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Whale Shark Positively selected genes

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Created page with "Contents: <ol> <li>Anti-clotting: FGG, FGB, SEPRINE2</li> <li>Cell division: HAUS1, CENPI, CENPK, MCM3AP, CHA..."

Contents:

<ol>
<li>Anti-clotting:   FGG, FGB, SEPRINE2</li>
<li>Cell division: HAUS1, CENPI, CENPK, MCM3AP, CHAF1A, HP1BP3, C1orF35 </li>
<li>Cancer associated: RET, GSS, SERPINF1, NFKBIE</li>
<li>Programmed cell death: CASP7, PDCD2, PDCD6IP</li>
<li>DNA repair genes: MSH6, RAD54B, MRE11A, XRCC3, MCM8, DCLRE1B </li>
<li>Other proteins: KIAA1143, GNL2, CTDP1, MTIF2, DECR1, ATE1, XXYLT1, PLEKHM3</li>
<li>Brain and neuron related: NCDN</li>
</ol>

 

(Anti-clotting:   FGG, FGB, SEPRINE2)

FGG

FGG    143     N         E         probably damaging  deleterious    fibrinogen gamma chain

FGG    167     D         G         probably damaging  deleterious    fibrinogen gamma chain

FGG    171     I           A         probably damaging  deleterious    fibrinogen gamma chain

FGG    176     G         A         probably damaging  deleterious    fibrinogen gamma chain

FGG    204     F          M         probably damaging  deleterious    fibrinogen gamma chain

FGG    254     L          I           probably damaging  neutral                          fibrinogen gamma chain

FGG    335     G         F          probably damaging  deleterious    fibrinogen gamma chain

FGG    375     Y         H         possibly damaging   deleterious    fibrinogen gamma chain

 

FGB    284     N         S         possibly damaging   deleterious    fibrinogen beta chain

FGB    352     V         L          probably damaging  neutral                          fibrinogen beta chain

FGB    409     D         N         probably damaging  deleterious    fibrinogen beta chain

FGB    470     W        A         probably damaging  deleterious    fibrinogen beta chain

 

Gene FGG together with fibrinogen alpha (FGA) and fibrinogen beta (FGB), polymerizes to form an insoluble fibrin matrix. Has a major function in hemostasis as one of the primary components of blood clots. In addition, functions during the early stages of wound repair to stabilize the lesion and guide cell migration during re-epithelialization.

 The FGG is positively selected genes in the whale shark genome. In my opinion above listed function altering amino acid changes in FGG makes shark blood anticlotting.  This may prevent blot clots from forming. Blood clots and coagulation to stop bleeding. However, if colts get into blood vessels, they can cause a heart attack or stroke. 

<h4>Below amino acid changes that in human FGG, which involve in disease</h4>

<h6>Congenital afibrinogenemia (CAFBN)</h6>

 

<table border="1" cellpadding="0" cellspacing="0" style="width:616px">
<tbody>
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<td style="height:28px; width:111px">
Feature key
</td>
<td style="height:28px; width:64px">
Position(s)
</td>
<td style="height:28px; width:441px">
DescriptionActions
</td>
</tr>
<tr>
<td style="height:38px; width:111px">
Natural variantiVAR_072726
</td>
<td style="height:38px; width:64px">
<a href="http://www.uniprot.org/blast/?about=P02679%5b303%5d&key=Natural%20variant&id=VAR_072726">303</a>
</td>
<td style="height:38px; width:441px">
<a href="http://web.expasy.org/variant_pages/VAR_072726.html">T → P</a> in CAFBN; hypofibrinogenemia; heterozygous; no effect on fibrinogen complex assembly; impaired fibrinogen complex secretion. 
</td>
</tr>
<tr>
<td style="height:38px; width:111px">
Natural variantiVAR_072727
</td>
<td style="height:38px; width:64px">
<a href="http://www.uniprot.org/blast/?about=P02679%5b327%5d&key=Natural%20variant&id=VAR_072727">327</a>
</td>
<td style="height:38px; width:441px">
<a href="http://web.expasy.org/variant_pages/VAR_072727.html">D → H</a> in CAFBN; hypofibrinogenemia; heterozygous; no effect on fibrinogen complex assembly; no effect on fibrinogen complex secretion.
</td>
</tr>
<tr>
<td style="height:38px; width:111px">
Natural variantiVAR_072728
</td>
<td style="height:38px; width:64px">
<a href="http://www.uniprot.org/blast/?about=P02679%5b345%5d&key=Natural%20variant&id=VAR_072728">345</a>
</td>
<td style="height:38px; width:441px">
<a href="http://web.expasy.org/variant_pages/VAR_072728.html">N → D</a> in CAFBN; hypofibrinogenemia; heterozygous; no effect on fibrinogen complex assembly; decreased fibrinogen complex secretion. 
</td>
</tr>
<tr>
<td style="height:33px; width:111px">
Natural variantiVAR_072729
</td>
<td style="height:33px; width:64px">
<a href="http://www.uniprot.org/blast/?about=P02679%5b401%5d&key=Natural%20variant&id=VAR_072729">401</a>
</td>
<td style="height:33px; width:441px">
<a href="http://web.expasy.org/variant_pages/VAR_072729.html">R → W</a> in CAFBN; hypofibrinogenemia; heterozygous.
</td>
</tr>
</tbody>
</table>

<h6>Dysfibrinogenemia, congenital (DYSFIBRIN)</h6>

 

<table border="1" cellpadding="0" cellspacing="0" style="width:510px">
<tbody>
<tr>
<td style="height:20px; width:114px">
Feature key
</td>
<td style="height:20px; width:60px">
Position(s)
</td>
<td style="height:20px; width:335px">
DescriptionActions
</td>
</tr>
<tr>
<td style="height:20px; width:114px">
Natural variantiVAR_002410
</td>
<td style="height:20px; width:60px">
<a href="http://www.uniprot.org/blast/?about=P02679%5b301%5d&key=Natural%20variant&id=VAR_002410">301</a>
</td>
<td style="height:20px; width:335px">
<a href="http://web.expasy.org/variant_pages/VAR_002410.html">R → H</a> in DYSFIBRIN; fibrinogen Bergamo-2/Essen/Haifa/Osaka-3/Perugia/Saga/Barcelona-3/Barcelona-4.
</td>
</tr>
<tr>
<td style="height:20px; width:114px">
Natural variantiVAR_002411
</td>
<td style="height:20px; width:60px">
<a href="http://www.uniprot.org/blast/?about=P02679%5b318%5d&key=Natural%20variant&id=VAR_002411">318</a>
</td>
<td style="height:20px; width:335px">
<a href="http://web.expasy.org/variant_pages/VAR_002411.html">G → V</a> in DYSFIBRIN; fibrinogen Baltimore-1; impaired polymerization. 
</td>
</tr>
<tr>
<td style="height:20px; width:114px">
Natural variantiVAR_002418
</td>
<td style="height:20px; width:60px">
<a href="http://www.uniprot.org/blast/?about=P02679%5b356%5d&key=Natural%20variant&id=VAR_002418">356</a>
</td>
<td style="height:20px; width:335px">
<a href="http://web.expasy.org/variant_pages/VAR_002418.html">D → V</a> in DYSFIBRIN; fibrinogen Milano-1; impaired polymerization. 
</td>
</tr>
<tr>
<td style="height:18px; width:114px">
Natural variantiVAR_072621
</td>
<td style="height:18px; width:60px">
<a href="http://www.uniprot.org/blast/?about=P02679%5b404%5d&key=Natural%20variant&id=VAR_072621">404</a>
</td>
<td style="height:18px; width:335px">
<a href="http://web.expasy.org/variant_pages/VAR_072621.html">S → P</a> in DYSFIBRIN; fibrinogen Philadelphia. 
</td>
</tr>
</tbody>
</table>

 

However, in whale shark genome, amino acid changes not in the same spots as in mutations. Since one amino acid mutation lead to dysfunction and to disease, functional changes -> in whale shark gene might lead to similar defects. 

In website human FGG described in detail: <a href="http://www.uniprot.org/uniprot/P02679">http://www.uniprot.org/uniprot/P02679</a>

 

FGG structure:

<table border="0" cellpadding="0" cellspacing="0" style="width:611px">
<tbody>
<tr>
<td style="height:9px">
Type
</td>
<td style="height:9px; width:77px">
Positions
</td>
<td style="height:9px; width:432px">
Description
</td>
</tr>
<tr>
<td style="height:10px">
Chain
</td>
<td style="height:10px; width:77px">
<a href="http://www.uniprot.org/blast/?about=P02679%5b27-453%5d">27 – 453</a>
</td>
<td style="height:10px; width:432px">
Fibrinogen gamma chain
</td>
</tr>
<tr>
<td style="height:10px">
Domain
</td>
<td style="height:10px; width:77px">
<a href="http://www.uniprot.org/blast/?about=P02679%5b170-416%5d">170 – 416</a>
</td>
<td style="height:10px; width:432px">
Fibrinogen C-terminal
</td>
</tr>
<tr>
<td style="height:10px">
Metal binding
</td>
<td style="height:10px; width:77px">
<a href="http://www.uniprot.org/blast/?about=P02679%5b344-344%5d">344 – 344</a>
</td>
<td style="height:10px; width:432px">
Calcium
</td>
</tr>
<tr>
<td style="height:10px">
Metal binding
</td>
<td style="height:10px; width:77px">
<a href="http://www.uniprot.org/blast/?about=P02679%5b346-346%5d">346 – 346</a>
</td>
<td style="height:10px; width:432px">
Calcium
</td>
</tr>
<tr>
<td style="height:10px">
Metal binding
</td>
<td style="height:10px; width:77px">
<a href="http://www.uniprot.org/blast/?about=P02679%5b348-348%5d">348 – 348</a>
</td>
<td style="height:10px; width:432px">
Calcium; via carbonyl oxygen
</td>
</tr>
<tr>
<td style="height:10px">
Metal binding
</td>
<td style="height:10px; width:77px">
<a href="http://www.uniprot.org/blast/?about=P02679%5b350-350%5d">350 – 350</a>
</td>
<td style="height:10px; width:432px">
Calcium; via carbonyl oxygen
</td>
</tr>
<tr>
<td style="height:10px">
Glycosylation
</td>
<td style="height:10px; width:77px">
<a href="http://www.uniprot.org/blast/?about=P02679%5b334-334%5d">334 – 334</a>
</td>
<td style="height:10px; width:432px">
N-linked (GlcNAc...); 
</td>
</tr>
<tr>
<td style="height:21px">
 

 
</td>
<td style="height:21px; width:77px">
 
</td>
<td style="height:21px; width:432px">
 

 
</td>
</tr>
<tr>
<td style="height:21px">
 
</td>
<td style="height:21px; width:77px">
 
</td>
<td style="height:21px; width:432px">
 
</td>
</tr>
</tbody>
</table>

<a href="http://web.expasy.org/variant_pages/VAR_015853.html">http://web.expasy.org/variant_pages/VAR_015853.html</a>

<table align="left" border="1" cellpadding="0" cellspacing="0" style="width:582px">
<tbody>
<tr>
<td style="width:306px">
Variant position: <a href="http://www.uniprot.org/blast/?about=P02679%5b335-335%5d">335</a>

 

Residue change: From Glycine (G) to Aspartate (D) at position <a href="http://www.uniprot.org/blast/?about=P02679%5b335%5d">335</a> (G335D, p.Gly335Asp).

Physico-chemical properties: Change from glycine (G) to medium size and acidic (D)

Variant description:  In Hillsborough; prolonged thrombin clotting time.

 
</td>
<td style="width:276px">
 

From Glycine (G) to Phenylalanine (F) at position 335

 

Change from glycine to large size aromatic and hydrophobic (F)
</td>
</tr>
</tbody>
</table>

 

  

 

 

 

 

 

 

  In common Pathway of Fibrin Clot formation 

 The common pathway consists of the cascade of activation events leading from the formation of activated factor X to the formation of active thrombin, the cleavage of fibrinogen by thrombin, and the formation of cleaved fibrin into a stable multimeric, cross-linked complex. Thrombin also efficiently catalyzes the activation of several factors required earlier in the clotting cascade, thus acting in effect as a positive regulator of clotting. At the same time, thrombin activates protein C, which in turn catalyzes the inactivation of several of these upstream factors, thereby limiting the clotting process. Thrombin can be trapped in stable, inactive complexes with: antithrombin-III (SERPINC1), a circulating blood protein; heparin cofactor II (SERPIND1) which inhibits thrombin in a dermatan sulfate dependent manner in the arterial vasculature; protein C inhibitor (SERPINA5) that inhibits thrombin in complex with thrombomodulin; and Protease nexin-1 (SERPINE2) that inhibits thrombin at the vessel wall and platelet surface. The quantitative interplay among these positive and negative modulators is critical to the normal regulation of clotting, facilitating the rapid formation of a protective clot at the site of injury, while limiting and physically confining the process.

From: <a href="http://www.reactome.org/PathwayBrowser/#R-HSA-140875">http://www.reactome.org/PathwayBrowser/#R-HSA-140875</a>

According to excel file SERPINE2 -> is positively selected gene in shark common ancestors:

SERPINE2          146     F    à Y  probably damaging  deleterious   

 

This gene encodes a member of the serpin family of proteins, a group of proteins that inhibit serine proteases. Thrombin, urokinase, plasmin and trypsin are among the proteases that this family member can inhibit. This gene is a susceptibility gene for chronic obstructive pulmonary disease and for emphysema.  .

The possible disease information based on polymorphism and mutation in SERPINE2:

<a href="https://hive.biochemistry.gwu.edu/cgi-bin/prd/biomuta/servlet.cgi?gpageid=11&searchfield1=gene_name&searchvalue1=SERPINE2">https://hive.biochemistry.gwu.edu/cgi-bin/prd/biomuta/servlet.cgi?gpageid=11&searchfield1=gene_name&searchvalue1=SERPINE2</a>

Most of diseases are related to cancers. However, there is no disease, which have same alteration as in whale shark gene. (SERINE2). Consequently, it means that that functional change is not damaging.  Beneficial for shark blood clotting.

Recent studies observed that SERPINE2 might prevent cartilage catabolism by inhibiting expression of MMP-13. The functional amino acid changes might me in order to prevent SERPINE2 suppression, because whole shark body consist from cartilage.

<h1>“SERPINE2 Inhibits IL-1α-Induced MMP-13 Expression in Human Chondrocytes: Involvement of ERK/NF-κB/AP-1 Pathway”</h1>

<a href="https://www.ncbi.nlm.nih.gov/pubmed/26305372">https://www.ncbi.nlm.nih.gov/pubmed/26305372</a>

 

(Cell division : HAUS1, CENPI, CENPK, MCM3AP, CHAF1A, HP1BP3, PARP11 )

HAUS1

HAUS1 is 1 of 8 subunits of the 390-kD human augmin complex, or HAUS complex.  The augmin complex is a microtubule-binding complex involved in microtubule generation within the mitotic spindle and is vital to mitotic spindle assembly.

<ul>
<li>Important in cell replication</li>
</ul>

Whale shark specific genes:

HAUS1             76    L          I           probably damaging    HAUS augmin like complex subunit 1

 

Whale shark and elephant shark common:

HAUS1             53    L          Q         probably damaging              HAUS augmin like complex subunit 1

 

 

CENPI

Component of the CENPA-CAD (nucleosome distal) complex, a complex recruited to centromere which is involved in assembly of kinetochore proteins, mitotic progression and chromosome segregation. May be involved in incorporation of newly synthesized CENPA into centromeres via its interaction with the CENPA-NAC complex. Required for the localization of CENPF, MAD1L1 and MAD2 (MAD2L1 or MAD2L2) to kinetochores. Involved in the response of gonadal tissues to follicle-stimulating hormone

CENPI            113     L          V         possibly damaging   deleterious    centromere protein I

CENPI            262     F          L          probably damaging  deleterious    centromere protein I

CENPI            446     W        Y         probably damaging  deleterious    centromere protein I

 

Estimated protein expression in Liver the highest ß shark liver is the biggest organ in their body, it means liver cells proliferate many times  

 

CENPK

Component of the CENPA-CAD (nucleosome distal) complex, a complex recruited to centromeres which is involved in assembly of kinetochore proteins, mitotic progression and chromosome segregation. May be involved in incorporation of newly synthesized CENPA into centromeres via its interaction with the CENPA-NAC complex. Acts in coordination with CASC5/KNL1 to recruit the NDC80 complex to the outer kinetochore.

<pre>
<a href="https://www.ncbi.nlm.nih.gov/protein/NP_068562.1?from=47&to=306&sat=4&sat_key=135313005">Region</a>          47..306</pre>

<pre>
                     /region_name="CENP-K"</pre>

<pre>
                     /note="Centromere-associated protein K; pfam11802"</pre>

<pre>
                     </pre>

The functional amino-acid changes in centrosome associated region à important for binding

CENPK          252     A         V         probably damaging  deleterious    centromere protein K

CENPK          257     E         D         probably damaging  neutral           centromere protein K

 

<div>
<h1>MCM3AP</h1>
</div>

The minichromosome maintenance protein 3 (MCM3) is one of the MCM proteins essential for the initiation of DNA replication. The protein encoded by this gene is an MCM3 binding protein. It was reported to have phosphorylation-dependent DNA-primase activity, which was up-regulated in antigen immunization induced germinal center. This protein was demonstrated to be an acetyltransferase that acetylates MCM3 and plays a role in DNA replication. The mutagenesis of a nuclear localization signal of MCM3 affects the binding of this protein with MCM3, suggesting that this protein may also facilitate MCM3 nuclear localization

 

MCM3AP       730     I           V       MCM component 3 associated protein

 

CHAF1A

Core component of the CAF-1 complex, a complex thought to mediate chromatin assembly in DNA replication and DNA repair. Assembles histone octamers onto replicating DNA in vitro. CAF-1 performs the first step of the nucleosome assembly process, bringing newly synthesized histones H3 and H4 to replicating DNA; histones H2A/H2B can bind to this chromatin precursor subsequent to DNA replication to complete the histone octamer. CHAF1A binds to histones H3 and H4. It may play a role in heterochromatin maintenance in proliferating cells by bringing newly synthesized cbx proteins to heterochromatic DNA replication foci

 

CHAF1A        423     R         K         unknown

CHAF1A        509     L          I           probably damaging

CHAF1A        555     G         C         probably damaging

 

<a href="http://www.uniprot.org/uniprot/Q13111">http://www.uniprot.org/uniprot/Q13111</a> according to the website information à above amino acids spots not functionally important changes.

HP1BP3

Component of heterochromatin that maintains heterochromatin integrity during G1/S progression and regulates the duration of G1 phase to critically influence cell proliferative capacity. Mediates chromatin condensation during hypoxia, leading to increased tumor cell viability, radio-resistance, chemo-resistance and self-renewal.  HP1BP3 is a key mediator of tumor progression and cancer cell acquisition of therapy-resistant traits, and thus might represent a novel therapeutic target in a range of human malignancies.

 

In bowhead whale this protein has extended amino acids chain from 171 - > 240. 

I would like to look to the whole peptide chain of the shark’s protein and compare with bowhead. Because, this protein gives condition to cancer, if some changes present like in bowhead whale protein seq., then it means they alter its function to suppress tumor.

 

PARP11

Plays a role in nuclear envelope stability and nuclear remodeling during spermiogenesis. 

PARP11        328     Q         H         probably damaging  deleterious

328TH position in PARP catalytic domain.

 

 

 (Cancer associated: RET, GSS, SERPINF1, NFKBIE)

RET

This gene, a member of the cadherin superfamily, encodes one of the receptor tyrosine kinases, which are cell-surface molecules that transduce signals for cell growth and differentiation. This gene plays a crucial role in neural crest development, and it can undergo oncogenic activation in vivo and in vitro by cytogenetic rearrangement. Mutations in this gene are associated with the disorders multiple endocrine neoplasia, type IIA, multiple endocrine neoplasia, type IIB, Hirschsprung disease, and medullary thyroid carcinoma.

The RET gene provides instructions for producing a protein that is involved in signaling within cells. This protein appears to be essential for the normal development of several kinds of nerve cells, including nerves in the intestine (enteric neurons) and the portion of the nervous system that controls involuntary body functions such as heart rate (the autonomic nervous system). The RET protein is also necessary for normal kidney development and the production of sperm (spermatogenesis).

The RET protein spans the cell membrane, so that one end of the protein remains inside the cell and the other end projects from the outer surface of the cell. This positioning of the protein allows it to interact with specific factors outside the cell and to receive signals that help the cell respond to its environment. When molecules that stimulate growth and development (growth factors) attach to the RET protein, a complex cascade of chemical reactions inside the cell is triggered. These reactions instruct the cell to undergo certain changes, such as dividing or maturing to take on specialized functions.

<a href="https://ghr.nlm.nih.gov/gene/RET#conditions">https://ghr.nlm.nih.gov/gene/RET#conditions</a>

 

RET    657     T          S         probably damaging  deleterious    ret proto-oncogene

 

Whale shark and elephant shark common:

RET    697     A         G         probably damaging  deleterious    ret proto-oncogene

RET    714     E         Q         probably damaging  neutral           ret proto-oncogene

 

 

 GSS    

(During hypoxia condition a lot oxidants form -> protection from free radicals *)

Glutathione is important for a variety of biological functions, including protection of cells from oxidative damage by free radicals, detoxification of xenobiotics, and membrane transport. The protein encoded by this gene functions as a homodimer to catalyze the second step of glutathione biosynthesis, which is the ATP-dependent conversion of gamma-L-glutamyl-L-cysteine to glutathione. Defects in this gene are a cause of glutathione synthetase deficiency.

ATP + gamma-L-glutamyl-L-cysteine + glycine = ADP + phosphate + glutathione

 

Whale shark:

GSS    152     F          Y         probably damaging  deleterious    prion protein

 

Whale shark and elephant shark common:

GSS    51        T          S         benign           deleterious    glutathione synthetase

GSS    456     H         F          probably damaging  deleterious    glutathione synthetase

 

SERPINF1

Pigment epithelium-derived factor (PEDF) also known as serpin F1 (SERPINF1), has a variety of functions including antiangiogenic, antitumorigenic, and neurotrophic properties. <a href="https://en.wikipedia.org/wiki/Endothelial_cell" title="Endothelial cell">Endothelial cell</a> <a href="https://en.wikipedia.org/wiki/Cell_migration" title="Cell migration">migration</a> is inhibited by PEDF. PEDF suppresses retinal <a href="https://en.wikipedia.org/wiki/Neovascularization" title="Neovascularization">neovascularization</a> and endothelial <a href="https://en.wikipedia.org/wiki/Cell_growth" title="Cell growth">cell proliferation</a>. The antiangiogenic residues 24-57 were shown to be sufficient at inhibiting angiogenesis. PEDF is also responsible for apoptosis of endothelial cells either through the <a href="https://en.wikipedia.org/wiki/P38_MAPK_pathway" title="P38 MAPK pathway">p38 MAPK pathway</a> or through the <a href="https://en.wikipedia.org/wiki/Fas_receptor" title="Fas receptor">FAS/FASL</a> pathway. Antiangiogenic function is also conferred by PEDF through inhibition of both <a href="https://en.wikipedia.org/wiki/FLT1" title="FLT1">VEGFR-1</a> and <a href="https://en.wikipedia.org/wiki/Kinase_insert_domain_receptor" title="Kinase insert domain receptor">VEGFR-2</a>.

The antitumorigenic effects of PEDF are not only due to inhibition of supporting vasculature, but also due to effects on the cancer cells themselves. PEDF was shown to inhibit cancer cell proliferation and increase apoptosis via the FAS/FASL pathway. VEGF expression by cancer cells is inhibited by PEDF.

PEDF also displays neurotrophic functions. Retinoblastoma cells differentiate into neurons due to the presence of PEDF.

 As it does not undergo the S (stressed) to R (relaxed) conformational transition characteristic of active serpins, it exhibits no serine protease inhibitory activity.

 

SERPINF1      106     R       G         probably damaging  deleterious    serpin family F member 1

SERPINF1       408    F       H         probably damaging  deleterious    serpin family F member 1

 

<a href="http://bioinf.umbc.edu/dmdm/generatelogo.php?domain=SERPIN&accession=smart00093&prot=313104314">http://bioinf.umbc.edu/dmdm/generatelogo.php?domain=SERPIN&accession=smart00093&prot=313104314</a>

In above website mutation spots are indicated, however whale shark amino acid changed spots not included there. In my opinion, those positively selected behavior is improved SERPINF1 function, giving anti-angiogenic, anti-tumorigenic specificity.  Residue change in 408th amino acid from Phe to His, would not lead big changes, due to these two side chains are similar in their structure. 

 

NFKBIE

The protein encoded by this gene binds to components of NF-kappa-B, trapping the complex in the cytoplasm and preventing it from activating genes in the nucleus. Phosphorylation of the encoded protein targets it for destruction by the ubiquitin pathway, which activates NF-kappa-B by making it available to translocate to the nucleus.

 

In tumor cells, NF-κB is active either due to mutations, some tumor cells secrete factors that cause NF-κB to become active. Blocking NF-κB can cause tumor cells to stop proliferating, to die, or to become more sensitive to the action of anti-tumor agents. 

Active NF-κB turns on the expression of genes that keep the cell proliferating and protect the cell from conditions that would otherwise cause it to die via <a href="https://en.wikipedia.org/wiki/Apoptosis" title="Apoptosis">apoptosis</a>.  

Whale shark:

NFKBIE         261     T          S         possibly damaging              deleterious

NFKBIE         411     A         S         probably damaging  deleterious

 

Whale shark and elephant shark:

NFKBIE         322     L          Q         probably damaging  deleterious

 

NFKBIE contains 6 ANK repeats.

The ankyrin repeat is a 33-residue <a href="https://en.wikipedia.org/wiki/Protein_motif" title="Protein motif">motif</a> in <a href="https://en.wikipedia.org/wiki/Protein" title="Protein">proteins</a> consisting of two <a href="https://en.wikipedia.org/wiki/Alpha_helix" title="Alpha helix">alpha helices</a> separated by <a href="https://en.wikipedia.org/wiki/Loop_(biochemistry)" title="Loop (biochemistry)">loops</a>. Domains consisting of ankyrin repeats mediate <a href="https://en.wikipedia.org/wiki/Protein%E2%80%93protein_interaction" title="Protein–protein interaction">protein–protein interactions</a> and are among the most common structural motifs in known proteins.

In following ANK repeats whale shark’s mutation occurs:

<table border="1" cellpadding="0" cellspacing="0">
<tbody>
<tr>
<td style="width:208px">
Repeat
</td>
<td style="width:208px">
258-291
</td>
<td style="width:208px">
ANK 1
</td>
</tr>
<tr>
<td style="width:208px">
Repeat
</td>
<td style="width:208px">
293-322
</td>
<td style="width:208px">
ANK 2
</td>
</tr>
<tr>
<td style="width:208px">
Repeat
</td>
<td style="width:208px">
403-432
</td>
<td style="width:208px">
ANK 5
</td>
</tr>
</tbody>
</table>

  

If those amino acid changes improve NFKBIE function, then that would be one of the agent that suppress tumor cells. However, due to whale shark body size big, so need increased cell replication rate. Maybe that’s why ANK repeat had some alterations à to decrease protein-protein interactions. Low interaction with NF-kB, increase cell proliferations.   

 

 

 

(Programmed cell death: CASP7, PDCD2, PDCD6IP,MYCBP2)

CASP7

catalytic activity: Strict requirement for an Asp residue at position P1 and has a preferred cleavage sequence of Asp-Glu-Val-Asp-|-.

 function: Involved in the activation cascade of caspases responsible for apoptosis execution. Cleaves and activates sterol regulatory element binding proteins (SREBPs). Proteolytically cleaves poly(ADP-ribose) polymerase (PARP) at a '216-Asp-|-Gly-217' bond.

Overexpression promotes programmed cell death.

PTM:Cleavages by granzyme B or caspase-10 generate the two active subunits. Propeptide domains can also be cleaved efficiently by caspase-3. Active heterodimers between the small subunit of caspase-7 and the large subunit of caspase-3, and vice versa, also occur.

similarity: Belongs to the peptidase C14A family.

subunit: Heterotetramer that consists of two anti-parallel arranged heterodimers, each one formed by a 20 kDa (p20) and a 11 kDa (p11) subunit.,

tissue specificity: Highly expressed in lung, skeletal muscle, liver, kidney, spleen and heart, and moderately in testis. No expression in the brain.

 

CASP7           168     G         E         probably damaging  deleterious

 

PDCD2

^ DNA-binding protein with a regulatory function. May play an important role in cell death and/or in regulation of cell proliferation.

^Programmed cell death 2 (PDCD2) is a highly conserved nuclear protein, and aberrant PDCD2 expression alters cell apoptosis. The data from the present study demonstrated that loss of PDCD2 expression could contribute to gastric cancer development and progression and that PDCD2-induced gastric cancer cell growth arrest at the early S phase of the cell cycle and apoptosis are p53-dependent.

Expression of this gene has been shown to be repressed by B-cell CLL/lymphoma 6 (BCL6), a transcriptional repressor required for lymph node germinal center development, suggesting that BCL6 regulates apoptosis by its effects on this protein.

 

* transfection of a VP16-BCL6 zinc fingers fusion protein, which competes with the binding of endogenous BCL6 in a Burkitt lymphoma cell line =>

   increases PDCD2 protein expression and apoptosis

    knockdown of the PDCD2 protein in this cell line by PDCD2-specific small interfering RNA duplexes inhibits apoptosis. 

These studies indicate that one function of PDCD2 is to promote apoptosis in several human and mammalian cell lines and tissues, including lymphoma.  

 It is plausible that repression of PDCD2 expression by BCL6, which, in turn, leads to downregulation of apoptosis, is one mechanism involved in BCL6-associated lymphomatous transformation. The usefulness of increasing PDCD2 expression in the treatment of certain lymphomas merits further investigation.

 

<pre>
<a href="https://www.ncbi.nlm.nih.gov/protein/NP_001186390.1?from=135&to=172&sat=4&sat_key=175005973">Region</a>          135-172</pre>

<pre>
                     /region_name="zf-MYND"</pre>

<pre>
                     /note="MYND finger; pfam01753"</pre>

<pre>
                    </pre>

Zync finger binding site amino acids changed à

 

PDCD2             150    H       R         benign           deleterious    programmed cell death 2

PDCD2             169    K       R         possibly damaging   deleterious    programmed cell death 2

 

 

PDCD6IP

overexpression of this protein can block apoptosis. In addition, the product of this gene binds to the product of the PDCD6 gene, a protein required for apoptosis, in a calcium-dependent manner. This gene product also binds to endophilins, proteins that regulate membrane shape during endocytosis. Overexpression of this gene product and endophilins results in cytoplasmic vacuolization, which may be partly responsible for the protection against cell death

 
PDCD6IP      118     Y         F          programmed cell death 6 interacting protein

PDCD6IP      171     L          M         neutral           programmed cell death 6 interacting protein

PDCD6IP      175     P         L          deleterious    programmed cell death 6 interacting protein

PDCD6IP      179     I           T          deleterious    programmed cell death 6 interacting protein

PDCD6IP      361     E         V         deleterious    programmed cell death 6 interacting protein

 

 

 

<div>
<h1>MYCBP2</h1>
</div>

 

 protein associates with myc 

PAM contains a <a href="https://en.wikipedia.org/wiki/N-terminus" title="N-terminus">N-terminal</a> <a href="https://en.wikipedia.org/wiki/Leucine_zipper" title="Leucine zipper">leucine zipper</a>, central <a href="https://en.wikipedia.org/wiki/Myc" title="Myc">MYC</a>-binding, and <a href="https://en.wikipedia.org/wiki/C-terminus" title="C-terminus">C-terminal</a> <a href="https://en.wikipedia.org/wiki/Histone" title="Histone">histone</a>-binding protein homology domains

 

Myc (c-Myc) is a <a href="https://en.wikipedia.org/wiki/Regulator_gene" title="Regulator gene">regulator gene</a> that <a href="https://en.wikipedia.org/wiki/Genetic_code" title="Genetic code">codes</a> for a <a href="https://en.wikipedia.org/wiki/Transcription_factor" title="Transcription factor">transcription factor</a>. The <a href="https://en.wikipedia.org/wiki/Protein" title="Protein">protein</a> encoded by this gene is a multifunctional, nuclear phosphoprotein that plays a role in <a href="https://en.wikipedia.org/wiki/Cell_cycle" title="Cell cycle">cell cycle</a> progression, <a href="https://en.wikipedia.org/wiki/Apoptosis" title="Apoptosis">apoptosis</a> and <a href="https://en.wikipedia.org/wiki/Cellular_transformation" title="Cellular transformation">cellular transformation</a>

 

PAM   285     A         T          probably damaging  deleterious    MYC binding protein 2, E3 ubiquitin protein ligase

PAM   602     V         I           probably damaging  neutral          

PAM   623     P         S         probably damaging  deleterious   

PAM   738     P         A         benign           deleterious   

PAM   768     I           L          probably damaging  neutral          

 

 

(DNA repair genes: MSH6,RAD54B, MRE11A,XRCC3, MCM8, DCLRE1B )

MSH6

Component of the post-replicative DNA mismatch repair system (MMR). Heterodimerizes with MSH2 to form MutS alpha, which binds to DNA mismatches thereby initiating DNA repair. When bound, MutS alpha bends the DNA helix and shields approximately 20 base pairs, and recognizes single base mismatches and dinucleotide insertion-deletion loops (IDL) in the DNA. After mismatch binding, forms a ternary complex with the MutL alpha heterodimer, which is thought to be responsible for directing the downstream MMR events, including strand discrimination, excision, and resynthesis. ATP binding and hydrolysis play a pivotal role in mismatch repair functions. The ATPase activity associated with MutS alpha regulates binding similar to a molecular switch: mismatched DNA provokes ADP-->ATP exchange, resulting in a discernible conformational transition that converts MutS alpha into a sliding clamp capable of hydrolysis-independent diffusion along the DNA backbone. This transition is crucial for mismatch repair. MutS alpha may also play a role in DNA homologous recombination repair. Recruited on chromatin in G1 and early S phase via its PWWP domain that specifically binds trimethylated 'Lys-36' of histone H3 (H3K36me3): early recruitment to chromatin to be replicated allowing a quick identification of mismatch repair to initiate the DNA mismatch repair reaction.

  Whale shark specific genes having function altering amino acid changes

MSH6           199      P         L          benign           deleterious

MSH6             451     F          Y         possibly damaging   neutral

MSH6             733    M         L          benign           deleterious

MSH6            1207   H         Y         possibly damaging   deleterious

MSH6            1330   L         F          probably damaging  deleterious

 

 

RAD54B

Involved in DNA repair and mitotic recombination. May play an active role in recombination processes in concert with other members of the RAD52 epistasis group

Abundantly expressed in testis and spleen.

 

RAD54B        194     M         T          possibly damaging   deleterious

RAD54B        482     L          I           probably damaging  neutral

RAD54B        598     L          F          probably damaging  deleterious

 

 Whale shark and elephant shark common genes having function altering amino acid changes:

RAD54B        383     I           L          possibly damaging   neutral

RAD54B        533     E         D         possibly damaging   neutral

 

 

MRE11A

 Component of the MRN complex, which plays a central role in double-strand break (DSB) repair, DNA recombination, maintenance of telomere integrity and meiosis. The complex possesses single-strand endonuclease activity and double-strand-specific 3'-5' exonuclease activity, which are provided by MRE11A. RAD50 may be required to bind DNA ends and hold them in close proximity. This could facilitate searches for short or long regions of sequence homology in the recombining DNA templates, and may also stimulate the activity of DNA ligases and/or restrict the nuclease activity of MRE11A to prevent nucleolytic degradation past a given point. The complex may also be required for DNA damage signaling via activation of the ATM kinase.  

MRE11A        304     V         I           probably damaging  neutral

MRE11A        403     E         D         possibly damaging   neutral

<pre>
 Region: 10..402</pre>

<pre>
                     /region_name="mre11"</pre>

<pre>
                     /note="DNA repair protein (mre11); TIGR00583"</pre>

<pre>
                     /db_xref="CDD:<a href="https://www.ncbi.nlm.nih.gov/Structure/cdd/cddsrv.cgi?uid=273153">273153</a>"</pre>

 

Defects in MRE11A can be a cause of nephronophthisis-related ciliopathies (NPHP-RC), a group of recessive diseases that affect kidney, retina and brain. A homozygous truncating mutation MRE11A has been found in patients with cerebellar vermis hypoplasia, ataxia and dysarthria.

 

XRCC3             

Involved in the homologous recombination repair (HRR) pathway of double-stranded DNA, thought to repair chromosomal fragmentation, translocations and deletions. Part of the RAD21 paralog protein complex CX3 which acts in the BRCA1-BRCA2-dependent HR pathway. Upon DNA damage, CX3 acts downstream of RAD51 recruitment; the complex binds predominantly to the intersection of the four duplex arms of the Holliday junction (HJ) and to junctions of replication forks. Plays a role in regulating mitochondrial DNA copy number under conditions of oxidative stress in the presence of RAD51 and RAD51C.

 

XRCC3              259             V         I           probably damaging  neutral          

     Whale shark and elephant shark common genes having function altering amino acid changes:

 XRCC3             133  L         Q         probably damaging  deleterious

 

<pre>
<a href="https://www.ncbi.nlm.nih.gov/protein/NP_001093588.1?from=2&to=337&sat=4&sat_key=176719491">Region</a>          2..337</pre>

<pre>
                     /region_name="recomb_DMC1"</pre>

<pre>
                     /note="meiotic recombinase Dmc1; TIGR02238"</pre>

<pre>
                     /db_xref="CDD:<a href="https://www.ncbi.nlm.nih.gov/Structure/cdd/cddsrv.cgi?uid=131292">131292</a>"</pre>

This model describes DMC1, a subfamily of a larger family of DNA repair and recombination proteins. It is eukaryotic only and most closely related to eukaryotic RAD51.

In this region function altering changes occurred in whale shark and elephant shark. 

 

MCM8

Component of the MCM8-MCM9 complex, a complex involved in homologous recombination repair following DNA interstrand cross-links and plays a key role during gametogenesis. The MCM8-MCM9 complex probably acts as a hexameric helicase downstream of the Fanconi anemia proteins BRCA2 and RAD51 and is required to process aberrant forks into homologous recombination substrates and to orchestrate homologous recombination with resection, fork stabilization and fork restart. May also play a non-essential for DNA replication: may be involved in the activation of the prereplicative complex (pre-RC) during G1 phase by recruiting CDC6 to the origin recognition complex (ORC). Binds chromatin throughout the cell cycle

*Highest levels in placenta, lung and pancreas. Low levels in skeletal muscle and kidney. Expressed in various tumors with highest levels in colon and lung cancers

 Whale shark specific genes having function altering amino acid changes

MCM8   608   N         S         probably damaging  deleterious

Domain part: 402-609  

In 608th amino acid change might bring conformational changes.

 

DCLRE1B    

5'-3' exonuclease that plays a central role in telomere maintenance and protection during S-phase. Participates in the protection of telomeres against non-homologous end-joining (NHEJ)-mediated repair, thereby ensuring that telomeres do not fuse. Plays a key role in telomeric loop (T loop) formation by being recruited by TERF2 at the leading end telomeres and by processing leading-end telomeres immediately after their replication via its exonuclease activity: generates 3' single-stranded overhang at the leading end telomeres avoiding blunt leading-end telomeres that are vulnerable to end-joining reactions and expose the telomere end in a manner that activates the DNA repair pathways. Together with TERF2, required to protect telomeres from replicative damage during replication by controlling the amount of DNA topoisomerase (TOP1, TOP2A and TOP2B) needed for telomere replication during fork passage and prevent aberrant telomere topology. Also involved in response to DNA damage: plays a role in response to DNA interstrand cross-links (ICLs) by facilitating double-strand break formation. In case of spindle stress, involved in prophase checkpoint.

 

DNA interstrand cross-links prevent strand separation, thereby physically blocking transcription, replication, and segregation of DNA. DCLRE1B is one of several evolutionarily conserved genes involved in repair of interstrand cross-links.

 

DCLRE1B   209        E         Q         possibly damaging   deleterious

 

Whale shark and elephant shark common genes having function altering amino acid changes

DCLRE1B   119        G         A         probably damaging  deleterious   DNA cross-link repair 1B

<pre>
<a href="https://www.ncbi.nlm.nih.gov/protein/NP_001306875.1?from=90&to=173&sat=4&sat_key=157385479">Region</a>          90..173</pre>

<pre>
                     /region_name="DRMBL"</pre>

<pre>
                     /note="DNA repair metallo-beta-lactamase; pfam07522"</pre>

<pre>
                     /db_xref="CDD:<a href="https://www.ncbi.nlm.nih.gov/Structure/cdd/cddsrv.cgi?uid=284854">284854</a>"</pre>

 

 

 

(Other proteins: KIAA1143, GNL2, CTDP1, MTIF2, DECR1, ATE1, XXYLT1, PLEKHM3)

 

KIAA1143

 

 KIAA1143     29        E         S         probably damaging  deleterious    KIAA1143

KIAA1143      95        I           H         probably damaging  deleterious    KIAA1143

KIAA1143      108     K         T          benign           deleterious    KIAA1143

On the uniprot website :

<table border="1" cellpadding="0" cellspacing="0" style="width:312px">
<tbody>
<tr>
<td style="height:30px; width:127px">
Modified residue
</td>
<td style="height:30px; width:53px">
108
</td>
<td style="height:30px; width:132px">
N6-acetyllysine
</td>
</tr>
</tbody>
</table>

 A lysine on 108th amino acid had post translational modification, however in shark’s case lysine changed to the Threonine. Thereby, acetylation won’t happen and changes structure of the protein. 

 

GNL2

GNL2  2          V         S         possibly damaging neutral                      G protein nucleolar 2

GNL2  7          K         Q         possibly damaging   neutral                       G protein nucleolar 2

GNL2  12        I           E         possibly damaging   deleterious    G protein nucleolar 2

GNL2  13        N         R         benign                                     deleterious     G protein nucleolar 2

GNL2  15        S         E         possibly damaging   deleterious    G protein nucleolar 2

GNL2  18        S         M         probably damaging  deleterious    G protein nucleolar 2

GNL2  20        N         I           probably damaging  deleterious    G protein nucleolar 2

GNL2  21        P         Q         probably damaging  deleterious    G protein nucleolar 2

GNL2  32        M         T          possibly damaging   deleterious    G protein nucleolar 2

GNL2  71        V         T          possibly damaging   deleterious    G protein nucleolar 2

GNL2  308     K         R         possibly damaging   deleterious    G protein nucleolar 2

 

function: GTPase that associates with pre-60S ribosomal subunits in the nucleolus and is required for their nuclear export and maturation.

similarity: Belongs to the MMR1/HSR1 GTP-binding protein family, NOG2 subfamily.

The brginning amino acids mostly changed -> possibly to improve signal sequence while exporting from nucleous. 

 

CTDP1 

This gene encodes a protein which interacts with the carboxy-terminus of transcription initiation factor TFIIF, a transcription factor which regulates elongation as well as initiation by RNA polymerase II. The protein may also represent a component of an RNA polymerase II holoenzyme complex.

Mutations in this gene are associated with congenital cataracts, facial dysmorphism and neuropathy syndrome. 

Whale Shark and Elephant shark:

CTDP1           153     V         I           probably damaging  neutral

CTDP1           176     R         W        probably damaging  deleterious

CTDP1           179     R         K         probably damaging  deleterious

 

 

 

DNAJB14

Acts as a co-chaperone with HSPA8 and promotes the degradation of misfolded transmembrane proteins in the ER-associated degradation (ERAD) pathway.

DNAJB14      346     A         S         possibly damaging   deleterious

 

 

<div>
<h1>MTIF2</h1>
</div>

During the initiation of protein biosynthesis, initiation factor-2 (IF-2) promotes the binding of the initiator tRNA to the small subunit of the ribosome in a GTP-dependent manner.

MTIF2 297     P         H         probably damaging  deleterious

MTIF2 380     T          S         probably damaging  deleterious

MTIF2 572     Y         F          benign            deleterious

 

DECR1

Auxiliary enzyme of beta-oxidation. It participates in the metabolism of unsaturated fatty enoyl-CoA esters having double bonds in both even- and odd-numbered positions. Catalyzes the NADP-dependent reduction of 2,4-dienoyl-CoA to yield trans-3-enoyl-CoA.

 DECR1            44    F          L          probably damaging  deleterious

Tissue specificity:  Heart = liver = pancreas > kidney >> skeletal muscle = lung

44th residue not a binding site or active site, so this change not involve big changes in the function of the protein. 

ATE1

This gene encodes an arginyltransferase, an enzyme that is involved in posttranslational conjugation of arginine to N-terminal aspartate or glutamate residues. Conjugation of arginine to the N-terminal aspartate or glutamate targets proteins for ubiquitin-dependent degradation.

 

ATE1  60        T          S         possibly damaging   deleterious

 

Changes from Threonine to serine cause not big change in structure and function, because they are similar amino acids.

 

XXYLT1

XXYLT1                      352   W         N       probably damaging  deleterious

XXYLT1         367     D         E         possibly damaging   deleterious

 

<table border="1" cellpadding="0" cellspacing="0" style="width:471px">
<tbody>
<tr>
<td style="height:44px; width:96px">
Region
</td>
<td style="height:44px; width:140px">
<a href="http://www.uniprot.org/blast/?about=Q8NBI6%5b104-106%5d&key=Region">104 – 106</a>
</td>
<td style="height:44px; width:235px">
UDP-alpha-D-xylose binding
</td>
</tr>
<tr>
<td style="height:44px; width:96px">
Regioni
</td>
<td style="height:44px; width:140px">
<a href="http://www.uniprot.org/blast/?about=Q8NBI6%5b263-266%5d&key=Region">263 – 266</a>
</td>
<td style="height:44px; width:235px">
Interaction with target protein
</td>
</tr>
</tbody>
</table>

 

Above protein domains and function described, and shark’s mutation spots not included.

PLEKHM3

 Whale shark only:

PLEKHM3     305     E         A         probably damaging  deleterious

PLEKHM3     413     V         I           probably damaging  neutral

PLEKHM3     444     A         T          probably damaging  deleterious

 

Domains:

PH1 domain:   211-308 positions

 PH2 domain: 362- 456 positions

 This domain can bind <a href="https://en.wikipedia.org/wiki/Phosphatidylinositol" title="Phosphatidylinositol">phosphatidylinositol</a> lipids within biological membranes, and proteins such as the βγ-subunits of heterotrimeric <a href="https://en.wikipedia.org/wiki/G_protein" title="G protein">G proteins</a>, and <a href="https://en.wikipedia.org/wiki/Protein_kinase_C" title="Protein kinase C">protein kinase C</a>. Through these interactions, PH domains play a role in recruiting proteins to different <a href="https://en.wikipedia.org/wiki/Cell_membrane" title="Cell membrane">membranes</a>, thus targeting them to appropriate <a href="https://en.wikipedia.org/wiki/Cell_compartment" title="Cell compartment">cellular compartments</a> or enabling them to interact with other components of the <a href="https://en.wikipedia.org/wiki/Signal_transduction_pathway" title="Signal transduction pathway">signal transduction pathways</a>.

 

In whale shark’s PLEKHM3 two domains have functional altering amino acid changes.

Whale shark and elephant shark:

PLEKHM3     380     F          Y         probably damaging  neutral

PLEKHM3     501     L          I           probably damaging  neutral

 

 

(Brain and neuron related: NCDN)

NCDN

 

This gene encodes a <a href="https://en.wikipedia.org/wiki/Leucine" title="Leucine">leucine</a>-rich cytoplasmic <a href="https://en.wikipedia.org/wiki/Protein" title="Protein">protein</a>, which is highly similar to a mouse protein norbin that negatively regulates Ca/calmodulin-dependent <a href="https://en.wikipedia.org/wiki/Protein" title="Protein">protein</a> kinase II phosphorylation and may be essential for spatial learning processes.  

Norbin can modulate signaling activity and expression of <a href="https://en.wikipedia.org/wiki/Metabotropic_glutamate_receptor_5" title="Metabotropic glutamate receptor 5">metabotropic glutamate receptor 5</a>; modulating mice with targeted deletion of NCDN in the brain have phenotypic traits usually found in the rodent models of <a href="https://en.wikipedia.org/wiki/Schizophrenia" title="Schizophrenia">schizophrenia</a>, including disruptions in prepulse inhibition. Furthermore, norbin protein expression is altered in the schizophrenia brain.

NCDN 250     P         A         possibly damaging   deleterious    neurochondrin

NCDN 379     L          F          probably damaging  deleterious    neurochondrin

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