.huge[The ‘omic coal face:]

# .huge[The ‘omic coal face:]
## <h2 id="classifying-human-genomic-and-epigenomic-inheritance">classifying human genomic and epigenomic inheritance</h2>
### <div style="white-space: pre-line;"><a href="http://sirselim.github.io/">Dr Miles Benton</a>
Genomics Research Centre, Institute of Health and Biomedical Innovation</div>
### IHBI Inspires: 23<sup>rd</sup> - 25<sup>th</sup> August 2017

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# .center[My presentation available online]

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<p>
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<img src="images/ihbi_qr_code.jpg" style="width: 202px; margin-right: 1%; margin-top: 1.5em;"/>
]
</p>

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# NORFOLK ISLAND

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<p>
.center[<img src="images/NorfolkIsland.png" style="width: 60%; margin-right: 1%; margin-top: 1.5em; border: 3px solid white;"/>]
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<p>
.center[<img src="images/NIpedigree.png" style="width: 70%; margin-right: 1%; margin-top: 1.5em; border: 3px solid white;"/>]
</p>

<p style="font-size: 14px">Macgregor S <i>et al.,:</i> <a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2987173/" target="blank"><i>Legacy of mutiny on the Bounty: founder effect and admixture on Norfolk Island.</i></a> Eur J Hum Genet. 2010; 18: 67–72.</p>

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<p> 
.center[<img src="images/NI_ped_mt.png" style="width: 95%; margin-right: 1%; margin-top: 1.5em; border: 3px solid white;"/>]
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40% of current population haplogroup <span style="color:lightblue">B4a1a[...]</span><br />

<p style="font-size: 14px">Benton MC <i>et al.,:</i> <a href="https://investigativegenetics.biomedcentral.com/articles/10.1186/s13323-015-0028-9" target="blank"><i>“Mutiny on the Bounty”: the genetic history of Norfolk Island reveals extreme gender-biased admixture.</i></a> Investigative Genetics 2015, 6:11.</p>

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# Founder Effect Variants

<p style="font-size: 20px">
Other contributors: <span style="color:lightblue">Rod Lea, David Eccles, Donia Macartney-Coxson, Heidi Sutherland, Larisa Haupt, Lyn Griffiths</span>
</p>

---

## Whole Genome Sequencing

Platform – **Illumina HiSeq-X10 (Garvan)**

Bioinformatics: 
  - BOWTIE2 –> SAMTOOLS -> VCF annotation –> dbSNP -> dbNSFP -> VEP -> custom beds

Coverage >25X
]

## Functional Founder Effect Variants

.medium[
<span style="color:darkblue">**Functional**</span> = Predicted damaging in *in silico* tests:
  - SIFT, POLYPHEN2, MUTATIONTASTER, PROVEAN, MUTATION ASSESSOR, CADD
  
<span style="color:darkblue">**Founder effect**</span> = increased allele freq in NI compared to general population
  - (MAF<0.01% in 1000G >5% in NI)

<span style="color:darkblue">**Variant**</span> = single nucleotide variant (SNV)
]

---

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---
class: middle

# *ACOT4* (Acyl-CoA Thioesterase 4)

- <span style="color:darkblue">**regulation of lipid metabolism**</span>
  
  - SNV = rs77408762 (T/A)
  
  - Chr14, pos 73593812 (Hg38)
  
  - Amino acid = p.TYR190ASN
  
  - freq A = 0.0099 (EUR), 0 (AFR) and 0 (EAS) 
  
  - freq A in NI = 0.26

<br />

.center[**Rare allele most likely came from England via Bounty Mutineers and then increased in frequency in NI due to founder effect**]

---
class: middle center

---
class: middle

### 3 variants meeting the 'damaging' criteria, >5% MAF in NI, all missense

- *JPH2* (<span style="color:darkblue">Junctophilin 2</span>) 
    + chr20:44186654; c.52T>G; p.Trp18Gly; [48 hets, **MAF=0.22**]  
    + mutations previously linked to inherited cardiomyopathy (Landstrom *et al*, 2007)

<br />

- *EPS15L1* (<span style="color:darkblue">Epidermal growth factor receptor substrate 15-like 1</span>) 
    + Chr19:16425252; c.623T>C; p.Leu208Pro; [35 hets, **MAF=0.16**]

<br />

- *UGT2B4* (<span style="color:darkblue">UDP glucuronosyltransferase 2 family, polypeptide B4</span>) 
    + chr4:69480794; c.1427T>A; p.Leu476His; [12 hets, **MAF=0.06**]

---
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# Summary

<br >

- Using WGS and founder effect in NI may reveal disease-related variants that are rare in general populations

<br >

- Focusing on “functional” SNVs has identified strong candidate variants  
  
    + performing genotyping in the rest of the pedigree

<br >

- Some early evidence of association with T2D and CVD-related traits

]

---
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# Allele-Specific Methylation

<p style="font-size: 20px">
Other contributors: <span style="color:lightblue">Rod Lea, Donia Macartney-Coxson, Nicole White, Daniel Kennedy, Heidi Sutherland, Larisa Haupt, Kerrie Mengersen, Lyn Griffiths</span>
</p>

---
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# Methylation - the punctuation of the genome

---
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- same cytosine is differentially methylated on the <span style="color:lightblue"><b>two alleles</b></span> of a diploid organism]

.large[ASM is a major mechanism of <span style="color:lightblue"><b>genomic imprinting</b></span> (aberrations can lead to disease)]

.center[
<img src="http://rstb.royalsocietypublishing.org/content/royptb/368/1609/20120151/F2.large.jpg?width=800&height=600&carousel=1" style="width: 45%; margin-right: 1%; margin-top: 1.5em; border: 3px solid white;"/>

<p style="font-size: 12px">image rights: Renfree MB <i>et al.,:</i> <a href="http://rstb.royalsocietypublishing.org/content/368/1609/20120151" target="blank"><i>“The origin and evolution of genomic imprinting and viviparity in mammals.</i></a> 2012</p>

]

---

### Identification of allele-specific methylation profiles across generations

measuring genome-wide allele-specific methylation (ASM)

- NGS bisulphite sequencing
  - SeqCap Epi CpGiant (Illumina HiSeq)
  
collected data for <span style="color:darkblue"><b>108</b></span> NI individuals</li>

- comprising a close 3 generation pedigree

<br />

fully customised QC and analysis pipeline:<span style="color:darkblue"><b>*</b></span>

- fastqc, trimgalore
  - bismark, sambamba, picard tools
  - methpipe (ASM estimation)
  - MethylDackel (originally PileOMeth), R and methylkit
  - Shiny webserver visualisation

parallel processing enabled for local and remote machines

.center[
<span style="color:darkblue; font-size: 75%"><b>*<i>once wrangled into shape scripts will be accessible via GitHub</i></b></span>
]

---
class: center middle

## Chromosome 15

.small[**15q11-q13**: Angelman syndrome (maternally active allele) | Prader-Willi syndrome (paternally active allele)]

---
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## Chromosome 21

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# Allele-specific Methylated Regions (AMRs)

#### Overlap with known imprinting genes

- there are <span style="color:lightblue"><b>91</b></span> known imprinted genes with strong evidence
  - we have identified <span style="color:lightblue"><b>12761</b></span> total AMR (>=2 CpG sites)
  - we recoup 72/91 (<span style="color:lightblue"><b>79%</b></span>) of the above known genes

#### Small AMRs (>=2 CpG sites and <= 200bp length)

- there are <span style="color:lightblue"><b>4731 small AMR</b></span> which collectively span 6987 genomic features
  - <span style="color:lightblue"><b>35.8%</b></span> promoter related

#### Large AMRs (>=200 CpG sites)

- <span style="color:lightblue"><b>11 large AMR</b></span> (spanning some really interesting regions, i.e. *PCDH*, *HOX*)

#### Genetic variation across AMR

- <span style="color:lightblue"><b>2,388</b></span> AMR have no common SNPs (very little genetic variation)

---
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<div id="htmlwidget-059bf6a48cdda497963f" style="width:100%;height:auto;" class="datatables html-widget"></div>
<script type="application/json" data-for="htmlwidget-059bf6a48cdda497963f">{"x":{"filter":"none","data":[["ChIP_seq_region","five_prime_utr","start_codon","miRNA","TF_binding_site","three_prime_utr","exon","gwascatalog","gene","transcript","lincRNA","piRNA"],[15496,12347,6851,406,34330,10341,43713,1326,10570,10578,1409,37108],[3766.844,3371.693,1890.07,128.725,14187.176,4325.146,19129.451,749.187,6342.178,6349.741,887.126,30761.966],[4.113,3.6612,3.6233,3.1374,2.4197,2.3906,2.285,1.7689,1.6665,1.6658,1.5876,1.2063],[0.001,0.001,0.001,0.001,0.001,0.001,0.001,0.001,0.001,0.001,0.001,0.001]],"container":"<table class=\"display\">\n  <thead>\n    <tr>\n      <th>annotation<\/th>\n      <th>observed<\/th>\n      <th>expected<\/th>\n      <th>fold<\/th>\n      <th>pvalue<\/th>\n    <\/tr>\n  <\/thead>\n<\/table>","options":{"pageLength":12,"dom":"t","columnDefs":[{"className":"dt-left","targets":"_all"},{"className":"dt-right","targets":[1,2,3,4]}],"order":[],"autoWidth":false,"orderClasses":false,"lengthMenu":[10,12,25,50,100]},"selection":{"mode":"multiple","selected":null,"target":"row"}},"evals":[],"jsHooks":[]}</script>

---
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# Inheritance of Allele-Specfic Methylation?

---
class: middle center

<p style="text-align: center; font-size: 18px;">
<b>ASM plot of chromosome 20 for a nuclear family</b> (<span style="color:darkred"><b>father</b></span>, <span style="color:pink"><b>mother</b></span>, <span style="color:lightblue"><b>son</b></span>, <span style="color:green"><b>daughter</b></span>)
</p>

---
class: middle center

---
class: middle center

---
class: middle inverse

# Summary
.large[
  - implemented a custom bioinformatic pipeline  
]
<br />
.large[
  - generated a genome-wide 'map' of AMRs  
  
    + allows exploration of the genomic landscape and features
]
<br />
.large[
  - identified **ASM hotspots** overlapping non-coding RNA and other important functional loci  
  
    + **might account for the number of GWAS hits outside of genes?**
]

---
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## Acknowledgments

.pull-left[.medium[
#### <span style="color:lightblue">QUT</span>  
Lyn Griffiths  
Rod Lea  
Larisa Haupt  
Heidi Sutherland  
Michelle Hanna  
...the rest of the GRC IHBI lab group  
Nicole White  
Daniel Kennedy  
Kerrie Mengersen

<span style="color:lightblue">**WGS sequencing:**</span> Garvan Institute of Medical Research / Kinghorn Centre for Clinical Genomics

<span style="color:lightblue">**Funding:**</span> NHMRC, QUT Strategic Funds
]]

.pull-right[.medium[
#### <span style="color:lightblue">STDOI @ UTRGV</span>
John Blangero  
Joanne Curran  
Harald Goring

Greg Gibson (Georgia Institute of Technology, USA)  
Melanie Carless (Texas Biomedical Research Institute)  
Claire Bellis (Genome Institute of Singapore)

#### <span style="color:lightblue">NZ collaborators</span>
Donia Macartney-Coxson (ESR)  
David Eccles (Gringene Bioinformatics)  
Geoff Chambers (VUW)
]]

<br />

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