View source for Whale Shark Positively selected genes

<p><em>Contents:</em></p>

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

<p>&nbsp;</p>

<p><strong><em>(Anti-clotting:&nbsp;&nbsp; FGG, FGB, SEPRINE2)</em></strong></p>

<p><strong>FGG</strong></p>

<p>FGG&nbsp;&nbsp;&nbsp; 143&nbsp;&nbsp;&nbsp;&nbsp; N&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp; E&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp; probably damaging&nbsp; deleterious&nbsp;&nbsp;&nbsp; fibrinogen gamma chain</p>

<p>FGG&nbsp;&nbsp;&nbsp; 167&nbsp;&nbsp;&nbsp;&nbsp; D&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp; G&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp; probably damaging&nbsp; deleterious&nbsp;&nbsp;&nbsp; fibrinogen gamma chain</p>

<p>FGG&nbsp;&nbsp;&nbsp; 171&nbsp;&nbsp;&nbsp;&nbsp; I&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp; A&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp; probably damaging&nbsp; deleterious&nbsp;&nbsp;&nbsp; fibrinogen gamma chain</p>

<p>FGG&nbsp;&nbsp;&nbsp; 176&nbsp;&nbsp;&nbsp;&nbsp; G&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp; A&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp; probably damaging&nbsp; deleterious&nbsp;&nbsp;&nbsp; fibrinogen gamma chain</p>

<p>FGG&nbsp;&nbsp;&nbsp; 204&nbsp;&nbsp;&nbsp;&nbsp; F&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp; M&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp; probably damaging&nbsp; deleterious&nbsp;&nbsp;&nbsp; fibrinogen gamma chain</p>

<p>FGG&nbsp;&nbsp;&nbsp; 254&nbsp;&nbsp;&nbsp;&nbsp; L&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp; I&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp; probably damaging&nbsp; neutral&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp; &nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp; fibrinogen gamma chain</p>

<p>FGG&nbsp;&nbsp;&nbsp; 335&nbsp;&nbsp;&nbsp;&nbsp; G&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp; F&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp; probably damaging&nbsp; deleterious&nbsp;&nbsp;&nbsp; fibrinogen gamma chain</p>

<p>FGG&nbsp;&nbsp;&nbsp; 375&nbsp;&nbsp;&nbsp;&nbsp; Y&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp; H&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp; possibly damaging&nbsp;&nbsp; deleterious&nbsp;&nbsp;&nbsp; fibrinogen gamma chain</p>

<p>&nbsp;</p>

<p>FGB&nbsp;&nbsp;&nbsp; 284&nbsp;&nbsp;&nbsp;&nbsp; N&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp; S&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp; possibly damaging&nbsp;&nbsp; deleterious&nbsp;&nbsp;&nbsp; fibrinogen beta chain</p>

<p>FGB&nbsp;&nbsp;&nbsp; 352&nbsp;&nbsp;&nbsp;&nbsp; V&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp; L&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp; probably damaging&nbsp; neutral&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp; &nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp; fibrinogen beta chain</p>

<p>FGB&nbsp;&nbsp;&nbsp; 409&nbsp;&nbsp;&nbsp;&nbsp; D&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp; N&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp; probably damaging&nbsp; deleterious&nbsp;&nbsp;&nbsp; fibrinogen beta chain</p>

<p>FGB&nbsp;&nbsp;&nbsp; 470&nbsp;&nbsp;&nbsp;&nbsp; W&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp; A&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp; probably damaging&nbsp; deleterious&nbsp;&nbsp;&nbsp; fibrinogen beta chain</p>

<p>&nbsp;</p>

<p>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 <strong>primary components of blood clots</strong>. In addition, functions during the early stages of wound repair to stabilize the lesion and guide cell migration during re-epithelialization.</p>

<p><em>&nbsp;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.&nbsp; 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. </em></p>

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

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

<p>&nbsp;</p>

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

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

<p>&nbsp;</p>

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

<p>&nbsp;</p>

<p><em>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 -&gt; in whale shark gene might lead to similar defects. </em></p>

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

<p>&nbsp;</p>

<p>FGG structure:</p>

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

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

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

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

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

			<p>&nbsp;</p>

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

			<p><u>Physico-chemical properties:</u> Change from glycine (G) to medium size and acidic (D)</p>

			<p><u>Variant description:</u>&nbsp; In Hillsborough; prolonged thrombin clotting time.</p>

			<p>&nbsp;</p>
			</td>
			<td style="width:276px">
			<p>&nbsp;</p>

			<p>From Glycine (G) to Phenylalanine (F) at position 335</p>

			<p>&nbsp;</p>

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

<p>&nbsp;</p>

<p>&nbsp;&nbsp;</p>

<p>&nbsp;</p>

<p>&nbsp;</p>

<p>&nbsp;</p>

<p>&nbsp;</p>

<p>&nbsp;</p>

<p>&nbsp;</p>

<p><strong>&nbsp;&nbsp;In common Pathway of Fibrin Clot formation </strong></p>

<p>&nbsp;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) <strong>that inhibits thrombin at the vessel wall and platelet surface. </strong>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.</p>

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

<p>According to excel file SERPINE2 -&gt; is positively selected gene in shark common ancestors:</p>

<p><strong>SERPINE2 </strong>&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;146&nbsp;&nbsp;&nbsp;&nbsp; F&nbsp;&nbsp;&nbsp; &agrave; Y&nbsp; probably damaging&nbsp; deleterious&nbsp;&nbsp;&nbsp;</p>

<p>&nbsp;</p>

<p>This gene encodes a member of the serpin family of proteins, a group of proteins <strong>that inhibit serine proteases</strong>. 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. &nbsp;.</p>

<p>The possible disease information based on polymorphism and mutation in SERPINE2:</p>

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

<p><em>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.&nbsp; Beneficial for shark blood clotting.</em></p>

<p><em>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.</em></p>

<h1>&ldquo;SERPINE2 Inhibits IL-1&alpha;-Induced MMP-13 Expression in Human Chondrocytes: Involvement of ERK/NF-&kappa;B/AP-1 Pathway&rdquo;</h1>

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

<p>&nbsp;</p>

<p><strong><em>(Cell division : HAUS1, CENPI, CENPK, MCM3AP, CHAF1A, HP1BP3, PARP11 )</em></strong></p>

<p>HAUS1</p>

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

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

<p>Whale shark specific genes:</p>

<p>HAUS1&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp; &nbsp;&nbsp; 76&nbsp;&nbsp;&nbsp; L&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp; I&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp; probably damaging&nbsp;&nbsp;&nbsp; HAUS augmin like complex subunit 1</p>

<p>&nbsp;</p>

<p>Whale shark and elephant shark common:</p>

<p>HAUS1&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp; &nbsp;&nbsp; 53&nbsp;&nbsp;&nbsp; L&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp; Q&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp; probably damaging&nbsp; &nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp; HAUS augmin like complex subunit 1</p>

<p>&nbsp;</p>

<p>&nbsp;</p>

<p>CENPI</p>

<p>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</p>

<p>CENPI&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp; 113&nbsp;&nbsp;&nbsp;&nbsp; L&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp; V&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp; possibly damaging&nbsp;&nbsp; deleterious&nbsp;&nbsp;&nbsp; centromere protein I</p>

<p>CENPI&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp; 262&nbsp;&nbsp;&nbsp;&nbsp; F&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp; L&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp; probably damaging&nbsp; deleterious&nbsp;&nbsp;&nbsp; centromere protein I</p>

<p>CENPI&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp; 446&nbsp;&nbsp;&nbsp;&nbsp; W&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp; Y&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp; probably damaging&nbsp; deleterious&nbsp;&nbsp;&nbsp; centromere protein I</p>

<p>&nbsp;</p>

<p><em>Estimated protein expression in Liver the highest </em><em>&szlig;</em><em> shark liver is the biggest organ in their body, it means liver cells proliferate many times&nbsp; </em></p>

<p>&nbsp;</p>

<p>CENPK</p>

<p>Component of the CENPA-CAD (nucleosome distal) complex, a complex recruited to centromeres which is involved <strong>in assembly of kinetochore proteins, mitotic progression and chromosome segregation</strong>. 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.</p>

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

<pre>
&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp; /region_name=&quot;CENP-K&quot;</pre>

<pre>
&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp; /note=&quot;Centromere-associated protein K; pfam11802&quot;</pre>

<pre>
&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp; </pre>

<p>The functional amino-acid changes in centrosome associated region &agrave; important for binding</p>

<p>CENPK&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp; 252&nbsp;&nbsp;&nbsp;&nbsp; A&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp; V&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp; probably damaging&nbsp; deleterious&nbsp;&nbsp;&nbsp; centromere protein K</p>

<p>CENPK&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp; 257&nbsp;&nbsp;&nbsp;&nbsp; E&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp; D&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp; probably damaging&nbsp; neutral&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp; centromere protein K</p>

<p>&nbsp;</p>

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

<p>The minichromosome maintenance protein 3 (MCM3) is one of the MCM proteins essential for the <strong>initiation of DNA replication</strong>. The protein encoded by this gene is an MCM3 binding protein. It was reported to have <strong>phosphorylation-dependent DNA-primase activity</strong>, 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</p>

<p>&nbsp;</p>

<p>MCM3AP&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp; 730&nbsp;&nbsp;&nbsp;&nbsp; I&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp; V&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp; MCM component 3 associated protein</p>

<p>&nbsp;</p>

<p><strong>CHAF1A</strong></p>

<p>Core component of the <strong>CAF-1 complex</strong>, a complex thought to mediate <strong>chromatin assembly in DNA replication and DNA repair</strong>. Assembles histone octamers onto replicating DNA in vitro. CAF-1 performs the first step of the <strong>nucleosome assembly process</strong>, 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</p>

<p>&nbsp;</p>

<p>CHAF1A&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp; 423&nbsp;&nbsp;&nbsp;&nbsp; R&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp; K&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp; unknown</p>

<p>CHAF1A&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp; 509&nbsp;&nbsp;&nbsp;&nbsp; L&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp; I&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp; probably damaging</p>

<p>CHAF1A&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp; 555&nbsp;&nbsp;&nbsp;&nbsp; G&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp; C&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp; probably damaging</p>

<p>&nbsp;</p>

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

<p><strong>HP1BP3</strong></p>

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

<p>&nbsp;</p>

<p><em>In bowhead whale this protein has extended amino acids chain from 171 - &gt; 240. </em></p>

<p><em>I would like to look to the whole peptide chain of the shark&rsquo;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.</em></p>

<p>&nbsp;</p>

<p><strong>PARP11</strong></p>

<p>Plays a role in nuclear envelope stability and nuclear remodeling during spermiogenesis.&nbsp;</p>

<p>PARP11&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp; 328&nbsp;&nbsp;&nbsp;&nbsp; Q&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp; H&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp; probably damaging&nbsp; deleterious</p>

<p>328<sup>TH</sup> position in PARP catalytic domain.</p>

<p>&nbsp;</p>

<p>&nbsp;</p>

<p><strong><em>&nbsp;(Cancer associated: RET, GSS, SERPINF1, NFKBIE)</em></strong></p>

<p><strong>RET</strong></p>

<p>This gene, a member of the cadherin superfamily, encodes one of the receptor tyrosine kinases, which are cell-surface molecules that transduce signals for <strong>cell growth and differentiation</strong>. 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.</p>

<p>The&nbsp;<em>RET</em>&nbsp;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).</p>

<p>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.</p>

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

<p>&nbsp;</p>

<p>RET&nbsp;&nbsp;&nbsp; 657&nbsp;&nbsp;&nbsp;&nbsp; T&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp; S&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp; probably damaging&nbsp; deleterious&nbsp;&nbsp;&nbsp; ret proto-oncogene</p>

<p>&nbsp;</p>

<p>Whale shark and elephant shark common:</p>

<p>RET&nbsp;&nbsp;&nbsp; 697&nbsp;&nbsp;&nbsp;&nbsp; A&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp; G&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp; probably damaging&nbsp; deleterious&nbsp;&nbsp;&nbsp; ret proto-oncogene</p>

<p>RET&nbsp;&nbsp;&nbsp; 714&nbsp;&nbsp;&nbsp;&nbsp; E&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp; Q&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp; probably damaging&nbsp; neutral&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp; ret proto-oncogene</p>

<p>&nbsp;</p>

<p>&nbsp;</p>

<p>&nbsp;GSS&nbsp;&nbsp;&nbsp;&nbsp;</p>

<p><em>(During hypoxia condition a lot oxidants form -&gt; protection from free radicals *)</em></p>

<p>Glutathione is important for a variety of biological functions, including protection of cells from <strong>oxidative damage by free radicals</strong>, 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-<strong>cysteine to glutathione</strong>. Defects in this gene are a cause of glutathione synthetase deficiency.</p>

<p>ATP + gamma-L-glutamyl-L-cysteine + glycine = ADP + phosphate + glutathione</p>

<p>&nbsp;</p>

<p>Whale shark:</p>

<p>GSS&nbsp;&nbsp;&nbsp; 152&nbsp;&nbsp;&nbsp;&nbsp; F&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp; Y&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp; probably damaging&nbsp; deleterious&nbsp;&nbsp;&nbsp; prion protein</p>

<p>&nbsp;</p>

<p>Whale shark and elephant shark common:</p>

<p>GSS&nbsp;&nbsp;&nbsp; 51&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp; T&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp; S&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp; benign&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp; deleterious&nbsp;&nbsp;&nbsp; glutathione synthetase</p>

<p>GSS&nbsp;&nbsp;&nbsp; 456&nbsp;&nbsp;&nbsp;&nbsp; H&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp; F&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp; probably damaging&nbsp; deleterious&nbsp;&nbsp;&nbsp; glutathione synthetase</p>

<p>&nbsp;</p>

<p>SERPINF1</p>

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

<p>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.&nbsp;VEGF expression by cancer cells is inhibited by PEDF.</p>

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

<p>&nbsp;As it does not undergo the S (stressed) to R (relaxed) conformational transition characteristic of active serpins, it exhibits no serine protease inhibitory activity.</p>

<p>&nbsp;</p>

<p>SERPINF1&nbsp;&nbsp;&nbsp;&nbsp;&nbsp; 106&nbsp;&nbsp;&nbsp;&nbsp; R&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp; G&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp; probably damaging&nbsp; deleterious&nbsp;&nbsp;&nbsp; serpin family F member 1</p>

<p>SERPINF1&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp; 408&nbsp;&nbsp;&nbsp; F&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp; H&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp; probably damaging&nbsp; deleterious&nbsp;&nbsp;&nbsp; serpin family F member 1</p>

<p>&nbsp;</p>

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

<p><em>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.&nbsp; Residue change in 408<sup>th</sup> amino acid from Phe to His, would not lead big changes, due to these two side chains are similar in their structure. </em></p>

<p>&nbsp;</p>

<p><strong>NFKBIE</strong></p>

<p>The protein encoded by this gene binds to components of <strong>NF-kappa-B</strong>, 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.</p>

<p>&nbsp;</p>

<p>In tumor cells, <strong>NF-</strong><strong>&kappa;</strong><strong>B is active</strong> either due to mutations, some tumor cells secrete factors that cause NF-&kappa;B to become active. <strong>Blocking NF-</strong><strong>&kappa;</strong><strong>B</strong> can cause tumor cells to stop proliferating, to die, or to become more sensitive to the action of anti-tumor agents.&nbsp;</p>

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

<p>Whale shark:</p>

<p><em>NFKBIE&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp; 261&nbsp;&nbsp;&nbsp;&nbsp; T&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp; S&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp; possibly damaging&nbsp;&nbsp; &nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp; deleterious</em></p>

<p><em>NFKBIE&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp; 411&nbsp;&nbsp;&nbsp;&nbsp; A&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp; S&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp; probably damaging&nbsp; deleterious</em></p>

<p>&nbsp;</p>

<p>Whale shark and elephant shark:</p>

<p>NFKBIE&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp; 322&nbsp;&nbsp;&nbsp;&nbsp; L&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp; Q&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp; probably damaging&nbsp; deleterious</p>

<p>&nbsp;</p>

<p>NFKBIE contains 6 ANK repeats.</p>

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

<p>In following ANK repeats whale shark&rsquo;s mutation occurs:</p>

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

<p>&nbsp;&nbsp;</p>

<p><em>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&rsquo;s why ANK repeat had some alterations </em><em>&agrave;</em><em> to decrease protein-protein interactions. Low interaction with NF-kB, increase cell proliferations.&nbsp;&nbsp; </em></p>

<p>&nbsp;</p>

<p>&nbsp;</p>

<p>&nbsp;</p>

<p><strong><em>(Programmed cell death: CASP7, PDCD2, PDCD6IP,MYCBP2)</em></strong></p>

<p>CASP7</p>

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

<p>&nbsp;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 &#39;216-Asp-|-Gly-217&#39; bond.</p>

<p>Overexpression promotes programmed cell death.</p>

<p>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.</p>

<p>similarity: Belongs to the peptidase C14A family.</p>

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

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

<p>&nbsp;</p>

<p>CASP7&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp; 168&nbsp;&nbsp;&nbsp;&nbsp; G&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp; E&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp; probably damaging&nbsp; deleterious</p>

<p>&nbsp;</p>

<p>PDCD2</p>

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

<p>^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 <strong>loss of PDCD2 expression</strong> could contribute to <strong>gastric cancer</strong> 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.</p>

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

<p>&nbsp;</p>

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

<p>&nbsp;&nbsp; <strong>increases PDCD2 protein expression and apoptosis</strong></p>

<p><strong>&nbsp;&nbsp;&nbsp; knockdown of the PDCD2 protein in this cell line by PDCD2-specific small interfering RNA duplexes inhibits apoptosis. </strong></p>

<p>These studies indicate that one function <strong>of PDCD2 is to promote apoptosis</strong> in several human and mammalian cell lines and tissues, including lymphoma. &nbsp;</p>

<p>&nbsp;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.</p>

<p>&nbsp;</p>

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

<pre>
&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp; /region_name=&quot;zf-MYND&quot;</pre>

<pre>
&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp; /note=&quot;MYND finger; pfam01753&quot;</pre>

<pre>
&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp; </pre>

<p><em>Zync finger binding site amino acids changed </em><em>&agrave;</em></p>

<p>&nbsp;</p>

<p>PDCD2&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp; &nbsp;&nbsp; 150&nbsp; &nbsp; H&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp; R&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp; benign&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp; deleterious&nbsp;&nbsp;&nbsp; programmed cell death 2</p>

<p>PDCD2&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp; &nbsp;&nbsp; 169&nbsp; &nbsp; K&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp; R&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp; possibly damaging&nbsp;&nbsp; deleterious&nbsp;&nbsp;&nbsp; programmed cell death 2</p>

<p>&nbsp;</p>

<p>&nbsp;</p>

<p><strong>PDCD6IP</strong></p>

<p>overexpression of this protein <strong>can block apoptosis</strong>. 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 <strong>protection against cell death</strong></p>

<p><br />
PDCD6IP&nbsp;&nbsp;&nbsp;&nbsp;&nbsp; 118&nbsp;&nbsp;&nbsp;&nbsp; Y&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp; F&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp; programmed cell death 6 interacting protein</p>

<p>PDCD6IP&nbsp;&nbsp;&nbsp;&nbsp;&nbsp; 171&nbsp;&nbsp;&nbsp;&nbsp; L&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp; M&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp; neutral&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp; programmed cell death 6 interacting protein</p>

<p>PDCD6IP&nbsp;&nbsp;&nbsp;&nbsp;&nbsp; 175&nbsp;&nbsp;&nbsp;&nbsp; P&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp; L&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp; deleterious&nbsp;&nbsp;&nbsp; programmed cell death 6 interacting protein</p>

<p>PDCD6IP&nbsp;&nbsp;&nbsp;&nbsp;&nbsp; 179&nbsp;&nbsp;&nbsp;&nbsp; I&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp; T&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp; deleterious&nbsp;&nbsp;&nbsp; programmed cell death 6 interacting protein</p>

<p>PDCD6IP&nbsp;&nbsp;&nbsp;&nbsp;&nbsp; 361&nbsp;&nbsp;&nbsp;&nbsp; E&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp; V&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp; deleterious&nbsp;&nbsp;&nbsp; programmed cell death 6 interacting protein</p>

<p>&nbsp;</p>

<p>&nbsp;</p>

<p>&nbsp;</p>

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

<p>&nbsp;</p>

<p>&nbsp;protein associates with myc&nbsp;</p>

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

<p>&nbsp;</p>

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

<p>&nbsp;</p>

<p>PAM&nbsp;&nbsp; 285&nbsp;&nbsp;&nbsp;&nbsp; A&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp; T&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp; probably damaging&nbsp; deleterious&nbsp;&nbsp;&nbsp; MYC binding protein 2, E3 ubiquitin protein ligase</p>

<p>PAM&nbsp;&nbsp; 602&nbsp;&nbsp;&nbsp;&nbsp; V&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp; I&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp; probably damaging&nbsp; neutral&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;</p>

<p>PAM&nbsp;&nbsp; 623&nbsp;&nbsp;&nbsp;&nbsp; P&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp; S&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp; probably damaging&nbsp; deleterious&nbsp;&nbsp;&nbsp;</p>

<p>PAM&nbsp;&nbsp; 738&nbsp;&nbsp;&nbsp;&nbsp; P&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp; A&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp; benign&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp; deleterious&nbsp;&nbsp;&nbsp;</p>

<p>PAM&nbsp;&nbsp; 768&nbsp;&nbsp;&nbsp;&nbsp; I&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp; L&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp; probably damaging&nbsp; neutral&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;</p>

<p>&nbsp;</p>

<p>&nbsp;</p>

<p><strong><em>(DNA repair genes: MSH6,RAD54B, MRE11A,XRCC3, MCM8, DCLRE1B )</em></strong></p>

<p><strong>MSH6</strong></p>

<p>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--&gt;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 &#39;Lys-36&#39; 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.</p>

<p>&nbsp; <em>Whale shark specific genes having function altering amino acid changes</em></p>

<p>MSH6 &nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp; 199&nbsp;&nbsp;&nbsp;&nbsp;&nbsp; P&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp; L&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp; benign&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp; deleterious</p>

<p>MSH6 &nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp; 451&nbsp;&nbsp;&nbsp;&nbsp; F&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp; Y&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp; possibly damaging&nbsp;&nbsp; neutral</p>

<p>MSH6 &nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp; 733&nbsp;&nbsp;&nbsp; M&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp; L&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp; benign&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp; deleterious</p>

<p>MSH6 &nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp; 1207 &nbsp; H&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp; Y&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp; possibly damaging&nbsp;&nbsp; deleterious</p>

<p>MSH6 &nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp; 1330&nbsp;&nbsp; L&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp; F&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp; probably damaging&nbsp; deleterious</p>

<p>&nbsp;</p>

<p>&nbsp;</p>

<p><strong>RAD54B</strong></p>

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

<p>Abundantly expressed in testis and spleen.</p>

<p>&nbsp;</p>

<p>RAD54B&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp; 194&nbsp;&nbsp;&nbsp;&nbsp; M&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp; T&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp; possibly damaging&nbsp;&nbsp; deleterious</p>

<p>RAD54B&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp; 482&nbsp;&nbsp;&nbsp;&nbsp; L&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp; I&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp; probably damaging&nbsp; neutral</p>

<p>RAD54B&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp; 598&nbsp;&nbsp;&nbsp;&nbsp; L&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp; F&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp; probably damaging&nbsp; deleterious</p>

<p>&nbsp;</p>

<p><em>&nbsp;Whale shark and elephant shark common genes having function altering amino acid changes:</em></p>

<p><em>RAD54B&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp; 383&nbsp;&nbsp;&nbsp;&nbsp; I&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp; L&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp; possibly damaging&nbsp;&nbsp; neutral</em></p>

<p><em>RAD54B&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp; 533&nbsp;&nbsp;&nbsp;&nbsp; E&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp; D&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp; possibly damaging&nbsp;&nbsp; neutral</em></p>

<p>&nbsp;</p>

<p>&nbsp;</p>

<p><strong>MRE11A</strong></p>

<p>&nbsp;Component of the MRN complex, which plays a central role <strong>in double-strand break</strong> (DSB) <strong>repair, DNA recombination, maintenance of telomere integrity and meiosis</strong>. The complex possesses single-strand endonuclease activity and double-strand-specific 3&#39;-5&#39; 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. &nbsp;</p>

<p>MRE11A&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp; 304&nbsp;&nbsp;&nbsp;&nbsp; V&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp; I&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp; probably damaging&nbsp; neutral</p>

<p>MRE11A&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp; 403&nbsp;&nbsp;&nbsp;&nbsp; E&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp; D&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp; possibly damaging&nbsp;&nbsp; neutral</p>

<pre>
<em>&nbsp;Region: </em>10..402</pre>

<pre>
&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp; /region_name=&quot;mre11&quot;</pre>

<pre>
&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp; /note=&quot;DNA repair protein (mre11); TIGR00583&quot;</pre>

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

<p>&nbsp;</p>

<p>Defects in MRE11A can be a cause of <strong>nephronophthisis-related ciliopathies</strong> (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.</p>

<p>&nbsp;</p>

<p><strong>XRCC3</strong>&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;</p>

<p>Involved in the <strong>homologous recombination repair</strong> (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.</p>

<p>&nbsp;</p>

<p>XRCC3&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp; 259&nbsp;&nbsp; &nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp; V&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp; I&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp; probably damaging&nbsp; neutral&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;</p>

<p>&nbsp;&nbsp;&nbsp;&nbsp; <em>Whale shark and elephant shark common genes having function altering amino acid changes:</em></p>

<p>&nbsp;XRCC3&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp; 133&nbsp; L&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp; Q&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp; probably damaging&nbsp; deleterious</p>

<p>&nbsp;</p>

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

<pre>
&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp; /region_name=&quot;recomb_DMC1&quot;</pre>

<pre>
&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp; /note=&quot;meiotic recombinase Dmc1; TIGR02238&quot;</pre>

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

<p>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.</p>

<p><em>In this region function altering changes occurred in whale shark and elephant shark. </em></p>

<p>&nbsp;</p>

<p>MCM8</p>

<p>Component of the <strong>MCM8-MCM9 complex</strong>, a complex involved in <strong>homologous recombination repair</strong> following DNA interstrand cross-links and plays a key role during <strong>gametogenesis</strong>. 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 G<sub>1</sub>&nbsp;phase by recruiting CDC6 to the origin recognition complex (ORC). Binds chromatin throughout the cell cycle</p>

<p>*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</p>

<p>&nbsp;Whale shark specific genes having function altering amino acid changes</p>

<p>MCM8 &nbsp; 608&nbsp;&nbsp; N&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp; S&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp; probably damaging&nbsp; deleterious</p>

<p>Domain part: 402-609&nbsp;&nbsp;</p>

<p>In 608<sup>th</sup> amino acid change might bring conformational changes.</p>

<p>&nbsp;</p>

<p>DCLRE1B&nbsp;&nbsp;&nbsp;&nbsp;</p>

<p>5&#39;-3&#39; exonuclease that plays a central role in <strong>telomere maintenance and protection</strong> during S-phase. Participates in the protection of telomeres against non-homologous end-joining (NHEJ)-mediated repair, thereby <strong>ensuring that telomeres do not fuse</strong>. 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&#39; 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.</p>

<p>&nbsp;</p>

<p>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.</p>

<p>&nbsp;</p>

<p>DCLRE1B&nbsp;&nbsp; 209&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp; E&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp; Q&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp; possibly damaging&nbsp;&nbsp; deleterious</p>

<p>&nbsp;</p>

<p>Whale shark and elephant shark common genes having function altering amino acid changes</p>

<p>DCLRE1B&nbsp;&nbsp; 119&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp; G&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp; A&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp; probably damaging&nbsp; deleterious&nbsp;&nbsp; DNA cross-link repair 1B</p>

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

<pre>
&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp; /region_name=&quot;DRMBL&quot;</pre>

<pre>
&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp; /note=&quot;DNA repair metallo-beta-lactamase; pfam07522&quot;</pre>

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

<p>&nbsp;</p>

<p>&nbsp;</p>

<p>&nbsp;</p>

<p><strong>(Other proteins: KIAA1143, GNL2, CTDP1, MTIF2, DECR1, ATE1, XXYLT1, PLEKHM3)</strong></p>

<p>&nbsp;</p>

<p>KIAA1143</p>

<p>&nbsp;</p>

<p>&nbsp;KIAA1143&nbsp;&nbsp;&nbsp;&nbsp; 29&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp; E&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp; S&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp; probably damaging&nbsp; deleterious&nbsp;&nbsp;&nbsp; KIAA1143</p>

<p>KIAA1143&nbsp;&nbsp;&nbsp;&nbsp;&nbsp; 95&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp; I&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp; H&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp; probably damaging&nbsp; deleterious&nbsp;&nbsp;&nbsp; KIAA1143</p>

<p>KIAA1143&nbsp;&nbsp;&nbsp;&nbsp;&nbsp; 108&nbsp;&nbsp;&nbsp;&nbsp; K&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp; T&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp; benign&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp; deleterious&nbsp;&nbsp;&nbsp; KIAA1143</p>

<p>On the uniprot website :</p>

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

<p><em>&nbsp;A lysine on 108<sup>th</sup> amino acid had post translational modification, however in shark&rsquo;s case lysine changed to the Threonine. Thereby, acetylation won&rsquo;t happen and changes structure of the protein. </em></p>

<p>&nbsp;</p>

<p>GNL2</p>

<p>GNL2&nbsp; 2&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp; V&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp; S&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp; possibly damaging neutral&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp; &nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp; G protein nucleolar 2</p>

<p>GNL2&nbsp; 7&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp; K&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp; Q&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp; possibly damaging&nbsp;&nbsp; neutral&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp; &nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp; G protein nucleolar 2</p>

<p>GNL2&nbsp; 12&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp; I&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp; E&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp; possibly damaging&nbsp;&nbsp; deleterious &nbsp;&nbsp; G protein nucleolar 2</p>

<p>GNL2&nbsp; 13&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp; N&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp; R&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp; benign&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp; &nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp; deleterious&nbsp;&nbsp;&nbsp;&nbsp; G protein nucleolar 2</p>

<p>GNL2&nbsp; 15&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp; S&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp; E&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp; possibly damaging&nbsp;&nbsp; deleterious&nbsp;&nbsp;&nbsp; G protein nucleolar 2</p>

<p>GNL2&nbsp; 18&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp; S&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp; M&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp; probably damaging&nbsp; deleterious&nbsp;&nbsp;&nbsp; G protein nucleolar 2</p>

<p>GNL2&nbsp; 20&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp; N&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp; I&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp; probably damaging&nbsp; deleterious&nbsp;&nbsp;&nbsp; G protein nucleolar 2</p>

<p>GNL2&nbsp; 21&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp; P&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp; Q&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp; probably damaging&nbsp; deleterious&nbsp;&nbsp;&nbsp; G protein nucleolar 2</p>

<p>GNL2&nbsp; 32&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp; M&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp; T&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp; possibly damaging&nbsp;&nbsp; deleterious&nbsp;&nbsp;&nbsp; G protein nucleolar 2</p>

<p>GNL2&nbsp; 71&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp; V&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp; T&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp; possibly damaging&nbsp;&nbsp; deleterious&nbsp;&nbsp;&nbsp; G protein nucleolar 2</p>

<p>GNL2&nbsp; 308&nbsp;&nbsp;&nbsp;&nbsp; K&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp; R&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp; possibly damaging&nbsp;&nbsp; deleterious&nbsp;&nbsp;&nbsp; G protein nucleolar 2</p>

<p>&nbsp;</p>

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

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

<p><em>The brginning amino acids mostly changed -&gt; possibly to improve signal sequence while exporting from nucleous. </em></p>

<p>&nbsp;</p>

<p><strong>CTDP1 </strong></p>

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

<p>Mutations in this gene are associated with congenital cataracts, facial dysmorphism and neuropathy syndrome.&nbsp;</p>

<p>Whale Shark and Elephant shark:</p>

<p>CTDP1&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp; 153&nbsp;&nbsp;&nbsp;&nbsp; V&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp; I&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp; probably damaging&nbsp; neutral</p>

<p>CTDP1&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp; 176&nbsp;&nbsp;&nbsp;&nbsp; R&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp; W&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp; probably damaging&nbsp; deleterious</p>

<p>CTDP1&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp; 179&nbsp;&nbsp;&nbsp;&nbsp; R&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp; K&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp; probably damaging&nbsp; deleterious</p>

<p>&nbsp;</p>

<p>&nbsp;</p>

<p>&nbsp;</p>

<p><strong>DNAJB14</strong></p>

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

<p><em>DNAJB14&nbsp;&nbsp;&nbsp;&nbsp;&nbsp; 346&nbsp;&nbsp;&nbsp;&nbsp; A&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp; S&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp; possibly damaging&nbsp;&nbsp; deleterious</em></p>

<p>&nbsp;</p>

<p>&nbsp;</p>

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

<p>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.</p>

<p><em>MTIF2 297&nbsp;&nbsp;&nbsp;&nbsp; P&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp; H&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp; probably damaging&nbsp; deleterious</em></p>

<p><em>MTIF2 380&nbsp;&nbsp;&nbsp;&nbsp; T&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp; S&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp; probably damaging&nbsp; deleterious</em></p>

<p><em>MTIF2 572&nbsp;&nbsp;&nbsp;&nbsp; Y&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp; F&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp; benign&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp; deleterious</em></p>

<p>&nbsp;</p>

<p><strong>DECR1</strong></p>

<p>Auxiliary enzyme of beta-oxidation. It participates in the <strong>metabolism of unsaturated fatty</strong> 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.</p>

<p>&nbsp;DECR1&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp; &nbsp;&nbsp; 44&nbsp;&nbsp;&nbsp; F&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp; L&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp; probably damaging&nbsp; deleterious</p>

<p>Tissue specificity:&nbsp; Heart = liver = pancreas &gt; kidney &gt;&gt; skeletal muscle = lung</p>

<p><em>44<sup>th</sup> residue not a binding site or active site, so this change not involve big changes in the function of the protein. </em></p>

<p><strong>ATE1</strong></p>

<p>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 <strong>ubiquitin-dependent degradation</strong>.</p>

<p>&nbsp;</p>

<p>ATE1&nbsp; 60&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp; T&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp; S&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp; possibly damaging&nbsp;&nbsp; deleterious</p>

<p>&nbsp;</p>

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

<p>&nbsp;</p>

<p><strong>XXYLT1</strong></p>

<p>XXYLT1&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp; &nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp; 352&nbsp;&nbsp; W&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp; &nbsp; N&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp; probably damaging&nbsp; deleterious</p>

<p>XXYLT1&nbsp; &nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp; 367&nbsp;&nbsp;&nbsp;&nbsp; D&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp; E&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp; possibly damaging&nbsp;&nbsp; deleterious</p>

<p>&nbsp;</p>

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

<p>&nbsp;</p>

<p><em>Above protein domains and function described, and shark&rsquo;s mutation spots not included.</em></p>

<p><strong>PLEKHM3</strong></p>

<p>&nbsp;Whale shark only:</p>

<p>PLEKHM3&nbsp;&nbsp;&nbsp;&nbsp; 305&nbsp;&nbsp;&nbsp;&nbsp; E&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp; A&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp; probably damaging&nbsp; deleterious</p>

<p>PLEKHM3&nbsp;&nbsp;&nbsp;&nbsp; 413&nbsp;&nbsp;&nbsp;&nbsp; V&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp; I&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp; probably damaging&nbsp; neutral</p>

<p>PLEKHM3&nbsp;&nbsp;&nbsp;&nbsp; 444&nbsp;&nbsp;&nbsp;&nbsp; A&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp; T&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp; probably damaging&nbsp; deleterious</p>

<p>&nbsp;</p>

<p>Domains:</p>

<p>PH1 domain:&nbsp;&nbsp; 211-308 positions</p>

<p>&nbsp;PH2 domain: 362- 456 positions</p>

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

<p>&nbsp;</p>

<p>In whale shark&rsquo;s PLEKHM3 two domains have functional altering amino acid changes.</p>

<p>Whale shark and elephant shark:</p>

<p>PLEKHM3&nbsp;&nbsp;&nbsp;&nbsp; 380&nbsp;&nbsp;&nbsp;&nbsp; F&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp; Y&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp; probably damaging&nbsp; neutral</p>

<p>PLEKHM3&nbsp;&nbsp;&nbsp;&nbsp; 501&nbsp;&nbsp;&nbsp;&nbsp; L&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp; I&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp; probably damaging&nbsp; neutral</p>

<p>&nbsp;</p>

<p>&nbsp;</p>

<p><strong><em>(Brain and neuron related: NCDN)</em></strong></p>

<p>NCDN</p>

<p>&nbsp;</p>

<p>This gene encodes a&nbsp;<a href="https://en.wikipedia.org/wiki/Leucine" title="Leucine">leucine</a>-rich cytoplasmic&nbsp;<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&nbsp;<a href="https://en.wikipedia.org/wiki/Protein" title="Protein">protein</a>&nbsp;kinase II phosphorylation and may be essential for <strong>spatial&nbsp;learning</strong>&nbsp;processes. &nbsp;</p>

<p>Norbin can modulate signaling activity and expression of&nbsp;<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&nbsp;<a href="https://en.wikipedia.org/wiki/Schizophrenia" title="Schizophrenia">schizophrenia</a>, including disruptions in&nbsp;prepulse inhibition.&nbsp;Furthermore, norbin protein expression is altered in the schizophrenia brain.</p>

<p>NCDN 250&nbsp;&nbsp;&nbsp;&nbsp; P&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp; A&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp; possibly damaging&nbsp;&nbsp; deleterious&nbsp;&nbsp;&nbsp; neurochondrin</p>

<p>NCDN 379&nbsp;&nbsp;&nbsp;&nbsp; L&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp; F&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp; probably damaging&nbsp; deleterious&nbsp;&nbsp;&nbsp; neurochondrin</p>

<p>&nbsp;</p>

<p>&nbsp;</p>