reveal.js

## Course overview and introduction to computational genomics
---
## Course overview

- Course website: https://cphg.github.io/compgen/
- Scribing assignments
- Final presentations
- Programming assignments: GitHub

---
## git and GitHub in 5 slides
---
### git/GitHub serve multiple purposes
1. Backup
2. Version control
3. Distributing/sharing code
4. Testing
5. Communication and collaboration
---
### Basics of git repos
1. A git repository is a folder with a `.git` subfolder
2. The `.git` subfolder stores an index of snapshots
3. Commits track the repository, not individual files.
4. Git uses a model of distributed *clones*
---
<div class="row">
<div class="col">
	Centralized (svn)
	<img src="images/introduction/centralized.png" style="margin-top:140px">
</div>
<div class="col">
	Distributed (git)
	<img src="images/introduction/distributed.png">
</div>
</div>
<span class="small"><a href="https://git-scm.com/">ProGit</a></span>
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### Basics of git branching
1. Branches are pointers to commits. They are cheap.
2. Combine branches with either *merge* or *rebase*.
3. Branching workflows can be opinionated<br>(*e.g*, gitflow, threeflow, trunk development)
---
<div class="row">
<div class="col">

<pre><code class="small" style="line-height:1em">$ git checkout -b hotfix
Switched to a new branch 'hotfix'
$ vim index.html
$ git commit -a -m 'Fix broken email address'
[hotfix 1fb7853] Fix broken email address
 1 file changed, 2 insertions(+)
</code></pre>

</div>
<div class="col fragment">
<img src="images/introduction/basic-branching-5.png" width="425">

<pre><code class="small">$ git checkout master
$ git merge hotfix
Updating f42c576..3a0874c
Fast-forward
 index.html | 2 ++
 1 file changed, 2 insertions(+)
</code></pre>

</div>
</div>
<span class="small"><a href="https://git-scm.com/">ProGit</a></span>

---
## Introduction to computational genomics

This intro will cover:
1. Definitions of genomics and related fields
2. Brief history of genomics
3. Core biological concepts and technology
4. Overview of sequencing technologies
5. The genomic data explosion and computation
6. How genomics links to business, ethics, and health
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### Genomics is the study of genomes What is a genome?

> A complete set of genetic information.

### What is genetic?

</div>
<div class="fragment">

> Relating to origin.

### What is genomics?

</div>
<div class="fragment">

> The study of the instructions needed to originate an organism.

</div>

---
### Early history of genomics

- Discovery of DNA (1871)
- Discovery of nucleotides (1910)
- DNA is the genetic material (1944)
- Discovery of structure of DNA (1953)
- The central dogma (1957)

<span class="small">See https://www.yourgenome.org/facts/timeline-history-of-genomics</span>
---

<div class="row">
<div class="col">
1910: Nucleotides
<img
	src="images/introduction/bases.png"
	height="320"
	style="background:white; padding: 10px; margin: 0px"><br>
<span class="small">Albrecht Kossel Nobel Prize:<br><a href="https://www.nobelprize.org/prizes/medicine/1910/summary/">The Chemical Composition of the Cell Nucleus</a></span>
</div>
<div class="col">
1944: DNA is genetic
<img
	src="images/introduction/avery_macleod_mccarty_experiment_02_yourgenome.png"
	height="520"
	style="background:white; padding: 10px; margin: 0px"><br>
<span class="small">Avery et al. 1944</span>
</div>
</div>
<span class="small">Image credits: Nobel, Genome Research Limited</span>

---
<div class="row">
<div class="col">
1953: Structure of DNA
<img
	src="images/introduction/dna_structure.png"
	height="520"
	style="background:white; padding: 10px; margin: 0px"><br>
<span class="small"><a href="https://www.nature.com/articles/171737a0">Watson and Crick</a>, <i>Nature</i>, 1953</span>
</div>
<div class="col">
1957: Central dogma
<img
	src="images/introduction/dna_central_dogma_yourgenome.png"
	height="520"
	style="background:white; padding: 10px; margin: 0px"><br>
<span class="small">Crick 1957</span>
</div>
</div>
<span class="small">Image credits: Genome Research Limited</span>

---
### Genomics is intertwined with sequencing technology

> DNA sequencing is the process of determining the *sequence* of nucleotides (ACTG) in a strand of DNA

DNA sequencing = measurement  (like a microscope)

---
### History of genome sequencing
- Sanger sequencing (1977-1980)
- The [Human Genome Project](https://www.genome.gov/human-genome-project) (1990-2003)
- The [ENCODE project](https://www.genome.gov/Funded-Programs-Projects/ENCODE-Project-ENCyclopedia-Of-DNA-Elements) (2003-2021)
- Sequencing by synthesis (2008-2012)
- Single-molecule sequencing
- 100k genomes sequenced

---

<div class="row">
<div class="col">
1977: Sanger sequencing
<img
	src="images/introduction/Radioactive_Fluorescent_Seq.jpg"
	height="520"
	style="background:white; padding: 10px; margin: 0px"><br>
<span class="small">Chain Termination Method</span>
</div>
<div class="col">
2001: Human genome
<img
	src="images/introduction/Logo_HGP.jpg"
	height="320"
	style="background:white; padding: 10px; margin-top: 90px"><br>
<span class="small"></span>
</div>
</div>
<span class="small">Image credits: Wikipedia</span>

---
### 2008: Sequencing by synthesis

<a href="https://www.youtube.com/embed/v10bUR2aL5g?start=35" class="small">Illumina</a>

---
### Single-molecule sequencing

<div class="row">
<div class="col">
<img src="images/introduction/pavlovic2020.png" height=620>
</div>
<div class="col">
<li>2004: Helicos</li>
<li>2009: SMRT</li>
<li>2009: Nanoball</li>
<li>2016: Nanopore</li>

<span class="small"><a href="https://doi.org/10.1016/B978-0-12-816664-2.00009-8">Pavlovic et al. 2020. Microbiomics.</a></span>
</div>
</div>

---
<div class="row">
<div class="col">

### Contrasting sequencing platforms

- Size of machine
- Length of reads
- Number of reads
- Cost of machine
- Cost of reads
- Accuracy of reads
- Technician time

</div>
<div class="col">
<img src="images/introduction/levy2016.png" height=340>
<span class="small"><a href="https://doi.org/10.1146/annurev-genom-083115-022413">Levy and Myers 2016</a></span>

<h4>Other systems</h4>
<div class="small">
	<li><a href="http://www.biorxiv.org/content/early/2016/04/13/048603">Bionano: Saphyr system</a></li>
	<li><a href="https://en.wikipedia.org/wiki/Pyrosequencing">Roche 454 Pyrosequencing</a></li>
	<li><a href="https://www.thermofisher.com/us/en/home/brands/ion-torrent.html">ThermoFisher IonTorrent</a></li>
	<li><a href="https://en.wikipedia.org/wiki/Polony_sequencing">Polony sequencing</a>
</div>
</div>
</div>

---

### Sequencing costs

- Sequencing technology doesn't just measure DNA

Genome → transcriptome → epigenome

<div class="fragment">Convert what you want to measure to DNA, then use DNA sequencing technology.</div>

---
### Transcriptomics

> The study of the RNA molecules produced by a cell.

<span class="fragment">
Complementary DNA (cDNA) is a DNA copy of a messenger RNA (mRNA) molecule produced by reverse transcriptase, a DNA polymerase that can use either DNA or RNA as a template. (Encyclopedia of Genetics)
</span>

---
### Epigenomics

> The study of the chemical modification and physical conformation of cellular DNA and bound proteins

---

<img src="images/introduction/rosa2013_chromatin.png" width="550"><br>
<span class="small">Protocols: Bisulfite-seq, ChIP-seq, ATAC-seq, Hi-C</span>
<br><span class="small">Rosa et al. 2013</span>

---
### Units
<div class="row">
	<div class="col">
		<b>Genomics</b>
		<li class="small">sequence alignment</li>
		<li class="small">genome assembly</li>
		<li class="small">variant calling</li>
	</div>
	<div class="col">
		<b>Epigenomics</b>
		<li class="small">short-read reference mapping</li>
		<li class="small">string models </li>
		<li class="small">genomic intervals</li>
	</div>
	<div class="col">
		<b>Transcriptomics</b>
		<li class="small">dimensionality reduction</li>
		<li class="small">k-mer algorithms</li>
		<li class="small">differential expression</li>
	</div>
</div><br><br>

### Focus

Algorithms and methods motivated by biology

<!-- 
- Public human genome funding comes from the [National Human Genome Research Institute](https://www.genome.gov).

-->

---
### Genomics today

- Genomics and health
- Genomics and business
- Genomics and evolution
- Genomics and privacy
- Genomics and ethics
- Genomics and computing

---
### Genomics and health: traits
![](images/introduction/polygenic.svg)
---
### Genomics and health: GWAS
![](images/introduction/GWAS_Fact-sheet2020.jpg)
---
### Genomics and health: GWAS

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</video>

---
### Genomics and health: gene/environment
![](images/introduction/gene-by-env.svg)
---
### Genomics and health:<br>personalized medicine
![](images/introduction/all_of_us.png)
---
### Genomics and health: epigenetics
- epimutations
- cancer classification
- clinical epigenetic assays
---
### Genomics and business
- Genome-stratified clinical trials
- mRNA vaccines: Pfizer, Moderna
- Clinical genetic tests
- Direct-to-consumer (DTC) genetic testing:
	- 23andme, ancestry.com, etc.
---
### Genomics and law
- Celera and the Human Genome Project
	- intended to patent human genes in the race to finish the genome
---
### Genomics and law
- Uni. of Utah/NIEHS/Myriad patent BRCA1 (1994)
- Myriad sold diagnostic tests for BCRA genes
- Supreme Court struck down gene patents (2013)

> A naturally occurring DNA segment is a product of nature and not patent eligible merely because it has been isolated, but cDNA is patent eligible because it is not naturally occurring.
---
### Genomics and law
- Lawrence Berkeley Laboratory tested employees without consent
- Norman-Bloodsaw v. Lawrence Berkeley Laboratory (1998)

> Holds that unauthorized employer testing for sensitive medical information [specifically including genetic testing] violates employees' right to informational privacy

---
### Genomics and law
- In the US: The Genetic Information Nondiscrimination Act of 2008

> To prohibit discrimination on the basis of genetic information with respect to health insurance and employment.

See also: [Genetic Information Nondiscrimination Act](https://www.eeoc.gov/statutes/genetic-information-nondiscrimination-act-2008)
---
### Genomics and ethics
- genetic ownership (patents, family dynamics)
- genetic discrimination (employment, insurance)
- genetically modified babies
- identification and privacy

---
### Genomics and privacy: Crypt4GH

![](images/introduction/Crypt4GH_comic.png)

See also: [Genome.gov on Genomic Privacy](https://www.genome.gov/about-genomics/policy-issues/Privacy)
---
### Computing is everywhere in genomics

<div class="row">
	<div class="col small">
		<li>Genome assembly</li>
		<li>Genome alignment</li>
		<li>Variant identification</li>
		<li>Variant associations</li>
		<li>Phylogenetics</li>
		<li>Viral evolution</li>
		<li>Comparative genomics</li>
		<li>Microbiome</li>		
	</div>
	<div class="col small">
		<li>Data privacy and encryption</li>
		<li>Data models</li>
		<li>Data integration</li>
		<li>Data sharing</li>
		<li>Data compression</li>
		<li>Data storage</li>
		<li>Computing reproducibility</li>
		<li>Single-cell sequencing</li>
	</div>
	<div class="col small">
		<li>Genomic data structures</li>
		<li>Outcome prediction</li>
		<li>Disease subtyping</li>
		<li>Gene prediction</li>
		<li>Gene network regulation</li>
		<li>Cell-type definition</li>
		<li>Epigenetics</li>
		<li>Metagenomics</li>
	</div>
</div>
---
### Conclusion

It's an interesting time for computational genomics.<br>

<div class="fragment">
	The world is starving for people who can apply advanced computation to growing genomic data.
</div><br>

<div class="fragment">
	Looking forward to a fun and enlightening semester.
</div>