Methods for analyzing non-coding genomic intervals and their applications in cancer biology

# Methods for analyzing non-coding genomic intervals and their applications in cancer biology

Nathan Sheffield

<span style="font-size:0.6em"><a href="http://www.databio.org/slides">www.databio.org/slides</a></span>

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### Outline

<div class="previewblock" style="width:20%">Background, LOLA/MIRA</div>
<div class="previewblock" style="width:35%">COCOA</div>
<div class="previewblock" style="width:35%">RegionSet2vec</div>
<div class="previewblock" style="width:10%">Other projects</div>

<div class="questionblock" style="background:#222; color:#eee; font-size: 0.6em; margin-top: 35px">&#9665; Questions &#9655;</div>
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# Biological motivation

<div class="col2">
<br><br>
<img src="/_modules/bio-motivation-regulatory-dna/dna_folding_diversity.svg" width="400"><br/>
Cells alter phenotype by using DNA differently. <br>
</div>

<div class="col2 fragment">
<img src="/_modules/bio-motivation-regulatory-dna/differentation_gone_awry.svg" width="500"><br/>
Breakdowns lead to disease
</div>
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# <span class="bullet"><img src="/_modules/region-pooling/merge.svg" width="50" class="bullet">Region pooling</span>

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![Region Pooling Step 1](/_modules/region-pooling/region_pooling1.svg)

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![Region Pooling Step 2](/_modules/region-pooling/region_pooling2.svg)

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![Region Pooling Step 3](/_modules/region-pooling/region_pooling3.svg)
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### Locus Overlap Analysis

<div class="small">
<a href="http://code.databio.org/LOLA/">http://code.databio.org/LOLA/</a><br>
</div>
<span class="small bullet"><img src="/_modules/lola-intro/paper.svg" height="25" class="bullet">Sheffield and Bock (2016). <i>Bioinformatics</i>.</span><br/>
<span class="small bullet"><img src="/_modules/lola-intro/paper.svg" height="25" class="bullet">Nagraj, Magee, and Sheffield (2018). <i>Nucleic Acids Research</i>.</span>
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<div class="small">
<a href="http://code.databio.org/LOLA/">http://code.databio.org/LOLA/</a><br>
</div>

<span style="font-size: 0.8em;"><img src="/shorts/lola/paper.svg" height="25" style="vertical-align: text-bottom; margin-right: 5px;">Sheffield and Bock (2016). *Bioinformatics*.</span><br/>
<span style="font-size: 0.8em;"><img src="/shorts/lola/paper.svg" height="25" style="vertical-align: text-bottom; margin-right: 5px;">Nagraj, Magee, and Sheffield (2018). *Nucleic Acids Research*.</span>

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![New data](/shorts/lola/01-new-data.svg)

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![New data connection](/shorts/lola/02-new-data-connection.svg)

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![GSEA](/shorts/lola/03-gsea.svg)

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![HTS](/shorts/lola/04-hts.svg)

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![Convert](/shorts/lola/05-convert.svg)

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![Introducing LOLA](/shorts/lola/06-introducing-lola.svg)

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![LOLA 1](/shorts/lola/07-lola1.svg)

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![LOLA 2](/shorts/lola/08-lola2.svg)

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![Test](/shorts/lola/09-test.svg)

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![Results](/shorts/lola/10-results.svg)

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![EWS vs others 2](/shorts/lola/ews_vs_others2.svg)

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![EWS vs others 3](/shorts/lola/ews_vs_others3.svg)

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## LOLAweb

A shiny app and server for interactive LOLA analysis.

Public server: [http://lolaweb.databio.org](http://lolaweb.databio.org)

GitHub: [https://github.com/databio/LOLAweb](https://github.com/databio/LOLAweb)

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### DEMO

<video controls width="800">
  <source src="lw.webm" type="video/webm">
Your browser does not support the video tag.
</video>
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## Methylation-based Inference of Regulatory Activity (MIRA)

<div class="small">
<a href="http://code.databio.org/MIRA/">http://code.databio.org/MIRA/</a><br>
</div>
<span class="small bullet"><img src="/_modules/mira/icons/paper.svg" height="25" class="bullet">Lawson et al. (2018). <i>Bioinformatics</i>.</span>
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<div class="small">
<a href="{{project_url}}">{{project_url}}</a><br>
</div>
<span class="small bullet"><img src="/_modules/project-cover/icons/paper.svg" height="25" class="bullet" style="vertical-align: text-bottom; margin-right: 5px;">{{project_citations}}</span>
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## MIRA concept

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## MIRA workflow

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## MIRA analysis

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## MIRA results: Differential activity

<span class="small bullet"><img src="/_modules/mira/icons/paper.svg" height="25" class="bullet">Sheffield et al. (2017). <i>Nature Medicine</i>.</span>

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## MIRA results: Activity scores

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## MIRA results: Enrichment analysis

<img src="/_modules/mira/ews_pat/MIRA_result_3.svg" width="800"/>
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## Coordinate Covariation Analysis (COCOA)

<div class="small">
<a href="http://code.databio.org/COCOA/">http://code.databio.org/COCOA/</a><br>
</div>

<span class="small bullet"><img src="/_modules/genomicdistributions/paper.svg" height="25" class="bullet">Lawson et al. (2020). <i>Genome Biology</i>.</span>
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# Methods for analyzing non-coding genomic intervals and their applications in cancer biology

Nathan Sheffield

<span style="font-size:0.6em"><a href="http://www.databio.org/slides">www.databio.org/slides</a></span>

</section>
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@title

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@cocoa

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## Acknowledgments

**Collaborators**
- Fran Garrett-Bakelman
- Stefan Bekiranov

</div>

**Sheffield lab**
- **John Lawson**
- **Jason Smith**
- Jianglin Feng
- Michal Stolarczyk
- Kristyna Kupkova
- Aaron Gu
- Jose Verdezoto
- Tessa Danehy

</div>

**Funding:**

UVA Cancer Center

</div>
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## Acknowledgments

**Collaborators**
- Fran Garrett-Bakelman
- Stefan Bekiranov

</div>

**Sheffield lab**
- **John Lawson**
- **Jason Smith**
- Jianglin Feng
- Michal Stolarczyk
- Kristyna Kupkova
- Aaron Gu
- Jose Verdezoto
- Tessa Danehy

</div>

**Funding:**

UVA Cancer Center

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### Region-set 2 Vec

Embeddings of genomic region sets <br> in lower dimensions.

<div class="small">
<a href="https://github.com/databio/regionset-embedding">https://github.com/databio/regionset-embedding</a><br>
</div>

<span class="small bullet"><img src="/_modules/regionset2vec/paper.svg" height="25" class="bullet"><a href="https://doi.org/10.1093/bioinformatics/btab439">Gharavi et al. (2021). <i>Bioinformatics</i>.</a></span>
<br>

<div style="padding:12px; font-size: 16pt; display:inline-block;">
<span style="border: 0px solid grey; float:right; margin: 0px 4px; padding: 0px 4px">
<img src="/_modules/regionset2vec-extension/Erfaneh.jpg" width="100" style="margin:0px;">
<br>Erfaneh Gharavi
</span>
</div>
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<div>
<h3>Region-set 2 Vec</h3>

Embeddings of genomic region sets <br> in lower dimensions.

<div class="small">
<a href="https://github.com/databio/regionset-embedding">https://github.com/databio/regionset-embedding</a><br>
</div>
</div>
<span class="small bullet"><img src="/_modules/regionset2vec/paper.svg" height="25" class="bullet"><a href="https://doi.org/10.1093/bioinformatics/btab439">Gharavi et al. (2021). <i>Bioinformatics</i>.</a></span>

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### Word embeddings

<div class="small">http://suriyadeepan.github.io</div>

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### Word2vec model

<img src="/_modules/regionset2vec/mikolov2013_fig1.png" width="680">
<br><span class="small bullet"><img src="/_modules/regionset2vec/paper.svg" height="25" class="bullet"><a href="https://arxiv.org/abs/1301.3781">Mikolov et al. (2013). <i>arXiv:1301.3781v3</i>.</a></span>

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### Word context

<div class="well">
	You shall know a word by the company it keeps. (Firth 1957)<br>
	Words that occur in similar contexts tend to have similar meanings.
</div>
<div class="small">Image credit: Shubham Agarwal</div>

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### Genomic context

<div class="well">
	A genomic interval is more likely to appear in a BED file with other genomic intervals of a similar function.
</div>

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### Genomic Interval Embeddings

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### Evaluation

We have created unsupervised 100-dimensional vector representations (embeddings) of region sets.<br>
Do relationships among vectors reflect biology?

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## Evaluation 1: Classification performance

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## Evaluation 1: Classification performance

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### Evaluation 1: Classification performance

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### Conclusion

<ul>
	<li>Regionset2vec adapts word2vec to learn genomic region embeddings</li>
	<li>Regionset2vec embeddings capture biological information</li>
	<li>NLP approaches can be adapted for applications in genomic interval analysis</li>
</ul>
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### Future applications

<div class="col2">Cancer mutations
<img src="/slides/methods-for-analyzing-non-coding-genomic-intervals-and-cancer/nlp/mutation_maf.svg" style="background:white">
</div>
<div class="col2">Single-cell
<img src="/slides/methods-for-analyzing-non-coding-genomic-intervals-and-cancer/nlp/single-cell.svg" style="background:white">
</div>

</section>

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### BEDbase

A high-performance server and API <br> for genomic interval data.

<br><span class="small bullet"><img src="/_modules/bedbase-teaser/paper.svg" height="25" class="bullet"><a href="https://bedbase.org">bedbase.org</a></span>
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Reference genome manager

<div class="small">
<a href="http://refgenie.databio.org">http://refgenie.databio.org</a><br>
</div>
<span class="small bullet"><img src="/_modules/refgenie-teaser/paper.svg" height="25" class="bullet"><a href="https://www.biorxiv.org/content/10.1093/gigascience/giz149">Stolarczyk et al. (2020).</a> <i>GigaScience</i>.</span><br/>
<span class="small bullet"><img src="/_modules/refgenie-teaser/paper.svg" height="25" class="bullet"><a href="https://doi.org/10.1093/nargab/lqab036">Stolarczyk, Xue, and Sheffield (2021).</a> <i>NAR Genomics and Bioinformatics</i>.</span><br/>
</div>

<pre><code>refgenie pull hg38/bowtie2_index</code></pre>

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<div>

### <span class="bullet"><img src="/_modules/pep/pep_logo_white.svg" width="60"> Portable Encapsulated Projects (PEP)</span>

A structure and toolkit for organizing large-scale, <br>
sample-intensive biological research projects<br>

</div>
<span class="small bullet"><img src="/_modules/genomicdistributions/paper.svg" height="25" class="bullet"><a href="http://dx.doi.org/10.1093/gigascience/giab077">Sheffield et al. (2021).</a> <i>GigaScience</i>. <a href="http://pep.databio.org/">http://pep.databio.org/</a></span>

<img src="/_modules/pep/pep_workflow.svg" width="550" style="align:center"><br/>
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# Thank You

<span class="small bullet"><img src="/images/external/github_bug_black.svg" height="20" class="bullet"><a href="http://github.com/nsheff">nsheff</a></span> &middot;
<span class="small bullet"><img src="/images/icons/web.svg" height="25" class="bullet"><a href="http://databio.org">databio.org</a></span> &middot;
<span class="small bullet"><img src="/images/icons/letter.svg" height="25" class="bullet"><a href="mailto:nsheffield@virginia.edu">nsheffield@virginia.edu</a></span>

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