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<select id="email-citation-format" name="citation-format" class="action-panel-selector email-citation-format">
<option selected="selected" value="summary">Summary</option>
<option value="summary-text">Summary (text)</option>
<option value="abstract">Abstract</option>
<option value="abstract-text">Abstract (text)</option>
</select>
</div>
<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="XuGgN0lXcdH5wbqdEsECgVdJtpkilY39ehqlqQOjMOuzqCw3hLhEK3Jn1t2uezBt">
<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="XuGgN0lXcdH5wbqdEsECgVdJtpkilY39ehqlqQOjMOuzqCw3hLhEK3Jn1t2uezBt">
<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="XuGgN0lXcdH5wbqdEsECgVdJtpkilY39ehqlqQOjMOuzqCw3hLhEK3Jn1t2uezBt">
<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="XuGgN0lXcdH5wbqdEsECgVdJtpkilY39ehqlqQOjMOuzqCw3hLhEK3Jn1t2uezBt">
<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="XuGgN0lXcdH5wbqdEsECgVdJtpkilY39ehqlqQOjMOuzqCw3hLhEK3Jn1t2uezBt">
<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="37414936">
<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/s41587-023-01863-z"
target="_blank"
rel="noopener"
ref="linksrc=fulltextorjournal_fulltext&amp;is_pmc=False&amp;PrId=3094&amp;itool=Abstract-def&amp;log$=linkouticon&amp;uid=37414936&amp;db=pubmed&amp;nlmid=9604648"
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data-ga-action="Nature Publishing Group"
data-ga-label="37414936"
><img src="https://cdn.ncbi.nlm.nih.gov/corehtml/query/egifs/https:--www.nature.com-static-images-logos-nature-portfolio-120.png" alt="Nature Publishing Group full text link"><span class="text">
Nature Publishing Group
</span></a><a class="link-item
pmc
"
href="https://pmc.ncbi.nlm.nih.gov/articles/pmid/37414936/"
target="_blank"
rel="noopener"
ref="linksrc=fulltextorjournal_fulltext&amp;is_pmc=True&amp;PrId=3494&amp;itool=Abstract-def&amp;log$=linkouticon&amp;uid=37414936&amp;db=pubmed&amp;nlmid=9604648"
title="Free full text at PubMed Central"
data-ga-category="full_text"
data-ga-action="PMC"
data-ga-label="37414936"
><span class="text">
Free PMC article
</span></a>
</div>
</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="/37414936/citations/"
data-citation-style="nlm"
data-pubmed-format-link="/37414936/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="37414936" 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%2F37414936%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="XuGgN0lXcdH5wbqdEsECgVdJtpkilY39ehqlqQOjMOuzqCw3hLhEK3Jn1t2uezBt"><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"
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data-ga-label="Ruoyan Li">Ruoyan Li</a><sup class="affiliation-links"><span class="author-sup-separator">&nbsp;</span><a class="affiliation-link" title="Wellcome Trust Sanger Institute, Wellcome Genome Campus, Hinxton, Cambridge, UK." href="#short-view-affiliation-2" ref="linksrc=author_aff">
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data-ga-label="Raheleh Rahbari">Raheleh Rahbari</a><sup class="affiliation-links"><span class="author-sup-separator">&nbsp;</span><a class="affiliation-link" title="Wellcome Trust Sanger Institute, Wellcome Genome Campus, Hinxton, Cambridge, UK." href="#short-view-affiliation-2" ref="linksrc=author_aff">
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data-ga-label="Thomas J Mitchell">Thomas J Mitchell</a><sup class="affiliation-links"><span class="author-sup-separator">&nbsp;</span><a class="affiliation-link" title="Wellcome Trust Sanger Institute, Wellcome Genome Campus, Hinxton, Cambridge, UK." href="#short-view-affiliation-2" ref="linksrc=author_aff">
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data-ga-label="Sahand Hormoz">Sahand Hormoz</a><sup class="affiliation-links"><span class="author-sup-separator">&nbsp;</span><a class="affiliation-link" title="Department of Systems Biology, Harvard Medical School, Boston, MA, USA." href="#short-view-affiliation-5" ref="linksrc=author_aff">
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</a><span class="author-sup-separator">&nbsp;</span><a class="affiliation-link" title="Department of Data Science, Dana-Farber Cancer Institute, Boston, MA, USA." href="#short-view-affiliation-6" ref="linksrc=author_aff">
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data-ga-label="Isidro Cortés-Ciriano">Isidro Cortés-Ciriano</a><sup class="affiliation-links"><span class="author-sup-separator">&nbsp;</span><a class="affiliation-link" title="European Molecular Biology Laboratory, European Bioinformatics Institute, Hinxton, Cambridge, UK. icortes@ebi.ac.uk." href="#short-view-affiliation-8" ref="linksrc=author_aff">
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><sup class="key">1</sup> European Molecular Biology Laboratory, European Bioinformatics Institute, Hinxton, Cambridge, UK.</li>
<li data-affiliation-id="short-view-affiliation-2"
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><sup class="key">2</sup> Wellcome Trust Sanger Institute, Wellcome Genome Campus, Hinxton, Cambridge, UK.</li>
<li data-affiliation-id="short-view-affiliation-3"
id="short-view-affiliation-3"
><sup class="key">3</sup> Cambridge University Hospitals NHS Foundation Trust and NIHR Cambridge Biomedical Research Centre, Cambridge, UK.</li>
<li data-affiliation-id="short-view-affiliation-4"
id="short-view-affiliation-4"
><sup class="key">4</sup> Department of Surgery, University of Cambridge, Cambridge, UK.</li>
<li data-affiliation-id="short-view-affiliation-5"
id="short-view-affiliation-5"
><sup class="key">5</sup> Department of Systems Biology, Harvard Medical School, Boston, MA, USA.</li>
<li data-affiliation-id="short-view-affiliation-6"
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><sup class="key">6</sup> Department of Data Science, Dana-Farber Cancer Institute, Boston, MA, USA.</li>
<li data-affiliation-id="short-view-affiliation-7"
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><sup class="key">7</sup> Broad Institute of MIT and Harvard, Cambridge, MA, USA.</li>
<li data-affiliation-id="short-view-affiliation-8"
id="short-view-affiliation-8"
><sup class="key">8</sup> European Molecular Biology Laboratory, European Bioinformatics Institute, Hinxton, Cambridge, UK. icortes@ebi.ac.uk.</li>
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<p>
Characterization of somatic mutations at single-cell resolution is essential to study cancer evolution, clonal mosaicism and cell plasticity. Here, we describe SComatic, an algorithm designed for the detection of somatic mutations in single-cell transcriptomic and ATAC-seq (assay for transposase-accessible chromatin sequence) data sets directly without requiring matched bulk or single-cell DNA sequencing data. SComatic distinguishes somatic mutations from polymorphisms, RNA-editing events and artefacts using filters and statistical tests parameterized on non-neoplastic samples. Using &gt;2.6 million single cells from 688 single-cell RNA-seq (scRNA-seq) and single-cell ATAC-seq (scATAC-seq) data sets spanning cancer and non-neoplastic samples, we show that SComatic detects mutations in single cells accurately, even in differentiated cells from polyclonal tissues that are not amenable to mutation detection using existing methods. Validated against matched genome sequencing and scRNA-seq data, SComatic achieves F1 scores between 0.6 and 0.7 across diverse data sets, in comparison to 0.2-0.4 for the second-best performing method. In summary, SComatic permits de novo mutational signature analysis, and the study of clonal heterogeneity and mutational burdens at single-cell resolution.
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<p xmlns:xlink="http://www.w3.org/1999/xlink" xmlns:mml="http://www.w3.org/1998/Math/MathML" xmlns:p1="http://pubmed.gov/pub-one">The authors declare no competing interests.</p>
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Figures
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data-pmc-id="PMC11098751"
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<img class="figure-thumb" itemprop="thumbnail"
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src="https://cdn.ncbi.nlm.nih.gov/pmc/blobs/91d6/11098751/b844994191b8/41587_2023_1863_Fig1_HTML.gif"
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<strong class="figure-label">
<p> Fig. 1. Overview of SComatic. </p>
</strong>
<div class="figure-caption-contents"><p> Methodology for… </p></div>
</div>
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<div class="figure-caption-medium figure-caption-text" aria-hidden="true">
<strong class="figure-label">
<p> Fig. 1. Overview of SComatic. </p>
</strong>
<div class="figure-caption-contents"><p> Methodology for detecting somatic mutations in high-throughput single-cell profiling data… </p></div>
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<figcaption id="figure-caption-0" class="figure-caption-full figure-caption-text" itemtype="http://schema.org/ImageObject" itemprop="description">
<strong class="figure-label">
Fig. 1. Overview of SComatic.
</strong>
<div class="figure-caption-contents">Methodology for detecting somatic mutations in high-throughput single-cell profiling data sets. The dashed red line shows an arbitrarily chosen level of significance for illustration purposes.</div>
</figcaption>
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<strong class="figure-label">
<p> Fig. 2. Validation of SComatic using matched… </p>
</strong>
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<strong class="figure-label">
<p> Fig. 2. Validation of SComatic using matched scRNA-seq and exome sequencing data. </p>
</strong>
<div class="figure-caption-contents"><b> a </b> , Mutational…</div>
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<figcaption id="figure-caption-1" class="figure-caption-full figure-caption-text" itemtype="http://schema.org/ImageObject" itemprop="description">
<strong class="figure-label">
Fig. 2. Validation of SComatic using matched scRNA-seq and exome sequencing data.
</strong>
<div class="figure-caption-contents"><b>a</b>, Mutational burdens for epithelial cells using the somatic SNVs detected by SComatic in cSCC and matched normal skin scRNA-seq data sets. The number of mutations is normalized to account for the variable number of callable sites in each sample. <b>b</b>, Fraction of somatic SNVs detected in epithelial cells attributed to COSMIC signatures. SBS signatures associated with ultraviolet radiation (SBS7a, SBS7b, SBS7c and SBS7d) and clock-like mutational processes (SBS5 and SBS40) are collapsed for visualization purposes. <b>c</b>, Mutational spectra computed for the mutations detected using SComatic in epithelial cells from cSCC and matched normal skin scRNA-seq data. The cosine similarities between the observed and reconstructed mutational spectra are shown. <b>d</b>, Venn diagram showing the overlap of the somatic SNVs detected by SComatic in epithelial cells using scRNA-seq data and WES data from the cSCC samples. WES-specific beta-binomial refers to mutations detected in WES with at least one alternative read count in scRNA-seq that are not significant for the beta-binomial test. <b>e</b>, Decomposition of the mutations detected in scRNA-seq data only (scRNA-seq-specific mutations) into COSMIC signatures. <b>f</b>, Correlation between the mutational burdens estimated using the mutations detected in WES and the mutations detected by SComatic in the scRNA-seq data. The correlation was assessed using a linear regression model. Only genomic regions with sufficient sequencing depth in both the WES and scRNA-seq data were considered for this analysis. Mb, megabase. Source data</div>
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<p> Fig. 3. Comparison of the performance of… </p>
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<strong class="figure-label">
<p> Fig. 3. Comparison of the performance of SComatic against other mutation detection methods. </p>
</strong>
<div class="figure-caption-contents"><b> a </b> –…</div>
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<strong class="figure-label">
Fig. 3. Comparison of the performance of SComatic against other mutation detection methods.
</strong>
<div class="figure-caption-contents"><b>a</b><b>c</b>, Performance of Strelka2, SAMtools, VarScan2, Monovar, SCReadCounts and SComatic for the detection of somatic mutations in the scRNA-seq data from cSCC (<b>a</b>), ovarian cancer (<b>b</b>) and kidney tumor samples (<b>c</b>). The bars represent the mean value, and the error bars are the 95% bootstrap confidence interval for each statistic computed using 50 bootstrap resamples. Significance with respect to SComatic in <b>a</b><b>c</b> was assessed using the two-sided Students <i>t</i>-test (***<i>P</i>&lt;0.0001). <b>d</b>, Decomposition into COSMIC signatures of the mutations detected in cSCC scRNA-seq data and in matched WES data. <b>e</b>, Decomposition into COSMIC signatures of the mutations detected in scRNA-seq and matched WGS data from ovarian cancer samples. <b>f</b>, Decomposition into COSMIC signatures of the mutations detected by SComatic in scRNA-seq from homologous recombination deficient (HRD) and homologous recombination proficient (HRP) ovarian cancer samples. <b>g,</b> Comparison between the mutational spectra of the mutations detected in cSCC samples using WES and scRNA-seq data for the algorithms benchmarked. The cosine similarities between the mutational spectra computed using the mutations detected in the scRNA-seq and the WES data are shown. Source data</div>
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<p> Fig. 4. Detection of somatic mutations in… </p>
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<strong class="figure-label">
<p> Fig. 4. Detection of somatic mutations in scRNA-seq data from colorectal cancer samples. </p>
</strong>
<div class="figure-caption-contents"><b> a </b> ,…</div>
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<figcaption id="figure-caption-3" class="figure-caption-full figure-caption-text" itemtype="http://schema.org/ImageObject" itemprop="description">
<strong class="figure-label">
Fig. 4. Detection of somatic mutations in scRNA-seq data from colorectal cancer samples.
</strong>
<div class="figure-caption-contents"><b>a</b>, Mutational burden of epithelial cells computed using SComatic. The number of mutations is normalized to the number of callable sites per sample. <b>b</b>, Distribution of the mutational burden of epithelial cells from MSI tumors detected using SComatic and the mutational burden of MSI tumors from TCGA computed using WES data. The red horizontal line shows the mean for each group, and <i>n</i> indicates the number of samples per group. Statistical significance was assessed using the two-sided Students <i>t</i>-test. <b>c,</b> Decomposition of the mutational spectra computed using SComatic into COSMIC signatures. Mutational signatures associated with MMR deficiency (MMRd) (SBS6, SBS14, SBS15, SBS21, SBS26 and SBS44), POLE deficiency (POLEd) (SBS10a, SBS10b and SBS28) and clock-like mutational processes (SBS5 and SBS40) are collapsed for visualization purposes. <b>d</b>, Trinucleotide context of somatic mutations detected by SComatic using the scRNA-seq data from colorectal cancer samples. CRC, colorectal cancer; TCGA, The Cancer Genome Atlas. Source data</div>
</figcaption>
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<p> Fig. 5. Detection of somatic mutations in… </p>
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<strong class="figure-label">
<p> Fig. 5. Detection of somatic mutations in samples with a low tumor mutational burden. </p>
</strong>
<div class="figure-caption-contents"><b> a… </b></div>
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<strong class="figure-label">
Fig. 5. Detection of somatic mutations in samples with a low tumor mutational burden.
</strong>
<div class="figure-caption-contents"><b>a</b>, Trinucleotide context of somatic mutations detected in HSCs from patients with MPNs. <b>b</b>, Decomposition of the somatic mutations detected in HSCs from patients with MPNs into COSMIC signatures. <b>c</b>, Correlation between the mutational burden of HSCs estimated using SComatic and the age of patients at the time of sampling (Pearsons correlation test). <b>d</b>, Average number of mutations detected per cell and genome in cardiomyocytes from the heart cell atlas across donors. <b>e</b>, Decomposition of the mutations detected in cardiomyocytes into COSMIC signatures. <b>f</b>, Trinucleotide context of mutations detected in cardiomyocytes from the heart cell atlas. <b>g</b>, Average mutational burden of individual cells across the tissues included in the GTEx scRNA-seq data set. <b>h</b>, Decomposition of the mutations detected across all cells from the GTEx data set into COSMIC signatures. <b>i</b>, Trinucleotide context of mutations detected across all single cells from the GTEx data set. The numbers on top of the bars in <b>d</b> and <b>g</b> indicate the number of cells per cell type analyzed, and the horizontal red dashed line corresponds to 1,000 mutations per cell. Source data</div>
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<p> Fig. 6. Analysis of intra-tumor heterogeneity using… </p>
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<p> Fig. 6. Analysis of intra-tumor heterogeneity using somatic mutations detected by SComatic in the scRNA-seq… </p>
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Fig. 6. Analysis of intra-tumor heterogeneity using somatic mutations detected by SComatic in the scRNA-seq data from a patient with ovarian cancer (SPECTRUM-OV-003).
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<div class="figure-caption-contents"><b>a</b>, Hierarchical clustering of single cells from all tumor regions (columns) by somatic mutations (rows; mutations are labeled arbitrarily). Mutations detected in the scRNA-seq data are shown in red. White denotes the absence of mutations in the scRNA-seq data in cases when the site was sufficiently covered (at least one sequencing read), and gray indicates that there was no coverage at the position to make a call. <b>b</b>, Hierarchical clustering of single cells collected from the upper right quadrant region from patient SPECTRUM-OV-003. Only the mutations shown in <b>a</b> that were detected in at least 20 cells are shown. The two clones defined by somatic mutations detected in scRNA-seq data are marked on the <i>y</i>axis. Single cells and mutations in <b>a</b> and <b>b</b> are ordered by hierarchical clustering (top and left-hand side dendrograms, respectively). The color bar indicates the cancer cell fraction (CCF) of the mutations in the WGS data. NA, no coverage in scRNA-seq. Source data</div>
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