GENOMIC ANALYSIS OF SCHIZOPHRENIA AND PHYLOGENETIC RELATIONSHIPS BETWEEN HOMO SAPIENS AND SELECTED MODEL ORGANISMS ON THE BASIS

OF HOMOLOGOUS GENES
Parul Raj Srivastava and Ranjeet Singh Deptt. of Biotechnology Engineering Institute of Engineering & Technology Bundelkhand University, Jhansi E mail:parulrajsrivastav@gmail.com

ITNTRODUCTION
Schizophrenia is a psychiatric diagnosis that describes a mental illness characterized by impairments in the perception or expression of reality, most commonly manifesting as auditory hallucinations, paranoid or bizarre delusions or disorganized speech and thinking in the context of significant social or occupational dysfunction. Studies suggest that genetics, early environment, neurobiology and psychological and social processes are important contributory factors. A person experiencing schizophrenia may demonstrate symptoms such as disorganized thinking, auditory hallucinations, and delusions. Diagnosis is based on the self-reported experiences of the person as well as abnormalities in behavior reported by family members, friends or co-workers, followed by secondary signs observed by a psychiatrist. It is a mental disorder which affects thinking, feeling and behaviour. It is most likely to start the ages of 15 to 35 and will affect about 1 in every 100 people during their lifetime. Schizophrenia is a mental disorder that makes it hard to: Tell the difference between what is real and not real Think clearly Have normal emotional response Act normally in social situations Types of Schizophrenia There are five types of schizophrenia. Although most people think of schizophrenia as a single mental illness, schizophrenia is a general term for several forms of the psychotic illness. Paranoid type schizophrenia typically consists of false beliefs and hearing things that arent there; may be more manageable than other types of schizophrenia. Disorganized type schizophrenia - typically consists of thoughts, speech and behavior that is inappropriate and incomprehensible Catatonic type schizophrenia consists of activity levels on either end of the spectrum; either a dazed, coma-like state or a hyperactive state

Undifferentiated type schizophrenia a form of schizophrenia that does not match any of the above types; sometimes this is called schizophrenia not otherwise specified Residual type schizophrenia consists of some schizophrenic symptoms of lesser severity

Detailed Symptoms of Various Types of Schizophrenia

Paranoid type schizophrenia Contains: preoccupation with delusions and frequent auditory hallucinations Is not prominent: disorganized (confused, incoherent) speech; disorganized or catatonic behavior; flat or inappropriate affect (emotion, mood) Disorganized type schizophrenia (disorganized type schizophrenia is also known as hebephrenia) Contains: disorganized speech and behavior and flat or inappropriate affect Is not prominent: delusions and hallucinations Catatonic type schizophrenia Contains two of the following: muscle immobility or stupor; excessive, pointless muscle activity; extreme negativism; inappropriate or bizarre postures; repetition of movement or speech Undifferentiated type schizophrenia Contains the diagnosis of schizophrenia but does not specifically meet one of the above three subtype criteria Residual type schizophrenia Contains: evidence of schizophrenia Is not prominent: delusions; hallucinations; disorganized speech; grossly disorganized or catatonic behavior.

Biological Causes of Schizophrenia

It is known that the brains of people with schizophrenia differ from brains of those in the average population. Brain imaging scans have shown that some areas of the brain are smaller or malformed in those with schizophrenia. One part of the brain that appears to be affected by schizophrenia is the hippocampus. This part of the brain is part of a system called the limbic system which is responsible for processing emotions and memories. The hippocampus is smaller in those with schizophrenia.

A brain chemical, dopamine, is also thought to be involved in the causes of schizophrenia. Effective antipsychotic medications (medications which reduce psychosis) inhibit the neurons that fire this chemical while drugs that exacerbate dopamine firing are known to induce psychosis. It is likely, though, that dopamine abnormalities vary across different regions of the brain. Glutamate, another brain chemical, is also likely involved in the causes of schizophrenia. It is not understood exactly how these brain anomalies are created but it appears they may exist before schizophrenia manifests. The brain abnormalities may only fully come to light as the person goes through puberty due to the rapid brain changes seen during this time in life. Brain damage Brain scans show that there are differences in the brains of some people with schizophrenia but not in others. Where this is the case, it may be that parts of the brain have not grown normally because of: a problem during birth that stops the babys brain from getting enough oxygen or a virus infection during the early months of pregnancy.

Genetic Causes of Schizophrenia

Family studies of people with schizophrenia reveal that the causes of schizophrenia are partly genetic. While the risk of developing schizophrenia in the average person is 1%, the risk for someone with a parent with schizophrenia is around six times that and siblings have a 9% chance of havi.ng schizophrenia. While the underlying specifics of the genetics are not well understood, these numbers do show the development

Symptoms of Schizophrenia
Schizophrenia symptoms usually develop slowly over months or years. Sometimes you may have many symptoms, and at other times you may only have a few symptoms. People with any type of schizophrenia may have trouble keeping friends and working. They may also have problems with anxiety, depression, and suicidal thoughts or behaviors. At first, you may have the following symptoms: Irritable or tense feeling Trouble concentrating Trouble sleeping

As the illness continues, you may have problems with thinking, emotions, and behavior, including: Bizarre behaviors Hearing or seeing things that are not there (hallucinations) Isolation Lack of emotion (flat affect)

Problems paying attention Strongly held beliefs that are not real (delusions) Thoughts that "jump" between different topics (loose associations)

Symptoms depend on the type of schizophrenia you have.

Paranoid schizophrenia symptoms may include:

1

Anxiety

Anger or arguing False beliefs that others are trying to harm you or your loved ones

Disorganized schizophrenia symptoms may include: Childlike behavior Problems thinking and explaining your ideas clearly Showing little emotion

Catatonic schizophrenia symptoms may include: Grimacing or other odd expressions on the face Lack of activity Rigid muscles and posture Not responding much to other people Undifferentiated schizophrenia may include symptoms of more than one other type of schizophrenia.

TOOLS AND METHODOLOGIES INVOLVED IN THE STUDY OF SCHIZOPHRENIA

National Centre For Biotechnology Information-is a database that contains all the information related to biology/biotechnology.It is a complete repository of various other databases having information about research papers,genetic diseases,biomedical literature,etc.

Entrez

The Entrez Global Query Cross-Database Search System is a powerful federated search engine, or web portal that allows users to search many discrete health sciences databases at the National Center for Biotechnology Information (NCBI) website. PubMed Central PubMed Central is a free digital database of full-text scientific literature in biomedical and life sciences PubChem PubChem is a database of chemical molecules and their activities against biological assays. The system is maintained by the National Center for Biotechnology Information (NCBI), a component of the National Library of2 Medicine, which is part of the United States National Institutes of Health (NIH). Protein Data Bank The Protein Data Bank (PDB) is a repository for the 3-D structural data of large biological molecules, such as proteins and nucleic acids PROSITE PROSITE is a protein database. It consists of entries describing the protein families, domains and functional sites as well as amino acid patterns, signatures, and profiles in them. European Molecular Biology Laboratory The European Molecular Biology Laboratory (EMBL) is a molecular biology research institution supported by 20 European countries and Australia as associate member state. BLAST In bioinformatics, Basic Local Alignment Search Tool, or BLAST, is an algorithm for comparing primary biological sequence information, such as the amino-acid sequences of differentproteins or the nucleotides of DNA sequences. A BLAST search enables a researcher to compare a query sequence with a library or database of sequences, and identify library sequences that resemble the query sequence above a certain threshold. ExPASy ExPASy is a bioinformatics resource portal operated by the Swiss Institute of Bioinformatics (SIB) and in particular the SIB Web Team. It is an extensible and integrative

portal accessing many scientific resources, databases and software tools in different areas of life sciences RasMol RasMol is a computer program written for molecular graphics visualization intended and used primarily for the depiction and exploration of biological macromolecule structures Clustal Clustal is a widely used multiple sequence alignment computer program Swiss-model SWISS-MODEL is a web-based expert system dedicated to homology modeling of protein 3D structures

Jalview
Jalview is a piece of bioinformatics software that is used to look at and edit multiple sequence alignments

RESULTS AND DEDUCTIONS

Genetic Analysis of Schizophrenia chromosome no.

3

no. of genes 1 2 3 4 5 6 7 8 9 10 11 12 13 21 12 9 9 10 19 12 7 3 6 16 6 8

locus 1q42.2/DISC1 2q32.1 3q13.31 4p13 18p 6p23 7q36.3 8p21 9q34.2 10q23.1 11q14-q21 12q24 13q14.2

gene name SCZD9 SCZD14 DRD3 PHOX2B MAFD1 SCZD3 SCZD16 SCZD6 DBH NRG3 SCZD2 DAO HTR2A

14 15 16 17 18 19 20 21 22 X Y MITOCHONDRIAL UNKNOWN TOTAL NO. OF GENES

6 8 10 9 6 8 4 4 31 15 0 0 7

14q32.33 15q13 16p11.2 17p13.3 18p 19p13.2 20p12.2 21q22.11 22q11.21 Xq23 0 0 6q26

AKT1 SCZD13 AUTS14A SRR SCZD8 DNMT1 SNAP25 OLIG2 SCZD4 MRX30 0 0 QKI

224

Homologous Genes Gene Disrupted In Schizophrenia 1

4

GENE I.D.

ORGANISM Homo sapiens Pan troglodytes Macaca mulatta Canis Lupus familiarus Bos taurus Mus musculus Rattus norvegicus Gallus gallus

CpG ISLAND no island detected no island detected no island detected no island detected no island detected no island detected no island detected 1

Disc1/SCZD9 Disc1/SCZD9 Disc1/SCZD9 Disc1/SCZD9 Disc1/SCZD9 Disc1/SCZD9 Disc1/SCZD9 Disc1/SCZD9

GENE I.D.

ORGANISM

CpG ISLAND

SCZD14

NO ORGANISM FOUND

44

GENE I.D.

ORGANISM

CpG ISLAND

GENES CONSERVED IN BILATERIA DRD3 DRD3 DRD3 DRD3 DRD3 DRD3 DRD3 DRD3 DRD3 DRD3 DRD3 DRD3 GENE I.D. Homo sapiens Pan troglodytes Macaca mulatta Canis Lupus familiarus Bos taurus Mus musculus Rattus norvegicus Gallus gallus Danio rerio Drosophila melanogaster Caenorhabditis elegans no island detected no island detected no island detected no island detected no island detected no island detected no island detected 1 1 2 1

ORGANISM

CpG ISLAND

GENES CONSERVED IN EUTELEOSTOMI PH5OX2B PHOX2B PHOX2B PHOX2B PHOX2B PHOX2B PHOX2B PHOX2B PHOX2B Homo sapiens Pan troglodytes Macaca mulatta Canis Lupus familiarus Bos taurus Mus musculus Rattus norvegicus Gallus gallus Danio rerio 3 4 3 1 1 1 1 1 1

GENE I.D.

ORGANISM

CpG ISLAND

MAFDI

NO ORGANISM FOUND

GENE I.D. SCZD3

ORGANISM NO ORGANISM FOUND

CpG ISLAND

GENE I.D.

ORGANISM

CpG ISLAND

GENES CONSERVED IN EUTELEOSTOMI SCZD16 SCZD16 SCZD16 SCZD16 SCZD16 SCZD16 SCZD16 SCZD16 SCZD16 Homo sapiens Pan troglodytes Macaca mulatta Canis Lupus familiarus Bos taurus Mus musculus Rattus norvegicus Gallus gallus Danio rerio 2 2 no island detected no island detected 1 no island detected no island detected no island detected no island detected

GENE I.D.

ORGANISM

CpG ISLAND

SC6ZD6

NO ORGANISM FOUND

GENE I.D.

ORGANISM DOPAMINE BETA HYDROXYLASE

CpG ISLAND

DBH DBH DBH DBH DBH DBH DBH DBH

Homo sapiens Pan troglodytes Macaca mulatta Canis Lupus familiarus Bos taurus Mus musculus Rattus norvegicus Gallus gallus

no island detected 2 1 1 2 no island detected no island detected 1

DBH DBH DBH

Danio rerio Drosophila melanogaster Caenorhabditis elegans Anopheles gambiae

no island detected 1 no island detected no island detected

GENE I.D.

ORGANISM

CpG ISLAND

GENE CONSERVED IN AMNIOTA NRG3 NRG3 NRG3 NRG3 NRG3 NRG3 NRG3 NRG3 Homo sapiens Pan troglodytes Macaca mulatta Canis Lupus familiarus Bos taurus Mus musculus Rattus norvegicus Gallus gallus 3 no island detected 2 2 2 1 no island detected 1

GENE I.D. SCZD2

ORGANISM NO ORGANISM FOUND

CpG ISLAND

GENE I.D.

ORGANISM

CpG ISLAND

GENE CONSERVED IN EUTHERIA DAO DAO DAO DAO DAO DAO DAO DAO Homo sapiens Pan troglodytes Macaca mulatta Canis Lupus familiarus Bos taurus Mus musculus Rattus norvegicus Gallus gallus no island detected no island detected no island detected no island detected no island detected no island detected no island detected 1

GENE I.D.

ORGANISM

CpG ISLAND

GENE CONSERVED IN EUTELEOSTOMI

HTR2A HTR2A HTR2A HTR2A HTR2A HTR2A HTR2A HTR2A HTR2A GENE I.D.

Homo sapiens Pan troglodytes Macaca mulatta Canis Lupus familiarus Bos taurus Mus musculus Rattus norvegicus Gallus gallus Danio rerio ORGANISM

no island detected no island detected no island detected no island detected 1 1 1 no island detected no island detected CpG ISLAND

GENE CONSERVVED IN BILATERIA AKT1 AKT1 AKT1 AKT1 AKT1 AKT1 AKT1 AKT1 AKT1 Homo sapiens Macaca mulatta Canis Lupus familiarus Bos taurus Mus musculus Rattus norvegicus Gallus gallus Danio rerio Caenorhabditis elegans 3 2 3 2 2 1 1 3 no island detected

GENE I.D.

ORGANISM

CpG ISLAND

SCZD13

NO ORGANISM FOUND

GENE I.D.

ORGANISM

CpG ISLAND

AUTS14A

NO ORGANISM FOUND

GENE I.D.

ORGANISM

CpG ISLAND

GENES CONSERVED IN EUKARYOTA

SRR SRR SRR SRR SRR SRR SRR SRR SRR SRR SRR SRR

Homo sapiens Pan troglodytes Macaca mulatta Canis Lupus familiarus Bos taurus Mus musculus Rattus norvegicus Gallus gallus Saccharomyces cerevisiae Schizosaccharomyces pombe Arabidopsis thaliana Oryza sativa japonioca

no island detected 1 no island detected no island detected no island detected no island detected no island detected 1 1 no island detected no island detected 1

GENE I.D.

ORGANISM

CpG ISLAND

SCZD8

NO ORGANISM FOUND

GENE I.D.

ORGANISM

CpG ISLAND

GENES CONSERVED IN EUKARYOTA DNMT1 DNMT1 DNMT1 DNMT1 DNMT1 DNMT1 DNMT1 DNMT1 DNMT1 Homo sapiens Pan troglodytes Canis Lupus familiarus Bos taurus Mus musculus Rattus norvegicus Gallus gallus Arabidopsis thaliana Oryza sativa japonioca 1 2 no island detected 5 no island detected 3 6 no island detected no island detected

GENE I.D.

ORGANISM

CpG ISLAND

GENES CONSERVED IN COELOMATA SNAP25 SNAP25 SNAP25 Homo sapiens Pan troglodytes Macaca mulatta 1 1 no island detected

SNAP25 SNAP25 SNAP25 SNAP25 SNAP25 SNAP25 SNAP25

Canis Lupus familiarus Bos taurus Mus musculus Rattus norvegicus Gallus gallus Danio rerio Drosophila melanogaster

no island detected no island detected no island detected no island detected no island detected no island detected 1

GENE I.D.

ORGANISM

CpG ISLAND

OLIG2 OLIG2 OLIG2 OLIG2 OLIG2 OLIG2 OLIG2 OLIG2 OLIG2

Homo sapiens Pan troglodytes Macaca mulatta Canis Lupus familiarus Bos taurus Mus musculus Rattus norvegicus Gallus gallus Danio rerio

2 2 3 1 3 2 2 1 1

GENE I.D.

ORGANISM

CpG ISLAND

GENES CONSERVED IN BILATERIA SCZD4 SCZD4 SCZD4 SCZD4 SCZD4 SCZD4 SCZD4 SCZD4 SCZD4 SCZD4 SCZD4 SCZD4 Homo sapiens Pan troglodytes Macaca mulatta Canis Lupus familiarus Bos taurus Mus musculus Rattus norvegicus Gallus gallus Danio rerio Drosophila melanogaster Anopheles gambiae Caenorhabditis elegans 1 1 1 1 3 1 1 no island detected 1 3 1 no island detected

GENE I.D.

ORGANISM

CpG ISLAND

GENES CONSERVED IN AMNIOTA MRX30 MRX30 MRX30 MRX30 MRX30 MRX30 MRX30 MRX30 MRX30 Homo sapiens Pan troglodytes Macaca mulatta Canis Lupus familiarus Bos taurus Mus musculus Rattus norvegicus Gallus gallus no island detected no island detected no island detected no island detected no island detected no island detected no island detected no island detected

GENE I.D.

ORGANISM

CpG ISLAND

GENES CONSERVED IN BILATERIA QKI QK7I QKI QKI QKI QKI QKI QKI QKI Homo sapiens Pan troglodytes Canis Lupus familiarus Bos taurus Mus musculus Rattus norvegicus Gallus gallus Danio rerio Caenorhabditis elegans 1 no island detected no island detected no island detected 1 1 1 2 2

PHYLOGENETIC TREES OF THE GENES HAVING MAXIMUM NO . OF CPG ISLANDS

Blast of The Serotonin Sequence Using Swiss Model Repository

SWISS-MODEL Workspace

Physiochemical Report of The Serotonin Protein Molecule Using Prot Param Tool of Expasy:
Prot Param
User-provided sequence:
Number of amino acids: 15 Molecular weight: 1832.0
8

Theoretical pI: 5.99

CSV format

Amino acid composition: Ala (A) 0 0.0% Arg (R) 1 6.7% Asn (N) 2 13.3% Asp (D) 1 6.7% Cys (C) 2 13.3% Gln (Q) 0 0.0%
8

Glu (E) 1 6.7% Gly (G) 0 0.0% His (H) 2 13.3% Ile (I) 0 0.0% Leu (L) 2 13.3% Lys (K) 0 0.0% Met (M) 0 Phe (F) 2 13.3% Pro (P) 1 6.7% Ser (S) 1 6.7% Thr (T) 0 0.0% Trp (W) 0 0.0% Tyr (Y) 0 0.0% Val (V) 0 0.0% Pyl (O) 0 0.0% Sec (U) 0 0.0% (B) 0 (Z) 0 (X) 0 0.0% 0.0%9 0.0%

0.0%

Total number of negatively charged residues (Asp + Glu): 2 Total number of positively charged residues (Arg + Lys): 1 Atomic composition: Carbon C Hydrogen H Nitrogen N Oxygen O Sulfur S 79 114 24 23 2

Formula: C79H114N24O23S2 Total number of atoms: 242

Extinction coefficients: This protein does not contain any Trp residues. Experience shows that this could result in more than 10% error in the computed extinction coefficient. Extinction coefficients are in units of M-1 cm-1, at 280 nm measured in water. Ext. coefficient 125 Ab10s 0.1% (=1 g/l) 0.068, assuming all pairs of Cys residues form cystines

Ext. coefficient 0 Abs 0.1% (=1 g/l) 0.000, assuming all Cys residues are reduced
9

Estimated half-life: The N-terminal of the sequence considered is C (Cys). The estimated half-life is: 1.2 hours (mammalian reticulocytes, in vitro). >20 hours (yeast, in vivo). >10 hours (Escherichia coli, in vivo).

Instability index: The instability index (II) is computed to be -1.71 This classifies the protein as stable.

Aliphatic index: 52.00 Grand average of hydropathicity (GRAVY): -0.607

CONCLUSION
Many people with schizophrenia now never have to go into hospital and are able to settle down, work and have lasting relationships. For every 5 people with schizophrenia: 1 will get better within five years of their first obvious symptoms 3 will get better, but will have times when they get worse again The present work has been devised in manner to bring to light the various psychoses of schizophrenia and related disorders by studying the cases of a wide range of schizophrenic patients.The study has been conducted with a bioinformatics perpective to find out the genetic relationships of the other organisms with that of Homo sapiens having evolutionary relatedness. A genetic analysis of the organism is made on the basis of homologous genes of the total pairs of chromosomes in Homo sapiens by finding their gene name and genetic loci corresonding to that of other similar model organisms ,which helps us to find a cure of the disease via a connecting link alongwith the phylogenetically related model organisms to find the number of common transmemebrane domains among them further finding the cPg islands among the related organisms so that they can be used as a means to the study the disease with respect to other genetically related organisms..

REFERENCES
1.www.ncbi.nlm.nih.gov 2.www.ncbi.nlm.nih.gov/org 3.www.expasy.org 4.www.googlescholar.com

5.www.embl.ac.in 6. pub med central-research papers 7.OMIM-genetic analysis of schizophrenia 8.www.psychenet-uk.com/dsm_iv_schizophrenia_disorder.htm 9. American Psychiatric Association. Diagnostic and Statistical Manual of Mental Disorders, Text Revision. 3. Washington, DC: American Psychiatric Association; 2000. 10.royal college of psychiatry-wikipedia 11.pub chem-ncbi.nlm.nih.gov 12.www.prosite.org 13.www.rcsb.org