6 State of the World’s Fungi State of the World’s Fungi 2018 6. Fungal genomes: Exploring, understanding and utilising their diversity Ilia J. Leitcha, Pepijn W. Kooija, Timothy Cokera, Igor V. Grigorievb, László G. Nagyc, Francis Martind, Jason Stajiche, Bryn T. M. Dentingerf, Ester Gayaa a Royal Botanic Gardens, Kew, UK; b U.S. Department of Energy Joint Genome Institute, USA; c Biological Research Centre, Hungarian Academy of Sciences, Hungary; d INRA, Université de Lorraine, France; e University of California-Riverside, USA; f Natural History Museum of Utah & School of Biological Sciences, University of Utah, USA 40 Positive interactions and insights Fungal genomes: exploring, understanding and utilising their diversity How many whole fungal genomes have been sequenced to date? How is this information being used to enhance our insights into medicine and climate change resilience and to find new fungi for use in everyday life, from food to antibiotics and biofuels? stateoftheworldsfungi.org/2018/fungal-genomes.html Fungal genomes: Exploring, understanding and utilising their diversity 41 Whole genomes have been sequenced for over 1,500 species of fungi, more than the number sequenced for plant and animal species combined 42 Positive interactions and insights FIGURE 1: CUMULATIVE NUMBER OF FUNGAL THE GENOMES OF FUNGI HAVE LONG SPECIES WITH WHOLE-GENOME SEQUENCES [Data collated from online genome databases including NCBI Genome BEEN OF INTEREST TO GENETICISTS database (ncbi.nlm.nih.gov/genome), JGI Genome Portal: MycoCosm BECAUSE MANY SPECIES ARE QUICK (genome.jgi.doe.gov/fungi), and EnsembleFungi (fungi.ensembl.org)] 1600 AND EASY TO GROW, THEIR DNA CAN BE Basidiomycota 1400 EASILY MANIPULATED, AND BECAUSE Ascomycota 1200 MANY OF THEIR ESSENTIAL CELL Mucoromycota 1000 PROCESSES ARE THE SAME AS IN ALL Zoopagomycota 800 EUKARYOTES*, INCLUDING HUMANS. Chytridiomycota 600 Blastocladiomycota Indeed, some of the earliest insights into how DNA encodes 400 Cummulative number of species the information needed to build life came from research on Cryptomycota & Microsporidia† the fungus Neurospora crassa[1]. More recent studies using 200 baker’s yeast (Saccharomyces cerevisiae) and fission yeast 0 (Schizosaccharomyces pombe) have led to many further breakthroughs in our understanding of human biology and 1996 1997 1998 1999 2000 2001 2002 2003 2004 2005 2006 2007 2008 2009 2010 2011 2012 2013 2014 2015 2016 2017 2018 disease[2,3] (see Box 1 and Chapter 4). In this chapter, we Year review the current status of our knowledge of fungal DNA † The current fungal status of species belonging to Cryptomycota and and how this is being utilised to address some of the Microsporidia is still debated by some mycologists as they possess some characters that suggest they fall outside Kingdom Fungi. However, increasing most pressing challenges facing humanity, such as climate amounts of genomic data support the inclusion of these phyla within Kingdom change, food security and human health[4–8]. Fungi (see Chapter 2: Box 2). WHOLE-GENOME SEQUENCING Baker’s yeast was the first eukaryote to have its whole across the fungal tree of life, with data for species from all genome sequenced (published in 1996[9]). Since then, the eight phyla (see Figure 1) and all 12 subphyla[18,19]. number of whole-genome sequences available for fungi has In addition to ensuring full coverage across the spectrum risen exponentially (see Figure 1). This has been driven of fungal diversity, many other factors have been important in by several factors, including: (i) rapid advances in DNA driving the choice of species for sequencing. The insights that sequencing technologies; (ii) the drop in sequencing costs; can arise from a knowledge of fungal genomes can be applied (iii) the typically small size of fungal genomes compared with to many different challenges, as we now describe. other eukaryotes (see Box 2); and (iv) several large-scale sequencing initiatives (e.g. the Fungal Genome Initiative by the Broad Institute[10] and projects like the 1000 Fungal 1. INSIGHTS THAT ENHANCE OUR Genomes[11,12] and the Mycorrhizal Genomics Initiative[13] from UNDERSTANDING OF FUNGAL DISEASES the US Department of Energy Joint Genome Institute (JGI)). AND HOW TO TREAT THEM Currently there are more whole-genome sequences for Applications in medicine and human health species of fungi than for plants and animals combined. By Many of the first fungal species sequenced were those of 31 March 2018, the number of fungal species with publicly medical importance, including Candida albicans – the most available whole-genome sequences was 1,532 (most available commonly encountered human fungal pathogen, causing, for [14] online in JGI’s MycoCosm ). This is in comparison to just 326 example, skin and mucosal infections such as nappy rash plant and 868 animal species with whole genome sequences and thrush[20]. Whole-genome sequences have since been available in the National Center for Biotechnology Information generated for over 100 additional fungal pathogens of humans. [15] (NCBI) genome database . However these fungal data still They include genome sequences for the top ten invasive represent just a tiny fraction of the estimated 2.2 to 3.8 fungal species, such as Pneumocystis jirovecii, which causes [16] million species . Most data come from species in the phyla a type of pneumonia with mortality rates that can reach 80% in Ascomycota and Basidiomycota (see Figure 1), which is hardly immunocompromised patients[21]. Together it is estimated that surprising since together they contain >90% of the currently these ten species may be responsible for more human deaths [17] described species (see Chapter 1). Nevertheless, species each year than are caused by either tuberculosis or malaria[21]. with whole-genome sequences also include representatives The emerging knowledge of the underpinning genes and metabolic pathways is also proving to be invaluable * Eukaryotes comprise any organism that packages the bulk of its DNA for designing effective therapies that target the fungus into chromosomes located within a membrane-bound nucleus. Eukaryotes while minimising toxic side effects in humans[22], and in include animals, fungi, plants and a huge diversity of single-celled organisms that are loosely referred to as protists. Eukaryotes are distinct the search for new antibiotics and other bioactive from prokaryotes, which include Bacteria and Archaea. compounds with potential as new pharmaceuticals[23]. Fungal genomes: Exploring, understanding and utilising their diversity 43 BOX 1: FUNGAL GENOMES AS GATEWAYS yeast and humans, these findings are now being explored TO UNDERSTANDING HUMAN BIOLOGY to identify potential features of the genome that can be AND DISEASE used to focus the development of new approaches for [41] Fungi, in particular the unicellular yeasts such as baker’s extending the lifespans of humans . yeast (Saccharomyces cerevisiae) and fission yeast As several major drugs have been shown to hit the (Schizosaccharomyces pombe), have been hugely important same gene targets and elicit the same responses in for understanding many aspects of human biology. This is Saccharomyces cerevisiae as they do in humans, this yeast because many of the genes involved in regulating molecular, is currently being used as a living test tube to test the metabolic and cellular processes in humans have efficacy of possible therapeutic toxins in the treatment of [3] equivalent genes in these yeasts[2,40]. They can therefore be Parkinson’s disease . used as powerful models to shed light on a diverse range of biological processes and on how errors in these genes Cells of the fission yeast Schizosaccharomyces pombe[2] and processes lead to diseases. The study of genes that are involved in controlling when cells divide in Saccharomyces cerevisiae and Schizosaccharomyces pombe has been pivotal in revealing how the cell cycle is regulated at the genomic level. Such discoveries have pioneered the development of a diverse array of treatments for cancer that are widely used today. Saccharomyces cerevisiae was recently used to uncover some of the molecular processes underpinning ageing and 15 μm longevity. Given the high similarity of these processes in 44 Positive interactions and insights In addition, the increasing availability of multiple genome which forms mycorrhizal associations with pine species and is sequences for different strains of the same species is used in commercial forestry to inoculate plantations in order providing insights into the rapid genomic evolution that can to enhance their growth and health. The growing volumes of occur during disease progression and treatment. This enables genomic data are opening up new opportunities to explore how the development of rapid diagnostic tools and identification mycorrhizal fungi can be manipulated to enhance plant health, of drug resistance and hence the delivery of tailor-made environmental sustainability and ecosystem resilience in the treatments for patients[24]. face of environmental change[34]. In the field of public health, recent analysis of genomic While mycorrhizal species have been targeted for whole- data from studies of the gut microbiome (the sum of all the genome sequencing[13], the genomes of endophytic fungi (i.e. microbes such as bacteria and fungi that live in the gut) those that grow inside plants – see Chapter 5) have received suggests that changes in the abundance of specific fungi and less attention. However, some endophytes, particularly those their