START Xchrom analysis

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<p style="font-weight: 900; font-family: helvetica; font-size: 3rem; color: yellow; text-shadow: 2px 2px black;">X-chromosome EWAS</p>

<p style="font-weight: 900; font-family: helvetica; font-size: 2.25rem; color: white; text-shadow: 2px 2px black;">what we found this far</p>

<br>
<p style="font-weight: 900; font-family: helvetica; font-size: 2.25rem; color: white; text-shadow: 2px 2px black;">Julia Romanowska</p>

<br>
<p style="font-weight: 900; font-family: helvetica; font-size: 1.5rem; color: white; text-shadow: 2px 2px black;">January 7, 2022</p>

<p style="font-size: 12pt; font-weight: bold; right: 10px; bottom: 20px; color: white; position: absolute; text-shadow: 2px 2px black;"> 
Photo by <a style="color: white;" href="https://unsplash.com/@robbiedown?utm_source=unsplash&utm_medium=referral&utm_content=creditCopyText">Robbie Down</a> on <a style="color: white;" href="https://unsplash.com/?utm_source=unsplash&utm_medium=referral&utm_content=creditCopyText">Unsplash</a>
</p>

---
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# OUTLINE

## <svg aria-hidden="true" role="img" viewBox="0 0 512 512" style="height:1em;width:1em;vertical-align:-0.125em;margin-left:auto;margin-right:auto;font-size:inherit;fill:currentColor;overflow:visible;position:relative;"><path d="M160 320h12v16c0 8.84 7.16 16 16 16h40c8.84 0 16-7.16 16-16v-16h12c17.67 0 32-14.33 32-32V64c0-17.67-14.33-32-32-32V16c0-8.84-7.16-16-16-16h-64c-8.84 0-16 7.16-16 16v16c-17.67 0-32 14.33-32 32v224c0 17.67 14.33 32 32 32zm304 128h-1.29C493.24 413.99 512 369.2 512 320c0-105.88-86.12-192-192-192v64c70.58 0 128 57.42 128 128s-57.42 128-128 128H48c-26.51 0-48 21.49-48 48 0 8.84 7.16 16 16 16h480c8.84 0 16-7.16 16-16 0-26.51-21.49-48-48-48zm-360-32h208c4.42 0 8-3.58 8-8v-16c0-4.42-3.58-8-8-8H104c-4.42 0-8 3.58-8 8v16c0 4.42 3.58 8 8 8z"/></svg> Data

## <svg aria-hidden="true" role="img" viewBox="0 0 640 512" style="height:1em;width:1.25em;vertical-align:-0.125em;margin-left:auto;margin-right:auto;font-size:inherit;fill:currentColor;overflow:visible;position:relative;"><path d="M255.03 261.65c6.25 6.25 16.38 6.25 22.63 0l11.31-11.31c6.25-6.25 6.25-16.38 0-22.63L253.25 192l35.71-35.72c6.25-6.25 6.25-16.38 0-22.63l-11.31-11.31c-6.25-6.25-16.38-6.25-22.63 0l-58.34 58.34c-6.25 6.25-6.25 16.38 0 22.63l58.35 58.34zm96.01-11.3l11.31 11.31c6.25 6.25 16.38 6.25 22.63 0l58.34-58.34c6.25-6.25 6.25-16.38 0-22.63l-58.34-58.34c-6.25-6.25-16.38-6.25-22.63 0l-11.31 11.31c-6.25 6.25-6.25 16.38 0 22.63L386.75 192l-35.71 35.72c-6.25 6.25-6.25 16.38 0 22.63zM624 416H381.54c-.74 19.81-14.71 32-32.74 32H288c-18.69 0-33.02-17.47-32.77-32H16c-8.8 0-16 7.2-16 16v16c0 35.2 28.8 64 64 64h512c35.2 0 64-28.8 64-64v-16c0-8.8-7.2-16-16-16zM576 48c0-26.4-21.6-48-48-48H112C85.6 0 64 21.6 64 48v336h512V48zm-64 272H128V64h384v256z"/></svg> Methods

## <svg aria-hidden="true" role="img" viewBox="0 0 512 512" style="height:1em;width:1em;vertical-align:-0.125em;margin-left:auto;margin-right:auto;font-size:inherit;fill:currentColor;overflow:visible;position:relative;"><path d="M167.02 309.34c-40.12 2.58-76.53 17.86-97.19 72.3-2.35 6.21-8 9.98-14.59 9.98-11.11 0-45.46-27.67-55.25-34.35C0 439.62 37.93 512 128 512c75.86 0 128-43.77 128-120.19 0-3.11-.65-6.08-.97-9.13l-88.01-73.34zM457.89 0c-15.16 0-29.37 6.71-40.21 16.45C213.27 199.05 192 203.34 192 257.09c0 13.7 3.25 26.76 8.73 38.7l63.82 53.18c7.21 1.8 14.64 3.03 22.39 3.03 62.11 0 98.11-45.47 211.16-256.46 7.38-14.35 13.9-29.85 13.9-45.99C512 20.64 486 0 457.89 0z"/></svg> Some results

## <svg aria-hidden="true" role="img" viewBox="0 0 512 512" style="height:1em;width:1em;vertical-align:-0.125em;margin-left:auto;margin-right:auto;font-size:inherit;fill:currentColor;overflow:visible;position:relative;"><path d="M504 256c0 136.997-111.043 248-248 248S8 392.997 8 256C8 119.083 119.043 8 256 8s248 111.083 248 248zM262.655 90c-54.497 0-89.255 22.957-116.549 63.758-3.536 5.286-2.353 12.415 2.715 16.258l34.699 26.31c5.205 3.947 12.621 3.008 16.665-2.122 17.864-22.658 30.113-35.797 57.303-35.797 20.429 0 45.698 13.148 45.698 32.958 0 14.976-12.363 22.667-32.534 33.976C247.128 238.528 216 254.941 216 296v4c0 6.627 5.373 12 12 12h56c6.627 0 12-5.373 12-12v-1.333c0-28.462 83.186-29.647 83.186-106.667 0-58.002-60.165-102-116.531-102zM256 338c-25.365 0-46 20.635-46 46 0 25.364 20.635 46 46 46s46-20.636 46-46c0-25.365-20.635-46-46-46z"/></svg> Discussion

---

- Boys <svg aria-hidden="true" role="img" viewBox="0 0 384 512" style="height:1em;width:0.75em;vertical-align:-0.125em;margin-left:auto;margin-right:auto;font-size:inherit;fill:currentColor;overflow:visible;position:relative;"><path d="M372 64h-79c-10.7 0-16 12.9-8.5 20.5l16.9 16.9-80.7 80.7c-22.2-14-48.5-22.1-76.7-22.1C64.5 160 0 224.5 0 304s64.5 144 144 144 144-64.5 144-144c0-28.2-8.1-54.5-22.1-76.7l80.7-80.7 16.9 16.9c7.6 7.6 20.5 2.2 20.5-8.5V76c0-6.6-5.4-12-12-12zM144 384c-44.1 0-80-35.9-80-80s35.9-80 80-80 80 35.9 80 80-35.9 80-80 80z"/></svg> and girls <svg aria-hidden="true" role="img" viewBox="0 0 288 512" style="height:1em;width:0.56em;vertical-align:-0.125em;margin-left:auto;margin-right:auto;font-size:inherit;fill:currentColor;overflow:visible;position:relative;"><path d="M288 176c0-79.5-64.5-144-144-144S0 96.5 0 176c0 68.5 47.9 125.9 112 140.4V368H76c-6.6 0-12 5.4-12 12v40c0 6.6 5.4 12 12 12h36v36c0 6.6 5.4 12 12 12h40c6.6 0 12-5.4 12-12v-36h36c6.6 0 12-5.4 12-12v-40c0-6.6-5.4-12-12-12h-36v-51.6c64.1-14.5 112-71.9 112-140.4zm-224 0c0-44.1 35.9-80 80-80s80 35.9 80 80-35.9 80-80 80-80-35.9-80-80z"/></svg> separately

- **models** and **sample sizes**:

1. CpG ~ ART + mat_age + smoking + mat_bmi + isPrimiparous

2. CpG ~ ART + mat_age + smoking + mat_bmi + isPrimiparous + mat_meth + pat_meth

3. CpG ~ ART + mat_age + smoking + mat_bmi + isPrimiparous + GA + BW

4. CpG ~ ART + mat_age + smoking + mat_bmi + isPrimiparous + GA + BW + mat_meth + pat_meth

<table style="width:100%">
  <tr>
    <th></th>
    <th colspan="2" style="border-left: 1px solid black;">Model 1</th>
    <th colspan="2" style="border-left: 1px solid black;">Model 2</th>
    <th colspan="2" style="border-left: 1px solid black;">Model 3</th>
    <th colspan="2" style="border-left: 1px solid black;">Model 4</th>
  </tr>
  <tr style="font-weight: bold; text-align: center;">
    <td></td>
    <td>ART</td>
    <td>control</td>
    <td>ART</td>
    <td>control</td>
    <td>ART</td>
    <td>control</td>
    <td>ART</td>
    <td>control</td>
  </tr>
  <tr style="text-align: center;">
    <td><img src="mars-solid.svg" style="width: 20px" alt="boys"></td>
    <td>495</td>
    <td>463</td>
    <td>488</td>
    <td>456</td>
    <td>494</td>
    <td>461</td>
    <td>487</td>
    <td>454</td>
  </tr>
  <tr style="text-align: center;">
    <td><img src="venus-solid.svg" style="width: 15px" alt="girls"></td>
    <td>446</td>
    <td>503</td>
    <td>440</td>
    <td>495</td>
    <td>446</td>
    <td>501</td>
    <td>440</td>
    <td>493</td>
  </tr>
</table>

???

The main models we're discussing in the paper are Models 1 & 2, while Models 
3 & 4 are mainly in the Supplementary.

Models 3 & 4 expand models 1 & 2 by adjusting also for gestational age &
birth weight; models 3 & 4 expand models 1 & 2, respectively, by adjusting
also for parental DNAm.

We saw that the most significant results were very similar in all the models,
specifically, adding adjustment for GA and BW did not change the outcome.

---

- linear regression

- **BACON** - to remove bias in p-values

- **DMRff** - to check for *differentially methylated regions*

- **ggcorrplot** to calculate and visualize *correlation of DNAm*

- **karyoploteR** & **biomaRt** - to visualize location of hits

???

Haakon Nustad did lot of work. Julia Romanowska did post-processing, bioinformatics
analyses, and plotting.

---

## EWAS

???

There were no big difference in the most significant findings across the models.

In the boys-only analyses, there were mainly 3 CpGs, with 2 extra being
significant in model 1.

In the girls-only analyses, there were the same 6 significant CpGs in _all_
the models.

---

**Significant CpGs** &nbsp;&nbsp;&nbsp; *significant if FDR < 0.05*

???

The significant CpGs were very similar in between the models - both effect size
and FDR-adjusted p-values did not change much.

There are no CpGs that are common among boys and girls, not even if we consider
genomic regions.

---

**DMRs** &nbsp;&nbsp;&nbsp; *significant if FDR < 0.01 and \#CpGs >= 3*

???

We've found also many DMRs - interestingly more among girls than boys.

Vast majority of the DMRs overlapped with promoter regions; several were co-located
with CTCF (an ubiquitous TF) binding site; and only in two cases the DMR was
within a gene body.

---

**Co-methylation patterns**

**Boys, near two most significant CpGs**

???

And now, for something really cool!

Co-methylation patterns around the significant EWAS findings.

Example plot - boys-only analyses showed two CpGs that were most significant
across all the models. These two are very near each other, only several bp
away, so it's actually good to see that they are both picked up in our
analyses. We also see that their DNAm levels are very highly correlated with
each other and there is a small cluster of CpGs around those. These were
picked up in the DMRff analyses.

This DMR is within a short gene, _UBE2DNL_. This gene is transcribed to a protein,
but its function is not known. Intriguingly, UBE2DNL protein is an enzyme that
lacks a crucial cytosine in its active site, thus it is probably inactive.
We know, however, that it's expressed almost only in testis.

---

**Girls, near cg13866977**

???

There were two equally significant results in the girls-only EWA calculations: cg25034591 and cg13866977. The last one being within a regulatory region and, at the same time, within an intron of angiomotin (AMOT) gene. Interestingly, one of the CpGs (cg13866977 was originally) annotated to a region originally defined as ‘enhancer’ in the GRCh37 genome build but this was changed to ‘promoter flanking region’ in the newer GRCh38 genome build (ensembl regulatory ID ENSR00000912938). It is not unprecedented for the definition and location of annotations to change from one genome version to another. For example, the distinction between promoter and enhancer is not always clear, especially when they have several properties and functions in common, and an update from old definitions might alter the original annotations [REF]. Hence, a more suitable annotation for cg13866977 might have been ‘transcription regulatory element’. Moreover, GeneHancer db (REF) lists this regulatory region as putative enhancer of the AMOT gene (GH ID GH0XJ112807, https://www.genecards.org/cgi-bin/carddisp.pl?gene=AMOT&keywords=AMOT#genomic_location).
This regulatory region is active in only six cell types, one of which is placenta. This is based on the ensembl visualization of experimental data showing various histone markers states and DNase1 activity (http://www.ensembl.org/Homo_sapiens/Regulation/Summary?db=core;fdb=funcgen;r=X:112806973-112809972;rf=ENSR00000912938). According to The Huma Protein Atlas, AMOT protein is mainly expressed in placenta and kidney (https://www.proteinatlas.org/ENSG00000126016-AMOT/tissue), however, AMOT gene is much more transcribed in epididymis (part of the male reproductive system). 
Our data shows that the DNAm level at cg13866977 is almost 1 in boys (i.e., full methylation of the cytosine) and above 0.7 in majority of cases in girls (Figure_AMOT_CpG_methylation). Since DNAm signals are mainly translated to the transcription level, we looked at whether the transcription factors (TFs) that were predicted to bind to cg13866977 have preferrence to bind to the unmethylated or methylated sequence. The JASPAR and MeDReaders (http://medreader.org/browse-tf) databases show that out of seven TFs none were shown to bind to the methylated sequence, thus suggesting that the methylated state of this CpG signalises inactivation of this regulatory region. Moreover, the methylation state is higher for the girls conceived through ART than those conceived naturally (effect size 0.32, Model 1) and does not change much when we adjusted for parental DNAm at this site (effect size 0.33, Model 2). This suggests that the regulatory region within AMOT is less activated after the ART procedure in girls.

---

**Zooming on DMRs...**

???

One of the significant DMRs in the girls-only analyses was co-located with a promoter (ensembl ID ENSR00000249590), which according to GeneHancer DB (GH ID GH0XJ153721) is putative promoter or enhancer for nine genes (ABCD1, BCAP31, HSALNG0140785, PNCK, SLC6A8, KRT18P48, PDZD4, HSALNG0140788, and PLXNB3). Six of these genes produce proteins (ABCD1, BCAP31, PNCK, SLC6A8, PDZD4, and PLXNB3) that form a network, according to evidence from text mining and co-expression arrays (STRING DB, https://version-11-5.string-db.org/cgi/network?networkId=bWgRg6ih0nDV). Deletions or duplications of many of these genes were reported to manifest as impairments or diseases, among those autism.
Right next to this DMR, the boys-only analysis showed a significant DMR co-located with a promoter (ensembl ID ENSR00002105690, GH ID GH0XJ153780) of genes SRPK3, PLXNB3, HSALNG0140793, and SSR4. Of these, only HSALNG0140793 is not a protein coding gene, however, the three other genes does not seem to have much in common. STRING DB shows no interactions (https://version-11-5.string-db.org/cgi/network?networkId=bCqD1tk1QVKv) and no common expression tissue (main RNA-expression profiles are: pancreas for SSR4 (https://www.proteinatlas.org/ENSG00000180879-SSR4/tissue), muscle for SRPK3 (https://www.proteinatlas.org/ENSG00000184343-SRPK3/tissue), and brain for PLXNB3 (https://www.proteinatlas.org/ENSG00000198753-PLXNB3/tissue)).

---

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class: top, center

<p style="font-weight: 600; font-family: helvetica; font-size: 2rem; color: black;"><svg aria-hidden="true" role="img" viewBox="0 0 512 512" style="height:1em;width:1em;vertical-align:-0.125em;margin-left:auto;margin-right:auto;font-size:inherit;fill:black;overflow:visible;position:relative;"><path d="M504 256c0 136.997-111.043 248-248 248S8 392.997 8 256C8 119.083 119.043 8 256 8s248 111.083 248 248zM262.655 90c-54.497 0-89.255 22.957-116.549 63.758-3.536 5.286-2.353 12.415 2.715 16.258l34.699 26.31c5.205 3.947 12.621 3.008 16.665-2.122 17.864-22.658 30.113-35.797 57.303-35.797 20.429 0 45.698 13.148 45.698 32.958 0 14.976-12.363 22.667-32.534 33.976C247.128 238.528 216 254.941 216 296v4c0 6.627 5.373 12 12 12h56c6.627 0 12-5.373 12-12v-1.333c0-28.462 83.186-29.647 83.186-106.667 0-58.002-60.165-102-116.531-102zM256 338c-25.365 0-46 20.635-46 46 0 25.364 20.635 46 46 46s46-20.636 46-46c0-25.365-20.635-46-46-46z"/></svg> Questions?</p>

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---

**Who wants to be on the author list?**

<p style="font-style: bold;"> LEGEND:</p>

<table style="width: 250px; right: 50px;">
  <tr>
    <th>symbol</th>
    <th style="border-left: 1px solid black;">responsibilities</th>
  </tr>
  <tr>
    <td style="text-align: center;"><svg aria-hidden="true" role="img" viewBox="0 0 384 512" style="height:1em;width:0.75em;vertical-align:-0.125em;margin-left:auto;margin-right:auto;font-size:inherit;fill:currentColor;overflow:visible;position:relative;"><path d="M120 72c0-39.765 32.235-72 72-72s72 32.235 72 72c0 39.764-32.235 72-72 72s-72-32.236-72-72zm254.627 1.373c-12.496-12.497-32.758-12.497-45.254 0L242.745 160H141.254L54.627 73.373c-12.496-12.497-32.758-12.497-45.254 0-12.497 12.497-12.497 32.758 0 45.255L104 213.254V480c0 17.673 14.327 32 32 32h16c17.673 0 32-14.327 32-32V368h16v112c0 17.673 14.327 32 32 32h16c17.673 0 32-14.327 32-32V213.254l94.627-94.627c12.497-12.497 12.497-32.757 0-45.254z"/></svg></td><td>playing with data</td>
  </tr>
  <tr>
    <td style="text-align: center;"><svg aria-hidden="true" role="img" viewBox="0 0 448 512" style="height:1em;width:0.88em;vertical-align:-0.125em;margin-left:auto;margin-right:auto;font-size:inherit;fill:currentColor;overflow:visible;position:relative;"><path d="M224 256c70.7 0 128-57.3 128-128S294.7 0 224 0 96 57.3 96 128s57.3 128 128 128zM104 424c0 13.3 10.7 24 24 24s24-10.7 24-24-10.7-24-24-24-24 10.7-24 24zm216-135.4v49c36.5 7.4 64 39.8 64 78.4v41.7c0 7.6-5.4 14.2-12.9 15.7l-32.2 6.4c-4.3.9-8.5-1.9-9.4-6.3l-3.1-15.7c-.9-4.3 1.9-8.6 6.3-9.4l19.3-3.9V416c0-62.8-96-65.1-96 1.9v26.7l19.3 3.9c4.3.9 7.1 5.1 6.3 9.4l-3.1 15.7c-.9 4.3-5.1 7.1-9.4 6.3l-31.2-4.2c-7.9-1.1-13.8-7.8-13.8-15.9V416c0-38.6 27.5-70.9 64-78.4v-45.2c-2.2.7-4.4 1.1-6.6 1.9-18 6.3-37.3 9.8-57.4 9.8s-39.4-3.5-57.4-9.8c-7.4-2.6-14.9-4.2-22.6-5.2v81.6c23.1 6.9 40 28.1 40 53.4 0 30.9-25.1 56-56 56s-56-25.1-56-56c0-25.3 16.9-46.5 40-53.4v-80.4C48.5 301 0 355.8 0 422.4v44.8C0 491.9 20.1 512 44.8 512h358.4c24.7 0 44.8-20.1 44.8-44.8v-44.8c0-72-56.8-130.3-128-133.8z"/></svg></td><td>contribute to discussion; biological expertise</td>
  </tr>
  <tr>
    <td style="text-align: center;"><svg aria-hidden="true" role="img" viewBox="0 0 448 512" style="height:1em;width:0.88em;vertical-align:-0.125em;margin-left:auto;margin-right:auto;font-size:inherit;fill:currentColor;overflow:visible;position:relative;"><path d="M383.9 308.3l23.9-62.6c4-10.5-3.7-21.7-15-21.7h-58.5c11-18.9 17.8-40.6 17.8-64v-.3c39.2-7.8 64-19.1 64-31.7 0-13.3-27.3-25.1-70.1-33-9.2-32.8-27-65.8-40.6-82.8-9.5-11.9-25.9-15.6-39.5-8.8l-27.6 13.8c-9 4.5-19.6 4.5-28.6 0L182.1 3.4c-13.6-6.8-30-3.1-39.5 8.8-13.5 17-31.4 50-40.6 82.8-42.7 7.9-70 19.7-70 33 0 12.6 24.8 23.9 64 31.7v.3c0 23.4 6.8 45.1 17.8 64H56.3c-11.5 0-19.2 11.7-14.7 22.3l25.8 60.2C27.3 329.8 0 372.7 0 422.4v44.8C0 491.9 20.1 512 44.8 512h358.4c24.7 0 44.8-20.1 44.8-44.8v-44.8c0-48.4-25.8-90.4-64.1-114.1zM176 480l-41.6-192 49.6 32 24 40-32 120zm96 0l-32-120 24-40 49.6-32L272 480zm41.7-298.5c-3.9 11.9-7 24.6-16.5 33.4-10.1 9.3-48 22.4-64-25-2.8-8.4-15.4-8.4-18.3 0-17 50.2-56 32.4-64 25-9.5-8.8-12.7-21.5-16.5-33.4-.8-2.5-6.3-5.7-6.3-5.8v-10.8c28.3 3.6 61 5.8 96 5.8s67.7-2.1 96-5.8v10.8c-.1.1-5.6 3.2-6.4 5.8z"/></svg></td><td>checking literature, making text shine</td>
  </tr>
  <tr>
    <td style="text-align: center;"><svg aria-hidden="true" role="img" viewBox="0 0 448 512" style="height:1em;width:0.88em;vertical-align:-0.125em;margin-left:auto;margin-right:auto;font-size:inherit;fill:currentColor;overflow:visible;position:relative;"><path d="M319.4 320.6L224 416l-95.4-95.4C57.1 323.7 0 382.2 0 454.4v9.6c0 26.5 21.5 48 48 48h352c26.5 0 48-21.5 48-48v-9.6c0-72.2-57.1-130.7-128.6-133.8zM13.6 79.8l6.4 1.5v58.4c-7 4.2-12 11.5-12 20.3 0 8.4 4.6 15.4 11.1 19.7L3.5 242c-1.7 6.9 2.1 14 7.6 14h41.8c5.5 0 9.3-7.1 7.6-14l-15.6-62.3C51.4 175.4 56 168.4 56 160c0-8.8-5-16.1-12-20.3V87.1l66 15.9c-8.6 17.2-14 36.4-14 57 0 70.7 57.3 128 128 128s128-57.3 128-128c0-20.6-5.3-39.8-14-57l96.3-23.2c18.2-4.4 18.2-27.1 0-31.5l-190.4-46c-13-3.1-26.7-3.1-39.7 0L13.6 48.2c-18.1 4.4-18.1 27.2 0 31.6z"/></svg></td><td>supervision</td>
  </tr>
  <tr>
    <td style="text-align: center;"><svg aria-hidden="true" role="img" viewBox="0 0 448 512" style="height:1em;width:0.88em;vertical-align:-0.125em;margin-left:auto;margin-right:auto;font-size:inherit;fill:currentColor;overflow:visible;position:relative;"><path d="M64 224h13.5c24.7 56.5 80.9 96 146.5 96s121.8-39.5 146.5-96H384c8.8 0 16-7.2 16-16v-96c0-8.8-7.2-16-16-16h-13.5C345.8 39.5 289.6 0 224 0S102.2 39.5 77.5 96H64c-8.8 0-16 7.2-16 16v96c0 8.8 7.2 16 16 16zm40-88c0-22.1 21.5-40 48-40h144c26.5 0 48 17.9 48 40v24c0 53-43 96-96 96h-48c-53 0-96-43-96-96v-24zm72 72l12-36 36-12-36-12-12-36-12 36-36 12 36 12 12 36zm151.6 113.4C297.7 340.7 262.2 352 224 352s-73.7-11.3-103.6-30.6C52.9 328.5 0 385 0 454.4v9.6c0 26.5 21.5 48 48 48h80v-64c0-17.7 14.3-32 32-32h128c17.7 0 32 14.3 32 32v64h80c26.5 0 48-21.5 48-48v-9.6c0-69.4-52.9-125.9-120.4-133zM272 448c-8.8 0-16 7.2-16 16s7.2 16 16 16 16-7.2 16-16-7.2-16-16-16zm-96 0c-8.8 0-16 7.2-16 16v48h32v-48c0-8.8-7.2-16-16-16z"/></svg></td><td>suddenly appearing and asking <i>the most to-the-point question</i></td>
  </tr>
  <tr>
    <td style="text-align: center;"><svg aria-hidden="true" role="img" viewBox="0 0 640 512" style="height:1em;width:1.25em;vertical-align:-0.125em;margin-left:auto;margin-right:auto;font-size:inherit;fill:currentColor;overflow:visible;position:relative;"><path d="M192 256c61.9 0 112-50.1 112-112S253.9 32 192 32 80 82.1 80 144s50.1 112 112 112zm76.8 32h-8.3c-20.8 10-43.9 16-68.5 16s-47.6-6-68.5-16h-8.3C51.6 288 0 339.6 0 403.2V432c0 26.5 21.5 48 48 48h288c26.5 0 48-21.5 48-48v-28.8c0-63.6-51.6-115.2-115.2-115.2zM480 256c53 0 96-43 96-96s-43-96-96-96-96 43-96 96 43 96 96 96zm48 32h-3.8c-13.9 4.8-28.6 8-44.2 8s-30.3-3.2-44.2-8H432c-20.4 0-39.2 5.9-55.7 15.4 24.4 26.3 39.7 61.2 39.7 99.8v38.4c0 2.2-.5 4.3-.6 6.4H592c26.5 0 48-21.5 48-48 0-61.9-50.1-112-112-112z"/></svg></td><td>friendly reviewing the bioinf. approach and implementation</td>
  </tr>
</table>

</div>

currently:

- <svg aria-hidden="true" role="img" viewBox="0 0 384 512" style="height:1em;width:0.75em;vertical-align:-0.125em;margin-left:auto;margin-right:auto;font-size:inherit;fill:currentColor;overflow:visible;position:relative;"><path d="M120 72c0-39.765 32.235-72 72-72s72 32.235 72 72c0 39.764-32.235 72-72 72s-72-32.236-72-72zm254.627 1.373c-12.496-12.497-32.758-12.497-45.254 0L242.745 160H141.254L54.627 73.373c-12.496-12.497-32.758-12.497-45.254 0-12.497 12.497-12.497 32.758 0 45.255L104 213.254V480c0 17.673 14.327 32 32 32h16c17.673 0 32-14.327 32-32V368h16v112c0 17.673 14.327 32 32 32h16c17.673 0 32-14.327 32-32V213.254l94.627-94.627c12.497-12.497 12.497-32.757 0-45.254z"/></svg> *Julia Romanowska*,

- <svg aria-hidden="true" role="img" viewBox="0 0 640 512" style="height:1em;width:1.25em;vertical-align:-0.125em;margin-left:auto;margin-right:auto;font-size:inherit;fill:currentColor;overflow:visible;position:relative;"><path d="M192 256c61.9 0 112-50.1 112-112S253.9 32 192 32 80 82.1 80 144s50.1 112 112 112zm76.8 32h-8.3c-20.8 10-43.9 16-68.5 16s-47.6-6-68.5-16h-8.3C51.6 288 0 339.6 0 403.2V432c0 26.5 21.5 48 48 48h288c26.5 0 48-21.5 48-48v-28.8c0-63.6-51.6-115.2-115.2-115.2zM480 256c53 0 96-43 96-96s-43-96-96-96-96 43-96 96 43 96 96 96zm48 32h-3.8c-13.9 4.8-28.6 8-44.2 8s-30.3-3.2-44.2-8H432c-20.4 0-39.2 5.9-55.7 15.4 24.4 26.3 39.7 61.2 39.7 99.8v38.4c0 2.2-.5 4.3-.6 6.4H592c26.5 0 48-21.5 48-48 0-61.9-50.1-112-112-112z"/></svg> *Christian M. Page*,

- <svg aria-hidden="true" role="img" viewBox="0 0 448 512" style="height:1em;width:0.88em;vertical-align:-0.125em;margin-left:auto;margin-right:auto;font-size:inherit;fill:currentColor;overflow:visible;position:relative;"><path d="M224 256c70.7 0 128-57.3 128-128S294.7 0 224 0 96 57.3 96 128s57.3 128 128 128zM104 424c0 13.3 10.7 24 24 24s24-10.7 24-24-10.7-24-24-24-24 10.7-24 24zm216-135.4v49c36.5 7.4 64 39.8 64 78.4v41.7c0 7.6-5.4 14.2-12.9 15.7l-32.2 6.4c-4.3.9-8.5-1.9-9.4-6.3l-3.1-15.7c-.9-4.3 1.9-8.6 6.3-9.4l19.3-3.9V416c0-62.8-96-65.1-96 1.9v26.7l19.3 3.9c4.3.9 7.1 5.1 6.3 9.4l-3.1 15.7c-.9 4.3-5.1 7.1-9.4 6.3l-31.2-4.2c-7.9-1.1-13.8-7.8-13.8-15.9V416c0-38.6 27.5-70.9 64-78.4v-45.2c-2.2.7-4.4 1.1-6.6 1.9-18 6.3-37.3 9.8-57.4 9.8s-39.4-3.5-57.4-9.8c-7.4-2.6-14.9-4.2-22.6-5.2v81.6c23.1 6.9 40 28.1 40 53.4 0 30.9-25.1 56-56 56s-56-25.1-56-56c0-25.3 16.9-46.5 40-53.4v-80.4C48.5 301 0 355.8 0 422.4v44.8C0 491.9 20.1 512 44.8 512h358.4c24.7 0 44.8-20.1 44.8-44.8v-44.8c0-72-56.8-130.3-128-133.8z"/></svg> *Maria C. Magnus*,

- <svg aria-hidden="true" role="img" viewBox="0 0 448 512" style="height:1em;width:0.88em;vertical-align:-0.125em;margin-left:auto;margin-right:auto;font-size:inherit;fill:currentColor;overflow:visible;position:relative;"><path d="M64 224h13.5c24.7 56.5 80.9 96 146.5 96s121.8-39.5 146.5-96H384c8.8 0 16-7.2 16-16v-96c0-8.8-7.2-16-16-16h-13.5C345.8 39.5 289.6 0 224 0S102.2 39.5 77.5 96H64c-8.8 0-16 7.2-16 16v96c0 8.8 7.2 16 16 16zm40-88c0-22.1 21.5-40 48-40h144c26.5 0 48 17.9 48 40v24c0 53-43 96-96 96h-48c-53 0-96-43-96-96v-24zm72 72l12-36 36-12-36-12-12-36-12 36-36 12 36 12 12 36zm151.6 113.4C297.7 340.7 262.2 352 224 352s-73.7-11.3-103.6-30.6C52.9 328.5 0 385 0 454.4v9.6c0 26.5 21.5 48 48 48h80v-64c0-17.7 14.3-32 32-32h128c17.7 0 32 14.3 32 32v64h80c26.5 0 48-21.5 48-48v-9.6c0-69.4-52.9-125.9-120.4-133zM272 448c-8.8 0-16 7.2-16 16s7.2 16 16 16 16-7.2 16-16-7.2-16-16-16zm-96 0c-8.8 0-16 7.2-16 16v48h32v-48c0-8.8-7.2-16-16-16z"/></svg> *Håkon K. Gjessing*,

- <svg aria-hidden="true" role="img" viewBox="0 0 448 512" style="height:1em;width:0.88em;vertical-align:-0.125em;margin-left:auto;margin-right:auto;font-size:inherit;fill:currentColor;overflow:visible;position:relative;"><path d="M319.4 320.6L224 416l-95.4-95.4C57.1 323.7 0 382.2 0 454.4v9.6c0 26.5 21.5 48 48 48h352c26.5 0 48-21.5 48-48v-9.6c0-72.2-57.1-130.7-128.6-133.8zM13.6 79.8l6.4 1.5v58.4c-7 4.2-12 11.5-12 20.3 0 8.4 4.6 15.4 11.1 19.7L3.5 242c-1.7 6.9 2.1 14 7.6 14h41.8c5.5 0 9.3-7.1 7.6-14l-15.6-62.3C51.4 175.4 56 168.4 56 160c0-8.8-5-16.1-12-20.3V87.1l66 15.9c-8.6 17.2-14 36.4-14 57 0 70.7 57.3 128 128 128s128-57.3 128-128c0-20.6-5.3-39.8-14-57l96.3-23.2c18.2-4.4 18.2-27.1 0-31.5l-190.4-46c-13-3.1-26.7-3.1-39.7 0L13.6 48.2c-18.1 4.4-18.1 27.2 0 31.6z"/></svg> *Per Magnus*,

- <svg aria-hidden="true" role="img" viewBox="0 0 448 512" style="height:1em;width:0.88em;vertical-align:-0.125em;margin-left:auto;margin-right:auto;font-size:inherit;fill:currentColor;overflow:visible;position:relative;"><path d="M319.4 320.6L224 416l-95.4-95.4C57.1 323.7 0 382.2 0 454.4v9.6c0 26.5 21.5 48 48 48h352c26.5 0 48-21.5 48-48v-9.6c0-72.2-57.1-130.7-128.6-133.8zM13.6 79.8l6.4 1.5v58.4c-7 4.2-12 11.5-12 20.3 0 8.4 4.6 15.4 11.1 19.7L3.5 242c-1.7 6.9 2.1 14 7.6 14h41.8c5.5 0 9.3-7.1 7.6-14l-15.6-62.3C51.4 175.4 56 168.4 56 160c0-8.8-5-16.1-12-20.3V87.1l66 15.9c-8.6 17.2-14 36.4-14 57 0 70.7 57.3 128 128 128s128-57.3 128-128c0-20.6-5.3-39.8-14-57l96.3-23.2c18.2-4.4 18.2-27.1 0-31.5l-190.4-46c-13-3.1-26.7-3.1-39.7 0L13.6 48.2c-18.1 4.4-18.1 27.2 0 31.6z"/></svg> *Siri E. Håberg*,

- <svg aria-hidden="true" role="img" viewBox="0 0 448 512" style="height:1em;width:0.88em;vertical-align:-0.125em;margin-left:auto;margin-right:auto;font-size:inherit;fill:currentColor;overflow:visible;position:relative;"><path d="M383.9 308.3l23.9-62.6c4-10.5-3.7-21.7-15-21.7h-58.5c11-18.9 17.8-40.6 17.8-64v-.3c39.2-7.8 64-19.1 64-31.7 0-13.3-27.3-25.1-70.1-33-9.2-32.8-27-65.8-40.6-82.8-9.5-11.9-25.9-15.6-39.5-8.8l-27.6 13.8c-9 4.5-19.6 4.5-28.6 0L182.1 3.4c-13.6-6.8-30-3.1-39.5 8.8-13.5 17-31.4 50-40.6 82.8-42.7 7.9-70 19.7-70 33 0 12.6 24.8 23.9 64 31.7v.3c0 23.4 6.8 45.1 17.8 64H56.3c-11.5 0-19.2 11.7-14.7 22.3l25.8 60.2C27.3 329.8 0 372.7 0 422.4v44.8C0 491.9 20.1 512 44.8 512h358.4c24.7 0 44.8-20.1 44.8-44.8v-44.8c0-48.4-25.8-90.4-64.1-114.1zM176 480l-41.6-192 49.6 32 24 40-32 120zm96 0l-32-120 24-40 49.6-32L272 480zm41.7-298.5c-3.9 11.9-7 24.6-16.5 33.4-10.1 9.3-48 22.4-64-25-2.8-8.4-15.4-8.4-18.3 0-17 50.2-56 32.4-64 25-9.5-8.8-12.7-21.5-16.5-33.4-.8-2.5-6.3-5.7-6.3-5.8v-10.8c28.3 3.6 61 5.8 96 5.8s67.7-2.1 96-5.8v10.8c-.1.1-5.6 3.2-6.4 5.8z"/></svg> *Astanand Jugessur*