Low-viscosity genotypes of filamentous fungi

Abstract

The present disclosure relates to genetically modified host cells exhibiting reduced viscosity when cultured and uses thereof for production of bioproducts. The present disclosure provides genetically modified host cell comprising one or more genetic modifications that result in the downregulation of: (a) spaA or a homolog thereof, and (b) ptaB or a homolog thereof.

Description

[0001] LOW-VISCOSITY GENOTYPES OF FILAMENTOUS FUNGI FIELD The present disclosure relates to genetically modified host cells exhibiting reduced viscosity when cultured, and uses thereof for production of bioproducts. BACKGROUND Fungal cells, such as Aspergillus niger, have been used in the production of bioproducts (e.g., proteins, nucleic acids, small molecules, etc.) due, at least in part, to their efficient production of said bioproducts. However, scale-up of fermentation-based methods of producing bioproducts using filamentous fungal host cells, including A. niger, is limited by the high viscosity produced by culturing these cells. SUMMARY Aspects of the disclosure provide, at least in part, genetically modified host cells comprising one or more genetic modifications that result in the downregulation of: (a) spaA (or SpaA) or a homolog thereof, and (b) ptaB (or PtaB) or a homolog thereof. In some embodiments, the level of expression level and / or activity of a protein encoded by (a) spaA or a homolog thereof, or (b) ptaB or a homolog thereof, in the genetically modified host cell, is less than 25% of the respective level in a host cell that is the same except that it lacks the one or more genetic modifications, when cultured under the same conditions. In some embodiments, downregulation of (a) spaA or a homolog thereof or (b) ptaB or a homolog thereof is mediated by complete or partial removal of a coding segment (or sequence); disruption of a coding, non-coding and / or regulatory sequence(s); introduction of a premature stop codon; introduction of a premature stop codon via incorporation of an orthogonal (e.g., heterologous) sequence in the open reading frame; and / or disruption or replacement of a native promoter upstream of the open reading frame for (a) spaA or a homolog thereof or (b) ptaB or a homolog thereof. In some embodiments, downregulation of (a) spaA or a homolog thereof, or (b) ptaB or a homolog thereof is mediated by incorporation of a non-native nucleic acid into the native promoter. In some embodiments, downregulation of (a) spaA or a homolog thereof, or (b) ptaB or a homolog thereof is mediated by replacement of the native promoter with a weaker promoter or an inducible promoter. In some embodiments, the genetically modified host cell comprises: (a) one or more genetic modifications in spaA or a homolog thereof, such that the genetically modified host cell does not express the protein encoded by spaA or the homolog thereof; and (b) one or more genetic modifications in ptaB or a homolog thereof, such that the genetically modified host cell does not express the protein encoded by ptaB or the homolog thereof. In some embodiments, the genetically modified host cell comprises: one or more genetic modifications in spaA or a homolog thereof, such that the genetically modified host cell does not express the protein encoded by spaA or the homolog thereof; and one or more genetic modifications in ptaB or a homolog thereof, such that the genetically modified host cell does not express the protein encoded by ptaB or the homolog thereof. In some embodiments, the protein encoded by spaA or the homolog thereof comprises the amino acid sequence of a spaA protein or homolog thereof identified in Tables 6-7, optionally wherein the protein encoded by spaA or the homolog thereof comprises the amino acid sequence of SEQ ID NO: 2. In some embodiments, the protein encoded by ptaB or the homolog thereof comprises the amino acid sequence of a ptaB or homolog thereof identified in Tables 6-7, optionally wherein the protein encoded by ptaB comprises the amino acid sequence of SEQ ID NO: 1. In some embodiments, the protein encoded by spaA or the homolog thereof comprises the amino acid sequence of a spaA protein or homolog thereof identified in Tables 6-7 or comprises the amino acid sequence of a spaA protein or homolog thereof having an amino acid sequence at least 90% identical to that of any identified in Tables 6-7, optionally wherein the protein encoded by spaA or the homolog thereof comprises the amino acid sequence of SEQ ID NO: 2 or comprises an amino acid sequence at least 30%, at least 40%, at least 50%, at least 60%, at least 70%, at least 80%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99% identical to the amino acid sequence of SEQ ID NO: 2. In some embodiments, the protein encoded by ptaB or the homolog thereof comprises the amino acid sequence of a ptaB protein or homolog thereof identified in Tables 6-7 or comprises the amino acid sequence of a ptaB protein or homolog thereof having an amino acid sequence at least 90% identical to that of any identified in Tables 6-7, optionally wherein the protein encoded by ptaB comprises the amino acid sequence of SEQ ID NO: 1 or comprises an amino acid sequence at least 30%, at least 40%, at least 50%, at least 60%, at least 70%, at least 80%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99% identical to the amino acid sequence of SEQ ID NO: 1. In some embodiments, the genetically modified host cell further comprises a heterologous gene. In some embodiments, the genetically modified host cell comprises a heterologous gene and produces a bioproduct. In some embodiments, the bioproduct: (a) is directly or indirectly produced by a protein encoded by the heterologous gene; or (b) is a mRNA or protein encoded by the heterologous gene. In some embodiments, the genetically modified host cell is a filamentous fungal cell. In some embodiments, the genetically modified host cell is an Aspergillus cell or a Penicillium cell. In some embodiments, the genetically modified host cell is an Aspergillus niger cell, an Aspergillus sojae cell, an Aspergillus oryzae cell, or a Penicillium rubens cell. In some embodiments, the genetically modified host cell exhibits reduced viscosity when cultured, compared to a control host cell that does not comprise the one or more genetic modifications that result in the downregulation of: (a) spaA or a homolog thereof, and (b) ptaB or a homolog thereof. In some embodiments, the genetically modified host cell exhibits an at least 2-fold reduced viscosity when cultured, compared to a control host cell that does not comprise the one or more genetic modifications that result in the downregulation of: (a) spaA or a homolog thereof, and (b) ptaB or a homolog thereof. In some embodiments, the genetically modified host cell exhibits reduced viscosity when cultured, compared to a control host cell that does not comprise the one or more genetic modifications that result in the downregulation of: (a) spaA or a homolog thereof, and (b) ptaB or a homolog thereof, wherein the viscosity measured at 72 hours of fermentation time is reduced by at least 40%. In some embodiments, the genetically modified host cell exhibits reduced viscosity when cultured, compared to a control host cell that does not comprise the one or more genetic modifications that result in the downregulation of: (a) spaA or a homolog thereof, and (b) ptaB or a homolog thereof, wherein the viscosity measured at 72 hours of fermentation time is reduced by at least 50%. In some embodiments, the genetically modified host cell exhibits reduced viscosity when cultured, compared to a control host cell that does not comprise the one or more genetic modifications that result in the downregulation of: (a) spaA or a homolog thereof, and (b) ptaB or a homolog thereof, wherein the viscosity measured at 72 hours of fermentation time is reduced by at least 60%. Aspects of the disclosure provide bioreactors comprising a plurality of genetically modified host cells associated with the disclosure. Aspects of the disclosure provide in vitro cultures comprising a plurality of genetically modified host cells associated with the disclosure. In some embodiments, the culture has a biomass of at least 40 gDW / L (grams of dry weight per liter) and a viscosity of less than 7000 cP (centipoise), less than 6000 cP, less than 5000 cP, less than 4000 cP, or less than 3000 cP, optionally wherein the genetically modified host cells are Penicillium rubens cells. In some embodiments, the culture has a biomass of at least 60 gDW / L and a viscosity of less than 3500 cP, less than 2500 cP, or less than 1000 cP, optionally wherein the genetically modified host cells are Aspergillus niger cells. In some embodiments, the culture has a biomass of at least 70 gDW / L. In some embodiments, the culture has a biomass of at least 10 gDW / L and a viscosity of less than 1000 cP or less than 500 cP, optionally wherein the genetically modified host cells are Aspergillus sojae cells. In some embodiments, the viscosity is measured at room temperature with a rotational speed of about 5-10 RPM. Aspects of the disclosure provide methods of producing a bioproduct comprising culturing genetically modified host cells associated with the disclosure. In some embodiments, production of the bioproduct is improved at least 2.5x relative to a control host cell that does not comprise the one or more genetic modifications that result in the downregulation of: (a) spaA or a homolog thereof, and (b) ptaB or a homolog thereof. In some embodiments, the method further comprises a step of obtaining the bioproduct from the host cell. In some embodiments, the method further comprises a step of obtaining the bioproduct from a culture, culture medium, cell-free spent culture medium, and / or cell-containing culture medium, and / or biomass used in, during or produced by culturing the genetically modified host cells. Aspects of the disclosure provide use of a genetically modified host cell associated with the disclosure, for the production of a bioproduct. BRIEF DESCRIPTION OF DRAWINGS The following drawings form part of the present specification and are included to further demonstrate certain aspects of the present disclosure, which may be better understood by reference to one or more of these drawings in combination with the detailed description of specific embodiments presented in this disclosure. The drawings are illustrative only and are not required for enablement of the disclosure. In the drawings: FIGs.1A-1B shows results of PCR amplification to assess transformants knocking out ptaB (FIG.1A) or spaA (FIG.1B). FIGs.2A-2C show growth phenotypes for Aspergillus niger strains with ptaB or spaA knocked out, relative to the growth phenotypes of A. niger strain CBS142952 (HFC1.1) and HFC2.5, a derivative of A. niger strain CBS142951 (HFC2) and the parent of ptaB / spA mutant strains. FIGs.2A-2B show plate growth phenotypes of knockout strains grown for 3 days (FIG. 2A) or 6 days (FIG.2B). FIG.2C shows small scale liquid culture phenotypes for the knockout strains. FIG.3 shows the plate growth phenotypes of A. niger strains. FIGs.4A-4C show PCR screening results confirming engineered knockout strains. FIG. 4A shows results for A. sojae strains with spaA knocked out. FIG.4B shows results for A. sojae strains with ptaB knocked out. FIG.4C shows results for P. rubens strains with spaA knocked-10 "2.0&% '&(+* / -1,)#$FIGs.5A-5B show plate growth phenotypes of P. rubens (FIG.5A) and A. sojae (FIG. 5B) strains with spaA and / or ptaB knocked out. FIGs.6A-6B show the results of fermentation trend analysis for wildtype P. rubens (parent) (FIG.6A) and a double knock-out of spaA and ptaB in P. rubens (mutant) (FIG.6B) strains. EFT denotes elapsed fermentation time. FIGs.7A-7B show the results of fermentation trend analysis for wildtype A. sojae (parent) (FIG.7A) and a double knock-out of spaA and ptaB in A. sojae (mutant) (FIG.7B) strains. DETAILED DESCRIPTION Aspects of the disclosure relate, at least in part, to genetically modified host cells that exhibit reduced viscosity when cultured. Aspects of the disclosure relate to host cells (filamentous host cells) comprising one or more genetic modifications, wherein the genetic modification(s) result in downregulation of: (a) spaA or a homolog thereof, and (b) ptaB or a homolog thereof. The inventors have found that host cells (filamentous host cells) having a knockout of both spaA (or a homolog thereof) and ptaB (or a homolog thereof) have surprisingly low viscosity when grown in culture – much lower than what was found from individual knockouts of either spaA (or a homolog thereof) or ptaB (or a homolog thereof). Filamentous fungi, such as Aspergillus spp. and Penicillium spp., are useful for producing bioproducts [such as nucleic acids, proteins, or compounds produced (directly or indirectly) by proteins], due, at least in part, to their naturally high levels of protein production and efficient secretion systems. Filamentous fungi are difficult to culture at high levels due to the viscosity exhibited by such cultures, caused by fungal growth in the form of long filamentous structures known as hyphae. High culture viscosity limits distribution of nutrients and oxygen in large culture volumes and also poses challenges for isolation of bioproducts from cultures of filamentous fungi. In some embodiments, genetically modified host cells exhibiting reduced viscosity are useful for industrial production of bioproducts. In some embodiments, lower viscosity cultures require less energy for stirring at the same biomass levels, contributing to lower cost of producing a bioproduct. In some embodiments, lower viscosity cultures may be maintained at a constant stirring rate, allowing for increased feed rate and oxygen transfer. In some embodiments, lower viscosity cultures yield higher biomass levels. In some embodiments, lower viscosity cultures yield increased production of bioproducts, such as improved protein titers, and decrease cycle time per batch. In some embodiments, lower viscosity cultures facilitate easier downstream processing and purification, simplifying the overall production workflow. Host Cells Aspects of the disclosure relate to genetically modified host cells, and methods of using them to express genes of interest (e.g., foreign or heterologous genes) and / or produce bioproducts. The term “genetically modified host cell” and like terms are used interchangeably and refer to host cells that have been genetically modified by, e.g., cloning and transformation methods, or by other methods known in the art (e.g., selective genetic editing methods). In some embodiments, a genetic modification results in (a) downregulation of spaA or a homolog thereof and / or the (b) downregulation of ptaB or a homolog thereof, as compared to a reference or control host cell which does not comprise the corresponding genetic modifications. As used herein, a “reference host cell” or a “control host cell” may be a wild-type or naturally-occurring host cell, such as a filamentous fungal host cell, or may be a genetically modified host cell that does not comprise a genetic modification that results in (a) downregulation of spaA or a homolog thereof and / or the (b) downregulation of ptaB or a homolog thereof. In some embodiments, a modified host cell and a control host cell are identical except for the genetic modification(s) in spaA and / or ptaB (e.g., the modified host cell and the control have the same genetic background, comprise the same heterologous gene under expression of the same promoter, etc.), and they are grown under identical conditions when comparisons are made of the expression level and / or activity of a heterologous protein produced by them. The term “cell,” as used in this application, may refer to a single cell or a population of cells, such as a population of cells belonging to the same cell line or strain. Use of the singular term “cell” or "host cell" should not be construed to refer explicitly to a single cell rather than a population of cells (e.g., a colony or a population of identical or nearly identical cells). In some embodiments, the genetically modified host cell is a filamentous fungal host cell. In some embodiments, said host cell comprises a filamentous fungal cell from Division Ascomycota, such as from Subdivision Pezizomycotina. In some embodiments, said filamentous fungal cell comprises a member of the Class Eurotiomycetes, such as from the Family Aspergillaceae, including Aspergillus niger, A. sojae, A. oryzae, and A. fumigatus. In some embodiments, said filamentous fungal cell comprises a member of the Class Sordariomycetes, such as from the Genus Trichoderma, including Trichoderma reesei, or of the genus Myceliophthora, including Myceliophthora thermophila. In some embodiments, said filamentous fungal cell is of the Order Saccharomycetales, including a Saccharomyces spp., such as S. cerevisiae, a Candida spp., such as C. albicans, a Yarrowia spp., such as Y. lipolytica, or a Komagataella spp., such as K. phaffii (formerly termed Pichia pastoris). In some embodiments, the host cell is an Aspergillus cell. In some embodiments, the host cell is an Aspergillus niger cell. In some embodiments, the host cell is an Aspergillus sojae cell. In some embodiments, the host cell is an Aspergillus oryzae cell. In some embodiments, the host cell is a Penicillium cell. In some embodiments, the host cell is a Penicillium rubens cell. In some embodiments, the host cell is an Aspergillus cell, a Trichoderma cell, a Chrysosporium cell, a Thielavia cell, a Talaromyces cell, a Thermomyces cell, a Thermoascus cell, a Neurospora cell, an Aureobasidium cell, a Filivasidium cell, a Piromyces cell, a Corynascus cell, a Cryptococcus cell, an Acremonium cell, a Tolypocaldium cell, a Scytalidium cell, a Schizophyllum cell, a Sporotrichum cell, a Penicillium cell, a Gibberella cell, a Myceliophthora cell, a Mucor cell, a Fusarium cell, a Humicola cell, or an anamorph or and teleomorph thereof. In some embodiments, filamentous fungal host cells in a plurality of filamentous fungal host cells may individually or as a collective group comprise genetic modifications according to any embodiment of the present disclosure. Genetic Modifications The host cells of the disclosure may comprise one or more genetic modifications, relative to a wild-type or naturally-occurring counterpart or an engineered cell lacking the genetic modifications of this disclosure. In some embodiments, a genetic modification comprises the insertion, deletion or change of at least one nucleotide in a component of the genome of an organism (e.g., a chromosome, plasmid or other nucleic acid); a genetic modification can comprise the deletion of a naturally-occurring nucleic acid from the organism, and / or the insertion of a nucleic acid which is not naturally-occurring in that organism; and a genetic modification can result in the downregulation of a gene (e.g., a decrease in the expression level (mRNA and / or protein) and / or activity of the gene and / or its gene product) or the upregulation of the a gene (e.g., an increase in the expression level and / or activity of the gene and / or its gene product). In some embodiments, a genetic modification can directly decrease the expression and / or activity of a gene or its gene product (e.g., by disrupting the coding segment or decreasing the activity of the gene’s promoter); or a genetic modification can indirectly decrease the expression and / or activity of a gene or its gene product (e.g., by introducing: an antisense oligonucleotide or siRNA that decreases expression of the gene or production of the gene product, a coding segment for an antibody that binds to the gene product, a coding segment for a protein such as a transcription factor which decreases expression of the gene, a coding segment for a protein which binds to and inactivates the gene product, a coding segment for a gene or genes that increase production of a small molecule that inhibits or decreases the expression and / or activity of the gene product, or a strong promoter that directs transcription through the coding segment but in the opposite direction, etc.). In some embodiments, the one or more genetic modifications downregulate (e.g., reduce the expression level and / or activity of) one or more endogenous genes. In some embodiments, the one or more endogenous genes include spaA, or a homolog thereof, and ptaB, or a homolog thereof. In some embodiments, the one or more genetic modifications result in the knockout of: (a) spaA or a homolog thereof; and (b) ptaB or a homolog thereof. As used herein, by “knockout” [e.g., of (a) spaA or a homolog thereof, or (b) ptaB or a homolog thereof] is meant: complete or partial removal of the coding sequence [e.g., of (a) spaA or a homolog thereof, or (b) ptaB or a homolog thereof]; disruption of the coding sequence (e.g. frameshift mutation, or insertion or deletion within the coding sequence); substitution or addition of amino acid(s) that interfere with the folding or activity of a protein encoded by a coding sequence; disruption of a non-coding and / or regulatory sequence(s) operably linked to the coding sequence; introduction of a premature stop codon via deletion or incorporation of orthogonal sequence in an open reading frame; silencing transcription of the coding sequence; disruption of the post-transcriptional processing of a transcript encoded by the coding sequence; disruption of post-translational processing of the protein encoded by the coding sequence; and / or disruption or replacement of a native promoter upstream of the coding sequence for (a) spaA or a homolog thereof or (b) ptaB or a homolog thereof. As used herein, a homolog is a homologous gene or protein, or (a) is a gene or protein which is similar in sequence to a gene or protein in another species, or (b) is a protein with characteristics [e.g., three-dimensional structure(s), epitope(s), active site(s), and / or function(s)] that are similar to a protein from a different species because the species come from a common ancestor, or a gene that encodes such a protein. In some embodiments, homologous proteins may arise in organisms without a common ancestor, if the proteins have similar structures and / or functions, and may have resulted from convergent evolution. As used in this application, homologous sequences are sequences (e.g., nucleic acid or amino acid sequences) that share a certain percent identity (e.g., at least 30%, at least 35%, at least 40%, at least 45%, at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 71%, at least 72%, at least 73%, at least 74%, at least 75%, at least 76%, at least 77%, at least 78%, at least 79%, at least 80%, at least 81%, at least 82%, at least 83%, at least 84%, at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% percent identity, including all values in between) and include but are not limited to paralogous sequences, orthologous sequences, or sequences arising from convergent evolution. Paralogous sequences arise from duplication of a gene within a genome of a species, while orthologous sequences diverge after a speciation event. Two different species may have evolved independently but may each comprise a sequence that shares a certain percent identity with a sequence from the other species as a result of convergent evolution. Unless otherwise noted, the term “sequence identity” refers to the relatedness of the sequences of two polypeptides or polynucleotides when the sequences are aligned, and the term “percent identity” refers to the percentage of residues (amino acids or nucleotides) that are identical when two or more polypeptide or polynucleotide sequences are aligned. In some embodiments, sequence identity and / or percent identity is determined across the entire length of a sequence, while in other embodiments, sequence identity and / or percent identity is determined over a region of a sequence. Percent identity of polypeptide or polynucleotide sequences can be calculated by any of the methods known to one of ordinary skill in the art. For example, percent identity can be determined using the algorithm of Karlin and Altschul 1990 Proc. Natl. Acad. Sci. U.S.A. 87:2264-68, modified as in Karlin and Altschul 1993 Proc. Natl. Acad. Sci. U.S.A.90:5873-77. Such an algorithm is incorporated into the NBLAST®and XBLAST®programs (version 2.0) of Altschul et al.1990 J. Mol. Biol.215:403-10. BLAST®protein searches can be performed, for example, with the XBLAST program, score=50, wordlength=3. Where gaps exist between two sequences, Gapped BLAST®can be utilized, for example, as described in Altschul et al.1997 Nucleic Acids Res.25(17):3389-3402. When utilizing BLAST®and Gapped BLAST®programs, the default parameters of the respective programs (e.g., XBLAST®and NBLAST®) can be used, or the parameters can be adjusted appropriately as would be understood by one of ordinary skill in the art. A second example of a local alignment technique is based on the Smith-Waterman algorithm (Smith, T.F. & Waterman, M.S.1981 J. Mol. Biol.147:195-197). An example of a global alignment technique is the Needleman–Wunsch algorithm (Needleman, S.B. & Wunsch, C.D.1970 J. Mol. Biol.48:443-453), which is based on dynamic programming. A further example of a global alignment technique is the Fast Optimal Global Sequence Alignment Algorithm (FOGSAA). In some embodiments, the identity of two polypeptide sequences is determined by aligning the two amino acid sequences of the polypeptides, calculating the number of identical amino acids, and dividing by the length of one of the polypeptide sequences. In some embodiments, the identity of two nucleic acid sequences is determined by aligning the two nucleotide sequences of the nucleic acids, calculating the number of identical nucleotides and dividing by the length of one of the nucleic acids. For multiple sequence alignments, computer programs including Clustal Omega (Sievers et al.2011 Mol Syst Biol.7:539) may be used. In preferred embodiments, a sequence, including a nucleic acid or amino acid sequence, is found to have a specified percent identity to a reference sequence, such as a sequence disclosed in this application and / or recited in the claims when sequence identity is determined using the algorithm of Karlin and Altschul 1990 Proc. Natl. Acad. Sci. U.S.A.87:2264-68, modified as in Karlin and Altschul 1993 Proc. Natl. Acad. Sci. U.S.A.90:5873-77 (e.g., BLAST®, NBLAST®, XBLAST®or Gapped BLAST®programs, using default parameters of the respective programs). In some embodiments, a sequence, including a nucleic acid or amino acid sequence, is found to have a specified percent identity to a reference sequence, such as a sequence disclosed in this application and / or recited in the claims when sequence identity is determined using the Smith-Waterman algorithm (Smith, T.F. & Waterman, M.S.1981 J. Mol. Biol.147:195-197) or the Needleman–Wunsch algorithm (Needleman, S.B. & Wunsch, C.D.1970 J. Mol. Biol. 48:443-453). In some embodiments, a sequence, including a nucleic acid or amino acid sequence, is found to have a specified percent identity to a reference sequence, such as a sequence disclosed in this application and / or recited in the claims when sequence identity is determined using a Fast Optimal Global Sequence Alignment Algorithm (FOGSAA). In some embodiments, a sequence, including a nucleic acid or amino acid sequence, is found to have a specified percent identity to a reference sequence, such as a sequence disclosed in this application and / or recited in the claims when sequence identity is determined using Clustal Omega (Sievers et al.2011 Mol Syst Biol.7:539). In some embodiments, a host cell is genetically modified to express a heterologous gene. The terms “heterologous”, “exogenous”, “recombinant” and “foreign” and the like, in regards to a gene, refer to a gene that has been: artificially supplied to a biological system; modified within a biological system; or whose expression or regulation has been manipulated within a biological system. A heterologous gene may be natural, synthetic or mutant, or may come from a different organism than the host cell, or may be a nucleic acid that is also endogenously expressed in the host cell (e.g., at a lower level than in a genetically modified host cell). For example, a gene that is endogenously expressed in a host cell may be considered heterologous to the host cell when, in that host cell, it is: situated non-naturally; expressed recombinantly (e.g., with a promoter other than its natural promoter); modified or edited; expressed in a non-natural copy number; or expressed in a non-natural way. In various embodiments, the heterologous gene can mediate production of a bioproduct such as a small molecule, or a product of the heterologous gene itself (e.g., a protein or mRNA) can be a useful bioproduct. Downregulation of genes to improve protein production In various embodiments, a host cell comprises a genetic modification which downregulates: (i) spaA, or a homolog thereof, and (ii) ptaB, or a homolog thereof. The downregulation of a gene or gene product (e.g., decreasing the expression level, and / or activity, of a gene or gene product) may be achieved using any method known in the art, including, by way of non-limiting example, by: reducing promoter strength, inserting a premature stop codon in the coding segment or changing a non-stop codon to a stop codon, knocking out the gene (e.g., by inserting a different nucleic acid into the gene, deleting all or some of the coding segments, or replacing all or some of the coding segments with a different nucleic acid), replacing a native gene with a less active or abundant homolog from another species, and / or mutating a native or heterologous gene to attenuate expression level or activity. Downregulation of a gene can be accomplished using any technique known in the art. In some embodiments, downregulation of a gene includes, in non-limiting examples: deleting the gene or a part thereof so that the gene no longer expresses a functional protein; making a frameshift mutation in the coding segment; deleting all or part of the native promoter for the gene (wherein a promoter includes any enhancer or operator sequence or any other sequences which are positively involved in transcription); inserting a heterologous nucleic acid in a coding segment and / or the promoter; replacing the native promoter with a weak or weaker promoter, or with a regulatable promoter which is then regulated to be inactive; deleting the start codon; deleting or altering the native ribosome binding site of the gene or the region between the native ribosome binding site and the translational start of the gene; introducing a premature stop codon in the gene; introducing a heterologous nucleic acid and / or making an alteration to the sequence of the gene such that the protein product thereof (or the mRNA encoding it) is unstable, inactive, less active, or no longer transported to a cellular compartment wherein it would normally function; introducing a promoter which is downstream (3') of the gene, is oriented in the opposite direction, and is stronger than the native promoter; altering the codon usage such that a decreased amount of the mRNA of the gene is translated; altering one or more of the intercistronic regions; introducing an agent such as a siRNA or antibody which interferes with and / or causes the destruction of the mRNA and / or protein corresponding to the gene; or using any other method known in the art now or in the future. As a non-limiting example, polymerase chain reaction (PCR)-based methods may be used (see, e.g., Gardner et al.2014 Methods Mol Biol., 1205:45-78) or gene-editing techniques may be used to genetically modify the host cells of the disclosure. For example, genes may be deleted through gene replacement (e.g., with a marker, including a selection marker). A gene may also be truncated through the use of a transposon system (see, e.g., Poussu et al.2005 Nucleic Acids Res., 33(12): e104). In some embodiments, downregulation of (a) spaA or a homolog thereof and / or (b) ptaB or a homolog thereof is mediated by complete or partial removal of a coding sequence; disruption of a coding, non-coding and / or regulatory sequence(s); introduction of a premature stop codon via incorporation of orthogonal sequence in the open reading frame; and / or disruption or replacement of a native promoter upstream of the open reading frame for (a) spaA or a homolog thereof or (b) ptaB or a homolog thereof. In some embodiments, disruption of the native promoter is mediated by incorporation of a non-native nucleic acid into the native promoter. Downregulation of spaA In some embodiments, one or more genetic modifications to a host cell associated with the disclosure result in the downregulation of (e.g., reduce the expression level and / or activity of) the protein encoded by spaA (or a homolog thereof). SpaA, the protein encoded by spaA, as described herein, is reportedly a cell polarity protein. SpaA is also reportedly a component of the polarisome and localizes to hyphal tips in filamentous fungal cells. Conserved domains in SpaA reportedly include a chromosome segregation ATPase involved in cell division and domains with a signaling function. In some embodiments, a SpaA homolog has at least one of these characteristics and / or activities. In some embodiments, the genetically modified host cell does not express the protein encoded by spaA or the homolog thereof. The amino acid sequence of SpaA in A. niger is provided in SEQ ID NO: 2. Non- limiting examples of homologs of SpaA are shown in Tables 6 and 7. In some embodiments, a host cell is any species described in Table 6 or Table 7 comprising one or more genetic modifications that result in the downregulation (e.g., knockout) of its endogenous spaA (or homolog). In some embodiments, the level of expression and / or activity of a protein encoded by (a) spaA or a homolog thereof in the genetically modified host cell, is less than 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, or less than 60% of the respective level in a host cell that is the same as the genetically modified host cell except that it lacks the one or more genetic modifications that provide downregulation of the protein encoded by spaA, when cultured under the same conditions. In some embodiments, host cells having downregulation of spaA (or a homolog thereof) exhibit reduced viscosity when cultured relative to host cells without downregulation of spaA (or a homolog thereof) alone. In some embodiments, host cells having downregulation of spaA (or a homolog thereof) exhibit viscosity when cultured that is reduced by about 1.5x, 2x, 2.5x, 3x, 3.5x, or 4x relative to host cells without downregulation of spaA (or a homolog thereof). In some embodiments, host cells having downregulation of spaA (or a homolog thereof) exhibit viscosity when cultured that is reduced by at least 1.5x, 2x, 2.5x, 3x, 3.5x, or 4x relative to host cells without downregulation of spaA (or a homolog thereof). Downregulation of ptaB In some embodiments, one or more genetic modifications to a host cell associated with the disclosure result in the downregulation of (e.g., reduce the expression level and / or activity of) the protein encoded by ptaB (or a homolog thereof). In some embodiments, PtaB, the protein encoded by ptaB, as described herein, is a lim-domain binding protein that interacts with the transcription factor Som. In some embodiments, PtaB binds to the LIM domain pfam00412 of LIM homeodomain proteins which are transcriptional regulators of development. In some embodiments, PtaB is reported to be required for normal conidiation and biofilm formation, and to be involved in promoting galactosaminogalactan (GAG) production in the fungal cell walls and / or wildtype conidiation in filamentous fungal cells. In some embodiments, a homolog of PtaB has at least one of these characteristics and / or activities. In some embodiments, the genetically modified host cell does not express the protein encoded by ptaB or the homolog thereof. The amino acid sequence of PtaB from A. niger is provided in SEQ ID NO: 1. Non- limiting examples of homologs of ptaB are shown in Table 6 and Table 7. In some embodiments, a host cell is any species described in Table 6 or Table 7 comprising one or more genetic modifications that result in the downregulation (e.g., knockout) of its endogenous ptaB (or homolog). In some embodiments, the level of expression and / or activity of a protein encoded by ptaB or a homolog thereof, in the genetically modified host cell, is less than 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, or less than 60% of the respective level in a host cell that is the same except that it lacks the one or more genetic modifications, when cultured under the same conditions. In some embodiments, host cells having downregulation of ptaB (or a homolog thereof) exhibit reduced viscosity when cultured relative to host cells without downregulation of ptaB (or a homolog thereof) alone. In some embodiments, host cells having downregulation of ptaB (or a homolog thereof) exhibit viscosity when cultured that is reduced by about 1.5x, 2x, 2.5x, 3x, 3.5x, or 4x relative to host cells without downregulation of ptaB (or a homolog thereof). In some embodiments, host cells having downregulation of ptaB (or a homolog thereof) exhibit viscosity when cultured that is reduced by at least 1.5x, 2x, 2.5x, 3x, 3.5x, or 4x relative to host cells without downregulation of ptaB (or a homolog thereof). Downregulation of spaA and ptaB In some embodiments, one or more genetic modifications to a host cell associated with the disclosure result in the downregulation of (e.g., reduce the expression level and / or activity of) spaA (or a homolog thereof) and ptaB (or a homolog thereof). PtaB is a lim-domain binding protein that interacts with the transcription factor SomA and is required for normal conidiation and biofilm formation. Zhang et al.2018 Cellular Microbiol.20 (1), e12799. Disruption of ptaB in A. fumigatus results in global changes such as reduced biofilm formation due to impaired galactosaminogalactan (GAG) production. In a different species, A. oryzae, disruption of GAG production led to reduced viscosity [Sakuragawa et al., J. Bioscience Bioengineering 132 (2), 140-147 (2021)], though Sakuragawa et al. did not appear to make a direct connection between ptaB disruption and decreased viscosity. Prior to the present work, no known reports described a direct measurement of viscosity of strains with a ptaB disruption and thus it had not been previously shown if such a disruption, which might cause other biochemical changes, might have an effect on total viscosity. In addition, various Aspergillus species differ significantly, and genotypical and phenotypical phenomena in one species do not necessarily and predictably occur in another Aspergillus species. Some homologous genes in different Aspergillus species reportedly have opposite effects. For example, FadA represses vegetative growth in A. oryzae, but stimulates it in A. fumigatus. Ogawa et al.2010 Fung. Genet. Biol.47: 10; Liebmann et al.2004 Infect. Immun.72: 5193; Shimizu et al.2001 Genetics 157: 591; and Krijgsheld et al.2013 Studies in Mycology 74: 1–29. Also, VeA suppresses asexual development in A. nidulans, but stimulates it in A. fumigatus. Kim et al.2002 Fungal Genetics and Biology 37: 72–80; Krappmann et al.2005 Eukaryotic Cell 4: 1298–1307; and Krijgsheld et al.2013 Studies in Mycology 74: 1–29. Different Aspergillus species have other significant differences. Various Aspergillus species differ in the production of mycotoxins such as aflatoxins, ochratoxins and patulin. Larsen et al. 2001 App. Env. Mic.67: 3630; Varga et al.2004 Eur. J. Plant Path.110: 627; Bayman et al. 2002 App. Env. Mic.68: 2326; Varga et al.2003 Ant. van Leeuwenhoek 83: 191; and Varga et al.2003 Food Tech. Biotech.41: 29. Various Aspergillus species also differ significantly in plant pathology hosts. Varga et al.2004 Eur. J. Plant Path.110: 627. The various Aspergillus species are reportedly different enough that they have been divided among several sections: Aspergillus fumigatus is in Section Fumigati; A. niger is in the Section Nigri; A. oryzae and A. sojae are in the Section Flavi; and A. nidulans is in the Section Nidulantes. Steenwyk et al.2024 Mic. Spectrum 12 (4): e03980-23; Varga et al.2000 Folia Microbiologica 45: 423–428; and Varga et al.2004 Eur. J. Plant Path.110: 627. Because of the various biochemical and genetic differences between Aspergillus species, it was also unpredictable prior to the present work what effect a disruption of ptaB would have on different Aspergillus species, especially members of different Sections of this genus. The spaA gene product is a component of the polarisome and therefore important for polar growth. A knockout of spaA led to global changes such an increased hyphal diameter, a reduced growth rate and polarity defects. Meyer et al.2008 Fungal Genetics Biology 45 (2), 152-164. Additionally, spaA mutations resulted in increased dichotomous branching in Aspergillus nidulans. Virag and Harris, Eukaryotic Cell 5 (6), 881-895 (2006); Virag et al. do not appear to report measuring viscosity in their text. In at least some cases, increasing branching results in reduced viscosity. Bocking et al., Biotechnology Bioengineering 65 (6), 638-648 (1999); Bocking et al. do not appear to mention spaA in their text. Prior to the present work, no known reports described a direct measurement of viscosity of strains with a spaA disruption and thus it was unknown if such a disruption, which might cause other changes, might have on total viscosity. In addition, branching and viscosity are complex phenomena and McIntyre reported that “Very little is known about how branching is regulated in filamentous fungi”; see McIntyre et al. Adv. Biochem. Eng. Biotech.73: 103. Thus, it was unpredictable what effect a ptaB-spaA double disruption might have on branching and viscosity. Furthermore, additional factors may affect viscosity, such as macroscopic morphology (e.g., whether cells are freely dispersed, clumped or pelleted), and it was unknown what effect the double disruption might have on this morphology. In addition, viscosity of Aspergillus cultures can be an unpredictable, non-Newtonian phenomenon, which is affected by a number of different factors, including agitation speed, medium composition, temperature and pH, each of which can in turn have complex biochemical and biological effects on the organisms. Ichigawa et al. J. Biosci. Bioeng.133: 39; Muller et al. 2003 Biotech. Bioeng.81: 525; Papagianni et al.2001 Food Tech. Biotech.39: 319; and Sandri et al. LWT Food Sci. Tech.61: 430. Furthermore, prior to the present work, it was unknown what the effect of the interactions of spaA and ptaB disruptions might be on viscosity. It was unknown prior to this work if a decrease in viscosity mediated by the spaA disruption might be antagonized by the PtaB disruption. A theoretical decrease in viscosity mediated by spaA disruption might be related to increased branching (see above), but branching is known to be affected by cAMP levels (see McIntyre et al. Adv. Biochem. Eng. Biotech.73: 103). Furthermore, in Aspergillus, ptaB is reportedly downstream of the cAMP / PKA pathway; and a disruption of PtaB in Metarhizium acridum reportedly led to down-regulation of several genes in the cyclic AMP- dependent protein kinase A (cAMP / PKA) pathway. Speth et al.2019 Virulence 10: 976; and Du et al. Pest Manag. Sci.81: 839. Because of the unknown effects of ptaB disruption on cAMP levels, and the known relationship between cAMP and branching and possibly viscosity, it was unpredictable prior to the present work if the disruption of ptaB might antagonize a decrease in viscosity mediated by spaA. The absence of the antagonism of a ptaB disruption and a spaA disruption on viscosity, or even an additive effect of the two disruptions on viscosity might be surprising results. Thus, prior to the present work, it had not yet been shown that an individual ptaB or spaA mutation in any Aspergillus species would necessarily and predictably result in decreased viscosity. It was even more unknown if the combination of ptaB disruption and spaA disruption in any host would result in decreased viscosity, and, if so, by what percentage. The present work shows that the single knockout of ptaB or spaA reduces culture viscosity, but also that the double knockout of ptaB and spaA surprisingly further decreases viscosity in Aspergillus niger and Aspergillus sojae (which are in different Sections of Aspergillus). We also show that the single and double knockouts surprisingly decrease viscosity in a different species in a different genus, Penicillium rubens. Various experiments described herein show that the double knockout of ptaB and spaA reduced viscosity at 72 hours of fermentation time by at least 40%, at least 50%, at least 60%, and in at least one case at least 70%. Based on the findings of the present work, it is clear that this double knockout is likely to be functional in reducing culture viscosity in host cells of many different fungal genera and species. In some embodiments, a host cell is any species described in Table 6 or Table 7 comprising one or more genetic modifications that result in the downregulation (e.g., knockout) of its endogenous ptaB (or homolog) and its endogenous spaA (or homolog). In some embodiments, the level of expression and / or activity of each of a protein encoded by (a) spaA or a homolog thereof and (b) ptaB or a homolog thereof, in the genetically modified host cell, is, independently from each other, less than 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, or less than 60% of the respective level in a host cell that is the same as the genetically modified host cell except that it lacks the one or more genetic modifications that provide downregulation of the protein encoded by spaA and of the protein encoded by ptaB, when cultured under the same conditions. In some embodiments, host cells having downregulation of spaA (or a homolog thereof) and ptaB (or a homolog thereof) exhibit reduced viscosity when cultured relative to host cells having downregulation of either spaA (or a homolog thereof) or ptaB (or a homolog thereof) alone. In some embodiments, host cells having downregulation of spaA (or a homolog thereof) and ptaB (or a homolog thereof) exhibit viscosity when cultured that is reduced by about 1.5x, 2x, 2.5x, 3x, 3.5x, or 4x relative to host cells having downregulation of either spaA (or a homolog thereof) or ptaB (or a homolog thereof) alone. In some embodiments, host cells having downregulation of spaA (or a homolog thereof) and ptaB (or a homolog thereof) exhibit viscosity when cultured that is reduced by at least 1.5x, 2x, 2.5x, 3x, 3.5x, or 4x relative to host cells having downregulation of either spaA (or a homolog thereof) or ptaB (or a homolog thereof) alone. Production of Bioproducts Expression of heterologous genes Aspects of the disclosure provide genetically modified host cells comprising a heterologous gene. In some embodiments, the genetically modified host cells comprise a heterologous gene and produce a bioproduct. In some embodiments, the bioproduct: (a) is directly or indirectly produced by expression of the heterologous gene; or (b) is a mRNA or protein encoded by the heterologous gene. In some embodiments, a bioproduct is a protein, holoprotein, nucleic acid (e.g., mRNA; or polynucleotide), small or large molecule, complex or supramolecular complex (or a component of either), or a compound or composition that is, directly or indirectly, synthesized (in whole or in part), modified, and / or converted into another, a final, or a more useful or stable form by the action of the protein or nucleic acid encoded by a gene of interest. In some embodiments, where a gene of interest expresses a protein, the protein is an enzyme, a structural protein, a signaling protein, a regulatory protein, a transport protein, a sensory protein, a motor protein, a defense protein, or a storage protein. In some embodiments, genetically modified host cells described in this disclosure provide for production of a bioproduct encoded by a gene of interest at a level that is greater than the level of the bioproduct produced in a host cell which does not comprise one or more genetic modifications of the disclosure, when cultured under the same conditions. In some embodiments, genetically modified host cells described in this disclosure provide for production of a bioproduct encoded by a gene of interest (or directly or indirectly produced by expression of a gene of interest) at a level that is at least 10% (e.g., 10% more), 11%, 12%, 13%, 14%, 15%, 16%, 17%, 18%, 19%, 20%, 21%, 22%, 23%, 24%, 25%, 26%, 27%, 28%, 29%, 30%, 31%, 32%, 33%, 34%, 35%, 36%, 37%, 38%, 39%, 40%, 41%, 42%, 43%, 44%, 45%, 46%, 47%, 48%, 49%, 50%, 51%, 52%, 53%, 54%, 55%, 56%, 57%, 58%, 59%, 60%, 61%, 62%, 63%, 64%, 65%, 66%, 67%, 68%, 69%, 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, 100%, 105%, 106%, 110%, 115%, 120%, 125%, 130%, 135%, 140%, 145%, 150%, 155%, 160%, 165%, 170%, 175%, 180%, 185%, 190%, 195%, 200%, 250%, 300%, 400%, 500%, 1,000%, or more than 1,000% greater than the level of the bioproduct produced in a control host cell which does not comprise the same one or more genetic modifications of the disclosure, when cultured under the same conditions. Culturing Host Cells Any of the cells disclosed in this application, including the genetically modified host cells associated with this disclosure, can be cultured in media of any type (rich or minimal) and any composition. The conditions of the culture or culturing process can be optimized through routine experimentation as would be understood by one of ordinary skill in the art. In some embodiments, the selected media is supplemented with various components. In some embodiments, the concentration and amount of a supplemental component is optimized. In some embodiments, other aspects of the media and growth conditions (e.g., pH, temperature, etc.) are optimized through routine experimentation. In some embodiments, the frequency that the media is supplemented with one or more supplemental components, and the amount of time that the cell is cultured, is optimized. Culturing of the cells described in this application can be performed in culture vessels known and used in the art. In some embodiments, an aerated reaction vessel (e.g., a stirred tank reactor) is used to culture the cells. In some embodiments, a bioreactor or fermenter is used to culture the cell. Thus, in some embodiments, the cells are used in fermentation. As used in this application, the terms “bioreactor” and “fermenter” are interchangeably used and refer to an enclosure, or partial enclosure, in which a biological, biochemical and / or chemical reaction takes place, involving a living organism, part of a living organism, or purified proteins. A “large-scale bioreactor” or “industrial-scale bioreactor” is a bioreactor that is used to generate a product on a commercial or quasi-commercial scale. Large scale bioreactors typically have volumes in the range of liters, hundreds of liters, thousands of liters, or more. Non-limiting examples of bioreactors include: stirred tank fermenters, bioreactors agitated by rotating mixing devices, chemostats, bioreactors agitated by shaking devices, airlift fermenters, packed-bed reactors, fixed-bed reactors, fluidized bed bioreactors, bioreactors employing wave induced agitation, centrifugal bioreactors, roller bottles, and hollow fiber bioreactors, roller apparatuses (for example benchtop, cart-mounted, and / or automated varieties), vertically-stacked plates, spinner flasks, stirring or rocking flasks, shaken multi-well plates, MD bottles, T-flasks, Roux bottles, multiple-surface tissue culture propagators, modified fermenters, and coated beads (e.g., beads coated with serum proteins, nitrocellulose, or carboxymethyl cellulose to prevent cell attachment). In some embodiments, the bioreactor includes a cell culture system where the genetically modified host cell (e.g., yeast cell) is in contact with moving liquids and / or gas bubbles. In some embodiments, the cell or cell culture is grown in suspension. In other embodiments, the cell or cell culture is attached to a solid phase carrier. Non-limiting examples of a carrier system includes microcarriers (e.g., polymer spheres, microbeads, and microdisks that can be porous or non-porous), cross-linked beads (e.g., dextran) charged with specific chemical groups (e.g., tertiary amine groups), 2D microcarriers including cells trapped in nonporous polymer fibers, 3D carriers (e.g., carrier fibers, hollow fibers, multi-cartridge reactors, and semi-permeable membranes that can comprising porous fibers), microcarriers having reduced ion exchange capacity, encapsulation cells, capillaries, and aggregates. In some embodiments, carriers are fabricated from materials such as dextran, gelatin, glass, or cellulose. In some embodiments, industrial-scale processes are operated in continuous, semi- continuous or non-continuous modes. Non-limiting examples of operation modes are batch, fed batch, extended batch, repetitive batch, draw / fill, rotating-wall, spinning flask, and / or perfusion mode of operation. In some embodiments, a bioreactor allows continuous or semi-continuous replenishment of the substrate stock, for example a carbohydrate source and / or continuous or semi-continuous separation of the product, from the bioreactor. In some embodiments, the bioreactor or fermenter includes a sensor and / or a control system to measure and / or adjust reaction parameters. Non-limiting examples of reaction parameters include biological parameters (e.g., growth rate, cell size, cell number, cell density, cell type, or cell state, etc.), chemical parameters (e.g., pH, redox-potential, concentration of reaction substrate and / or product, concentration of dissolved gases, such as oxygen concentration and CO2 concentration, nutrient concentrations, metabolite concentrations, concentration of an oligopeptide, concentration of an amino acid, concentration of a vitamin, concentration of a hormone, concentration of an additive, serum concentration, ionic strength, concentration of an ion, relative humidity, molarity, osmolarity, concentration of other chemicals, for example buffering agents, adjuvants, or reaction by-products), physical / mechanical parameters (e.g., density, conductivity, degree of agitation, pressure, and flow rate, shear stress, shear rate, viscosity, color, turbidity, light absorption, mixing rate, conversion rate, as well as thermodynamic parameters, such as temperature, light intensity / quality, etc.). Sensors to measure the parameters described in this application are well known to one of ordinary skill in the relevant mechanical and electronic arts. Control systems to adjust the parameters in a bioreactor based on the inputs from a sensor described in this application are well known to one of ordinary skill in the art in bioreactor engineering. Cultures Aspects of the disclosure provide cultures comprising a plurality of genetically modified host cells associated with the disclosure. In some embodiments, a bioreactor comprises a plurality of genetically modified host cells associated with the disclosure. In some embodiments, an in vitro culture comprises a plurality of genetically modified host cells associated with the disclosure. In some embodiments, a culture associated with the disclosure exhibits a beneficial viscosity at a determined biomass concentration. Viscosity and biomass concentration may be measured by any known means. In some embodiments, the viscosity is measured in a viscometer at room temperature with a rotational spindle speed of about 5-10 RPM. In some embodiments, the culture has a biomass of at least 40 gDW / L and a viscosity of less than 7000 centipoise (cP), less than 6000 cP, less than 5000 cP, less than 4000 cP, or less than 3000 cP. In some embodiments, the culture has a biomass of at least 40 gDW / L and a viscosity of less than 7000 cP, less than 6000 cP, less than 5000 cP, less than 4000 cP, or less than 3000 cP and the genetically modified host cells are Penicillium rubens cells. In some embodiments, the culture has a biomass of at least 60 gDW / L and a viscosity of less than 3500 cP, less than 2500 cP, or less than 1000 cP. In some embodiments, the culture has a biomass of at least 60 gDW / L and a viscosity of less than 3500 cP, less than 2500 cP, or less than 1000 cP and the genetically modified host cells are Aspergillus niger cells. In some embodiments, the culture has a biomass of at least 70 gDW / L. In some embodiments, the culture has a biomass of at least 10 gDW / L and a viscosity of less than 1000 cP or less than 500 cP. In some embodiments, the culture has a biomass of at least 10 gDW / L and a viscosity of less than 1000 cP or less than 500 cP and the genetically modified host cells are Aspergillus sojae cells. In some embodiments, the viscosity is measured at room temperature with a rotational speed of about 5-10 RPM. Obtaining Bioproducts Aspects of the disclosure provide methods of producing a bioproduct comprising culturing genetically modified host cells associated with the disclosure. In some embodiments, production of the bioproduct is improved relative to a control host cell that does not comprise the one or more genetic modifications that result in the downregulation of: (a) spaA or a homolog thereof, and (b) ptaB or a homolog thereof. In some embodiments, production of a bioproduct is improved at least 1.5x, 2x, 2.5x, 3x, 3.5x, 4x, 4.5x, 5x, 5.5x, 6x, 6.5x, 7x, 7.5x, 8x, 8.5x, 9x, 9.5x, or 10x relative to a control host cell that does not comprise the one or more genetic modifications that result in the downregulation of: (a) spaA or a homolog thereof, and (b) ptaB or a homolog thereof. In some embodiments, the method further comprises a step of obtaining the bioproduct from a host cell. In some embodiments, obtaining the bioproduct from a host cell comprises lysing the host cell. In some embodiments, the method further comprises a step of obtaining the bioproduct from a culture, culture medium, cell-free spent culture medium, and / or cell-containing culture medium, and / or biomass used in, during or produced by culturing the genetically modified host cells. The present invention is further illustrated by the following Examples, which should not be construed as limiting. The entire contents of all of the references (including literature references, issued patents, published patent applications, and co-pending patent applications) cited throughout this application are hereby expressly incorporated by reference. If a reference incorporated in this application contains a term whose definition is incongruous or incompatible with the definition of same term as defined in the present disclosure, the meaning ascribed to the term in this disclosure shall govern. Mention of any reference, article, publication, patent, patent publication, and patent application cited in this application is not, and should not be taken as, an acknowledgment or suggestion that they constitute valid prior art or form part of the common general knowledge of a skilled artisan. EXAMPLES In order that the invention described in this application may be more fully understood, the following examples are set forth. The examples described in this application are offered to illustrate the systems and methods provided in this application and are not to be construed as limiting their scope. Example 1. Target gene identification Materials and Methods Bioinformatic tools Structural variance analysis between high and low viscosity strains was executed using the open-source bioinformatics tool Snippy (GitHub repository, T. Seemann et al., available at github.com / tseemann / snippy) versus the CBS513.88 refseq sequence [https: / / gold.jgi.doe.gov / organism?id=Go0000211]. SNP phylogeny was constructed and visualized using the open-source bioinformatics tool ‘Phylo’ in the Variant Call Format (VCF) kit (Andersen Lab, Johns Hopkins University, licensed under the 2014 MIT license). Parasexual crossing Parasexual crossing was performed as described in Niu et al, Arch Microbiol 198(9): 861-8 (2016). Target gene identification Structural variant analysis of low vs high viscosity A. niger strains In order to elucidate genetic differences between low viscosity and higher viscosity Aspergillus niger strain variants, a bioinformatics approach was taken to identify high impact structural variants (SVs) and therewith potential candidate gene targets that may form the genetic basis for reduced viscosity. These candidate gene targets may, thus, be suitable for optimizing viscosity in other A. niger strains, other Aspergillus species, or further distanced fungal species with homologues, paralogues and / or orthologues of these identified genes. A. niger strain CBS142952 (HFC1) was categorized as low viscosity strain, while A. niger strain CBS142951 (HFC2) was categorized as a higher viscosity strain. SVs were identified using Snippy to compare against the CBS513.88 NCBI refseq genome (Pel et al., Nat. Biotechnol 25 (2), 221–231 (2007)). Results are shown below (Table 1). Table 1. Structural variants relative to CBS513.88 A. niger strain Total variants versus CBS513.88 HFC1 Illumina 2787 HFC1 PacBio 2978 HFC2 1872 Of the identified SVs, a total of 1004 SVs compared to CBS513.88 were determined to be differentiating the low viscosity strain CBS142952 and the higher viscosity strain CBS142951. Out of these 1004 SVs, 542 SVs fell in coding regions. However, some intronic SVs resulted in splice-variants and were thus not discarded. Selection of target gene options The SVs were then further down-selected by predicted severity of the SNP for gene function (blosum62 values of -1 or lower) and having significant expression levels with a transcript per million (TPM) >10 and predicted (putative) function. This allowed down-selection to 17 potential high-impact target genes. Parasexual analysis to reduce target gene options (Generation of Parasexual crossing – segregants) Haploid segregants obtained from a parasexual crossing between low viscosity A. niger strain CBS142952 and higher viscosity A. niger strain CBS142951 that had the CBS142951-like higher viscosity plate and liquid culture phenotype were selected for genome sequencing. Any of the 17 CBS142952 specific SNP variants among the 17 selected high-impact targets that would be still retained in these higher-viscosity segregants could not be responsible for the low viscosity phenotype of CBS142952. This segregant variant analysis allowed it to rule out another 6 of the potential target genes. Two targets of interest are shown below in Table 2. Table 2. Description of targets of interest Locus_tag Description Mutation Nucl. Change AA Change An02g01620 protein PtaB, RNAseq confirms splice splice donor c.1683+1G>A variant (PtaB, a lim-domain binding protein variant & in Aspergillus fumigatus regulates biofilm intron variant formation and conidiation through distinct pathways: exopolysaccharide galactosaminogalactan (GAG) Disruption of ptaB resulted in impaired GAG production and conidiation in association with a markedly reduced expression of GAG biosynthetic genes) An07g08290 cell polarity protein (The polarisome stop gained c.33G>A p.Trp11* component SpaA localises to hyphal tips of Aspergillus niger and is important for polar growth.) Example 2. Gene disruption Preparation of knock-out strains 11 selected target genes from Example 1 were knocked out in Aspergillus niger using CRISPR-Cas9. A. niger HFC2 was transformed with the hygromycin cas vector and two gRNA expression cassettes [Leeuwe et al., Fungal Biol. Biotechn.6 (13) (2019), Song et al., Applied Microbiol. Biotechn.103:6919–6932 (2018)] by a PEG mediated protoplast transformation. Transformants were screened by PCR. Selection of knock-out mutants was based on different sizes of PCR products compared to the parent strain (FIGs.1A-1B). Selected strains were purified by single streaking and spore plates were inoculated. Genomic DNA of the selected knock-out mutants and their parental strain was isolated from frozen and ground mycelium by using a classic chloroform / phenol extraction [Arentshorst et al., Plant Fungal Pathogens 835, 133–150, (2012)]. The genomic DNA samples were sequenced by paired-end Illumina sequencing. The data were used to confirm the gene deletions. Table 3. crRNA sequences used for gRNA expression cassettes, used for targeting ptaB and spA. gRNA name sequence SEQ ID NO: An02g01620_1 GCCAGCACCGGGATGAGCAT 3 An02g01620_2 GCGGGAGATGCAAATTGGTT 4 An07g08290_1 CGCTGCGAGTCGAGAAGGTC 5 An07g08290_2 CGCGGAATCTCGAAGGCGAT 6 To characterize the phenotype of the verified knock-out mutants, they were cultivated in 48 well microtiter plate (mtp) for 3 days at 850 rpm at 35°C. Medium containing 50 g / L glucose, 20 g / L GISTEX®LS yeast extract, 8.5 g / L NaNO3, 5 g / L KH2PO4, 3 g / L MgSO4·7H2O, 0.5 g / L Tween®80, 0.1 g / L CaCl2, 22 mg / L ZnSO4·7H2O, 4.3 mg / L MnSO4·H2O, 4.9 mg / L FeCl3·6H2O, 1.7 mg / L CoCl2·6H2O, 1.6 mg / L CuSO4·5H2O and 1.5 mg / L Na2MoO4·2H2O. (e.g., as shown in FIG.2C, which shows small-scale liquid cultures). For the plate phenotype, minimal media was inoculated with 100 or 1000 spores, respectively, per spot and incubated at 35°C for 3 and 6 days (e.g., as shown in FIGs.2A-2B, which shows plate growth). Double knock-out strains were created by sequential transformation events and screened as described above. The non-integrative hygromycin cas vector is curable in the absence of selection pressure and therefore can be reused for recurrent transformations [Leeuwe et al., Fungal Biol. Biotechn.6 (13) (2019)]. Example 3. Mutant strain analysis Spores of the knock-out mutants were spotted on solid media and incubated for 3 days (FIG.2A) or 6 days (FIG.2B). A compact colony phenotype was observed for An02g01620 and An07g08290. The colonies of An02g01620 knock-out also appeared yellow initially. The phenotype of the knock-out mutants in liquid culture was assessed in 48 well microtiter plate (FIG.2C). A comparison is given in Table 4 below. Table 4. Knock-out mutants generated and phenotypes on plate in MTP Target gene Plate phenotype Mtp phenotype An02g01620 very fine mycelium was observed, similar to the (ptaB) compact growth, yellow colour low viscosity strain HFC1 (wells 7,8,9) An07g08290 smaller pellet size compared to parent (wells (spaA) compact growth 10,11,12) The knock-out mutants An07g08290 (wells 10, 11, 12 of FIG.2C), showed smaller pellet size compared to HFC2.5 (wells 1, 2). For An02g01620 mutants (wells 7, 8, 9 of FIG. 2C) very fine mycelium was observed, similar to the low viscosity strain HFC1 (wells 3, 4 of FIG.2C). Out of these 17 targets, two genes: An02g01620 (ptaB), An07g08290 (spaA), were shown to generate a clear growth phenotype reminiscent of the low viscosity strain CBS142952. Example 4. Mutation stacking Based on the compact growth phenotype and the fine growth in liquid culture, An02g01620 (ptaB) and An07g08290 (spaA) were combined and resulted in a double knock-out strain. Spores of the double knock-out mutant were spotted on solid media and incubated. A compact colony phenotype similar to the An02g01620 single knock-out was observed for the An02g01620 / An07g08290 double knock-out (FIG.3). Example 5. Mutation validation Materials and Methods for Fermentation: Aspergillus niger The HFC2 strains were cultivated in aerobic, glucose-rich fed-batch cultures at 5L working volume in Eppendorf BioFlo320®fermentation vessels. The fermentations were inoculated with 400 ml of a 72h old pre-culture grown in shake-flasks at 200 RPM and 35°C on a cultivation medium containing 50 g / L glucose, 20 g / L yeast extract (GISTEX®LS, DSM), 8.5 g / L NaNO3, 5 g / L KH2PO4, 3 g / L MgSO4·7H2O, 0.5 g / L Tween®80, 0.1 g / L CaCl2, and with Trace Metals according to Braaksma et al 2009 Microbiology 155(10): 3430-3439. The fermentation batch cultivation medium consisted of 100 g / L glucose, 10 g / L MgSO4·7H2O, 10 g / L KH2PO4, 6.6 g / L (NH4)2SO4, 44.0 mg / L ZnSO4·7H2O, 30.8 mg / L, MnSO4·H2O, 48.4 mg / L, FeCl3·6H2O, 3.90 mg / L, CuSO4·5H2O, 20 g / L yeast extract (GISTEX®LS, DSM) and 0.25 ml / L antifoam (Struktol J673, Schill and Seilacher, Hamburg, Germany). The setpoints for running these fermentations were: temperature 37°C, pH 5.5 (1-sided control with 25% NH3 as base), sparger gas-flow at 1.5 L / min and Dissolved Oxygen at 50% (cascade control with stirrer between 300 and 1000 RPM and optional addition of pure O2-gas into the sparger Air inflow). Consumed sugar was tracked through CO2evolution as measured in the off-gas and was used to start the feed (750 g / L glucose) when a glucose concentration of 50 g / L was reached. The feed maintained the 50 g / L glucose concentration based on the CO2in the off-gas. Biomass accumulation was monitored by taking daily samples and determining the biomass dry-weight concentration via the following procedure. For each sample the exact sample-amount was determined by weighing the sampling tube both before and after sampling. The biomass in each sample was harvested by filtration of the sample through the pre-weighted dry paper-filters (Whatman) and washed with demineralized water. Subsequently, the harvested biomass with the filter was dried overnight in an oven at 90°C and weighed. The biomass dry- weight was established by subtracting the weight of the dry filter. Parent and Mutant strains showed similar fermentation characteristics during cultivation other than viscosity. Samples taken for viscosity measurements were at the same cultivation age and the biomass concentration did not deviate more than 10% between samples of Parent and Mutant. Materials and Method: Viscosity analysis Viscosity of fermentation samples was determined with a BROOKFIELD DV2T Viscometer.25 ml of fermentation broth sample was put in a 50 ml conical tube and a disk-type LV2 or LV3 spindle was inserted. The measurements were done at room temperature with a rotational speed setting of 10 RPM and data logging of the measured viscosity in centiPoise (cP) every second during an interval of 300 seconds. Every sample was measured at least in duplicate with thorough remixing in between measurements. As during the first 150 seconds the measurements were unstable (usually they show a sharp decline), the final reported viscosity result is the average of the measurements between 150 sec and 300 sec. Results: Mutant validation Samples were taken at approximately 72 hours fermentation time. Biomass and viscosity were measured for each strain as shown in the table below. Table 5. Biomass and viscosity measured for A. niger strains Strain Biomass Viscosity (cP) (gDW / L) HFC1.4 73.7 ± 2.7 852 ± 71HFC2 WT 72.3 ± 1.1 4013 ± 845HFC2 dptaB 63.0 ± 0.9 2070 ± 248HFC2 dspaA 72.7 ± 0.8 1656 ± 273HFC2 dptaB dspaA 71.3 ± 1.7 846 ±101Example 6. Genome mining and sequence identification Amino acid sequences of A. niger target genes were used as a query for a protein BLAST search at NCBI. (blast.ncbi.nlm.nih.gov.) A.niger protein sequences: ptaB: MMMAQPFPAHQGIPQHPGLPPGHPMAPGQHPNAHPGAGMVQQVHPGVSAPGGPQVSQGGPVMGGMPPGAG TTGPGGAVQAHALSHLGPAQAHMFQQPHFAQQFANNPQLLQQHQQQQYLRQRMMLQHQHQQQQQQQHGGL PVQLPNGTPALNAAQIAAMQANPAMRPVNLQMQLQQMPHGQPQNLQQQQQFFAMQQAQQQAHQAQVQQAA AAGQPGQQTPQQRAAAQPQNVHDAQSVTPQPQPGPPPHQGSATPQPNPPPVPTSQPPQQQPAAPQPQPTP NPPPQQLPQAQQPGQQPQAPQAAQAQPQPQPNQQGPQQGQQQQPMTAQEAQIKAQQQQNPAAMMMQQQQQ RMNMKGAAILQLNSFAESLSYISGTENASTDFNQWHGFVLRFYSPGGVLRHTVCNPQANSSKQFEIATPA LARYYLTQCTSGIKHIQMLVDGARERDSPNGGHIVESAKTAFIYWFANGSQLFARANMTAHFDMNNKIEM LDIAVLDHNEYLPRSQLQALELSDQQKQSPKVSKNMGKRAQAKQAQQPAFTLPESMVTPNGVPTAVMSFL EVAETISHMQVLFQFSQQNPHLTPSEALRTLVNTMQAPAPNAAYVQGPMNPALQQGQPRAPSMSMPNQFA SPAMTHLGLPGAQGSPHLTGSAHPSPAQSHLAGPPGMVPQGQVQGNMAQGTSASASPNVGNKRRRASTVKMENDETGGGPEVNGTAGQAAPKVKASPRVGAKKQKGGG (SEQ ID NO: 1) spaA: MNAPSGTMSPVSVDGSDWSGINQYQKSDPPFSPTFSTRSALATPPTSGVPSGSNGAGLTNGASGPVSDAG NPSPPSSVAARSSDGTLSDQRSKRHKRMEEVLGQHYVALRRFLNASHRDDRASKSSKARDKLLRLSATQF HELSTDVYDELLRRQAAMPAPNRPPRPDIPPFLPPRKDFHEKRNQARQKLASLQHQRFRDLATDVYTELE RRFPQFPSRESRRLSPAPSYRGRPSNGYPPNGYPPTPGGPRSQSRGPPSRMGYPSGGPPASPMYPPRQGS LGGPPPGMNGDGPMAKSFQSNTIVPNKSTMVEDDDDGVGTEDDYDARSDAFALDAVLQSRRGTGATLADA DRKALAETQSQVSALQDKVNKLEDLLKSKDEEISKYQEDQNKVETLEDLVKSKDEELTKYRESQNTSDVS SSERQEWEDLKSDLESKISQAEDLNSNLQLELDKVRAEHEAIENDLRNQLEEASRQSSGDPELQARFADL EIKHQSLQTELQEQRSVTEEVRREAAGFLREMRELSEQSQSRWEHEEQLTTEVHRLEEQVKQWKTRYEKA KAQAGHLRTSSIGTEIRSDAATLTRDRDIFHENGLVKDVHVAKFQISIDELLHTARHDDYHVVTRQINAV VIAVRHMLQDVQESQDPSDGSSALRSKAISKLSTTANNLITAAKNFVKSNGLSPVSLLDAAASHLSAAVI ELIRLVKIRSTPPDESHEDDDEVQLSQLKSPDYFSVAPSQSRHSRNDSVYSAIGPPPDAPNGISVTVQDY TSQAETHELQEMKLYVEDQTNGLVQSIQTLIDSIRAERDLTTISTHVSAISSVVTNVTSSTQHFIKRPET SPALRQRIDPILEMLEYHKHRLVGAAAEGDASSSPEGLREVTNKLPPIAFEIPRVTKELAHQLDPASLEE DDDFR (SEQ ID NO: 2) As a result of protein BLAST, orthologs of ptaB and spaA were identified in several fungal species (Tables 6-7). Aspergillus sojae showed the highest sequence identity compared to A. niger. Aspergillus and Penicillium species belong to the same taxonomic family, which is also reflected in the higher sequence identity relative to A. niger compared to Thermothelomyces and Trichoderma, which belong to a different order of the class Sordariomycetes and are quite distant from Aspergillus and Penicillium. Target sequences for A.sojae and P. rubens were extracted from the following genomes: Aspergillus sojae NBRC 4239 and Penicillium rubens Wisconsin 54-1255. Table 6. Sequence identity of target proteins in different species. Species ptaB locus tag ptaB spaA locus tag spaA % ID* % ID* An02g01620 An07g08290 Aspergillus niger (ANI_1_214024) (ANI_1_1024064) Aspergillus sojae NBRC 4239 g1397, FUN_005844 73% g6499 68% Penicillium rubens Wisconsin 54- Pc12g07570 59% Pc18g05200 55% 1255Thermothelomyces thermophilus MYCTH_2311839 35% MYCTH_2296224 38% ATCC 42464Trichoderma reesei RUT C-30 M419DRAFT_11171 36% M419DRAFT_25397 36%Table 7. Sequence identity of target proteins in different species. In this table, the Uniprot accession numbers for the homologs of PtaB and SpaA are provided. “% identity” is identity relative to A. niger PtaB (SEQ ID NO: 1) and A. niger SpaA (SEQ ID NO: 2). Organism PtaB % SpaA % Identity Identity Ajellomyces capsulatus C0NCX3 50.1% C0NBB4 48.4% (strain G186AR / H82 / ATCC MYA-2454 / RMSCC 2432) (Darling's disease fungus) (Histoplasma capsulatum) Amorphotheca resinae A0A2T3APA3 39.9% A0A2T3AR66 42.1% ATCC 22711 Aplosporella prunicola A0A6A6BAY6 39.8% A0A6A6B516 40% CBS 121167 Arthroderma benhamiae D4AKK5 49.8% D4AVQ8 46.1% (strain ATCC MYA-4681 / CBS 112371) (Trichophyton mentagrophytes) Arthroderma otae (strain C5FND6 45.4% C5FSK1 47.2% ATCC MYA-4605 / CBS 113480) (Microsporum canis) Aspergillus aculeatus A0A1L9WXC0 71.7% A0A1L9X3L7 70.2% (strain ATCC 16872 / CBS 172.66 / WB 5094) Aspergillus arachidicola A0A2G7EPZ1 70.1% A0A2G7GA21 67.1% Aspergillus avenaceus A0A5N6TN79 71.7% A0A5N6TPR9 67.9% Aspergillus awamori (Black A0A401KI06 100% A0A401KEJ8 99.6% koji mold) Aspergillus bertholletiae A0A5N7B4Y8 71.3% A0A5N7ATQ5 69.5% Aspergillus bombycis A0A1F7ZPS6 72.3% A0A1F7ZUK3 70.6% Aspergillus brasiliensis A0A1L9UY32 96.3% A0A1L9UMH4 96.6% (strain CBS 101740 / IMI 381727 / IBT 21946) Aspergillus caelatus A0A5N6ZX90 73.4% A0A5N6ZSE9 70.1% Aspergillus calidoustus A0A0U5FPT8 69.9% A0A0U5GTA3 66.3% Aspergillus candidus A0A2I2FHX1 57.4% A0A2I2FB47 68.5% Aspergillus chevalieri A0A7R7VP57 69% A0A7R7VIA6 64.2% (Eurotium chevalieri) Aspergillus clavatus (strain A1C6W9 74.5% A1CET9 67.4% ATCC 1007 / CBS 513.65 / DSM 816 / NCTC 3887 / NRRL 1 / QM 1276 / 107) Aspergillus coremiiformis A0A5N6Z7T7 71.4% A0A5N6YXQ8 69.8% Aspergillus cristatus A0A1E3B530 69.4% A0A1E3BCX2 64.6% (Chinese Fuzhuan brick tea- fermentation fungus) (Eurotium cristatum) Aspergillus ellipticus CBS A0A319DPU2 79.5% A0A319D4X8 81.7% 707.79 Aspergillus felis A0A8H6R1L9 74.5% A0A8H6QMK2 68.6% Aspergillus fumigatiaffinis A0A8H4H443 75.7% A0A8H4MAY7 68.5% Aspergillus fumigatus Q4X0N1 75.2% Q4WHZ0 67.6% (strain ATCC MYA-4609 / CBS 101355 / FGSC A1100 / Af293) (Neosartorya fumigata) Aspergillus glaucus CBS A0A1L9V9R3 68.2% A0A1L9VSV0 65.3% 516.65 Aspergillus heteromorphus A0A317VMT5 76.8% A0A317X3P1 81.3% CBS 117.55 Aspergillus hiratsukae A0A8H6PGW0 75.2% A0A8H6P1A7 66.8% Aspergillus homomorphus A0A395IC73 73.9% A0A395HU24 71.7% (strain CBS 101889) Aspergillus ibericus CBS A0A395GLN2 86.6% A0A395GQI1 87.5% 121593 Aspergillus kawachii A0A7R8A9F8 98% A0A7R7ZVA1 96.3% (White koji mold) (Aspergillus awamori var. kawachi) Aspergillus leporis A0A5N5WRK2 72% A0A5N5WZR6 69.8% Aspergillus A0A5N6JJV0 73.5% A0A5N6IVZ0 69.5% minisclerotigenes Aspergillus mulundensis A0A3D8SVP4 63.5% A0A3D8T5R9 65.9% Aspergillus niger (strain A2QBY3 100% A2QP58 100% ATCC MYA-4892 / CBS 513.88 / FGSC A1513) Aspergillus nomiae NRRL A0A0L1IJT5 80.4% A0A0L1J9A5 70.5% 13137 Aspergillus nomiae NRRL A0A0L1J9M1 69.9% A0A0L1J9A5 70.5% 13137 Aspergillus novofumigatus A0A2I1CNC5 73.4% A0A2I1CKZ8 66.6% (strain IBT 16806) Aspergillus novoparasiticus A0A5N6EIF7 73.3% A0A5N6EM69 69.6% Aspergillus oryzae (strain Q2UF54 73.6% Q2U6J0 69.2% ATCC 42149 / RIB 40) (Yellow koji mold) Aspergillus oryzae (Yellow A0A1S9E0V6 73.6% A0A1S9D8W4 69.2% koji mold) Aspergillus parasiticus A0A5N6E103 73.6% A0A5N6D697 69.6% Aspergillus parasiticus A0A0F0I3C3 65.8% A0A0F0IMK4 69.6% (strain ATCC 56775 / NRRL 5862 / SRRC 143 / SU-1) Aspergillus pseudonomiae A0A5N7DG56 73% A0A5N7D4D8 70.6% Aspergillus pseudotamarii A0A5N6SC70 72.7% A0A5N6SDE8 69.6% Aspergillus puulaauensis A0A7R7XT76 68% A0A7R7XMT0 66.7% Aspergillus rambellii A0A0F8X2Q3 70.5% A0A0F8WTX5 67.6% Aspergillus ruber (strain A0A017SM78 68.5% A0A017SMG4 64.2% CBS 135680) Aspergillus saccharolyticus A0A318ZXG6 66% A0A318ZPY9 70.4% JOP 1030-1 Aspergillus sclerotialis A0A3A2ZJG3 70.5% A0A3A2ZQF3 61.8% Aspergillus A0A319EBU5 86.3% A0A319E107 86.2% sclerotiicarbonarius (strain CBS 121057 / IBT 28362) Aspergillus sclerotioniger A0A317WT89 82.5% A0A317VXR6 86.8% CBS 115572 Aspergillus sp. HF37 A0A3M2T164 70.2% A0A3M2T5I0 54.6% Aspergillus steynii IBT A0A2I2G4C5 76.2% A0A2I2FYE1 71.5% 23096 Aspergillus sydowii CBS A0A1L9THR7 67.6% A0A1L9TKC1 67.1% 593.65 Aspergillus tamarii A0A5N6V598 69.9% A0A5N6ULK2 69.9% Aspergillus tanneri A0A4S3JCW9 72.5% A0A4S3J4B6 68.7% Aspergillus terreus A0A5M3YPI5 72.3% A0A5M3ZBM0 69.5% Aspergillus terreus (strain Q0CYI2 67.1% Q0C9W5 69.1% NIH 2624 / FGSC A1156) Aspergillus thermomutatus A0A397GCM0 75% A0A397GG18 70.3% Aspergillus tubingensis A0A1L9NA35 97.3% A0A1L9MZ07 96.6% (strain CBS 134.48) Aspergillus turcosus A0A397GT24 75.1% A0A229Z405 68.2% Aspergillus udagawae A0A8H3RSG8 75.6% A0A8E0QI51 68.8% Aspergillus uvarum CBS A0A319CH51 71.9% A0A319DMU0 70.6% 121591 Aspergillus versicolor CBS A0A1L9PJ74 66.3% A0A1L9PLK8 66.2% 583.65 Aspergillus violaceofuscus A0A2V5HJR7 72.5% A0A2V5GUS0 70.6% (strain CBS 115571) Aspergillus welwitschiae A0A3F3PZF9 100% A0A3F3QKF1 99.6% Aspergillus wentii DTO A0A1L9RC04 76.9% A0A1L9RKP5 64.6% 134E9 Blastomyces gilchristii A0A179UP40 49.7% A0A179UMK5 45.3% (strain SLH14081) (Blastomyces dermatitidis) Blastomyces parvus A0A2B7X824 48.7% A0A2B7WPP6 46% Blastomyces percursus A0A1J9QV36 48.3% A0A1J9RFB3 44.8% Botryosphaeria dothidea A0A8H4N0I8 41.2% A0A8H4J4Z5 40.1% Byssochlamys spectabilis V5G6K8 63.5% V5HSP4 56.2% (strain No.5 / NBRC 109023) (Paecilomyces variotii) Cadophora malorum A0A8H7T764 42% A0A8H7W8J9 42% Cadophora sp. M221 A0A8H8BXX3 40.5% A0A8H7XJA1 42.4% Calycina marina A0A9P8CC51 38.6% A0A9P7Z9G4 41.2% Capronia coronata CBS W9ZLR7 40.9% W9Y225 39.8% 617.96 Capronia epimyces CBS W9Y9G1 38% W9Y3P0 40.4% 606.96Cladophialophora immunda A0A0D2CX37 39.7% A0A0D2CHX1 40.9%Cladophialophora W9WCK6 39.2% W9WNB1 41.3% psammophila CBS 110553 Coccidioides immitis (strain A0A0E1RYP2 53.5% J3KDL0 46.7% RS) (Valley fever fungus) Coccidioides posadasii E9D8J4 52.4% E9D926 46.7% (strain RMSCC 757 / Silveira) (Valley fever fungus) Coleophoma cylindrospora A0A3D8S7X1 42.8% A0A3D8RGZ1 42.6% Colletotrichum asianum A0A8H3WKK7 40.6% A0A8H3W922 40.1% Colletotrichum fructicola A0A7J6IWZ8 36.1% A0A7J6IS89 39.8% (strain Nara gc5) (Anthracnose fungus) (Colletotrichum gloeosporioides (strain Nara gc5)) Colletotrichum A0A8H4FFP9 40% A0A8H4CK09 40.2% gloeosporioides (Anthracnose fungus) (Glomerella cingulata) Colletotrichum T0KG88 37.0% T0KR25 40.1% gloeosporioides (strain Cg- 14) (Anthracnose fungus) (Glomerella cingulata) Colletotrichum graminicola E3QQ46 39.1% E3QAE8 39.4% (strain M1.001 / M2 / FGSC 10212) (Maize anthracnose fungus) (Glomerella graminicola) Colletotrichum A0A4T0VZM2 40.2% A0A4T0WJ67 40.2% higginsianum Colletotrichum incanum A0A166WG08 40% A0A166SEE4 40.6% Colletotrichum karsti A0A9P6I7T2 39% A0A9P6I9S1 40.2% Colletotrichum musicola A0A8H6KJ30 39.4% A0A8H6JNU2 40.7% Colletotrichum A0A9W4WMN7 39.5% A0A9W4WEF8 39.9% noveboracense Colletotrichum plurivorum A0A8H6KYH0 39.8% A0A8H6NM86 40.6% Colletotrichum shisoi A0A5Q4BT98 37.7% A0A5Q4BZI5 39% Colletotrichum sublineola A0A066XGT2 39% A0A066WXK2 39.9% (Sorghum anthracnose fungus) Colletotrichum tanaceti A0A4U6XMG0 39.5% A0A4U6XUT1 39.5% Colletotrichum tofieldiae A0A166Z107 40.7% A0A166VYI2 40.7% Colletotrichum trifolii A0A4R8QRL9 37.2% A0A4R8RXL2 39.3% Cyphellophora europaea W2RME0 39% W2S544 38.6% CBS 101466 Daldinia sp. EC12 A0A1Y2WMT3 33.0% A0A1Y2XBF5 39.4% Diplodia corticola A0A1J9R5W8 41.5% A0A1J9RJW7 40.4% Emergomyces africanus A0A1B7P5A0 47.8% A0A1B7NWI4 46.1% Emergomyces pasteurianus A0A1J9QCG9 48.1% A0A1J9QFQ5 47.2% Ep9510 Emericella nidulans (strain C8V1H8 58.5% Q5B6L5 68.9% FGSC A4 / ATCC 38163 / CBS 112.46 / NRRL 194 / M139) (Aspergillus nidulans) Emmonsia crescens A0A2B7ZU86 48.1% A0A2B7Z071 48.2% Endocarpon pusillum A0A8H7AS84 41.6% A0A8H7E434 43.9% Endocarpon pusillum U1GPI6 41.3% U1G0W0 44.7% (strain Z07020 / HMAS-L- 300199) (Lichen-forming fungus) Exophiala aquamarina A0A072PCP0 39.5% A0A072PBB0 41.8% CBS 119918 Exophiala mesophila A0A0D1X853 39.5% A0A0D1ZPV5 40.8% (Black yeast) Exophiala oligosperma A0A0D2AYZ6 39.7% A0A0D2BT36 41.1% Exophiala sideris A0A0D1YBJ9 38.8% A0A0D1Z3U3 41.1% Exophiala spinifera A0A0D2BWR8 39.3% A0A0D2C673 41.5% Exophiala xenobiotica A0A0D2E2G1 39.5% A0A0D2CYP2 40.3% Fonsecaea erecta A0A178ZIR3 38.7% A0A178ZW84 41.3% Fonsecaea multimorphosa A0A0D2KKP1 39.3% A0A0D2JFX3 41.3% CBS 102226 Fonsecaea pedrosoi CBS A0A0D2DJ57 38.4% A0A0D2HJJ1 41% 271.37 Fusarium duplospermum A0A428QXR5 35.8% A0A428QAS9 39.7% Fusarium falciforme A0A9W8R9Z9 36.7% A0A9W8QW42 39.5% Fusarium kuroshium A0A3M2RUC9 36.0% A0A3M2RPG0 38.8% Fusarium vanettenii (strain C7YZD0 37.5% C7YI68 39.4% ATCC MYA-4622 / CBS 123669 / FGSC 9596 / NRRL 45880 / 77-13-4) (Fusarium solani subsp. pisi) Glarea lozoyensis (strain S3DVR0 37.1% S3CGW2 41.4% ATCC 20868 / MF5171) Glonium stellatum A0A8E2EQE2 41.4% A0A8E2F921 39.2% Glutinoglossum A0A9P8ICU9 39.6% A0A9P8I9X9 45.2% americanum Helicocarpus griseus A0A2B7XV34 50.9% A0A2B7XTY8 49.5% UAMH5409 Helotiales sp. A0A8S9B3Y8 40.2% A0A8S9BV60 41% DMI_Dod_QoI Heterodermia speciosa A0A8H3FES8 38.3% A0A8H3EZL6 40.8% Hyaloscypha bicolor E A0A2J6T9H8 40.4% A0A2J6TEH6 41.7% Hyaloscypha hepaticicola A0A2J6Q8N6 40.4% A0A2J6Q3Y6 42.3% Hymenoscyphus fraxineus A0A9N9L407 39.3% A0A9N9KVF9 41.4% Hyphodiscus hymeniophilus A0A9P6SNT1 40.6% A0A9P7AZZ7 41.1% Hypoxylon sp. CO27-5 A0A1Y2V0Y0 35.4% A0A1Y2V1P1 39.6% Lachnellula cervina A0A7D8YQ19 39.4% A0A7D8UPM2 42.3% Lachnellula hyalina A0A8H8TYQ2 39.3% A0A8H8TXM1 41.4% Lachnellula occidentalis A0A8H8REE5 38.3% A0A8H8RZF7 41.1% Lachnellula subtilissima A0A8H8U314 38.9% A0A8H8RBM4 40.5% Lachnellula suecica A0A8T9C240 40.4% A0A8T9BVK7 42.8% Marssonina brunnea f. sp. K1WVP6 40.3% K1X076 40.6% multigermtubi (strain MB_m1) (Marssonina leaf spot fungus) Mollisia scopiformis A0A194WZV9 40.1% A0A194XVX4 41.1% (Conifer needle endophyte fungus) (Phialocephala scopiformis) Monascus purpureus (Red A0A507QNY7 62.4% A0A507QXT9 52.8% mold) (Monascus anka) Neonectria ditissima A0A0P7BXU0 37.4% A0A0P7B1G1 39.2% Neosartorya fischeri (strain A1DHJ6 75.9% A1CZ64 68% ATCC 1020 / DSM 3700 / CBS 544.65 / FGSC A1164 / JCM 1740 / NRRL 181 / WB 181) (Aspergillus fischerianus) Paracoccidioides A0A0A0HUG0 49.9% C1GK12 41.7% brasiliensis (strain Pb18) Penicilliopsis zonata CBS A0A1L9SJ13 67.8% A0A1L9SIF7 55.8% 506.65 Penicillium alfredii A0A9W9FT07 65% A0A9W9F8S5 60.4% Penicillium angulare A0A9W9F4X5 51.6% A0A9W9K5Q3 58.9% Penicillium antarcticum A0A1V6PVQ0 66.5% A0A1V6QD00 57.6% Penicillium argentinense A0A9W9K1L3 62.6% A0A9W9FPC7 57.7% Penicillium arizonense A0A1F5LE95 67% A0A1F5LY28 57.8%Penicillium atrosanguineum A0A9W9Q586 55.5% A0A9W9GY76 57.1% Penicillium bovifimosum A0A9W9KZU8 56% A0A9W9GUX2 57.8% Penicillium brasilianum A0A0F7VEF9 63.9% A0A0F7TLK6 58.2% Penicillium A0A9W9R5R0 54.9% A0A9W9UJ67 55% brevicompactum Penicillium canariense A0A9W9I8K0 60.7% A0A9W9IC53 57.4% Penicillium capsulatum A0A9W9IAS6 63.1% A0A9W9HT35 59.2% Penicillium cataractarum A0A9W9SQC3 64.6% A0A9W9VV60 58.8%Penicillium cf. griseofulvum A0A9W9J4E7 56.3% A0A9W9M0Y4 57.8%Penicillium cf. viridicatum A0A9W9MDJ6 56% A0A9W9MVX6 57.4% Penicillium chermesinum A0A9W9NTQ8 56.7% A0A9W9P0Y6 51.8% Penicillium cinerascens A0A9W9M6V2 59.9% A0A9W9N304 58.8% Penicillium citrinum A0A9W9TG02 60.8% A0A9W9P5F3 57.3% Penicillium concentricum A0A9W9SS02 55.9% A0A9W9SV69 57.5% Penicillium coprophilum A0A1V6V927 58.1% A0A1V6V7H7 57.6% Penicillium A0A9W9VQN1 46.8% A0A9W9VN89 57.8% cosmopolitanum Penicillium crustosum A0A9P5GNR0 54.3% A0A9P5GJW9 57.2% (Blue mold fungus) Penicillium decumbens A0A1V6P659 59% A0A1V6PMF3 59% Penicillium desertorum A0A9W9WYC6 58.4% A0A9X0BWQ7 58.1% Penicillium digitatum K9GGX7 52.3% K9G3Z9 55.8% (strain PHI26 / CECT 20796) (Green mold) Penicillium egyptiacum A0A9W4KCX9 52.1% A0A9W4P807 57.7% Penicillium expansum (Blue A0A0A2JU43 58% A0A0A2J587 57.4% mold rot fungus) Penicillium fimorum A0A9W9XZX1 57.7% A0A9W9Y2C8 57.3% Penicillium flavigenum A0A1V6T8F3 56.3% A0A1V6TW84 58% Penicillium freii A0A101MCI1 52.9% A0A117NQG2 57.1% Penicillium italicum (Blue A0A0A2KWI6 51.2% A0A0A2LDK9 57% mold) Penicillium nalgiovense A0A1V6YLZ0 55.5% A0A1V6YSC6 57.7% Penicillium nordicum A0A0M9WAH5 53.9% A0A0M9WCD0 57.1% Penicillium occitanis (nom. A0A2H3J3C7 48.5% A0A2H3IHQ1 54.4% inval.) Penicillium olsonii A0A9W4MII2 58.6% A0A9W4HYV1 56.7% Penicillium oxalicum (strain S7ZY74 62.2% S7ZJC2 54.4% 114-2 / CGMCC 5302) (Penicillium decumbens) Penicillium patulum A0A135LGM9 52.3% A0A135L902 57.8% (Penicillium griseofulvum) Penicillium polonicum A0A1V6NAS9 53.7% A0A1V6NRR4 56.7% Penicillium rubens (strain B6GX29 56.2% B6HC12 58% ATCC 28089 / DSM 1075 / NRRL 1951 / Wisconsin 54-1255) (Penicillium chrysogenum) Penicillium salamii A0A9W4NRC6 58.3% A0A9W4I666 57.2% Penicillium solitum A0A1V6QZT9 52.3% A0A1V6RGE5 57.6% Penicillium steckii A0A1V6SRE2 61.1% A0A1V6TRV0 59% Penicillium subrubescens A0A1Q5UKY6 64% A0A1Q5SSK6 58.6% Penicillium ucsense A0A8J8W7M9 61% A0A8J8VYT5 54.9% Penicillium vulpinum A0A1V6S257 57.6% A0A1V6S054 55.7% Petromyces alliaceus A0A5N6FZL6 72.5% A0A5N6G0M8 71.2% (Aspergillus alliaceus) Phaeomoniella A0A0G2EIH0 44.3% A0A0G2E6S7 46% chlamydospora Phialocephala subalpina A0A1L7WJF5 40.9% A0A1L7WR61 41.2% Polytolypa hystricis A0A2B7YR51 53.3% A0A2B7XIF3 50.6% UAMH7299 Pseudogymnoascus sp. A0A1B8EEG8 38.3% A0A1B8EFC4 40.6% 23342-1-I1 Pseudomassariella vexata A0A1Y2DGZ9 33.2% A0A1Y2EF58 39.3% Rasamsonia emersonii CBS A0A0F4YKG1 56.9% A0A0F4YFM0 57.1% 393.64 Rhynchosporium commune A0A1E1LRH1 39.6% A0A1E1KBB4 41.7% Rosellinia necatrix (White A0A1W2TVZ6 35.2% A0A1W2TBP7 38.3% root-rot fungus) Talaromyces amestolkiae A0A364KTI2 50.5% A0A364L367 53.5% Talaromyces atroroseus A0A225ASN9 50% A0A225B330 50.5% Talaromyces islandicus A0A0U1M1N8 48.5% A0A0U1LXI6 54.4% (Penicillium islandicum) Talaromyces marneffei B6QH10 50.5% B6QNY7 54.2% (strain ATCC 18224 / CBS 334.59 / QM 7333) (Penicillium marneffei) Talaromyces rugulosus A0A7H8R0P4 47.7% A0A7H8R8X7 53.4% Talaromyces stipitatus B8ML15 49% B8M8E3 47.1% (strain ATCC 10500 / CBS 375.48 / QM 6759 / NRRL 1006) (Penicillium stipitatum) Thermothielavioides G2RHK8 35.7% G2R3A6 40.2% terrestris (strain ATCC 38088 / NRRL 8126) (Thielavia terrestris) Tolypocladium A0A0L0NEG5 33.9% A0A0L0NAK6 39.5% ophioglossoides (strain CBS 100239) (Elaphocordyceps ophioglossoides) Trichophyton interdigitale A0A9P4YJX6 50% A0A9P5CUC4 45% Trichophyton interdigitale A0A059J8Y0 49.7% A0A059JG06 45.1% (strain MR816) Trichophyton rubrum A0A178ERH9 49.1% A0A178EZ82 45.4% (Athlete's foot fungus) (Epidermophyton rubrum) Venustampulla A0A370TXI2 40.1% A0A370U3Z3 43.1% echinocandica Xylaria flabelliformis A0A553HSZ8 34.4% A0A553I1W9 39.4% Xylaria grammica A0A439CRW9 35.7% A0A439D4R4 39.4% Xylaria multiplex A0A7C8MLP3 34.2% A0A7C8IU31 39.9% Xylariales sp. No.14919 A0A1V1TMT5 35.7% A0A1V1SSZ2 39.2% Xylona heveae (strain CBS A0A165A322 44.3% A0A165I5J3 39.9% 132557 / TC161) Example 7. Gene disruption in A. sojae and P. rubens The same target genes as identified to be relevant for generating low viscosity mutant strain for Aspergillus niger were also targeted for knock out in Aspergillus sojae and Penicillium rubens using CRISPR-cas9. A. sojae ATCC11906 pyrG5 (pyrG-) was transformed with the hygromycin cas vector, two gRNA expression cassettes per target gene [Leeuwe et al., Fungal Biol. Biotechn.6 (13) (2019); Song et al., Applied Microbiol. Biotechn.103:6919–6932 (2018)] (Table 8) and a pyrG selection marker cassette by a PEG mediated protoplast transformation. Transformants were screened by PCR (Table 9). P. rubens CBS 307.48 was transformed with the phleomycin cas vector and two gRNA expression cassettes per target gene [Leeuwe et al., Fungal Biol. Biotechn.6 (13) (2019), Song et al., Applied Microbiol. Biotechn.103:6919–6932 (2018)] (Table 8) by a PEG mediated protoplast transformation. Transformants were selected on minimal medium with phleomycin and screened by PCR (Table 9). Selection of knock-out mutants was based on different sizes of PCR products compared to the parent strain (FIGs.4A-4C). Selected strains were purified by single streaking and spore plates were inoculated. Table 8. crRNA sequences used for gRNA expression cassettes. gRNA name sequence SEQ ID NO: PrptaB_gRNA1 CAACATCCAAATGGACACCC 7 PrptaB_gRNA2 AAAATGGAATCCGAGGACGG 8 PrptaB_gRNA3 CCACCTATGCCTATGAACCA 9 PrptaB_gRNA4 CCAGCTGTCCCAGCGCCCGG 10 AOptaB_gRNA1 CCCGGAGTATCAGCTCCGGG 11 AOptaB_gRNA2 CCTGTGGCACCATACCTGGA 12 PrspaA_gRNA1 AGCGCACCCTTAAGTCCCAG 13 PrspaA_gRNA2 AAGCCAGGGACAAATTGCTG 14 PrspaA_gRNA3 GAGCTCACGCAATTGCTCAG 15 PrspaA_gRNA4 GGTGGCCAGTATCCGAGCCG 16 AOspaA_gRNA1 ATGTCGCCTGTCTCAGTGGA 17 AOspaA_gRNA2 TAAGCGATACCGCCAGATGG 18 AOspaA_gRNA3 TTTATGGATGAAATGCTCCG 19 AOspaA_gRNA4 TTAATGGGGACAGCAACTGA 20 Table 9. Primers used for screening knock-out mutants. Primer sequence SEQ ID NO: PrptaB 985 CACGGTTTTGCGCATTCAGA 21 PrptaB 986 TCTTGGATGTGGGGTTGGTG 22 PrspaA 1103 CCGCAGAGTTCAACTACACTAAAA 23 C PrspaA 1104 CAGTCGGCAGAACATGGTGAG 24 AsptaB 991 GGGGCACCTTATCACCACC 25 AsptaB 992 AGGGGCGATTCAGAGATAGTAAA 26 AsspaA 1105 AGCGGCACTAATTGATCTGTTCCT 27 AsspaA 1107 GGACAACACGGACAAGGAAATTC 28 Genomic DNA of the selected knock-out mutants and their parental strain was isolated using the Qiagen AllPrep Fungal DNA / RNA / Protein Kit. The genomic DNA samples were sequenced by paired-end Illumina sequencing. The data were used to confirm the gene deletions. Spores of the knock-out mutants were spotted on solid media and incubated for 2 days (A. sojae) or 8-10 days (P. rubens) (FIGs.5A-5B). A slightly reduced colony size was observed for the P. rubens single knock-out compared to the parent, while the double knock-out mutant showed a more compact colony. Both mutants had a sporulation phenotype. For A. sojae both, single and double mutant colonies, appeared more compact compared to the parent. Like for P. rubens, A. sojae mutants had a sporulation phenotype. However, a sporulating double mutant could be isolated during subculturing. Example 8. Mutant validation Materials and Methods Penicillium rubens cultivation: P. rubens strains were cultivated in aerobic, glucose limited fed-batch cultures at 5L working volume in Eppendorf BioFlo320®fermentation vessels. The fermentations were inoculated with 400 ml of a 72h old pre-culture grown in shake-flasks at 200 RPM and 30°C on a cultivation medium containing 50 g / L glucose, 20 g / L GISTEX®LS yeast extract, 8.5 g / L NaNO3, 5 g / L KH2PO4, 3 g / L MgSO4·7H2O, 0.5 g / L Tween®80, 0.1 g / L CaCl2, and with Trace Metals according to Braaksma et al., Microbiology, Volume 155, Issue 10, pp 3430-3439 (2009). The fermentation batch cultivation medium consisted of 30 g / L glucose, 3 g / L MgSO4·7H2O, 10 g / L KH2PO4, 13.2 g / L (NH4)2SO4, 40 g / L Corn Steep Solids (Solulys 095E, Roquette), with Trace Metals according to Braaksma et al, 2009 and 0.5 ml / L antifoam (Struktol J673, Schill and Seilacher, Hamburg, Germany). The setpoints for running these fermentations were: temperature 32°C, pH 6.5 (2-sided control with 25% NH4OH as base and 2M H2SO4as acid), Sparger gas-flow at 1.5 L / min and Dissolved Oxygen at 40% (cascade control with stirrer between 400 and 1000 RPM and optional addition of pure O2-gas into the sparger air inflow). Eight hours after inoculation an anti- starvation feed was started at 0.1 ml / min of a 279 g / L glucose feed. Upon detection of a rise in pH, indicating that the batch glucose was fully consumed, the feed speed was increased to 0.5 ml / min. Biomass accumulation was monitored by taking daily samples and determining the biomass dry-weight concentration via the following procedure: For each sample the exact sample-amount was determined by weighing the sampling tube both before and after sampling. The biomass in each sample was harvested by filtration of the sample through the pre-weighted dry paper-filters (Whatman) and washed with demineralized water. Subsequently, the harvested biomass with the filter was dried overnight in an oven at 90°C and weighed. The biomass dry- weight was established by subtracting the weight of the dry filter. Results: Penicilium rubens fermentations: For good viscosity comparisons between strains the samples of the different fermentations must have comparable biomass concentrations. Also, the biomass present needs to have grown under comparable conditions (e.g. glucose concentration, oxygen availability and shear stress) so the morphology of the hyphae is the same. The fermentation trends of both the P. rubens Parent and Mutant strains were similar to each other on all these points, as can be seen in FIGs.6A-6B, therefore the quality of the fermentations was judged to be okay for reliable viscosity comparisons. Materials and Methods Aspergillus sojae cultivation: The A. sojae strains were cultivated in aerobic fed-batch cultures at 5L working volume in Eppendorf BioFlo320®fermentation vessels. The fermentations were inoculated with 400 ml of a 40h old pre-culture grown in shake-flasks at 200 RPM and 30°C on a cultivation medium containing 50 g / L glucose, 20 g / L GISTEX®LS yeast extract, 13.2 g / L (NH4)2SO4, 5 g / L KH2PO4, 3 g / L MgSO4·7H2O, 0.5 g / L Tween®80, 0.1 g / L CaCl2 and with Trace Metals according to Braaksma et al, 2009. The fermentation batch cultivation medium consisted of 100 g / L glucose, 10 g / L MgSO4·7H2O, 10 g / L KH2PO4, 6.6 g / L (NH4)2SO4, 20 g / L Yeast extract (GISTEX®LS, DSM), with Trace Metals according to Braaksma et al, 2009 and 1.5 mg / L Na2MoO4·2H2O and 0.5 ml / L antifoam (Struktol J673, Schill and Seilacher, Hamburg, Germany). The setpoints for running these fermentations were: temperature 35°C, pH 5.5 (2-sided control with 25% NH4OH as base and 2M H2SO4 as acid), Sparger gas-flow at 1.5 L / min and dissolved oxygen (DO) initially at 50% (cascade control with stirrer between 400 and 1000 RPM and optional addition of pure O2-gas into the sparger air inflow). As soon as the offgas CO2output reached 35 mmol / L / hour this stirrer control was switched to keeping the CO2 output stable instead of the DO. However, the new control mode did not work correctly and from 26 hours cultivation time onwards the stirrer speed was set at a fixed speed, first 600 RPM and from 43h onwards 800 RPM. To prevent sporulation the glucose concentration was kept at ca.50 g / L by feeding with a 400 g / L glucose feed. The startpoint of feeding (at 17.5 hours) and the feed- speed settings (0.55 ml / min for the Parent and 0.68 ml / min for the Mutant) were estimated based on data from previous fermentations and the feedspeed was adjusted daily based on the measured glucose concentrations. After 71h of cultivation the feed was stopped. Biomass accumulation was monitored by taking daily samples and determining the biomass dry-weight concentration via the following procedure: For each sample the exact sample-amount was determined by weighing the sampling tube both before and after sampling. The biomass in each sample was harvested by filtration of the sample through the pre-weighted dry paper-filters (Whatman) and washed with demineralized water. Subsequently, the harvested biomass with the filter was dried overnight in an oven at 90 °C and weighed. The biomass dry- weight was established by subtracting the weight of the dry filter. Results Aspergillus sojae fermentations: For good viscosity comparisons between strains the samples of the different fermentations must have comparable biomass concentrations. Also, the biomass present needs to have grown under comparable conditions (e.g. glucose concentration, oxygen availability and shear stress) so the morphology of the hyphae is the same. The fermentation trends of both the A. sojae Parent and Mutant strains were similar to each other on all these points (FIGs.7A-7B), therefore the quality of the fermentations was judged to be okay for reliable viscosity comparisons. Materials and Method: Viscosity of fermentation samples was determined with a BROOKFIELD DV2T Viscometer.200 ml of fermentation broth sample was put in a wide-mouth 250 ml beaker and a Vane-type spindle was inserted, a V72 spindle for A. sojae and a V73 spindle for P. rubens. The measurements were done at room temperature with a rotational speed setting of 5 RPM and data logging of the measured viscosity in centiPoise (cP) every second during an interval of 300 seconds. Every sample is measured at least in duplicate with thorough remixing in between measurements. As during the first 150 seconds the measurements are unstable (usually they show a sharp decline), the final reported viscosity result is the average of the measurements between 150 sec and 300 sec. Results: Viscosities measured in comparable fermentation broth samples, i.e. Parent and Mutant strains showed similar fermentation characteristics during cultivation and the samples were taken at the same cultivation age with similar biomass concentration. Results are shown in Table 10 below. Table 10: Viscosities of fermentation broth after approximately 90 hours of cultivation. Fungal strain Viscosity Parent Viscosity double Fold reduction in strain (cP) ptaB spaA disruption viscosity Parent to Mutant (cP) Mutant: Penicillium rubens 7922 ± 86 2895 ± 116 2.7x at 44.5 g / L biomass at 38.2 g / L biomass Aspergillus sojae 1382 ± 71 435 ± 6 3.2x at 16.3 g / L biomass at 15.7 g / L biomass

[0002] Clauses 1. A genetically modified host cell comprising one or more genetic modifications that result in the knockout of: (a) spaA or a homolog thereof; and (b) ptaB or a homolog thereof. 2. The genetically modified host cell of clause 1, wherein the level of expression, and / or activity of a protein encoded by (a) spaA or a homolog thereof, or (b) ptaB or a homolog thereof, in the genetically modified host cell, is less than 25% of the respective level in a host cell that is the same except that it lacks the one or more genetic modifications, when cultured under the same conditions. 3. The genetically modified host cell of clause 1 or clause 2, wherein the knockout of (a) spaA or a homolog thereof, or (b) ptaB or a homolog thereof is mediated by: complete or partial removal of the coding sequence of (a) spaA or a homolog thereof, or (b) ptaB or a homolog thereof; disruption of the coding sequence; substitution or addition of amino acid(s) that interfere with the folding or activity of a protein encoded by a coding sequence; disruption of a non-coding and / or regulatory sequence(s) operably linked to the coding sequence; introduction of a premature stop codon via deletion or incorporation of orthogonal sequence in an open reading frame; silencing transcription of the coding sequence; disruption of the post- transcriptional processing of a transcript encoded by the coding sequence; disruption of post- translational processing of the protein encoded by the coding sequence; and / or disruption or replacement of a native promoter upstream of the coding sequence for (a) spaA or a homolog thereof or (b) ptaB or a homolog thereof. 4. The genetically modified host cell of clause 1 or clause 2, wherein the knockout of (a) spaA or a homolog thereof, or (b) ptaB or a homolog thereof is mediated by incorporation of a non-native nucleic acid into the native promoter. 5. The genetically modified host cell of clause 1 or clause 2, wherein the knockout of (a) spaA or a homolog thereof, or (b) ptaB or a homolog thereof is mediated by replacement of the native promoter with a weaker promoter or an inducible promoter. 6. The genetically modified host cell of any one of clauses 1-5, wherein the genetically modified host cell comprises: (a) one or more genetic modifications in spaA or a homolog thereof, such that the genetically modified host cell does not express the protein encoded by spaA or the homolog thereof; and / or (b) one or more genetic modifications in ptaB or a homolog thereof, such that the genetically modified host cell does not express the protein encoded by ptaB or the homolog thereof. 7. The genetically modified host cell of any one of clauses 1-6, wherein the genetically modified host cell comprises: one or more genetic modifications in spaA or a homolog thereof, such that the genetically modified host cell does not express the protein encoded by spaA or the homolog thereof; and one or more genetic modifications in ptaB or a homolog thereof, such that the genetically modified host cell does not express the protein encoded by ptaB or the homolog thereof. 8. The genetically modified host cell of clause 6 or clause 7, wherein the protein encoded by spaA or the homolog thereof comprises the amino acid sequence of a spaA protein or homolog thereof identified in Tables 6-7 or comprises the amino acid sequence of a spaA protein or homolog thereof having an amino acid sequence at least 90% identical to that of any identified in Tables 6-7, optionally wherein the protein encoded by spaA or the homolog thereof comprises the amino acid sequence of SEQ ID NO: 2 or comprises an amino acid sequence at least 30% identical to the amino acid sequence of SEQ ID NO: 2. 9. The genetically modified host cell of any one of clauses 6-8, wherein the protein encoded by ptaB or the homolog thereof comprises the amino acid sequence of a ptaB protein or homolog thereof identified in Tables 6-7 or comprises the amino acid sequence of a ptaB protein or homolog thereof having an amino acid sequence at least 90% identical to that of any identified in Tables 6-7, optionally wherein the protein encoded by ptaB comprises the amino acid sequence of SEQ ID NO: 1 or comprises an amino acid sequence at least 30% identical to the amino acid sequence of SEQ ID NO: 1. 10. The genetically modified host cell of any one of clauses 1-9, wherein the genetically modified host cell further comprises a heterologous gene. 11. The genetically modified host cell of any one of clauses 1-10, wherein the genetically modified host cell comprises a heterologous gene and produces a bioproduct. 12. The genetically modified host cell of clause 11, wherein the bioproduct: (a) is directly or indirectly produced by a protein encoded by the heterologous gene; or (b) is a mRNA or protein encoded by the heterologous gene. 13. The genetically modified host cell of any one of clauses 1-12, wherein the genetically modified host cell is a filamentous fungal cell. 14. The genetically modified host cell of any one of clauses 1-13, wherein the genetically modified host cell is an Aspergillus cell or a Penicillium cell. 15. The genetically modified host cell of any one of clauses 1-14, wherein the genetically modified host cell is an Aspergillus niger cell, an Aspergillus sojae cell, or a Penicillium rubens cell. 16. The genetically modified host cell of any one of clauses 1-15, wherein the genetically modified host cell exhibits reduced viscosity when cultured, compared to a control host cell that does not comprise the one or more genetic modifications that result in the knockout of: (a) spaA or a homolog thereof, and (b) ptaB or a homolog thereof. 17. The genetically modified host cell of clause 16, wherein the genetically modified host cell exhibits an at least 2-fold reduced viscosity when cultured, compared to a control host cell that does not comprise the one or more genetic modifications that result in the knockout of: (a) spaA or a homolog thereof, and (b) ptaB or a homolog thereof. 18. A bioreactor comprising a plurality of genetically modified host cells according to any one of clauses 1-17. 19. An in vitro culture comprising a plurality of genetically modified host cells according to any one of clauses 1-17. 20. The in vitro culture of cells of clause 19, wherein the culture has a biomass of at least 40 gDW / L and a viscosity of less than 7000 cP, less than 6000 cP, less than 5000 cP, less than 4000 cP, or less than 3000 cP, optionally wherein the genetically modified host cells are Penicillium rubens cells. 21. The in vitro culture of cells of clause 19, wherein the culture has a biomass of at least 60 gDW / L and a viscosity of less than 3500 cP, less than 2500 cP, or less than 1000 cP, optionally wherein the genetically modified host cells are Aspergillus niger cells. 22. The in vitro culture of clause 21, wherein the culture has a biomass of at least 70 gDW / L. 23. The in vitro culture of clause 19, wherein the culture has a biomass of at least 10 gDW / L and a viscosity of less than 1000 cP or less than 500 cP, optionally wherein the genetically modified host cells are Aspergillus sojae cells. 24. The in vitro culture of any one of clauses 20-23, wherein the viscosity is measured at room temperature with a rotational speed of about 5-10 RPM. 25. A method of producing a bioproduct comprising culturing the genetically modified host cell of any one of clauses 1-17. 26. The method of clause 25, wherein production of the bioproduct is improved at least 2.5x relative to a control host cell that does not comprise the one or more genetic modifications that result in the knockout of: (a) spaA or a homolog thereof; and (b) ptaB or a homolog thereof. 27. The method of clause 25 or clause 26, further comprising a step of obtaining the bioproduct from the host cell. 28. The method of clause 25 or clause 26, further comprising a step of obtaining the bioproduct from a culture, culture medium, cell-free spent culture medium, and / or cell- containing culture medium, and / or biomass used in, during or produced by culturing the genetically modified host cell. 29. The method of clause 28, wherein the viscosity measured at 72 hours of fermentation time is reduced by at least 40%. 30. The method of clause 28, wherein the viscosity measured at 72 hours of fermentation time is reduced by at least 50%. 31. The method of clause 28, wherein the viscosity measured at 72 hours of fermentation time is reduced by at least 60%. 32. The genetically modified host cell of any one of clauses 1-8, wherein the genetically modified host cell exhibits reduced viscosity when cultured, compared to a control host cell that does not comprise the one or more genetic modifications that result in the knockout of: (a) spaA or a homolog thereof, and (b) ptaB or a homolog thereof; and the viscosity is reduced by the knockout of both spaA and ptaB by at least 40%. 33. The genetically modified host cell of clause 32, wherein the viscosity is reduced by the knockout of both spaA and ptaB by at least 50%. 34. The genetically modified host cell of clause 32, wherein the viscosity is reduced by the knockout of both spaA and ptaB by at least 60%.

Claims

CLAIMS What is claimed is:

1. A genetically modified host cell comprising one or more genetic modifications that result in the knockout of: (a) spaA or a homolog thereof; and (b) ptaB or a homolog thereof.

2. The genetically modified host cell of claim 1, wherein the level of expression and / or activity of a protein encoded by (a) spaA or a homolog thereof, or (b) ptaB or a homolog thereof, in the genetically modified host cell, is less than 25% of the respective level in a host cell that is the same except that it lacks the one or more genetic modifications, when cultured under the same conditions.

3. The genetically modified host cell of claim 1 or claim 2, wherein the knockout of (a) spaA or a homolog thereof, or (b) ptaB or a homolog thereof is mediated by: complete or partial removal of the coding sequence of (a) spaA or a homolog thereof, or (b) ptaB or a homolog thereof; disruption of the coding sequence; substitution or addition of amino acid(s) that interfere with the folding or activity of a protein encoded by a coding sequence; disruption of a non-coding and / or regulatory sequence(s) operably linked to the coding sequence; introduction of a premature stop codon via deletion or incorporation of orthogonal sequence in an open reading frame; silencing transcription of the coding sequence; disruption of the post- transcriptional processing of a transcript encoded by the coding sequence; disruption of post- translational processing of the protein encoded by the coding sequence; and / or disruption or replacement of a native promoter upstream of the coding sequence for (a) spaA or a homolog thereof or (b) ptaB or a homolog thereof.

4. The genetically modified host cell of any one of claims 1-3, wherein the genetically modified host cell comprises: (a) one or more genetic modifications in spaA or a homolog thereof, such that the genetically modified host cell does not express the protein encoded by spaA or the homolog thereof; and / or (b) one or more genetic modifications in ptaB or a homolog thereof, such that the genetically modified host cell does not express the protein encoded by ptaB or the homolog thereof.

5. The genetically modified host cell of any one of claims 1-4, wherein the protein encoded by spaA or the homolog thereof comprises the amino acid sequence of a spaA protein or homolog thereof identified in Tables 6-7 or comprises the amino acid sequence of a spaA protein or homolog thereof having an amino acid sequence at least 90% identical to that of anyidentified in Tables 6-7, optionally wherein the protein encoded by spaA or the homolog thereof comprises the amino acid sequence of SEQ ID NO: 2 or comprises an amino acid sequence at least 30% identical to the amino acid sequence of SEQ ID NO:

2.

6. The genetically modified host cell of any one of claims 1-5, wherein the protein encoded by ptaB or the homolog thereof comprises the amino acid sequence of a ptaB protein or homolog thereof identified in Tables 6-7 or comprises the amino acid sequence of a ptaB protein or homolog thereof having an amino acid sequence at least 90% identical to that of any identified in Tables 6-7, optionally wherein the protein encoded by ptaB comprises the amino acid sequence of SEQ ID NO: 1 or comprises an amino acid sequence at least 30% identical to the amino acid sequence of SEQ ID NO:

1.

7. The genetically modified host cell of any one of claims 1-6, wherein the genetically modified host cell further comprises a heterologous gene.

8. The genetically modified host cell of any one of claims 1-7, wherein the genetically modified host cell is a filamentous fungal cell.

9. The genetically modified host cell of any one of claims 1-8, wherein the genetically modified host cell exhibits reduced viscosity when cultured, compared to a control host cell that does not comprise the one or more genetic modifications that result in the knockout of: (a) spaA or a homolog thereof, and (b) ptaB or a homolog thereof.

10. The genetically modified host cell of any one of claims 1-9, wherein the genetically modified host cell is an Aspergillus niger cell, an Aspergillus sojae cell, or a Penicillium rubens cell.

11. A bioreactor comprising a plurality of genetically modified host cells according to any one of claims 1-10.

12. An in vitro culture comprising a plurality of genetically modified host cells according to any one of claims 1-10.

13. A method of producing a bioproduct comprising culturing the genetically modified host cell of any one of claims 1-10.

14. The method of claim 13, wherein production of the bioproduct is improved at least 2.5x relative to a control host cell that does not comprise the one or more genetic modifications that result in the knockout of: (a) spaA or a homolog thereof; and (b) ptaB or a homolog thereof.

15. The method of claim 13 or claim 14, further comprising a step of obtaining the bioproduct from the host cell.

16. The method of any one of claims 13-15, wherein the viscosity measured at 72 hours of fermentation time is less than 1500 cP.

17. The method of any one of claims 13-16, wherein the viscosity measured at 72 hours of fermentation time is less than 1250 cP.

18. The method of any one of claims 13-17, wherein the viscosity measured at 72 hours of fermentation time is less than 1000 cP.

19. Use of a genetically modified host cell according to any one of claims 1-10, for the production of a bioproduct.

20. The genetically modified host cell of any one of claims 1-10, wherein the genetically modified host cell exhibits reduced viscosity when cultured, compared to a control host cell that does not comprise the one or more genetic modifications that result in the knockout of: (a) spaA or a homolog thereof, and (b) ptaB or a homolog thereof; and the viscosity is reduced by the knockout of both spaA and ptaB.

21. The genetically modified host cell of claim 20, wherein the viscosity measured at 72 hours of fermentation time is reduced by at least 40%.

22. The genetically modified host cell of claim 20 or claim 21, wherein the viscosity measured at 72 hours of fermentation time is reduced by at least 50%.

23. The genetically modified host cell of any one of claims claim 20-22, wherein the viscosity measured at 72 hours of fermentation time is reduced by at least 60%.

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