylogenomic analysis. However, single-nucleotide polymorphisms (SNPs) recovered from the few available Illumina reads and Sanger sequences derived from PCR products allowed us to assign this second M.leprae strain from Cte dIvoire to the same genotype as TNP-418 (Supplementary Note5). Overall, phylogenomic analyses show that M.leprae strains in chimpanzee populations at CNP and TNP are not closely related.

The finding of M.leprae-induced leprosy in wild chimpanzee populations raises the question of the origin(s) of these infections. Mycobacteriumleprae is considered a human-adapted pathogen and previous cases of leprosy affecting wildlife were compatible with anthroponosis. Therefore, the prime hypothesis would be human-to-chimpanzee transmission. Potential routes of transmission include direct (such as skin-to-skin) contact and inhalation of respiratory droplets and/or fomites, with the assumption that, in all cases, prolonged and/or repeated exposure is required for transmission11. Chimpanzees at CNP are not habituated to humans and are not approached at distances that would allow for transmission via respiratory droplets. Although these chimpanzees inhabit an agroforest landscape and share access to natural and cultivated resources with humans28, present-day humanchimpanzee direct contact is uncommon. The exact nature of historic humanchimpanzee interactions at CNP remains, however, unknown. For example, robust data on whether chimpanzees were kept as pets or were hunted for meat are lacking. Long-term humanchimpanzee coexistence in this shared landscape makes humans the most probable source of chimpanzee infection. However, multiple individuals from several chimpanzee communities across CNP show symptomatic leprosy demonstrating that M.leprae is now probably transmitted between individuals within this population.

At TNP, the south chimpanzee community is distant from human settlements and agriculture. Human-to-animal transmission of pathogens has been shown at TNP29,30 but involved respiratory pathogens (pneumoviruses and human coronavirus OC43) that transmit easily and do not require prolonged exposure. In addition, M.leprae is thought to be transmitted from symptomatic humans31 and no cases of leprosy have been reported among researchers or local research assistants. Although a human source is impossible to rule out, low human contact coupled with the rarity of the M.leprae genotype detected in TNP chimpanzees among human populations in West Africa suggests that recent human-to-chimpanzee transmission is unlikely. This is supported by the absence of drug-resistant mutations (Supplementary Note6). The relatively old age of the lineage leading to the chimpanzee strain at TNP nevertheless raises the possibility of an ancient human-to-chimpanzee transmission. However, the human population density 1,5002,000 years ago was probably even lower than it is currently, making this unlikely. If such an ancient transmission had occurred and the bacterium had persisted for a long time in chimpanzees, it should have spread more broadly as observed in M.leprae-infected squirrels and armadillos3,16,17. Therefore, an ancient human-to-chimpanzee transmission is not the most plausible mechanism to explain the presence of M.leprae in chimpanzees at TNP.

These findings may be better explained by the presence of a nonhuman leprosy reservoir. As chimpanzees hunt frequently, transmission may originate from their mammalian prey32. Nonhuman primates are the most hunted prey at TNP33 and are hunted at CNP (Supplementary Note3). Chimpanzees also consume other mammalian prey such as ungulates. Notably, this scenario assumes that the animal host range of M.leprae is even broader than is currently known. Perhaps more intriguingly, an environmental source may be at the origin of chimpanzee infections. Other mycobacteria can survive in water, including M. ulcerans and other non-tuberculous mycobacteria34,35, and molecular investigations have reported that M.leprae can survive in soil36. Experimental data also show that M.leprae multiplies in amoebae37, arthropods38 and ticks39, which could contribute to the persistence of the bacteria in the environment. Testing these hypotheses will require thorough investigation of the distribution of M.leprae in wildlife and the environment and so shed light on the overall transmission pathways of the pathogen.

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Leprosy in wild chimpanzees - Nature.com

The weird and wonderful genome of dinoflagellates looks nothing like other eukaryotic genomes.

The genome of single-celled plankton, known as dinoflagellates, is organized in an incredibly strange and unusual way, according to new research. The findings lay the groundwork for further investigation into these important marine organisms and dramatically expand our picture of what a eukaryotic genome can look like.

Researchers from KAUST, the U.S. and Germany have investigated the genomic organization of the coral-symbiont dinoflagellate Symbiodinium microadriaticum. The S. microadriaticum genome had already been sequenced and assembled into segments known as scaffolds but lacked a chromosome-level assembly.

The team used a technique known as Hi-C to detect interactions in the dinoflagellates chromatin, the combination of DNA and protein that makes up a chromosome. By analyzing these interactions, they could figure out how the scaffolds were connected together into chromosomes, giving them a view into the spatial and structural organization of the genome.

The international research team discovered that the genome of dinoflagellates is organized in a unique way compared to other eukaryotic genomes. Credit: 2021 KAUST

A striking finding was that the genes in the genome tended to be organized in alternating unidirectional blocks. Thats really, really different to what you see in other organisms, says Octavio Salazar, a Ph.D. student in Manuel Arandas group at KAUST and one of the lead authors of the study. The orientation of genes on a chromosome is usually random. In this case, however, genes were consistently oriented one way and then the other, with the boundaries between blocks showing up clearly in the chromatin interaction data.

Nature can work in a completely different way than we thought.

This organization is also reflected in the three-dimensional structure of the genome, which the team inferred comprises rod-shaped chromosomes that fold into structural domains at the boundaries where gene blocks converge. Even more intriguingly, this structure appears to be dependent on transcriptional activity. When the researchers treated cells with a chemical that blocks gene transcription, the structural domains disappeared.

This unusual link is consistent with another strange fact about dinoflagellates they have very few transcription factors in their genome and do not seem to respond to environmental changes by altering gene expression. They may use gene dosage to control expression and adapt to the environment by losing or gaining chromosomes or perhaps via epigenetic structural modifications. The researchers plan to explore all of these questions.

Another open question is the origin of this exceptional genome structure. Dinoflagellates produce very few histones, the proteins used by other eukaryotes to structure their DNA, instead using viral proteins incorporated into their genome long ago. The extraordinary genome structure and genetic regulation may be a consequence of how these viral proteins work, but that remains to be confirmed.

The dinoflagellate genome defies the expectation and dogmas built from studying other eukaryotes. It shows that nature can work in a completely different way than we thought, says Salazar. There are so many possibilities for what could have happened as life evolved.

Reference: Genetic and spatial organization of the unusual chromosomes of the dinoflagellate Symbiodinium microadriaticum by Ankita Nand, Ye Zhan, Octavio R. Salazar, Manuel Aranda, Christian R. Voolstra and Job Dekker, 29 April 2021, Nature Genetics.DOI: 10.1038/s41588-021-00841-y

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Weird and Wonderful: Coral Symbionts Have a Genome Like No Other - SciTechDaily

NIH: Francis Collins

Francis Collins is stepping down as director of the National Institutes of Health at the end of this year. He is the longest-serving presidentially appointed NIH director, serving in this role since August 2009. Before that, he was the director of the National Human Genome Research Institute from 1993 to 2008, where he led the international Human Genome Project. During his tenure as NIH director, helaunched the All of Us Research Program,worked with then-Vice President Joe Biden to launch the Cancer Moonshot Initiative, and was involved in establishing numerous other programs and initiatives. Collins will continue to lead his research laboratory at NHGRI, which focuses on type 2 diabetes and new genetic therapies for Hutchinson-Gilfordprogeria syndrome.

To read more about Collins' departure, click here.

Oncocyte: Gisela Paulsen

Oncocyte has appointedGisela Paulsenas its chief operating officer. She joins the company havingmost recently served as general manager of Genomic Healthfollowing its acquisition by Exact Sciences. She has also held senior roles at Roche/Genentech and Health Learning Systems, the founding medical education unit of Ogilvy. Paulsen is currently an entrepreneur in residence atDigitalDX Venturesand has served on the board of directors of the healthcare businesswomen association, CuriOdyssey, and theGenentech Foundation.

Roswell Biotechnologies: Mike Aicher

Roswell Biotechnologies, a company developing single-molecular analysis platforms based on semiconductor chip technology, has appointed Mike Aicher as chairman of its board of directors. Aicher was president and founder of Alveo Technologies, an infectious disease testing startup. He cofounded and served as CEO of the National Genetics Institute (which became part of LabCorp in 2000) for more than two decades. He is also an executive director at Genetic Signatures, chairman of CytoBay, and a member of Techcyte's board of directors. Aicher previously served on the board of directors for Fabric Genomics, and was a board member of Ariosa until its acquisition by Roche.

For additional recent items on executive appointments and promotions in omics and molecular diagnostics, please see the People in the News page on our website.

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People in the News: Collins to Depart NIH; Appointments at Oncocyte, Roswell Biotech; and More - GenomeWeb

The methylomes of Lake Malawi cichlids feature conserved vertebrate characteristics

To characterise the methylome variation and assess possible functional relationships in natural populations of Lake Malawi cichlids, we performed high-coverage whole-genome bisulfite sequencing of methylomes (WGBS) from liver tissues of six different cichlid species. Muscle methylome (WGBS) data for three of the six species were also generated to assess the extent to which methylome divergence was tissue-specific. Moreover, to examine the correlation between transcriptome and methylome divergences, total transcriptomes (RNAseq) from both liver and muscle tissues of four species were generated. Only wild-caught male specimens (23 biological replicates for each tissue and each species) were used for all sequencing datasets (Fig.1ac, Supplementary Fig.1, Supplementary Data1, and Supplementary Table1). The species selected were: Rhamphochromis longiceps (RL), a pelagic piscivore (Rhamphochromis group); Diplotaxodon limnothrissa (DL), a deep-water pelagic carnivore (Diplotaxodon group); Maylandia zebra (MZ) and Petrotilapia genalutea (PG), two rock-dwelling algae eaters (Mbuna group); Aulonocara stuartgranti (AS), a benthic invertebrate-eating sand/rock-dweller that is genetically part of the deep-benthic group; Astatotilapia calliptera (AC), a species of rivers and lake margins40 (Fig.1b).

a Map of Africa (main river systems are highlighted in white) and magnification of Lake Malawi (scale bar: 40km). b Photographs (not to scale) of the six Lake Malawi cichlid species part of this study spanning five of the seven described eco-morphological groups. The symbols represent the different habitats (pelagic/benthic [wave symbol], rock/sand-dwelling/littoral [rock symbol]and adjacent rivers part of Lake Malawi catchment), and the type of diet (fish, fish/zooplankton, algae, invertebrates) for each group. The species representing each group are indicated by their initials (see below). c Diagram summarising the sampling and sequencing strategies for liver and muscle methylome (whole-genome bisulfite sequencing, WGBS) and whole transcriptome (RNAseq) datasets. See Methods, Supplementary Fig.1 and Supplementary Table1. d Violin plots showing the distribution of liver DNA methylation levels in CG sequence context (averaged mCG/CG levels over 50bp-long bins genome-wide) in different genomic regions: overall, gene bodies, exons, promoter regions (TSS500bp), CpG-islands in promoters and outside (orphan) and in repeat/transposon regions. mC levels for two different repeat classes are given: DNA transposon superfamily Tc2-Mariner (n=5,378) and LINE I (n=407). e Average liver mCG profiles across genes differ depending on their transcriptional activity in liver: from non-expressed (0) to genes showing low (1), intermediate (2), high (3) and highest (4) expression levels (Methods). Results shown in (d, e) are for Mbuna MZ (liver, n=3) and are representative of the results for all other species, and are based on average mC/C in 50bp non-overlapping windows. RL, Rhamphochromis longiceps; DL, Diplotaxodon limnothrissa; MZ, Maylandia zebra; PG, Petrotilapia genalutea; AS, Aulonocara stuartgranti; AC, Astatotilapia calliptera. CreditsFish photographs: Hannes Svardal and M. Emlia Santos. Geographical map modified from http://www.d-maps.com/.

On average, 285.5155.6 million paired-end reads (see Supplementary Data1) for liver and muscle methylomes were generated with WGBS, yielding ~1015x per-sample coverage at CG dinucleotide sites (Supplementary Fig.2ad; see Methods and Supplementary Notes). To account for species-specific genotype and avoid methylation biases due to species-specific single nucleotide polymorphism (SNP), WGBS reads were mapped to SNP-corrected versions of the Maylandia zebra reference genome (UMD2a; see Methods). Mapping rates were not significantly different among all WGBS samples (Dunns test with Bonferroni correction, p>0.05; Supplementary Fig.2e), reflecting the high level of conservation at the DNA sequence level across the Malawi radiation (Supplementary Fig.3). In parallel, liver and muscle transcriptomes were generated for four species using the same specimens as used for WGBS, yielding on average 11.90.7 million paired-end reads (meansd; Fig.1c, Supplementary Data1 and Methods).

We first characterised global features of the methylome of Lake Malawi cichlids. The genome of Lake Malawi cichlid was found to have copies of DNA methyltransferases (DNMTs) and ten-eleven translocation methylcytosine dioxygenases (TETs), the readers and erasers of DNA methylation respectively (Supplementary Fig.4ac). Like that of mammals and other teleost fish, the genomes of Lake Malawi cichlids have high levels of DNA methylation genome-wide in the CG dinucleotide sequence context, consistently across all samples in both tissues analysed (Fig.1d and Supplementary Fig.2ac). Gene bodies generally show higher methylation levels than the genome-wide average, while the majority of promoter regions are unmethylated (Fig.1d). CpG islands (CGIs; i.e., CpG-rich regionsabundant in Lake Malawi cichlid genomes; Supplementary Fig.5ai, Supplementary Notes and Methods) are almost entirely devoid of methylation in promoters, while orphan CGIs, residing outside promoters, are mostly highly methylated (Fig.1d and Supplementary Fig.5f, g). While 70% of mammalian promoters contain CGIs41, only 1520% of promoters in Lake Malawi cichlids harbour CGIs (Supplementary Fig.5d), similar to frog and zebrafish genomes41. Notably, orphan CGIs, which may have important cis-regulatory functions42, compose up to 80% of all predicted CGIs in Lake Malawi cichlids (Supplementary Fig.5e). Furthermore, repetitive regions, as well as transposable elements, are particularly enriched for cytosine methylation, suggesting a methylation-mediated silencing of their transcription (Fig.1d, Supplementary Fig.6ad), similar to that observed in zebrafish and other animals8,18. Interestingly, certain transposon families, such as LINE I and Tc2-Mariner, part of the DNA transposon familythe most abundant TE family predicted in Lake Malawi cichlid genome (Supplementary Fig.6a, b, Supplementary Notes, and ref. 38)have recently expanded considerably in the Mbuna genome (Supplementary Fig.6c and refs. 38,43). While Tc2-Mar DNA transposons show the highest median methylation levels, LINE I elements have some of the lowest, yet most variable, methylation levels of all transposon families, which correlates with their evolutionary recent expansion in the genome (Fig.1d, e and Supplementary Fig.6d, e). Finally, transcriptional activity in liver and muscle tissues of Lake Malawi cichlids was negatively correlated with methylation in promoter regions (Spearmans correlation test, =0.40, p<0.002), while being weakly positively correlated with methylation in gene bodies (=0.1, p<0.002; Fig.1e and Supplementary Fig.7ad and Supplementary Table2). This is consistent with previous studies highlighting high methylation levels in bodies of active genes in plants and animals, and high levels of methylation at promoters of weakly expressed genes in vertebrates8,24. We conclude that the methylomes of Lake Malawi cichlids share many regulatory features, and possibly associated functions, with those of other vertebrates, which renders Lake Malawi cichlids a promising model system in this context.

To assess the possible role of DNA methylation in phenotypic diversification, we then sought to quantify and characterise the differences in liver and muscle methylomes across the genomes of Lake Malawi haplochromine cichlids. Despite overall very low sequence divergence36 (Supplementary Fig.3), Lake Malawi cichlids were found to show substantial methylome divergence across species within each tissue type, while within-species biological replicates always clustered together (Fig.2a). The species relationships inferred by clustering of the liver methylomes at conserved individual CG dinucleotides recapitulate some of the genetic relationship inferred from DNA sequence36, with one exceptionthe methylome clusters A. calliptera samples as an outgroup, not a sister group to Mbuna (Fig.2a and Supplementary Fig.3a, b). This is consistent with its unique position as a riverine species, while all species are obligate lake dwellers (Fig.1b).

a Unbiased hierarchical clustering and heatmap of Spearmans rank correlation scores for genome-wide methylome variation in Lake Malawi cichlids at conserved CG dinucleotides. Dotted boxes group samples by species within each tissue. b Observed/Expected ratios (O/E ratio, enrichment) for some genomic localisations of differentially methylated regions (DMRs) predicted between livers (green) and between muscles (purple) of three Lake Malawi cichlid species, and between tissues (within-species, grey); 2 tests for between categories (p<0.0001), for O/E between liver and muscle DMRs (p=0.99) and between Liver+Muscle vs Tissues (p=0.04). Expected values were determined by randomly shuffling DMRs of each DMR type across the genome (1000 iterations). Categories are not mutually exclusive. c Gene ontology (GO) enrichment for DMRs found between liver methylomes localised in promoters. GO terms: Kyoto Encyclopaedia of Genes and Genomes (KEGG), molecular functions (MF), cellular component (CC), and biological processes (BP). Only GO terms with FDR<0.05 shown. N indicates the number of genes associated with each GO term. Only GO terms with p<0.05 (BenjaminiHochberg false discovery rate [FDR]-corrected p-values) are shown. d Genomic localisation of liver DMRs containing repeats/transposons (TE-DMRs). e. O/E ratios for species TE-DMRs for each TE family. Only O/E2 and 0.5 shown. 2 tests, p<0.0001. f Violin plots showing TE sequence divergence (namely, CpG-adjusted Kimura substitution level as given by RepeatMasker) in M. zebra genome for species TE-DMRs, TEs outside species DMRs (outside) and randomly shuffled TE-DMRs (500 iterations, shuffle). Mean values indicated by red dots, median values by black lines and shown above each graph. Total DMR counts indicated below each graph. Two-sided p-values for KruskalWallis test are shown above the graph. DMR, differentially methylated region; TE, repeat/transposon regions; CGI, predicted CpG islands.

As DNA methylation variation tends to correlate over genomic regions consisting of several neighbouring CG sites, we defined and sought to characterise differentially methylated regions (DMRs) among Lake Malawi cichlid species (50bp-long, 4 CG dinucleotide, and 25% methylation difference across any pair of species, p<0.05; see Methods). In total, 13,331 between-species DMRs were found among the liver methylomes of the six cichlid species (Supplementary Fig.8a). We then compared the three species for which liver and muscle WGBS data were available and found 5,875 and 4,290 DMRs among the liver and muscle methylomes, respectively. By contrast, 27,165 within-species DMRs were found in the between-tissue comparisons (Supplementary Fig.8b). Overall, DMRs in Lake Malawi cichlids were predicted to be as long as 5,000bp (95% CI of median size: 282298bp; Supplementary Fig.8c). While the methylation differences between liver and muscle were the most prominent at single CG dinucleotide resolution (Fig.2a) and resulted in the highest number of DMRs, we found DMRs to be slightly larger and methylation differences within them substantially stronger among species than between tissues (Dunns test, p<2.21016; Supplementary Fig.8c, d).

Next, we characterised the genomic features enriched for between-species methylome divergence in the three cichlid species for which both muscle and liver WGBS data were available (i.e., RL, PG, DL; Fig.1c). In the liver, promoter regions and orphan CGIs have 3.0- and 3.6-fold enrichment respectively for between-species liver DMRs over random expectation (2 test, p<0.0001; Fig.2b)between-species muscle DMRs show similar patterns as well (p=0.99, compared to liver O/E ratios). Methylome variation at promoter regions has been shown to affect transcription activity via a number of mechanisms (e.g., transcription factor binding affinity, chromatin accessibility)21,44 and, in this way, may participate in phenotypic adaptive diversification in Lake Malawi cichlids. In particular, genes with DMRs in their promoter regions show enrichment for enzymes involved in hepatic metabolic functions (Fig.2c). Furthermore, the high enrichment of DMRs in intergenic orphan CGIs (Fig.2b), accounting for n=691 (11.94%) of total liver DMRs, suggests that intergenic CGIs may have DNA methylation-mediated regulatory functions.

The majority of between-species liver DMRs (65.0%, n=3,764) are within TE regions (TE-DMRs; Supplementary Fig.8a, b, e), approximately two-thirds of which are located in unannotated intergenic regions (Fig.2d). However, a small fraction of TE-DMRs are located in gene promoters (12% of all TE-DMRs) and are significantly enriched in genes associated with metabolic pathways (Fig.2d and Supplementary Fig.8f). While there is only a 1.1-fold enrichment of DMRs globally across all TEs (Fig.2b), some TE families are particularly enriched for DMRs, most notably the DNA transposons hAT (hAT6, 10.5-fold), LINE/l (>3.7-fold) and the retrotransposons SINE/Alu (>3.5-fold). On the other hand, the degree of methylation in a number of other TE families shows unexpected conservation among species, with substantial DMR depletion (e.g., LINE/R2-Hero, DNA/Maverick; Fig.2e). Overall, we observe a pattern whereby between-species methylome differences are significantly localised in younger transposon sequences (Dunns test, p=2.21016; Fig.2f). Differential methylation in TE sequences may affect their transcription and transposition activities, possibly altering or establishing new transcriptional activity networks via cis-regulatory functions45,46,47. Indeed, the movement of transposable elements has recently been shown to contribute to phenotypic diversification in Lake Malawi cichlids48.

In contrast to the between-species liver DMRs, within-species DMRs based on comparison of liver against muscle methylomes show much less variation in enrichment across genomic features. Only gene bodies show weak enrichment for methylome variation (Fig.2b). Moreover, both CGI classes, as well as repetitive and intergenic regions show considerable tissue-DMR depletion, suggesting a smaller DNA methylation-related contribution of these elements to tissue differentiation (Fig.2b and Supplementary Fig.8e).

We hypothesised that adaptation to different diets in Lake Malawi cichlids could be associated with distinct hepatic functions, manifesting as differences in transcriptional patterns which, in turn, could be influenced by divergent methylation patterns. To investigate this, we first performed differential gene expression analysis. In total, 3,437 genes were found to be differentially expressed between livers of the four Lake Malawi cichlid species investigated (RL, DL, MZ, and PG; Wald test, false discovery rate adjusted two sided p-value using BenjaminiHochberg[FDR]<0.01; Fig.3a and Supplementary Fig.9ac; see Methods). As with methylome variation, transcriptome variation clustered individuals by species (Supplementary Fig.9d), consistent with species-specific functional liver transcriptome activity.

a Heatmap and unsupervised hierarchical clustering of gene expression values (Z-score) of all differentially expressed genes (DEGs) found among livers of four Lake Malawi cichlid species (Wald tests corrected for multiple testing using false discovery rate FDR<1%). GO enrichment analysis for three DEG clusters are shown in Supplementary Fig.9c. b Significant overlap between DEG and differentially expressed regions (DMRs; p<0.05) linked to a gene (exact hypergeometric test, p=4.71105), highlighting putative functional DMRs (pfDMRs). c Bar plot showing the percentage of pfDMRs localised in either promoters, intergenic regions (0.54kbp away from genes), or in gene bodies, with the proportion of TE content for each group. d Heatmap representing significant GO terms for DEGs associated with pfDMRs for each genomic feature. GO categories: BP, Biological Process; MF, Molecular Function. Only GO terms with BenjaminiHochberg FDR-corrected p-values < 0.05 are shown.Examples of pfDMRs significantly associated with species-specific liver transcriptional changes for the genes thiosulfate:glutathione sulfurtransferase tstd1-like (LOC101468457; q=6.821016) (e), carbonyl reductase [NADPH]-1 cbr1-like (LOC101465189; MZ vs DL, q=0.002; MZ vs RL, q=1.18107) (f) and perforin-1 prf1-like (LOC101465185; MZ vs DL, q=3.681019; MZ vs RL, q=0.00034) (g). Liver and muscle methylome profiles in green and purple, respectively (averaged mCG/CG levels [%] in 50bp bins; n=3 biological replicates for liver DL, PG, and MZ; n=2 biological replicates for liver RL, AS, and AC, and muscle DL, RL, and PG). hj Boxplots showing gene expression values (transcript per million) for the genes in (eg). in livers (green) and muscle (pink). n=3 biological replicates for liver DL, MZ, PG; n=2 biological replicates for liver RL and muscle DL, MZ, PG, and RL. Two-sided q values for Wald tests corrected for multiple testing (BenjaminiHochberg FDR) are shown in graphs. Box plots indicate median (middle line), 25th, 75th percentile (box), and 5th and 95th percentile (whiskers) as well as outliers (single points). CGI, CpG islands; Repeats, transposons and repetitive regions.

Next, we checked for the association between liver DMRs and transcriptional changes. Of the 6,797 among-species DMRs that could be assigned to a specific gene (i.e., DMRs within promoters, gene bodies or located 0.54kbp away from a gene; see Methods), 871 were associated with differentially expressed genes, which is greater than expected by chance (Fig.3b; p<4.7105), suggesting that DMRs are significantly associated with liver gene expression. Of these 871 putative functional DMRs (pfDMRs), the majority (42.8%) are localised over gene bodies, hinting at possible intronic cis-regulatory elements or alternative splicing49. The remaining pfDMRs are in intergenic (30.2%) or promoters (27%) (Fig.3c). The majority of pfDMRs contain younger TE sequences, in particular in intronic regions, while only few contain CGIs (Supplementary Fig.10ac). In promoters and intergenic regions, 63% of pfDMR sequences contain TEs (Fig.3c). As methylation levels at cis-regulatory regions may be associated with altered transcription factor (TF) activity22,24,25, we performed TF binding motif enrichment analysis using between-species liver DMRs and found significant enrichment for specific TF recognition binding motifs. Several TF genes known to recognise some of the enriched binding motifs are differentially expressed among the livers of the three cichlid species and have liver-associated functions (Supplementary Fig.10d, e). For example, the gene of the transcription factor hepatocyte nuclear factor 4 alpha (hnf4a), with important functions in lipid homeostasis regulation and in liver-specific gene expression50, is >2.5x-fold downregulated (q9105) in the rock-dwelling algae-eater P. genalutea compared to the pelagic piscivores D. limnothrissa and R. longiceps, possibly in line with adaptation to different diets (Supplementary Fig.10e).

Furthermore, genomic regions containing pfDMRs are also significantly associated in the livers with altered transcription of many other genes involved in hepatic and metabolic oxidation-reduction processes (Fig.3d and Supplementary Fig.10f). These include genes encoding haem-containing cytochrome P450 enzymes (such as cyp3a4, cy7b1; Supplementary Fig.10f), which are important metabolic factors in steroid and fatty acid metabolism, as well as genes encoding other hepatic enzymes involved in energy balance processes. This enrichment is associated with significant methylome divergence among species, in particular in promoter regions and gene bodies (Fig.3d). For example, the gene sulfurtransferase tstd1-like, an enzyme involved in energy balance and the mitochondrial metabolism, is expressed exclusively in the liver of the deep-water pelagic species D. limnothrissa, where it shows ~80% reduced methylation levels in a gene-body DMR compared to all the other species (Fig.3e, h). Another example is the promoter of the enzyme carbonyl reductase [NADPH] 1 (cbr1) which shows significant hypomethylation (2.2kbp-long DMR) in the algae-eaters MZ and PG, associated with up to ~60-fold increased gene expression in their livers compared to the predatory Rhamphochromis and Diplotaxodon (Fig.3f, i). Interestingly, cbr1 is involved in the metabolism of various fatty acids in the liver and has been associated with fatty acid-mediated cellular signalling in response to environmental perturbation51. As a final example, we highlight the cytotoxic effector perforin 1-like (prf1-like), an important player in liver-mediated energy balance and immune functions52. Its promoter is hypermethylated (>88% mCG/CG) exclusively in the liver of the deep-water species DL, while having low methylation levels (~25%) in the four other species (Fig.3g). This gene is not expressed in DL livers but is highly expressed in the livers of the other species that all show low methylationlevels at their promoters (Fig.3j). Taken together, these results suggest that species-specific methylome divergence is associated with transcriptional remodelling of ecologically-relevant genes, which might facilitate phenotypic diversification associated with adaption to different diets.

We further hypothesised that between-species DMRs that are found in both the liver and muscle methylomes could relate to functions associated with early development/embryogenesis. Given that liver is endoderm-derived and muscle mesoderm-derived, such shared multi-tissue DMRs could be involved in processes that find their origins prior to or early in gastrulation. Such DMRs could also have been established early on during embryogenesis and may have core cellular functions. Therefore, we focussed on the three species for which methylome data were available for both tissues (Fig.1c) to explore the overlap between muscle and liver DMRs (Fig.4a). Based on pairwise species comparisons (Supplementary Fig.11a, b), we identified methylome patterns unique to one of the three species. We found that 4048% of these were found in both tissues (multi-tissue DMRs), while 3943% were liver-specific and only 1318% were muscle-specific (Fig.4b).

a Distinct species-specific methylome patterns in Lake Malawi cichlids can be found in liver or muscle tissues, or in both tissues (multi-tissue). b Histograms showing the total counts of species DMRs that are either liver-, muscle-specific or present in both (multi). Only species DMRs showing distinct DNA methylation patterns in one species are shown. c GO enrichment plots for each DMR class. Only GO terms with BenjaminiHochberg FDR-corrected p-values < 0.05 are shown. df Examples of species multi-tissue DMRs in genes related to embryonic and developmental processes. Namely, in the genes coding for visual system homeobox 2 vsx2 (LOC101486458), growth-associated protein 43 gap43 (LOC101472990) and teneurin transmembrane protein 2 tenm2 (LOC101470261). Liver and muscle methylome profiles shownin green and purple, respectively (averaged mCG/CG levels [%] in 50bp bins for 2 samples per tissue per species; scale indicated below each graph).

The relatively high proportion of multi-tissue DMRs suggests there may be extensive among-species divergence in core cellular or metabolic pathways. To investigate this further, we performed GO enrichment analysis. As expected, liver-specific DMRs are particularly enriched for hepatic metabolic functions, while muscle-specific DMRs are significantly associated with muscle-related functions, such as glycogen catabolic pathways (Fig.4c). Multi-tissue DMRs, however, are significantly enriched for genes involved in development and embryonic processes, in particular related to cell differentiation and brain development (Fig.4cf), and show different properties from tissue-specific DMRs. Indeed, in all the three species, multi-tissue DMRs are three times longer on average (median length of multi-tissue DMRs: 726bp; Dunns test, p<0.0001; Supplementary Fig.11c), are significantly enriched for TE sequences (Dunns test, p0.03; Supplementary Fig.11d) and are more often localised in promoter regions (Supplementary Fig.11e) compared to liver and muscle DMRs. Furthermore, multi-tissue species-specific methylome patterns show significant enrichment for specific TF binding motif sequences. These binding motifs are bound by TFs with functions related to embryogenesis and development, such as the transcription factors Forkhead box protein K1 (foxk1) and Forkhead box protein A2 (foxa2), with important roles during liver development53 (Supplementary Fig.11f), possibly facilitating core phenotypic divergence early on during development.

Several examples of multi-tissue DMRs are worth highlighting as generating hypotheses for potential future functional studies (Fig.4df). The visual system homeobox 2 (vsx2) gene in the offshore deep-water species Diplotaxodon limnothrissa is almost devoid of methylation in both liver and muscle, in contrast to the other species (1.9kbp-long DMR; Fig.4d and Supplementary Fig.11g). vsx2 has been reported to play an essential role in the development of the eye and retina in zebrafish with embryonic and postnatal active transcription localised in bipolar cells and retinal progenitor cells54. D. limnothrissa populates the deepest parts of the lake of all cichlid species (down to approximately 250m, close to the limits of oxygenation) and features morphological adaptations to dimly-lit environments, such as larger eye size55. vsx2 may therefore participate in the visual adaptation of Diplotaxodon to the dimmer parts of the lake via DNA methylation-mediated gene regulation during development. Another example of a multi-tissue DMR specific to D. limnothrissa is located in the promoter of the gene coding for the growth-associated protein 43 (gap43) involved in neural development and plasticity, and also neuronal axon regeneration56. The promoter of gap43 is largely devoid of methylation (overall <5% average mCG/CG levels over this 5.2 kbp-long DMR) in both muscle and liver tissues of D. limnothrissa, while being highly methylated (>86% mCG/CG) in the other species (Fig.4e). In A. calliptera, the transcription of gap43 is restricted to the brain and embryo (Supplementary Fig.11h), consistent with a role in neural development and in the adult brain. Finally, another multi-tissue DMR potentially involved in neural embryonic functions is located in the promoter region of the gene tenm2, coding for teneurin transmembrane protein (Fig.4f). tenm2 is a gene expressed early on during zebrafish embryogenesis as well as in cichlid brain and embryo (Supplementary Fig.11i) and is involved in neurodevelopment and neuron migration-related cell signalling57. This 2.7kbp-long DMR is completely unmethylated in the algae-eating rock-dweller Petrotilapia genalutea (almost 80% reduction in methylation levelsoverall compared to the other species) and may mediate species-specific adaptive phenotypic plasticity related to synapse formation and neuronal networks.

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BOSTON (PRWEB) October 11, 2021

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Day Zero Diagnostics, Inc., based in Boston, is pioneering a new class of infectious disease diagnostics using whole-genome sequencing and machine learning to revolutionize how the world fights the growing threat of antibiotic resistance. The companys mission is to change the way infectious diseases are diagnosed and treated by rapidly identifying both the species and the antibiotic resistance profile of severe infections without the need for a culture. By using sequencing, Day Zero also enables big data approaches for managing healthcare-associated infection outbreaks. Day Zero Diagnostics was founded in 2016 by a team of clinicians and scientists from Harvard University and Massachusetts General Hospital. The company has been recognized as a leading innovator by CARB-X, MedTech Innovator, TedMed Hive, Xconomy, HealthTech Arkansas, and MassChallenge HealthTech. For more information visit http://www.dayzerodiagnostics.com or follow us on Twitter at @dayzerodx.

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