Kalyani rajalingham maoa

Molecular Characterization of monoamine oxidase A By Kalyani Rajalingham

Molecular Characterization of monoamine oxidase A

1 ABSTRACT

The MAO-A gene – involved in the degradation of amine neurotransmitters - is one that is associated with violent tendencies, aggressive behaviour, and low intelligence. Low expression levels are usually yoked to the said tendencies. In this study, I try to characterize the MAO-A gene via a bioinformatics analysis. Analysis shows that sites 374, and 406 in the human MAO-A were conserved in 106 sequences; however, mutations in sites 374, and 406 results in the complete loss of activity of the protein. Natural variant sites 15, 188, 314, and 520 were not found to be conserved in all 106 organisms; however, amongst the PhyTrels, sites 188, 314, and 520 were found to be conserved. Further, gene, and protein expression levels were not found to be linearly correlated in Homo sapiens; protein levels of MAO-A was found to be high in most tissue. Gene expression of MAO-A was found to vary between organisms.

INTRODUCTION

The MAO-A gene is one that is associated with antisocial behaviour, and aggression (Hunter 2010,

Bortolato et al. 2012); antisocial tendencies, and MAO-A expression in the brain were found to be

inversely correlated (Bortolato et al. 2012). Located on the X chromosome (Xp11.3), the MAO-A gene

has been linked to a number of diseases; in particular, a nonsense mutation in the MAO-A gene, in

humans, has been linked to Brunner’s syndrome, a form of mental retardation. Low levels of MAO-A in

Brunner’s Syndrome results in an increased level of amine neurotransmitters which is accompanied by

particular behavioural tendencies – hypersexuality, sleep disorder, mood swings, and violent tendencies

(Hunter 2010). Moreover, Brunner syndrome is associated with violence, antisocial behaviour (ex: rape,

murder, exhibitionism, voyeurism, arson) usually as a result of minor stresses (Bortolato and Shih 2011).

Brunner’s syndrome, however, is very rare – low frequency. There exists two MAO genes in humans –

MAOA, and MAOB; with 70% sequence similarity, loss of both MAO genes would result in severe mental

retardation (Cases et al. 2010). MAO-A, an enzyme in the mitochondrion (Cases et al. 2010), is involved

in the degradation of various amine neurotransmitters (ex: dopamine, serotonin, and norepinephrine)

(Bortolato et al. 2012). Inhibitors of MAO, usually targeting MAO-A, have antidepressant properties –

which results in an increase in the synaptic concentrations of 5-HT, and modifies neuronal firing rates

(Bortolato and Shih 2011). One variant - responsible for low expression of MAOA - with a frequency of


2 40% in the general population is also known as MAOA-L (Hunter 2010). MRI data shows that

individuals with MAOA-L have a small limbic system which is involved in emotion, behaviour, and

memory; individuals with MAOA-L had a poor impulse control (Hunter 2010). However, Hunter (2010)

notes that individuals who possess the MAOA-L variant require a “trigger” to induce the violent

tendencies. Amongst the number of diseases that is associated with MAO-A are sociopathy, antisocial

personality disorder, and psychopathy. Many have wondered about the link between MAO-A, and many a

disease. In this paper, I seek to analyze the MAO-A protein, to characterize both function, and structure as

well as determine whether expression in animals is similar to humans.

RESULTS

DOMAINS, MOTIFS, INTERACTIONS AND PATHWAYS

Located on the outer membrane of the mitochondrion, this integral membrane protein functions in

synaptic transmission, and metabolic processes (Supplementary Figure S1); MAO-A is an oxidoreductase.

The MAO-A gene was found to be associated with an Amine oxidase domain (IPR002937), which

possesses oxidoreductase activity, and belongs to the flavin amine oxidase family (IPR001613)

(Supplementary Figure S2). MAO-A requires FAD as a cofactor, and was found to interact with ALDH2,

CYP2C19, SLC6A4, COMT, DRD4, DBH, DDC, PNMT, CYP2C9, and AOX1. MAO-A is involved

in the degradation of the following compounds: dopamine, melatonin, putrescine, serotonin, tryptophan,

noradrenaline and adrenaline; it is also involved in the biosynthesis of isoquinoline alkaloids, secondary

metabolites, and salidroside. MAO-A is involved in the metabolism of the following compounds: glycine,

serine, threonine, arginine, proline, tyrosine, histidine, phenylalanine, tryptophan, and drugs. It has also

been implicated in cocaine, and amphetamine addiction as well as alcoholism. MAO-A targets the

dopaminergic, and sertonergic synapses, and thus targets the nervous system.


3 STRUCTURAL ANALYSIS

The MAO-A gene – 527 amino acids in length - has two important sites: site 335, and site 374. The

cytoplasmic region spans amino acids 1 to 497; the mitochondrial membrane region spans amino acids 519

to 627; the transmembrane region spans amino acids 498 to 518. Site 335 is responsible for substrate

specificity, and site 374 is required for catalytic activity. Mutations at sites 374, and 406 results in the

complete loss of activity of the protein (Supplementary Figure S2). Natural variants of MAO-A include

the following: site 15 from D to E (s15-DE), s188-EK, s314-FV, and s520-KR.

PHYLOGENETIC ANALYSIS

Figure 1: Molecular phylogenetic analysis by Maximum Likelihood method for the MAOA gene. A Maximum Likelihood tree was constructed (JTT model, Gamma distribution (5 categories, +G, parameter = 0.5703), Bootstrap (50)). The tree shows branches with bootstrap values greater than 70. [MAO-A= Monoamine oxidases A; MAO-B= Monoamine oxidases B; MAO-A I = isoform 1; MAO-A 2=isoform 2; MAO-A K where K is a variant; unrooted tree] Phylogenetic analyses were performed in MEGA6.

Both isoforms of the MAO-A gene in Homo sapiens were found to be similar to the MAO-A gene present

in Pan paniscus, Pan troglodytes, Nomascus leucogenys, Gorilla gorilla gorilla, Pongo abelii, Macaca

mulatta, Chlorocebus_sabaeus, and Papio Anubis – this group will be referred to as the PhyTrel (Figure

1). Conserved sites were observed between amino acid 174, and 497 of the Homo sapiens MAO-A I in all

106 sequences. In particular, two stretches of conserved sites are noteworthy; the first gapped stretch of

conserved sites was observed between amino acids 174, and 258 of the Homo sapiens MAO-A gene, and


4 the second gapped stretch was observed between amino acids 386 to 452 in the Homo sapiens

(Supplementary Figure S4). Mapping this region onto the MAO-A I Homo sapiens gene, it falls into the

Amino oxidase domain. In particular, although site 335 (of the Homo sapiens MAO-A) was not found to

be conserved in all 106 sequences, sites 374, and 406 were found to be conserved in all 106 sequences.

Sites 15, 188, 314, and 520 were not found to be conserved in all 106 organisms. Amongst the PhyTrels,

sites 188, 314, and 520 were found to be conserved (Supplementary Table S1).

COMPARING GENE EXPRESSION OF MAO-A IN ORGANISMS

Gene Expression

The EST profile of the MAO-A gene in Homo sapiens

shows high levels of gene expression in the bladder, the

PNS, the placenta, the prostate, the small intestine, and

soft tissue; non-zero gene expression levels were observed

in the bone, the bone marrow, the brain, the colon, the

eye, the heart, the kidney, liver, lung, muscle, ovary,

pancreas, skin, testis, and uterus (Supplementary Figure

S5). Differential gene expression was observed between

organisms (Figure 3). For instance, relative gene

expression of MAO-A in the kidney was low in

Monodelphis domestica, Gallus gallus, and Bos Taurus,

and high in Xenopus tropicalis, and Anolis carolinensis. In another instance, gene expression was found to

be low in the heart of Xenopus tropicalis, Monodelphis domestica, Gallus gallus, and Bos Taurus; in

Anolis carolinensis, however, expression is high in the heart.


5

Figure 3: Gene expression of MAO-A in various tissues. [Information gathered from the Expression Atlas; A= Bos Taurus; B= Anolis carolinensis; C= Gallus gallus; D=Monodelphis domestica; E= Xenopus tropicalis] Protein Expression

Gene expression, and protein expression were not linearly

correlated (Figure 4). Oddly enough, the MAO-A protein was

found to be absent only in the lateral ventricle, hippocampus,

lymph node, and bone marrow. Protein levels are quite high in

most tissue (of Homo sapiens) – heart muscle, lung, endocrine

glands, tonsil, skin, and soft tissues, the reproductive system, the

urinary system, the digestive system, as well as the liver, the

gallbladder, and the pancreas. Further, a protein expression

analysis showed that for most cancers, the cancer staining level of

MAO-A did not differ from the normal level (Figure 5).

However, in some tissues, the expression of MAO-A was either


6 higher or lower than the normal level.

Figure 5: Protein expression of MAO-A in cancer cells. (Source – Protein Atlas; The cancer staining bar represents 12 replicates in total, wherein we observe low, medium, or high protein expression levels.)

DISCUSSION

The MAO-A gene has been linked to a number of functional breakdowns that are known to occur in

humans which in particular results in psychiatric and neurological problems; lack of MAO-A proteins

primarily affects the central nervous system. In this particular study, a bioinformatics analysis of the MAO-

A gene was conducted in an attempt to characterize the protein. Results show that a few sites are conserved

amongst 106 organisms. Amongst the conserved sites were sites 374, and 406 – mutations at this site

would result in the complete loss of function of MAO-A. Sites 188, 314, and 520 – natural variants in

humans - were found to be conserved in the PhyTrels (primates). Lack of MAO-A proteins primarily

affects the central nervous system; serotonin, dopamine, and norepinephrine. Further, concentrations of

MAO-A knockout mice were found to be elevated; adult MAO-A knockout mice displayed aggressive

behaviours; MAO-A-/- mice (Tg8) showed altered behaviours that could be reversed by supplying the

mouse with an inhibitor (acts like MAO-A) (Cases et al. 2010). In this particular paper, I found that

MAO-A expression was different between organisms. MAO-A levels were found to be higher in the brain

of Anolis carolinesis, and very low in that of Xenopus tropicalis. Dopamine, for instance, controls

movement, memory, alertness, attention, emotions, pleasure, and pain; high levels of dopamine results in


7 impulsive behaviour, and paranoia. One must ask whether we can assess behaviour of a number of animals

based on similarity of the MAO-A gene, and expression profiles.

METHODS

BLAST, and Phylogenetic Analysis. The protein sequence of MAO-A for Homo sapiens was

acquired at NCBI (http://www.ncbi.nlm.nih.gov/; NP_000231.1, NP_001257387.1). Two isoforms

were present; for the purposes of this paper, isoform variant 1 was selected (NP_000231.1). BLASTp

(protein BLAST, refseq_proteins, BLOSUM62 matrix, gap opening= 11, gap extention=1) was

performed using the protein sequence of isoform 1; output was downloaded in FASTA format. These

sequences were complemented with the protein sequences of orthologs that were obtained from the

Ortholog from Annotation Pipeline list, and HomoloGene at NCBI. MUSCLE was used to perform a

multiple sequence alignment (MEGA6.06, Gap opening penalty -2.9, Gap extending penalty 0,

Hydrophobicity multiplier 1.2, UPGMB clustering method). Phylogenic reconstruction was carried out

using the Maximum-likelihood method (MEGA6.06, bootstrap method 50, Jones-Taylor-Thornton

(JTT) model, Gamma distribution (G) 5, Nearest-Neighbour-Interchange (NNI)). No out-group was

used.

Domains, Motifs, and Interactions. To determine the domains, and motifs present, the SMART

(http://smart.embl-heidelberg.de/) database was accessed. InterPro (http://www.ebi.ac.uk/interpro/)

was used to confirm domains, and assess function of said domain. STING (http://string-db.org/) was

used to determine the partners of MAO-A (proteins with which it interacts).

Pathways. KEGG (http://www.genome.jp/kegg/) was accessed to determine pathway

information. ExPASy Enzyme (enzyme.expasy.or/), and BRENDA (http://www.brenda-enzymes.info/)

were accessed for information about the enzyme. UniPROT (www.uniprot.org/) was used to access

information about mutagenesis.


8 Comparing Gene Expression of MAO-A in organisms. UniGene

(http://www.ncbi.nlm.nih.gov/unigene) was accessed to retrieve EST profiles of MAO-A for a number of

species. Further, the Expression Atlas

(http://www.ebi.ac.uk/gxa/home;jsessionid=6116099BA8CB7DCA2F73E3843432C153) was also

accessed to collect gene expression profiles (for comparison). The Protein Atlas

(www.phosphosite.org/proteinAction.do?id=1911538&showAllSites=true) was used to determine levels

of MAO-A protein in various tissues.

REFERENCES Hunter, P. (2010). The psycho gene. EMBO Rep, 11(9), pp.667-669. Bortolato, M., Godar, S., Melis, M., Soggiu, A., Roncada, P., Casu, A., Flore, G., Chen, K., Frau, R., Urbani, A., Castelli, M., Devoto, P. and Shih, J. (2012). NMDARs Mediate the Role of Monoamine Oxidase A in Pathological Aggression. Journal of Neuroscience, 32(25), pp.8574-8582. Bortolato, M. and Shih, J. (2014). Behavioral outcomes of monoamine oxidase deficiency: Preclinical and clinical evidence. International Review of Neurobiology, 100(2011), pp.13-42. Cases, O., Seif, I., Grimsby, J., Gaspar, P., Chen, K., Pournin, S., Muller, U., Aguet, M., Babinet, C., Shih, J. and et, a. (1995). Aggressive behavior and altered amounts of brain serotonin and norepinephrine in mice lacking MAOA. Science, 268(5218), pp.1763-1766.


9 SUPPLEMENTARY MATERIAL

Figure S1: Reaction catalyzed by MAO-A. [Source – BRENDA]


10

Figure S2: Secondary, and 3D structure of MAO-A [Structures were obtained from the PDB]


11 Table S1: List of MAO-A sequences used for phylogenetic analysis.

>gi|4557735|ref|NP_000231.1| amine oxidase [flavin-containing] A isoform 1 [Homo sapiens] >gi|332860606|ref|XP_003317484.1| PREDICTED: amine oxidase [flavin-containing] A-like [Pan troglodytes] >gi|55741561|ref|NP_001002969.1| amine oxidase [flavin-containing] A [Canis lupus familiaris] >gi|114326284|ref|NP_851357.2| amine oxidase [flavin-containing] A [Bos taurus] >gi|255759902|ref|NP_776101.3| amine oxidase [flavin-containing] A [Mus musculus] >gi|270288740|ref|NP_387502.1| amine oxidase [flavin-containing] A [Rattus norvegicus] >gi|512821168|ref|XP_002932844.2| PREDICTED: amine oxidase [flavin-containing] A-like isoform X1 [Xenopus (Silurana) tropicalis] >gi|395132504|ref|NP_001257387.1| amine oxidase [flavin-containing] A isoform 2 [Homo sapiens] >gi|297303663|ref|XP_001096840.2| PREDICTED: amine oxidase [flavin-containing] A [Macaca mulatta] >gi|719756952|ref|XP_010215009.1| PREDICTED: amine oxidase [flavin-containing] A [Tinamus guttatus] >gi|410988387|ref|XP_004000467.1| PREDICTED: amine oxidase [flavin-containing] A [Felis catus] >gi|71895251|ref|NP_001025970.1| monoamine oxidase A [Gallus gallus] >gi|674034908|ref|XP_008841403.1| PREDICTED: amine oxidase [flavin-containing] A [Nannospalax galili] >gi|584069823|ref|XP_006755251.1| PREDICTED: amine oxidase [flavin-containing] A [Myotis davidii] >gi|555958932|ref|XP_005891579.1| PREDICTED: amine oxidase [flavin-containing] A [Bos mutus] >gi|704179704|ref|XP_010134921.1| PREDICTED: amine oxidase [flavin-containing] A, partial [Buceros rhinoceros silvestris] >gi|700322686|ref|XP_009927895.1| PREDICTED: amine oxidase [flavin-containing] A [Haliaeetus albicilla] >gi|675624372|ref|XP_008940411.1| PREDICTED: LOW QUALITY PROTEIN: amine oxidase [flavin-containing] A [Merops nubicus] >gi|667309052|ref|XP_008583930.1| PREDICTED: amine oxidase [flavin-containing] A [Galeopterus variegatus] >gi|664771491|ref|XP_008504928.1| PREDICTED: amine oxidase [flavin-containing] A [Equus przewalskii] >gi|663281319|ref|XP_008498559.1| PREDICTED: amine oxidase [flavin-containing] A [Calypte anna] >gi|641722897|ref|XP_008151246.1| PREDICTED: amine oxidase [flavin-containing] A [Eptesicus fuscus] >gi|640776697|ref|XP_008052177.1| PREDICTED: amine oxidase [flavin-containing] A [Tarsius syrichta] >gi|426395651|ref|XP_004064079.1| PREDICTED: amine oxidase [flavin-containing] A isoform 1 [Gorilla gorilla gorilla] >gi|197099200|ref|NP_001124913.1| amine oxidase [flavin-containing] A [Pongo abelii] >gi|694984598|ref|XP_003317484.2| PREDICTED: amine oxidase [flavin-containing] A [Pan


12 troglodytes] >gi|332243814|ref|XP_003271068.1| PREDICTED: amine oxidase [flavin-containing] A isoform 1 [Nomascus leucogenys] >gi|685621052|ref|XP_003919084.2| PREDICTED: amine oxidase [flavin-containing] A [Papio anubis] >gi|635143113|ref|XP_007989644.1| PREDICTED: amine oxidase [flavin-containing] A [Chlorocebus sabaeus] >gi|403297577|ref|XP_003939638.1| PREDICTED: amine oxidase [flavin-containing] A [Saimiri boliviensis boliviensis] >gi|395857318|ref|XP_003801045.1| PREDICTED: amine oxidase [flavin-containing] A-like [Otolemur garnettii] >gi|675766444|ref|XP_002762857.2| PREDICTED: amine oxidase [flavin-containing] A [Callithrix jacchus] >gi|511974496|ref|XP_004805214.1| PREDICTED: uncharacterized protein LOC101673386 [Mustela putorius furo] >gi|511866964|ref|XP_004754983.1| PREDICTED: uncharacterized protein LOC101673386 [Mustela putorius furo] >gi|671032262|ref|XP_008706937.1| PREDICTED: amine oxidase [flavin-containing] A [Ursus maritimus] >gi|591316143|ref|XP_007084416.1| PREDICTED: amine oxidase [flavin-containing] A [Panthera tigris altaica] >gi|126352690|ref|NP_001075301.1| amine oxidase [flavin-containing] A [Equus caballus] >gi|344292703|ref|XP_003418065.1| PREDICTED: amine oxidase [flavin-containing] A-like [Loxodonta africana] >gi|478521726|ref|XP_004435072.1| PREDICTED: amine oxidase [flavin-containing] A isoform 1 [Ceratotherium simum simum] >gi|478521728|ref|XP_004435073.1| PREDICTED: amine oxidase [flavin-containing] A isoform 2 [Ceratotherium simum simum] >gi|593711059|ref|XP_007102094.1| PREDICTED: amine oxidase [flavin-containing] A [Physeter catodon] >gi|625217725|ref|XP_003510347.2| PREDICTED: amine oxidase [flavin-containing] A isoform X1 [Cricetulus griseus] >gi|472384186|ref|XP_004411465.1| PREDICTED: amine oxidase [flavin-containing] A isoform 1 [Odobenus rosmarus divergens] >gi|466076048|ref|XP_004283458.1| PREDICTED: amine oxidase [flavin-containing] A isoform 1 [Orcinus orca] >gi|301775051|ref|XP_002922945.1| PREDICTED: amine oxidase [flavin-containing] A-like [Ailuropoda melanoleuca] >gi|532035608|ref|XP_005360700.1| PREDICTED: amine oxidase [flavin-containing] A [Microtus ochrogaster] >gi|602689629|ref|XP_007457032.1| PREDICTED: amine oxidase [flavin-containing] A [Lipotes vexillifer] >gi|560982464|ref|XP_006213459.1| PREDICTED: amine oxidase [flavin-containing] A [Vicugna pacos] >gi|594050885|ref|XP_006049784.1| PREDICTED: amine oxidase [flavin-containing] A [Bubalus bubalis] >gi|585168648|ref|XP_006736388.1| PREDICTED: amine oxidase [flavin-containing] A


13 [Leptonychotes weddellii] >gi|533192469|ref|XP_005409056.1| PREDICTED: amine oxidase [flavin-containing] A [Chinchilla lanigera] >gi|532076495|ref|XP_005324039.1| PREDICTED: amine oxidase [flavin-containing] A [Ictidomys tridecemlineatus] >gi|594664370|ref|XP_007180326.1| PREDICTED: amine oxidase [flavin-containing] A [Balaenoptera acutorostrata scammoni] >gi|562839527|ref|XP_006148928.1| PREDICTED: amine oxidase [flavin-containing] A [Tupaia chinensis] >gi|48675943|ref|NP_001001640.1| amine oxidase [flavin-containing] A [Sus scrofa] >gi|655875522|ref|XP_008270740.1| PREDICTED: amine oxidase [flavin-containing] A [Oryctolagus cuniculus] >gi|507969399|ref|XP_004690018.1| PREDICTED: amine oxidase [flavin-containing] A [Condylura cristata] >gi|556728852|ref|XP_005960154.1| PREDICTED: amine oxidase [flavin-containing] A [Pantholops hodgsonii] >gi|589928229|ref|XP_006976937.1| PREDICTED: amine oxidase [flavin-containing] A [Peromyscus maniculatus bairdii] >gi|675766440|ref|XP_008987423.1| PREDICTED: amine oxidase [flavin-containing] A-like [Callithrix jacchus] >gi|426256882|ref|XP_004022065.1| PREDICTED: amine oxidase [flavin-containing] A [Ovis aries] >gi|548531575|ref|XP_005700962.1| PREDICTED: amine oxidase [flavin-containing] A [Capra hircus] >gi|471378424|ref|XP_004377014.1| PREDICTED: amine oxidase [flavin-containing] A [Trichechus manatus latirostris] >gi|507704679|ref|XP_004645373.1| PREDICTED: amine oxidase [flavin-containing] A-like [Octodon degus] >gi|507564285|ref|XP_004665815.1| PREDICTED: amine oxidase [flavin-containing] A [Jaculus jaculus] >gi|512975964|ref|XP_004850052.1| PREDICTED: amine oxidase [flavin-containing] A [Heterocephalus glaber] >gi|617625010|ref|XP_007528286.1| PREDICTED: amine oxidase [flavin-containing] A [Erinaceus europaeus] >gi|586467491|ref|XP_006864355.1| PREDICTED: amine oxidase [flavin-containing] A [Chrysochloris asiatica] >gi|586526043|ref|XP_006917967.1| PREDICTED: amine oxidase [flavin-containing] A-like [Pteropus alecto] >gi|524961338|ref|XP_005080602.1| PREDICTED: amine oxidase [flavin-containing] A [Mesocricetus auratus] >gi|505838936|ref|XP_004612999.1| PREDICTED: amine oxidase [flavin-containing] A [Sorex araneus] >gi|554578713|ref|XP_005880942.1| PREDICTED: amine oxidase [flavin-containing] A [Myotis brandtii] >gi|504151382|ref|XP_004588039.1| PREDICTED: amine oxidase [flavin-containing] A [Ochotona princeps] >gi|560935202|ref|XP_006193430.1| PREDICTED: amine oxidase [flavin-containing] A [Camelus


14 ferus] >gi|558133152|ref|XP_006090628.1| PREDICTED: LOW QUALITY PROTEIN: amine oxidase [flavin-containing] A [Myotis lucifugus] >gi|625270688|ref|XP_007626891.1| PREDICTED: amine oxidase [flavin-containing] A isoform X2, partial [Cricetulus griseus] >gi|634889379|ref|XP_007953802.1| PREDICTED: LOW QUALITY PROTEIN: amine oxidase [flavin-containing] A [Orycteropus afer afer] >gi|507691947|ref|XP_004713284.1| PREDICTED: amine oxidase [flavin-containing] A, partial [Echinops telfairi] >gi|620961138|ref|XP_007665426.1| PREDICTED: amine oxidase [flavin-containing] A isoform X1 [Ornithorhynchus anatinus] >gi|530624546|ref|XP_005301830.1| PREDICTED: amine oxidase [flavin-containing] A [Chrysemys picta bellii] >gi|470596203|ref|XP_004310916.1| PREDICTED: amine oxidase [flavin-containing] A [Tursiops truncatus] >gi|591379920|ref|XP_007064505.1| PREDICTED: amine oxidase [flavin-containing] A [Chelonia mydas] >gi|612016585|ref|XP_007493381.1| PREDICTED: amine oxidase [flavin-containing] A isoform X6 [Monodelphis domestica] >gi|564262979|ref|XP_006270360.1| PREDICTED: amine oxidase [flavin-containing] A [Alligator mississippiensis] >gi|558227956|ref|XP_006137957.1| PREDICTED: amine oxidase [flavin-containing] A isoform X1 [Pelodiscus sinensis] >gi|556995056|ref|XP_006001398.1| PREDICTED: amine oxidase [flavin-containing]-like [Latimeria chalumnae] >gi|612016583|ref|XP_007493380.1| PREDICTED: amine oxidase [flavin-containing] A isoform X5 [Monodelphis domestica] >gi|514460149|ref|XP_003469476.2| PREDICTED: amine oxidase [flavin-containing] A [Cavia porcellus] >gi|543366406|ref|XP_005526561.1| PREDICTED: amine oxidase [flavin-containing] B [Pseudopodoces humilis] >gi|426395653|ref|XP_004064080.1| PREDICTED: amine oxidase [flavin-containing] A isoform 2 [Gorilla gorilla gorilla] >gi|557260099|ref|XP_006015701.1| PREDICTED: amine oxidase [flavin-containing] A [Alligator sinensis] >gi|543721014|ref|XP_005501709.1| PREDICTED: amine oxidase [flavin-containing] B isoform X1 [Columba livia] >gi|543721016|ref|XP_005501710.1| PREDICTED: amine oxidase [flavin-containing] B isoform X2 [Columba livia] >gi|612016571|ref|XP_001377998.3| PREDICTED: amine oxidase [flavin-containing] B [Monodelphis domestica] >gi|530624548|ref|XP_005301831.1| PREDICTED: amine oxidase [flavin-containing] B [Chrysemys picta bellii] >gi|301606444|ref|XP_002932838.1| PREDICTED: amine oxidase [flavin-containing]-like [Xenopus (Silurana) tropicalis] >gi|327268401|ref|XP_003218986.1| PREDICTED: amine oxidase [flavin-containing] B-like [Anolis carolinensis] >gi|441673976|ref|XP_004092482.1| PREDICTED: amine oxidase [flavin-containing] A isoform 2


15

[Nomascus leucogenys] >gi|617625023|ref|XP_007528290.1| PREDICTED: amine oxidase [flavin-containing] B [Erinaceus europaeus] >gi|589928227|ref|XP_006976936.1| PREDICTED: amine oxidase [flavin-containing] B [Peromyscus maniculatus bairdii] >gi|699629338|ref|XP_009902638.1| PREDICTED: amine oxidase [flavin-containing] B-like [Picoides pubescens] >gi|637283079|ref|XP_008105637.1| PREDICTED: amine oxidase [flavin-containing] A-like [Anolis carolinensis] >gi|701382733|ref|XP_009988386.1| PREDICTED: amine oxidase [flavin-containing] B-like [Tauraco erythrolophus] >gi|514715497|ref|XP_005012568.1| PREDICTED: amine oxidase [flavin-containing] B [Anas platyrhynchos] >gi|719756963|ref|XP_010215013.1| PREDICTED: amine oxidase [flavin-containing] B-like, partial [Tinamus guttatus] >gi|698464129|ref|XP_009704325.1| PREDICTED: amine oxidase [flavin-containing] B-like, partial [Cariama cristata] >gi|677598580|ref|XP_009081961.1| PREDICTED: amine oxidase [flavin-containing] B-like, partial [Acanthisitta chloris] >gi|686609523|ref|XP_009281385.1| PREDICTED: amine oxidase [flavin-containing] B-like [Aptenodytes forsteri] >gi|524978419|ref|XP_005037297.1| PREDICTED: amine oxidase [flavin-containing] B [Ficedula albicollis] >gi|586467415|ref|XP_006864317.1| PREDICTED: amine oxidase [flavin-containing] B [Chrysochloris asiatica] >gi|697496325|ref|XP_009677864.1| PREDICTED: amine oxidase [flavin-containing] B isoform X2 [Struthio camelus australis]


16

Figure S3: Conserved sites in multiple sequence alignment using MEGA 6.0.


17

Figure S4: Molecular phylogenetic analysis by Maximum Likelihood method for the MAO gene. A Maximum Likelihood tree was constructed (JTT model, Gamma distribution (5 categories, +G, parameter = 0.5703), Bootstrap (50)). [MAO-A= Monoamine oxidases A; MAO-B= Monoamine oxidases B; MAO-A I = isoform 1; MAO-A 2=isoform 2; MAO-A K=isoform K where K is a variant; unrooted tree] Phylogenetic analyses were performed in MEGA6.


18

Figure S5: MAO-A gene expression in humans. [Source –TiGER]


19 Table S1: Conserved sites in all 106 sequences. (Positions use the human MAO-A gene as the reference gene.)

Site in the Human MAO-A Amino Acid

174 A

177 F

179 N

183 T

185 E

189 V

190 S

192-197 LWFLWY

201-204 CGGT

206 R

212-219 NGGQERKF

221-222 GG

228 E

234 L

238 V

240 L

243-244 PV

249 Q

258 T

287-288 LP

294 L

321 C

326 I

338-339 DD

341-342 KP

351-353 GFI


20 369 R

374 C

386 A

392-394 YEE

397 W

402-408 YSGGCYT

412-414 PPG

420 G

424 R

432-439 FAGTETAT

441-444 WSGY

447-448 GA

451-452 AG

460 L

475-476 EP

490 F

492-493 ER

495-497 LPS

Kalyani rajalingham maoa

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