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<div class="include-supplemental-container">
<input type="checkbox" aria-label="Include MeSH and other data" name="include-supplemental" id="email-include-supplemental" class="email-include-supplemental">
<label for="email-include-supplemental" class="email-include-supplemental-label">MeSH and other data</label>
</div>
<div class="form-field recaptcha ">
<div class="g-recaptcha" id="id-recaptcha" data-sitekey="6LfsWHMdAAAAAClKbtOpjQ2pMjgsGxvv7NdZW9uI"></div>
</div>
<div id="captcha-error-message" class="usa-input-error-message captcha-validation-message" role="alert"></div>
<div class="action-panel-actions">
<button class="action-panel-submit"
type="submit"
data-loading-label="Sending..."
data-ga-category="save_share"
data-ga-action="email"
data-ga-label="send">
Send email
</button>
<button class="action-panel-cancel"
aria-label="Close 'Email citations' panel"
ref="linksrc=close_email_panel"
aria-controls="email-action-panel"
aria-expanded="false"
data-ga-category="save_share"
data-ga-action="email"
data-ga-label="cancel">
Cancel
</button>
</div>
<input type="hidden" name="email-search-details" value="" />
<input type="hidden" name="email-search-details-hash" value="0e42663a6c3bd85498fcb88798998fed7bfdc45d457db35281e41afe13cc0524" />
</form>
</div>
</div>
<div id="collections-action-panel"
class="collections-action-panel action-panel in-progress-dots-panel"
aria-hidden="true"
data-collections-open-panel-enabled="false"
data-collections-open-panel-url-hash="#open-collections-panel">
<div class="inner-wrap">
<h3 class="action-panel-heading">
Add to Collections
</h3>
<form id="collections-action-panel-form"
class="collections-action-panel-form action-panel-content action-form action-panel-smaller-selectors"
data-existing-collections-url="/list-existing-collections/"
data-add-to-existing-collection-url="/add-to-existing-collection/"
data-create-and-add-to-new-collection-url="/create-and-add-to-new-collection/"
data-get-article-ids-by-search-url="/get-article-ids-by-search/"
data-myncbi-max-collection-name-length="100"
data-add-to-collection-max-amount="1000"
data-collections-root-url="https://www.ncbi.nlm.nih.gov/myncbi/collections/">
<input type="hidden" name="csrfmiddlewaretoken" value="iKFXxK9oBIS4OTjWHvgbSUzLjbLhe16xzxp2aACKbjFyIkpMkOTdm25pRftt7CER">
<div class="choice-group" role="radiogroup">
<ul class="radio-group-items">
<li>
<input type="radio"
id="collections-action-panel-new"
class="collections-new"
name="collections"
value="new"
data-ga-category="save_share"
data-ga-action="collections"
data-ga-label="collections_radio_new">
<label for="collections-action-panel-new">Create a new collection</label>
</li>
<li>
<input type="radio"
id="collections-action-panel-existing"
class="collections-existing"
name="collections"
value="existing"
checked="true"
data-ga-category="save_share"
data-ga-action="collections"
data-ga-label="collections_radio_existing">
<label for="collections-action-panel-existing">Add to an existing collection</label>
</li>
</ul>
</div>
<div class="controls-wrapper">
<div class="action-panel-control-wrap new-collections-controls">
<label for="collections-action-panel-add-to-new" class="action-panel-label required-field-asterisk">
Name your collection:
</label>
<input
type="text"
name="add-to-new-collection"
id="collections-action-panel-add-to-new"
class="collections-action-add-to-new"
pattern="[^&quot;&amp;=&lt;&gt;\/]*" title="The following characters are not allowed in the Name field: &quot;&amp;=&lt;&gt;/"
maxlength="100"
data-ga-category="save_share"
data-ga-action="create_collection"
data-ga-label="non_favorties_collection">
<div class="collections-new-name-too-long usa-input-error-message selection-validation-message">
Name must be less than 100 characters
</div>
</div>
<div class="action-panel-control-wrap existing-collections-controls">
<label for="collections-action-panel-add-to-existing" class="action-panel-label">
Choose a collection:
</label>
<select id="collections-action-panel-add-to-existing"
class="action-panel-selector collections-action-add-to-existing"
data-ga-category="save_share"
data-ga-action="select_collection"
data-ga-label="($('#collections-action-add-to-existing').val() === 'Favorites') ? 'Favorites' : 'non_favorites_collection'">
</select>
<div class="collections-retry-load-on-error usa-input-error-message selection-validation-message">
Unable to load your collection due to an error<br>
<a href="#">Please try again</a>
</div>
</div>
</div>
<div class="action-panel-actions">
<button class="action-panel-submit"
type="submit"
data-loading-label="Adding..."
data-pinger-ignore
data-ga-category="save_share"
data-ga-action="collections"
data-ga-label="add">
Add
</button>
<button class="action-panel-cancel"
aria-label="Close 'Add to Collections' panel"
ref="linksrc=close_collections_panel"
aria-controls="collections-action-panel"
aria-expanded="false"
data-ga-category="save_share"
data-ga-action="collections"
data-ga-label="cancel">
Cancel
</button>
</div>
</form>
</div>
</div>
<div id="bibliography-action-panel"
class="bibliography-action-panel action-panel in-progress-dots-panel"
aria-hidden="true"
data-bibliography-open-panel-enabled="false"
data-bibliography-open-panel-url-hash="#open-bibliography-panel">
<div class="inner-wrap">
<h3 class="action-panel-heading">
Add to My Bibliography
</h3>
<form id="bibliography-action-panel-form"
class="bibliography-action-panel-form action-panel-content action-form action-panel-smaller-selectors"
data-add-to-bibliography-max-amount="100"
data-add-to-bibliography-batch-size="10"
data-bibliography-delegates-url="/list-bibliography-delegates/"
data-add-to-bibliography-url="/add-to-bibliography/"
data-get-article-ids-by-search-url="/get-article-ids-by-search/"
data-mybib-root-url="https://www.ncbi.nlm.nih.gov/myncbi/collections/mybibliography/">
<input type="hidden" name="csrfmiddlewaretoken" value="iKFXxK9oBIS4OTjWHvgbSUzLjbLhe16xzxp2aACKbjFyIkpMkOTdm25pRftt7CER">
<div class="action-panel-control-wrap bibliographies-controls">
<div class="choice-group">
<ul class="bibliographies-action-add radio-group-items">
<li>
<input name="bibliography" id="my-bibliography" class="my-bibliography" type="radio" checked/>
<label for="my-bibliography">My Bibliography</label>
</li>
</ul>
</div>
</div>
<div class="bibliographies-retry-load-on-error usa-input-error-message selection-validation-message">
Unable to load your delegates due to an error<br>
<a href="#">Please try again</a>
</div>
<div class="action-panel-actions">
<button class="action-panel-submit"
type="submit"
data-loading-label="Adding..."
data-pinger-ignore>
Add
</button>
<button class="action-panel-cancel"
aria-label="Close 'Add to bibliography' panel"
ref="linksrc=close_bibliography_panel"
aria-controls="bibliography-action-panel"
aria-expanded="false"
data-ga-category="save_share"
data-ga-action="mybib"
data-ga-label="cancel">
Cancel
</button>
</div>
</form>
</div>
</div>
<div id="saved-search-action-panel" class="saved-search-action-panel action-panel " aria-hidden="true"
data-saved-search-open-panel-enabled="false"
data-saved-search-open-panel-url-hash="#open-saved-search-panel">
<div class="inner-wrap">
<h2 class="action-panel-heading">
Your saved search
</h2>
<form id="saved-search-action-panel-form"
class="saved-search-action-panel-form action-panel-content action-form"
data-create-saved-search-url="/create-saved-search/"
data-try-search-terms-url="/try-search-term/"
data-saved-search-root-url="https://www.ncbi.nlm.nih.gov/myncbi/searches/">
<input type="hidden" name="csrfmiddlewaretoken" value="iKFXxK9oBIS4OTjWHvgbSUzLjbLhe16xzxp2aACKbjFyIkpMkOTdm25pRftt7CER">
<div class="action-panel-control-wrap">
<label for="saved-search-name" class="action-panel-label saved-search-name-label required-field-asterisk">
Name of saved search:
</label>
<input maxlength="200"
type="text"
name="saved-search-name"
id="saved-search-name"
class="saved-search-name"
value=""
required
pattern="[^&quot;&amp;=&lt;&gt;\/]*" title="The following characters are not allowed in the Name field: &quot;&amp;=&lt;&gt;/">
</div>
<div class="action-panel-control-wrap">
<label for="saved-search-term" class="action-panel-label required-field-asterisk">
Search terms:
</label>
<textarea name="saved-search-term" id="saved-search-term" class="saved-search-term" required></textarea>
</div>
<div class="test-search-term-wrap">
<a href="#" class="try-search-term">Test search terms</a>
</div>
<div class="choice-group action-panel-extra-margin-top">
<span class="action-panel-label" id="fieldset-label">
Would you like email updates of new search results?
</span>
<fieldset id="saved-search-alert" aria-describedby="fieldset-label">
<legend class="usa-sr-only">Saved Search Alert Radio Buttons</legend>
<ul class="radio-group-items">
<li>
<input type="radio" id="saved-search-alert-yes" class="saved-search-alert-yes" name="saved-search-alert" value="yes" checked>
<label for="saved-search-alert-yes" class="action-panel-label">Yes</label>
</li>
<li>
<input aria-label="No radio input" type="radio" id="saved-search-alert-no" class="saved-search-alert-no" name="saved-search-alert" value="no">
<label for="saved-search-alert-no" class="action-panel-label">No</label>
</li>
</ul>
</fieldset>
</div>
<div class="alert-schedule-wrap">
<div class="action-panel-control-wrap">
<label class="action-panel-label">
Email:
</label>
<span aria-label="Email address" id="saved-search-email" class="action-panel-label"><span class="action-panel-label-bold"></span> (<a class="myncbi-account-settings" href="https://www.ncbi.nlm.nih.gov/account/settings/">change</a>)</span>
</div>
<div class="action-panel-control-wrap action-panel-extra-margin-top">
<label for="saved-search-frequency" class="action-panel-label">
Frequency:
</label>
<select id="saved-search-frequency" class="no-border-panel-selector saved-search-frequency">
<option value="monthly">Monthly</option>
<option value="weekly">Weekly</option>
<option value="daily">Daily</option>
</select>
</div>
<div class="action-panel-control-wrap saved-search-monthly-additional">
<label for="saved-search-monthly-on-day" class="action-panel-label">
Which day?
</label>
<select id="saved-search-monthly-on-day" class="no-border-panel-selector">
<option value="Sunday">The first Sunday</option>
<option value="Monday">The first Monday</option>
<option value="Tuesday">The first Tuesday</option>
<option value="Wednesday">The first Wednesday</option>
<option value="Thursday">The first Thursday</option>
<option value="Friday">The first Friday</option>
<option value="Saturday">The first Saturday</option>
<option value="day">The first day</option>
<option value="weekday">The first weekday</option>
</select>
</div>
<div class="action-panel-control-wrap saved-search-weekly-additional">
<label for="saved-search-weekly-on-day" class="action-panel-label">
Which day?
</label>
<select id="saved-search-weekly-on-day" class="no-border-panel-selector saved-search-weekly-on-day">
<option value="Sunday">Sunday</option>
<option value="Monday">Monday</option>
<option value="Tuesday">Tuesday</option>
<option value="Wednesday">Wednesday</option>
<option value="Thursday">Thursday</option>
<option value="Friday">Friday</option>
<option value="Saturday">Saturday</option>
</select>
</div>
<div class="action-panel-control-wrap">
<label for="saved-search-report" class="action-panel-label">
Report format:
</label>
<select id="saved-search-report" class="no-border-panel-selector saved-search-report">
<option value="DocSum">Summary</option>
<option value="DocSumText">Summary (text)</option>
<option value="Abstract">Abstract</option>
<option value="AbstractText">Abstract (text)</option>
<option value="MEDLINE">PubMed</option>
</select>
</div>
<div class="action-panel-control-wrap">
<label for="saved-search-amount" class="action-panel-label">
Send at most:
</label>
<select id="saved-search-amount" class="no-border-panel-selector saved-search-amount">
<option value="1">1 item</option>
<option value="5" selected>5 items</option>
<option value="10">10 items</option>
<option value="20">20 items</option>
<option value="50">50 items</option>
<option value="100">100 items</option>
<option value="200">200 items</option>
</select>
</div>
<div>
<input type="checkbox" id="saved-search-send-if-no-result" class="saved-search-send-if-no-result" name="saved-search-send-if-no-result">
<label for="saved-search-send-if-no-result" class="action-panel-label smaller-checkbox">
Send even when there aren't any new results
</label>
</div>
<div class="action-panel-control-wrap option-text-in-email-wrap">
<label for="saved-search-email-text" class="action-panel-label">
Optional text in email:
</label>
<textarea name="saved-search-email-text"
id="saved-search-email-text"
class="saved-search-email-text"></textarea>
</div>
</div>
<div class="action-panel-actions">
<button class="action-panel-submit"
type="submit"
data-loading-label="Saving..."
data-ga-category="save_share"
data-ga-action="alert"
data-ga-label="save">
Save
</button>
<button class="action-panel-cancel"
aria-label="Close 'Your saved search' panel"
ref="linksrc=close_saved_search_panel"
aria-controls="saved-search-action-panel"
aria-expanded="false"
data-ga-category="save_share"
data-ga-action="alert"
data-ga-label="cancel">
Cancel
</button>
</div>
</form>
</div>
</div>
<div id="citation-manager-action-panel" class="citation-manager-action-panel action-panel" aria-hidden="true">
<div class="inner-wrap">
<h2 class="action-panel-heading">
Create a file for external citation management software
</h2>
<form id="citation-manager-action-panel-form"
class="action-panel-content action-form"
action="/results-export-ids/"
data-by-search-action="/results-export-search-data/"
data-by-ids-action="/results-export-ids/"
method="post"
data-by-search-method="post"
data-by-ids-method="post">
<input type="hidden" name="csrfmiddlewaretoken" value="iKFXxK9oBIS4OTjWHvgbSUzLjbLhe16xzxp2aACKbjFyIkpMkOTdm25pRftt7CER">
<input name="results-format" type="hidden" value="pubmed"/>
<div class="action-panel-actions">
<button class="action-panel-submit"
type="submit"
data-loading-label="Sending..."
data-ga-category="save_share"
data-ga-action="citation_manager"
data-ga-label="save">
Create file
</button>
<button class="action-panel-cancel"
aria-label="Close 'Send citations to citation manager' panel"
ref="linksrc=close_citation_manager_panel"
aria-controls="citation-manager-action-panel"
aria-expanded="false"
data-ga-category="save_share"
data-ga-action="citation_manager"
data-ga-label="cancel">
Cancel
</button>
</div>
</form>
</div>
</div>
<div id="rss-action-panel" class="rss-action-panel action-panel " aria-hidden="true">
<div class="inner-wrap">
<h2 class="action-panel-heading">
Your RSS Feed
</h2>
<form id="rss-action-panel-form"
class="rss-action-panel-form action-panel-content action-form"
data-create-rss-feed-url="/create-rss-feed-url/"
data-search-form-term-value="">
<input type="hidden" name="csrfmiddlewaretoken" value="iKFXxK9oBIS4OTjWHvgbSUzLjbLhe16xzxp2aACKbjFyIkpMkOTdm25pRftt7CER">
<div class="action-panel-control-wrap">
<label for="rss-name" class="action-panel-label required-field-asterisk">
Name of RSS Feed:
</label>
<input maxlength="200"
placeholder="Name"
type="text"
name="rss-name"
id="rss-name"
class="rss-name"
value=''
required
pattern="[^&quot;&amp;=&lt;&gt;\/]*" title="The following characters are not allowed in the Name field: &quot;&amp;=&lt;&gt;/">
</div>
<div class="rss-limit-wrap">
<div class="action-panel-control-wrap action-panel-extra-margin-top">
<label for="rss-limit" class="action-panel-label">
Number of items displayed:
</label>
<select id="rss-limit" class="no-border-panel-selector rss-limit">
<option value="5">5</option>
<option value="10">10</option>
<option value="15" selected="selected">15</option>
<option value="20">20</option>
<option value="50">50</option>
<option value="100">100</option>
</select>
</div>
</div>
<div class="action-panel-actions">
<button class="action-panel-submit"
type="submit"
data-loading-label="Creating..."
data-ga-category="save_share"
data-ga-action="alert"
data-ga-label="save">
Create RSS
</button>
<button class="action-panel-cancel"
aria-label="Close 'Your RSS' panel"
ref="linksrc=close_rss_panel"
aria-controls="rss-action-panel"
aria-expanded="false"
data-ga-category="save_share"
data-ga-action="alert"
data-ga-label="cancel">
Cancel
</button>
</div>
<div class="action-panel-control-wrap rss-link-copy-wrap">
<label for="rss-link" class="usa-sr-only">RSS Link</label>
<input placeholder="Your RSS Feed Link" type="text" name="rss-link" id="rss-link" class="rss-link" title="RSS Link">
<button
type="button"
disabled
class="rss-link-copy-button disabled"
data-ga-category="save_share"
data-ga-action="rss"
data-ga-label="copy">
Copy
</button>
</div>
</form>
</div>
</div>
</div>
</div>
<div class="article-page" id="article-page" data-article-pmid="26656846">
<aside class="page-sidebar">
<div class="inner-wrap">
<div class="full-text-links">
<div class="full-view">
<h3 class="title">
Full text links
</h3>
<div class="full-text-links-list">
<a class="link-item
dialog-focus"
href="https://doi.org/10.1038/ng.3469"
target="_blank"
rel="noopener"
ref="linksrc=fulltextorjournal_fulltext&amp;is_pmc=False&amp;PrId=3094&amp;itool=Abstract-def&amp;log$=linkouticon&amp;uid=26656846&amp;db=pubmed&amp;nlmid=9216904"
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Nature Publishing Group
</span></a><a class="link-item
pmc
"
href="https://pmc.ncbi.nlm.nih.gov/articles/pmid/26656846/"
target="_blank"
rel="noopener"
ref="linksrc=fulltextorjournal_fulltext&amp;is_pmc=True&amp;PrId=3494&amp;itool=Abstract-def&amp;log$=linkouticon&amp;uid=26656846&amp;db=pubmed&amp;nlmid=9216904"
title="Free full text at PubMed Central"
data-ga-category="full_text"
data-ga-action="PMC"
data-ga-label="26656846"
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Free PMC article
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</div>
<div class="short-view">
<a href="#" class="full-text-links-button full-text-links-dialog-trigger">
Full text links
</a>
</div>
</div>
<div class="actions-buttons sidebar"><h3 class="title">Actions</h3><div class="inner-wrap"><button class="citation-button citation-dialog-trigger"
aria-label="Open dialog with citation text in different styles"
data-ga-category="save_share"
data-ga-action="cite"
data-ga-label="open"
data-all-citations-url="/26656846/citations/"
data-citation-style="nlm"
data-pubmed-format-link="/26656846/export/"><span class="button-label">Cite</span></button><link type="text/css" href="ncbi-overlay-block/src/overlay-block.css"><div class="collections-button-container" data-article-id="26656846" data-article-db="pubmed"><button class="collections-button collections-dialog-trigger"
aria-label="Save article in MyNCBI collections."
data-ga-category="collections_button"
data-ga-action="click"
data-ga-label="collections_button"
data-collections-open-dialog-enabled="false"
data-collections-open-dialog-url="https://account.ncbi.nlm.nih.gov/?back_url=https%3A%2F%2Fpubmed.ncbi.nlm.nih.gov%2F26656846%2F%23open-collections-dialog"
data-in-collections="false"><span class="button-label">Collections</span></button><div class="overlay" role="dialog"><div id="collections-action-dialog"
class="dialog collections-dialog"
aria-hidden="true"><div class="title">Add to Collections</div><div class="collections-action-panel action-panel"><form id="collections-action-dialog-form"
class="collections-action-panel-form action-panel-content action-form action-panel-smaller-selectors"
data-existing-collections-url="/list-existing-collections/"
data-add-to-existing-collection-url="/add-to-existing-collection/"
data-create-and-add-to-new-collection-url="/create-and-add-to-new-collection/"
data-myncbi-max-collection-name-length="100"
data-collections-root-url="https://www.ncbi.nlm.nih.gov/myncbi/collections/"><input type="hidden" name="csrfmiddlewaretoken" value="iKFXxK9oBIS4OTjWHvgbSUzLjbLhe16xzxp2aACKbjFyIkpMkOTdm25pRftt7CER"><div class="choice-group" role="radiogroup"><ul class="radio-group-items"><li><input type="radio"
id="collections-action-dialog-new"
class="collections-new"
name="collections"
value="new"
data-ga-category="collections_button"
data-ga-action="click"
data-ga-label="collections_radio_new"><label for="collections-action-dialog-new">Create a new collection</label></li><li><input type="radio"
id="collections-action-dialog-existing"
class="collections-existing"
name="collections"
value="existing"
checked="true"
data-ga-category="collections_button"
data-ga-action="click"
data-ga-label="collections_radio_existing"><label for="collections-action-dialog-existing">Add to an existing collection</label></li></ul></div><div class="controls-wrapper"><div class="action-panel-control-wrap new-collections-controls"><label for="collections-action-dialog-add-to-new" class="action-panel-label required-field-asterisk">
Name your collection:
</label><input
type="text"
name="add-to-new-collection"
id="collections-action-dialog-add-to-new"
class="collections-action-add-to-new"
pattern="[^&quot;&amp;=&lt;&gt;\/]*" title="The following characters are not allowed in the Name field: &quot;&amp;=&lt;&gt;/"
maxlength="100"
data-ga-category="collections_button"
data-ga-action="create_collection"
data-ga-label="non_favorties_collection"><div class="collections-new-name-too-long usa-input-error-message selection-validation-message">
Name must be less than 100 characters
</div></div><div class="action-panel-control-wrap existing-collections-controls"><label for="collections-action-dialog-add-to-existing" class="action-panel-label">
Choose a collection:
</label><select id="collections-action-dialog-add-to-existing"
class="action-panel-selector collections-action-add-to-existing"
data-ga-category="collections_button"
data-ga-action="select_collection"
data-ga-label="($('.collections-action-add-to-existing').val() === 'Favorites') ? 'Favorites' : 'non_favorites_collection'"></select><div class="collections-retry-load-on-error usa-input-error-message selection-validation-message">
Unable to load your collection due to an error<br><a href="#">Please try again</a></div></div></div><div class="action-panel-actions"><button class="action-panel-submit"
type="submit"
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<h1 class="heading-title">
Timing, rates and spectra of human germline mutation
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data-ga-label="Houfeng Zheng">Houfeng Zheng</a><span class="comma">,&nbsp;</span></span><span class="authors-list-item "><a class="full-name"
href="/?term=Palotie+A"
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data-ga-label="Aarno Palotie">Aarno Palotie</a><span class="comma">,&nbsp;</span></span><span class="authors-list-item "><a class="full-name"
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data-ga-label="Michael Owen">Michael Owen</a><span class="comma">,&nbsp;</span></span><span class="authors-list-item "><a class="full-name"
href="/?term=Barrett+J"
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data-ga-label="Jeff Barrett">Jeff Barrett</a><span class="comma">,&nbsp;</span></span><span class="authors-list-item "><a class="full-name"
href="/?term=Rehnstr%C3%B6m+K"
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href="/?term=Ayub+M"
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data-ga-label="Mohammad Ayub">Mohammad Ayub</a><span class="comma">,&nbsp;</span></span><span class="authors-list-item "><a class="full-name"
href="/?term=Blackwood+D"
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data-ga-label="Douglas Blackwood">Douglas Blackwood</a><span class="comma">,&nbsp;</span></span><span class="authors-list-item "><a class="full-name"
href="/?term=Bolton+P"
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data-ga-label="Patrick Bolton">Patrick Bolton</a><span class="comma">,&nbsp;</span></span><span class="authors-list-item "><a class="full-name"
href="/?term=Breen+G"
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data-ga-label="Gerome Breen">Gerome Breen</a><span class="comma">,&nbsp;</span></span><span class="authors-list-item "><a class="full-name"
href="/?term=Collier+D"
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data-ga-label="David Collier">David Collier</a><span class="comma">,&nbsp;</span></span><span class="authors-list-item "><a class="full-name"
href="/?term=Craddock+N"
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data-ga-label="Nick Craddock">Nick Craddock</a><span class="comma">,&nbsp;</span></span><span class="authors-list-item "><a class="full-name"
href="/?term=Crooks+L"
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data-ga-label="Lucy Crooks">Lucy Crooks</a><span class="comma">,&nbsp;</span></span><span class="authors-list-item "><a class="full-name"
href="/?term=Curran+S"
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data-ga-label="Sarah Curran">Sarah Curran</a><span class="comma">,&nbsp;</span></span><span class="authors-list-item "><a class="full-name"
href="/?term=Gallagher+L"
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data-ga-label="Louise Gallagher">Louise Gallagher</a><span class="comma">,&nbsp;</span></span><span class="authors-list-item "><a class="full-name"
href="/?term=Geschwind+D"
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data-ga-label="Daniel Geschwind">Daniel Geschwind</a><span class="comma">,&nbsp;</span></span><span class="authors-list-item "><a class="full-name"
href="/?term=Gurling+H"
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data-ga-label="Hugh Gurling">Hugh Gurling</a><span class="comma">,&nbsp;</span></span><span class="authors-list-item "><a class="full-name"
href="/?term=Holmans+P"
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data-ga-label="Peter Holmans">Peter Holmans</a><span class="comma">,&nbsp;</span></span><span class="authors-list-item "><a class="full-name"
href="/?term=Kilpinen+H"
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data-ga-label="Helena Kilpinen">Helena Kilpinen</a><span class="comma">,&nbsp;</span></span><span class="authors-list-item "><a class="full-name"
href="/?term=Kolder+I"
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data-ga-label="Iris Kolder">Iris Kolder</a><span class="comma">,&nbsp;</span></span><span class="authors-list-item "><a class="full-name"
href="/?term=Lee+I"
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data-ga-label="Irene Lee">Irene Lee</a><span class="comma">,&nbsp;</span></span><span class="authors-list-item "><a class="full-name"
href="/?term=L%C3%B6nnqvist+J"
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href="/?term=McCarthy+S"
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data-ga-label="Shane McCarthy">Shane McCarthy</a><span class="comma">,&nbsp;</span></span><span class="authors-list-item "><a class="full-name"
href="/?term=McGuffin+P"
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data-ga-label="Peter McGuffin">Peter McGuffin</a><span class="comma">,&nbsp;</span></span><span class="authors-list-item "><a class="full-name"
href="/?term=McIntosh+A"
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data-ga-label="Andrew McIntosh">Andrew McIntosh</a><span class="comma">,&nbsp;</span></span><span class="authors-list-item "><a class="full-name"
href="/?term=McQuillin+A"
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data-ga-label="Andrew McQuillin">Andrew McQuillin</a><span class="comma">,&nbsp;</span></span><span class="authors-list-item "><a class="full-name"
href="/?term=Muddyman+D"
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data-ga-label="Dawn Muddyman">Dawn Muddyman</a><span class="comma">,&nbsp;</span></span><span class="authors-list-item "><a class="full-name"
href="/?term=O%27Donovan+M"
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data-ga-label="Michael O&#x27;Donovan">Michael O&#x27;Donovan</a><span class="comma">,&nbsp;</span></span><span class="authors-list-item "><a class="full-name"
href="/?term=Parr+J"
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data-ga-label="Jeremy Parr">Jeremy Parr</a><span class="comma">,&nbsp;</span></span><span class="authors-list-item "><a class="full-name"
href="/?term=Paunio+T"
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data-ga-label="Tiina Paunio">Tiina Paunio</a><span class="comma">,&nbsp;</span></span><span class="authors-list-item "><a class="full-name"
href="/?term=Pietilainen+O"
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data-ga-label="Olli Pietilainen">Olli Pietilainen</a><span class="comma">,&nbsp;</span></span><span class="authors-list-item "><a class="full-name"
href="/?term=Skuse+D"
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data-ga-label="David Skuse">David Skuse</a><span class="comma">,&nbsp;</span></span><span class="authors-list-item "><a class="full-name"
href="/?term=Clair+DS"
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data-ga-label="David St Clair">David St Clair</a><span class="comma">,&nbsp;</span></span><span class="authors-list-item "><a class="full-name"
href="/?term=Stalker+J"
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data-ga-label="Jim Stalker">Jim Stalker</a><span class="comma">,&nbsp;</span></span><span class="authors-list-item "><a class="full-name"
href="/?term=Suvisaari+J"
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data-ga-label="Jaana Suvisaari">Jaana Suvisaari</a><span class="comma">,&nbsp;</span></span><span class="authors-list-item "><a class="full-name"
href="/?term=Walter+K"
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data-ga-label="Klaudia Walter">Klaudia Walter</a><span class="comma">,&nbsp;</span></span><span class="authors-list-item "><a class="full-name"
href="/?term=Williams+H"
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data-ga-label="Hywel Williams">Hywel Williams</a><span class="comma">,&nbsp;</span></span><span class="authors-list-item "><a class="full-name"
href="/?term=Hurles+M"
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data-ga-label="Matt Hurles">Matt Hurles</a><span class="comma">,&nbsp;</span></span><span class="authors-list-item "><a class="full-name"
href="/?term=Fitzpatrick+D"
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data-ga-label="David Fitzpatrick">David Fitzpatrick</a><span class="comma">,&nbsp;</span></span><span class="authors-list-item "><a class="full-name"
href="/?term=Al-Turki+S"
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data-ga-label="Saeed Al-Turki">Saeed Al-Turki</a><span class="comma">,&nbsp;</span></span><span class="authors-list-item "><a class="full-name"
href="/?term=Anderson+C"
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data-ga-label="Carl Anderson">Carl Anderson</a><span class="comma">,&nbsp;</span></span><span class="authors-list-item "><a class="full-name"
href="/?term=Barroso+I"
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data-ga-label="Inês Barroso">Inês Barroso</a><span class="comma">,&nbsp;</span></span><span class="authors-list-item "><a class="full-name"
href="/?term=Beales+P"
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data-ga-label="Phil Beales">Phil Beales</a><span class="comma">,&nbsp;</span></span><span class="authors-list-item "><a class="full-name"
href="/?term=Bentham+J"
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data-ga-label="James Morris">James Morris</a><span class="comma">,&nbsp;</span></span><span class="authors-list-item "><a class="full-name"
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data-ga-label="So-Youn Shin">So-Youn Shin</a><span class="comma">,&nbsp;</span></span><span class="authors-list-item "><a class="full-name"
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data-ga-label="Nic Timpson">Nic Timpson</a><span class="comma">,&nbsp;</span></span><span class="authors-list-item "><a class="full-name"
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data-ga-label="Jane Kaye">Jane Kaye</a><span class="comma">,&nbsp;</span></span><span class="authors-list-item "><a class="full-name"
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href="/?term=Bobrow+M"
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href="/?term=Bolton+P"
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href="/?term=Fitzpatrick+D"
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data-ga-label="David Fitzpatrick">David Fitzpatrick</a><span class="comma">,&nbsp;</span></span><span class="authors-list-item "><a class="full-name"
href="/?term=Jewell+D"
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href="/?term=Kennedy+K"
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data-ga-label="Karen Kennedy">Karen Kennedy</a><span class="comma">,&nbsp;</span></span><span class="authors-list-item "><a class="full-name"
href="/?term=Kent+A"
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Timing, rates and spectra of human germline mutation
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<span class="authors-list-item "><span class="full-name">Raheleh Rahbari</span><span class="citation-separator">&nbsp;et al.</span></span>
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</a><span class="author-sup-separator">&nbsp;</span><a class="affiliation-link" title="Department of Human Genetics and Department of Bioinformatics and Computational Biology, Genentech Inc, 1 DNA Way, CA 94080 South San Francisco, USA." href="#short-view-affiliation-2" ref="linksrc=author_aff">
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</a></sup><span class="comma">,&nbsp;</span></span><span class="authors-list-item "><a class="full-name"
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data-ga-label="Martin Tobin">Martin Tobin</a><span class="comma">,&nbsp;</span></span><span class="authors-list-item "><a class="full-name"
href="/?term=Wain+L"
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data-ga-label="Louise Wain">Louise Wain</a><span class="comma">,&nbsp;</span></span><span class="authors-list-item "><a class="full-name"
href="/?term=Walter+K"
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href="/?term=Wang+J"
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data-ga-label="Jun Wang">Jun Wang</a><span class="comma">,&nbsp;</span></span><span class="authors-list-item "><a class="full-name"
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href="/?term=Wilson+S"
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data-ga-label="Scott Wilson">Scott Wilson</a><span class="comma">,&nbsp;</span></span><span class="authors-list-item "><a class="full-name"
href="/?term=Wong+K"
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data-ga-label="Kim Wong">Kim Wong</a><span class="comma">,&nbsp;</span></span><span class="authors-list-item "><a class="full-name"
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href="/?term=Zheng+H"
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data-ga-label="Houfeng Zheng">Houfeng Zheng</a><span class="comma">,&nbsp;</span></span><span class="authors-list-item "><a class="full-name"
href="/?term=Palotie+A"
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data-ga-label="Aarno Palotie">Aarno Palotie</a><span class="comma">,&nbsp;</span></span><span class="authors-list-item "><a class="full-name"
href="/?term=Owen+M"
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href="/?term=Barrett+J"
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href="/?term=Rehnstr%C3%B6m+K"
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href="/?term=Ayub+M"
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data-ga-label="Mohammad Ayub">Mohammad Ayub</a><span class="comma">,&nbsp;</span></span><span class="authors-list-item "><a class="full-name"
href="/?term=Blackwood+D"
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data-ga-label="Douglas Blackwood">Douglas Blackwood</a><span class="comma">,&nbsp;</span></span><span class="authors-list-item "><a class="full-name"
href="/?term=Bolton+P"
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data-ga-label="Patrick Bolton">Patrick Bolton</a><span class="comma">,&nbsp;</span></span><span class="authors-list-item "><a class="full-name"
href="/?term=Breen+G"
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data-ga-label="Gerome Breen">Gerome Breen</a><span class="comma">,&nbsp;</span></span><span class="authors-list-item "><a class="full-name"
href="/?term=Collier+D"
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data-ga-label="David Collier">David Collier</a><span class="comma">,&nbsp;</span></span><span class="authors-list-item "><a class="full-name"
href="/?term=Craddock+N"
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data-ga-label="Nick Craddock">Nick Craddock</a><span class="comma">,&nbsp;</span></span><span class="authors-list-item "><a class="full-name"
href="/?term=Crooks+L"
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data-ga-label="Lucy Crooks">Lucy Crooks</a><span class="comma">,&nbsp;</span></span><span class="authors-list-item "><a class="full-name"
href="/?term=Curran+S"
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data-ga-label="Sarah Curran">Sarah Curran</a><span class="comma">,&nbsp;</span></span><span class="authors-list-item "><a class="full-name"
href="/?term=Gallagher+L"
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data-ga-label="Louise Gallagher">Louise Gallagher</a><span class="comma">,&nbsp;</span></span><span class="authors-list-item "><a class="full-name"
href="/?term=Geschwind+D"
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data-ga-label="Daniel Geschwind">Daniel Geschwind</a><span class="comma">,&nbsp;</span></span><span class="authors-list-item "><a class="full-name"
href="/?term=Gurling+H"
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data-ga-label="Hugh Gurling">Hugh Gurling</a><span class="comma">,&nbsp;</span></span><span class="authors-list-item "><a class="full-name"
href="/?term=Holmans+P"
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data-ga-label="Peter Holmans">Peter Holmans</a><span class="comma">,&nbsp;</span></span><span class="authors-list-item "><a class="full-name"
href="/?term=Kilpinen+H"
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data-ga-label="Helena Kilpinen">Helena Kilpinen</a><span class="comma">,&nbsp;</span></span><span class="authors-list-item "><a class="full-name"
href="/?term=Kolder+I"
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data-ga-label="Iris Kolder">Iris Kolder</a><span class="comma">,&nbsp;</span></span><span class="authors-list-item "><a class="full-name"
href="/?term=Lee+I"
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data-ga-label="Irene Lee">Irene Lee</a><span class="comma">,&nbsp;</span></span><span class="authors-list-item "><a class="full-name"
href="/?term=L%C3%B6nnqvist+J"
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data-ga-label="Jouko Lönnqvist">Jouko Lönnqvist</a><span class="comma">,&nbsp;</span></span><span class="authors-list-item "><a class="full-name"
href="/?term=McCarthy+S"
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data-ga-label="Shane McCarthy">Shane McCarthy</a><span class="comma">,&nbsp;</span></span><span class="authors-list-item "><a class="full-name"
href="/?term=McGuffin+P"
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data-ga-label="Peter McGuffin">Peter McGuffin</a><span class="comma">,&nbsp;</span></span><span class="authors-list-item "><a class="full-name"
href="/?term=McIntosh+A"
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data-ga-label="Andrew McIntosh">Andrew McIntosh</a><span class="comma">,&nbsp;</span></span><span class="authors-list-item "><a class="full-name"
href="/?term=McQuillin+A"
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data-ga-label="Sarah Metrustry">Sarah Metrustry</a><span class="comma">,&nbsp;</span></span><span class="authors-list-item "><a class="full-name"
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data-ga-label="James Morris">James Morris</a><span class="comma">,&nbsp;</span></span><span class="authors-list-item "><a class="full-name"
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href="/?term=Richards+B"
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><sup class="key">1</sup> Wellcome Trust Sanger Institute, Hinxton, Cambridge, United Kingdom.</li>
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><sup class="key">2</sup> Department of Human Genetics and Department of Bioinformatics and Computational Biology, Genentech Inc, 1 DNA Way, CA 94080 South San Francisco, USA.</li>
<li data-affiliation-id="short-view-affiliation-3"
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><sup class="key">3</sup> Institute of Cardiovascular and Medical Sciences, College of Medical, Veterinary and Life Sciences, University of Glasgow, Glasgow, United Kingdom.</li>
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><sup class="key">4</sup> Medical Research Institute, University of Dundee, Dundee, United Kingdom.</li>
<li data-affiliation-id="short-view-affiliation-5"
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><sup class="key">5</sup> Institute of Genetics and Molecular Medicine, University of Edinburgh, Edinburgh, Scotland, United Kingdom.</li>
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<div class="equal-contrib-explanation" id="short-view-equal-contrib-explanation"><sup class="key">#</sup> Contributed equally.</div>
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<p>
Germline mutations are a driving force behind genome evolution and genetic disease. We investigated genome-wide mutation rates and spectra in multi-sibling families. The mutation rate increased with paternal age in all families, but the number of additional mutations per year differed by more than twofold between families. Meta-analysis of 6,570 mutations showed that germline methylation influences mutation rates. In contrast to somatic mutations, we found remarkable consistency in germline mutation spectra between the sexes and at different paternal ages. In parental germ line, 3.8% of mutations were mosaic, resulting in 1.3% of mutations being shared by siblings. The number of these shared mutations varied significantly between families. Our data suggest that the mutation rate per cell division is higher during both early embryogenesis and differentiation of primordial germ cells but is reduced substantially during post-pubertal spermatogenesis. These findings have important consequences for the recurrence risks of disorders caused by de novo mutations.
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id="article-image-0"
src="https://cdn.ncbi.nlm.nih.gov/pmc/blobs/2cef/4731925/549c2530b224/emss-66128-f0001.gif"
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<p> Figure 1. Pedigrees of sequenced families </p>
</strong>
<div class="figure-caption-contents"><p> Identifiers… </p></div>
</div>
</div>
<div class="figure-caption-medium figure-caption-text" aria-hidden="true">
<strong class="figure-label">
<p> Figure 1. Pedigrees of sequenced families </p>
</strong>
<div class="figure-caption-contents"><p> Identifiers and relationship between the individuals in the three… </p></div>
</div>
<figcaption id="figure-caption-0" class="figure-caption-full figure-caption-text" itemtype="http://schema.org/ImageObject" itemprop="description">
<strong class="figure-label">
Figure 1. Pedigrees of sequenced families
</strong>
<div class="figure-caption-contents">Identifiers and relationship between the individuals in the three families in this study. Individuals that were sequenced are symbolised by full circles and squares, other individuals by dotted circles and squares. Age of mother and father at the conception of each child and phasing information are summarised in the table. SFHS5165321 was only used for the part of the analysis related to mosaicism.</div>
</figcaption>
</figure>
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id="article-image-1"
src="https://cdn.ncbi.nlm.nih.gov/pmc/blobs/2cef/4731925/0fc739b61c05/emss-66128-f0002.gif"
alt="Figure 2" />
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<p> Figure 2. Paternal age vs. number of… </p>
</strong>
</div>
</div>
<div class="figure-caption-medium figure-caption-text" aria-hidden="true">
<strong class="figure-label">
<p> Figure 2. Paternal age vs. number of <i> de novo </i> mutations </p>
</strong>
<div class="figure-caption-contents"><p> The number of DNMs has… </p></div>
</div>
<figcaption id="figure-caption-1" class="figure-caption-full figure-caption-text" itemtype="http://schema.org/ImageObject" itemprop="description">
<strong class="figure-label">
Figure 2. Paternal age vs. number of <i>de novo</i> mutations
</strong>
<div class="figure-caption-contents">The number of DNMs has been corrected to take into account genomic regions inaccessible to our methods. Red: Family 244. Yellow: Family 569. Blue: Family 603. Gray areas denote the regions covered by the 95% confidence interval of the intercept and slope of the linear regression line for each separate family. We note that the confidence intervals for families 244 and 603 do not overlap for younger fathers.</div>
</figcaption>
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aria-describedby="figure-caption-2"
role="button"
data-image-width="800"
data-image-height="512"
data-image-alt="Figure 3"
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data-figure-id="F3">
<img class="figure-thumb" itemprop="thumbnail"
id="article-image-2"
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<strong class="figure-label">
<p> Figure 3. Detection of mutations mosaic in… </p>
</strong>
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<strong class="figure-label">
<p> Figure 3. Detection of mutations mosaic in parents </p>
</strong>
<div class="figure-caption-contents"><p> (A) Simulation of detection power for ranges… </p></div>
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Figure 3. Detection of mutations mosaic in parents
</strong>
<div class="figure-caption-contents">(A) Simulation of detection power for ranges of mosaicism levels in the parents blood using the Miseq depth of coverage for all the <i>de novo</i> mutations (n=768). For mean validation coverage (Miseq platform) of 567X in the parents, we have &gt;0.94 power to detect mosaicism of 2% and higher in the parents blood. (B) Comparison of parental Alt ratios between <i>de novo</i> mutations vs. germline mosaic sites. M is mosaic sites with significant excess of alt in the mothers blood, P is the sites with significant excess of alt in the fathers blood, S is corresponding to the sites that are shared between the siblings but we could not detect any excess of alt allele in the either of the parents blood. SM/SP refer to the mosaic sites that are shared between the siblings and we have detected significant excess of alt in the mothers blood (SM presented in pink dots) or fathers blood (SP shown in dark blue dot).</div>
</figcaption>
</figure>
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data-pmc-id="PMC4731925"
data-figure-id="F4">
<img class="figure-thumb" itemprop="thumbnail"
id="article-image-3"
src="https://cdn.ncbi.nlm.nih.gov/pmc/blobs/2cef/4731925/2d7332243d16/emss-66128-f0004.gif"
alt="Figure 4" />
</a>
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<strong class="figure-label">
<p> Figure 4. Mutational spectra </p>
</strong>
<div class="figure-caption-contents"><p> (A) Frequency of… </p></div>
</div>
</div>
<div class="figure-caption-medium figure-caption-text" aria-hidden="true">
<strong class="figure-label">
<p> Figure 4. Mutational spectra </p>
</strong>
<div class="figure-caption-contents"><p> (A) Frequency of all mutation types in the catalogue of 6,570… </p></div>
</div>
<figcaption id="figure-caption-3" class="figure-caption-full figure-caption-text" itemtype="http://schema.org/ImageObject" itemprop="description">
<strong class="figure-label">
Figure 4. Mutational spectra
</strong>
<div class="figure-caption-contents">(A) Frequency of all mutation types in the catalogue of 6,570 high confidence DNMs (B) Difference in the frequency of maternal and paternal mutations for the subset of DNMs with phasing information (n=556) (C) Difference in the frequency of mutations of children fathers younger and older than 30 years (n=680). Error bars represent 95% confidence intervals.</div>
</figcaption>
</figure>
<figure class="figure-item "
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itemprop="associatedMedia"
data-slide-index="4"
data-label-slug="figure-5">
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itemprop="contentUrl"
aria-describedby="figure-caption-4"
role="button"
data-image-width="800"
data-image-height="545"
data-image-alt="Figure 5"
data-pmc-id="PMC4731925"
data-figure-id="F5">
<img class="figure-thumb" itemprop="thumbnail"
id="article-image-4"
src="https://cdn.ncbi.nlm.nih.gov/pmc/blobs/2cef/4731925/c197138a5516/emss-66128-f0005.gif"
alt="Figure 5" />
</a>
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<div class="caption-wrap">
<strong class="figure-label">
<p> Figure 5. Mutational spectrum and signatures </p>
</strong>
<div class="figure-caption-contents"><p> (A)… </p></div>
</div>
</div>
<div class="figure-caption-medium figure-caption-text" aria-hidden="true">
<strong class="figure-label">
<p> Figure 5. Mutational spectrum and signatures </p>
</strong>
<div class="figure-caption-contents"><p> (A) High resolution mutational spectrum of <i> de novo </i> mutations.… </p></div>
</div>
<figcaption id="figure-caption-4" class="figure-caption-full figure-caption-text" itemtype="http://schema.org/ImageObject" itemprop="description">
<strong class="figure-label">
Figure 5. Mutational spectrum and signatures
</strong>
<div class="figure-caption-contents">(A) High resolution mutational spectrum of <i>de novo</i> mutations. Each of the six possible point mutations is subdivided into 16 subclasses based on the 3 and 5 nucleotide flanking the mutation. We note that C:G&gt;T:A and T:A&gt;C:G transitions are more common. Within those categories, CpG sites are particularly frequent (B) Correlation of mutational signatures with observed mutations in mutational catalogue, correlation of each of the 30 signatures, with signatures 1 and 5 highlighted in orange (C) Combination of all possible pairs of signatures, with the combination of signatures 1 and 5 shown with an arrow.</div>
</figcaption>
</figure>
<figure class="figure-item "
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data-label-slug="figure-6">
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itemprop="contentUrl"
aria-describedby="figure-caption-5"
role="button"
data-image-width="800"
data-image-height="334"
data-image-alt="Figure 6"
data-pmc-id="PMC4731925"
data-figure-id="F6">
<img class="figure-thumb" itemprop="thumbnail"
id="article-image-5"
src="https://cdn.ncbi.nlm.nih.gov/pmc/blobs/2cef/4731925/df60aa3e0e75/emss-66128-f0006.gif"
alt="Figure 6" />
</a>
<meta itemprop="width" itemtype="http://schema.org/ImageObject" content="800">
<meta itemprop="height" itemtype="http://schema.org/ImageObject" content="334">
<div class="figure-caption figure-caption-text" itemtype="http://schema.org/ImageObject" itemprop="caption" aria-hidden="true">
<div class="caption-wrap">
<strong class="figure-label">
<p> Figure 6. Mutation rate model during gametogenesis </p>
</strong>
</div>
</div>
<div class="figure-caption-medium figure-caption-text" aria-hidden="true">
<strong class="figure-label">
<p> Figure 6. Mutation rate model during gametogenesis </p>
</strong>
<div class="figure-caption-contents"><p> Comparison of mutation rate between spermatogenesis (blue-box) vs.… </p></div>
</div>
<figcaption id="figure-caption-5" class="figure-caption-full figure-caption-text" itemtype="http://schema.org/ImageObject" itemprop="description">
<strong class="figure-label">
Figure 6. Mutation rate model during gametogenesis
</strong>
<div class="figure-caption-contents">Comparison of mutation rate between spermatogenesis (blue-box) vs. oogenesis (red-box). <i>μ<sub>p</sub></i> and <i>μ<sub>m</sub></i> are mutation rate in paternal and maternal genome in respective order and mutation rate per each stage of gametogenesis is denoted by number. Gametogenesis is divided into three stages with different ranges of mutation rates. Stage 1: Pre-PGC specification (8-12 cell divisions in both maternal and paternal germline) ~0.2-0.6 mutations per haploid genome per cell division and this rate is the similar in both maternal and paternal gametogenesis, stage 2: post-PGC specification, in maternal germline there are ~20 cell divisions, in paternal germline there are ~24 cell divisions post-PGC up to puberty, mutation rate is similar at this stage in both sexes, (~0.5-0.7 mutations per haploid genome per cell division). Stage 3: post-puberty (only applicable to the paternal germline) sperm are continuously produced through the asymmetric division of self-renewing spermatogonial stem cells with ~23 cell divisions per year. The mutation rate falls to a range of ~0.09 to 0.17 mutations per haploid genome per cell division. This model is tentative and does not yet take all possible sources of uncertainty into account.</div>
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