Proposed structural homology between zebrafish and humans for brain regions associated with human neurodevelopmental disorders and neurodegenerative diseases. (A) Adult zebrafish sections for I. telencephalon, brain and II. spinal chord. (B) Adult human sections for i., ii. telencephalon (anterior forebrain), brain and iii. spinal chord (transverse). Two hemi-sections were used (i. and ii.) to illustrate basal ganglia, hippocampus and amygdala. Regions associated with developmental disorders (blue) include cortical and subcortical structures that are vital for language, communication, memory, emotion and intellectual ability (Amaral et al., 2011; Bakhshi and Chance, 2015; Hampson and Blatt, 2015). Homologous forebrain regions for zebrafish are based on models that propose vertebrate structures that may be conserved for aspects of cognition and emotional behavior (Mueller and Wullimann, 2009; Mueller, 2012; Maximino et al., 2013; Filippi et al., 2014; Ganz et al., 2014; Wullimann, 2014). Conserved regions associated with axon degenerative diseases (red) include portions of the motor circuit and optic nerve (De Jonghe et al., 1997; Abrams et al., 2015). Zebrafish brain illustrations were adapted from Wullimann et al. (1996) and Mueller (2012). Am, amygdala; BG, basal ganglia; Ce, cerebellum; Ctx, cortex; Dc, dorsal central pallium; Dl, dorsal lateral pallium; Dm, dorsal medial pallium; DTele, dorsal telencephalon; Hip, hippocampus; Hy, hypothalamus; MN, motor neuron; PT, posterior tuberculum; Th, thalamus; ON, optic nerve.

Zebrafish orthologs of human neurological disease genes vary with respect to duplicate retention and average protein size. (A) Gene duplicate retention rates in zebrafish are graphed for neurodevelopmental and neurodegenerative disease groups. Yellow numbers at the base of bars represent sample size. (B) Protein sizes of zebrafish orthologs of human disease genes with floating box plots (median with upper and lower quartile-box and range-whiskers). Note some larger proteins are outliers that fall outside of the calculated range. These gene sets for each human disease only incorporate a small percentage of associated genes and selection criteria varied because of the heterogeneity in genes linked to each disease and an emphasis on producing conservative lists. Each gene set was selected using data from research groups and review articles with the goal of including only the highest confidence disease genes based on either statistical thresholds and/or reoccurrence. Autism spectrum disorders (ASD) genes were chosen from the Simons Foundation Autism Initiative (SFARI.org) “high confidence” and “strong candidate” gene lists, which uses a multi-variable scoring analysis that includes sample size, statistical significance, replication, and functional analysis (Basu et al., 2009). ASD-intellectual disability (ID) genes were found in four separate reviews that provide evidence for reoccurrence in both ASD and ID (Kaufman et al., 2010; Krumm et al., 2014; Srivastava et al., 2014; Vissers et al., 2016). Schizophrenia (SCZ) genes were chosen from a SCZ genetics review, however this list is small and does not provide a confidence level for the disease contribution of each gene (Escudero and Johnstone, 2014). X-linked ID genes (Piton et al., 2013) and Charcot-Marie Tooth Disease (CMT; Timmerman et al., 2014) genes were chosen from recent meta-analyses to which we included a threshold of >5 cases per gene. Autosomal dominant and recessive and X-linked ataxia (ATX; Bird, 2016) and Hereditary Spastic Paraplegia (HSP; Fink, 2014) genes were chosen with well-known inheritance pedigrees. Human proteins for these gene lists were generated using BioMart (Kinsella et al., 2011) and the longest isoforms were used to identify zebrafish orthologs (Supplementary Material, Tables S1–7). Human proteins were then Blasted (Flicek et al., 2014) against the zebrafish proteome and ortholog information was recorded. Zebrafish proteins with low percent coverage, protein identity, e-value and ambiguous gene annotation (e.g., gene-like, LOC1084, etc.) were reciprocally blasted to confirm orthology.

Comparing relative central nervous system (CNS) gene expression for developmental and degenerative disease gene orthologs in zebrafish. Previously published in situ hybridization data was collected from the zebrafish model organism database (ZFIN.org). Expression level was scored for each gene proportionally from 0 to 3; 0, no expression; 1, expression; 2, moderate expression; and 3, high level of expression, (i.e., gene x showed expression in the telencephalon (1) at 12 hpf and comparatively high expression in the telencephalon (3) at 36 hpf). Zebrafish larvae illustrations were adapted from Kimmel et al. (1995). D, diencephalon; M, mesencephalon; R, rhombencephalon; T, telencephalon and SC, spinal cord (De Jonghe et al., 1997; Kudoh et al., 2001; Thisse et al., 2001; Wurst and Bally-Cuif, 2001; Groth et al., 2002; Rauch et al., 2003; Thisse and Thisse, 2004, 2005; Croushore et al., 2005; Imamura and Kishi, 2005; Meyer et al., 2005; Thompson et al., 2005; Yimlamai et al., 2005; Liu et al., 2006; Mendelsohn et al., 2006; Meyer and Smith, 2006; Cheng et al., 2007; George et al., 2007; Goruppi et al., 2007; Katsuyama et al., 2007; Patten et al., 2007; Anichtchik et al., 2008; Stuebe et al., 2008; Sun et al., 2008; Yoshida and Mishina, 2008; Zhou et al., 2008; Emond et al., 2009; Ferrante et al., 2009; Monnich et al., 2009; Patten and Ali, 2009; Titus et al., 2009; Wood et al., 2009; Appelbaum et al., 2010; Davey et al., 2010; Fassier et al., 2010; Rissone et al., 2010; Takada and Appel, 2010; Mapp et al., 2011; Yeh et al., 2011; Artuso et al., 2012; Dresner et al., 2012; Gomez et al., 2012; Imai et al., 2012; Mueller, 2012; Pujol-Martí et al., 2012; Xing et al., 2012; Yanicostas et al., 2012; Baraban et al., 2013; Campbell and Marlow, 2013; Haug et al., 2013; Ng et al., 2013; Recher et al., 2013; Suls et al., 2013; Vatine et al., 2013; Bernier et al., 2014; Garbarino et al., 2014; Housley et al., 2014; Hsieh et al., 2014; Galizia et al., 2015; Kozol et al., 2015; Wakayama et al., 2015).