Forgotten but not gone

Life is said to have originated in the RNA world.  We all know about the big 3 important RNAs for the cell, mRNA, ribosomal RNA and transfer RNA.  But just like the water, sewer, power and subway systems under Manhattan, there is another world down there in the cell which doesn’t much get talked about.  These are RNAs, whose primary (and possibly only) function is to interact with other RNAs.

Start with microRNAs (of which we have at least 1,500 as of 12/12).  Their function is to bind to messenger RNA (mRNA) and inhibit translation of the mRNA into protein.  The effects aren’t huge, but they are a more subtle control of protein expression, than the degree of transcription of the gene.

Then there are ceRNAs (competitive endogenous RNAs) which have a large number of binding sites for microRNAs — humans have a variety of them all with horrible acronyms — HULC, PTCSC3 etc. etc. They act as sponges for microRNAs keeping them bound and quiet.

Then there are circular RNAs.  They’d been missed until recently, because typical RNA sequencing methods isolate only RNAs with characteristic tails, and a circular RNA doesn’t have any.  One such is called CiRS7/CDR1) which contain 70 binding sites for one particular microRNA (miR-7).  They are unlike to be trivial.  They are derived from 15% of actively transcribed genes.  They ‘can be’ 10 times as numerous as linear RNAs (like mRNA and everything else) — probably because they are hard to degrade < Science vol. 340 pp. 440 – 441 ’17 >. So some of them are certainly RNA sponges — but all of them?

The latest, and most interesting class are the nonCoding RNAs found in viruses. Some of them function to attack cellular microRNAs and help the virus survive. Herpesvirus saimiri a gamma-herpes virus establishes latency in the T lymphocytes of New World primates, by expressing 7 small nuclear uracil-rich nonCoding RNAs (called HSURs).  They associate with some microRNAs, and rather than blocking their function act as chaperones < Nature vol. 550 pp. 275 – 279 ’17 >.  They HSURs also bind to some mRNAs inhibiting their function — they do this by helping miR-16 bind to their targets — so they are chaperones.  So viral Sm-class RNAs may function as microRNA adaptors.

Do you think for one minute, that the cell isn’t doing something like this.

I have a tendency to think of RNAs as always binding to other RNAs by classic Watson Crick base pairing — this is wrong as a look at any transfer RNA structure will show. https://en.wikipedia.org/wiki/Transfer_RNA.  Far more complicated structures may be involved, but we’ve barely started to look.

Then there are the pseudogenes, which may also have a function, which is to be transcribed and sop up microRNAs and other things — I’ve already written about this — https://luysii.wordpress.com/2010/07/14/junk-dna-that-isnt-and-why-chemistry-isnt-enough/.  Breast cancer cells think one (PTEN1) is important enough to stop it from being transcribed, even though it can’t be translated into protein.

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Does she or doesn’t she? Only her geneticist knows for sure

Back in the day there was a famous ad for Claroil — Does she or doesn’t she? Only her hairdresser knows for sure.  Now it’s the geneticist who can sequence genes for Two Pore Channels in pigment forming cells (melanocytes) who really knows.

Except for redheads, skin and hair color is determined by how much eumelanin you have.  All human melanins are  polymers of oxidation products of tyrosine (DOPA, DOPAquinone) and indole 5,6 quinone, so its chemical structure isn’t certain.  It is made inside a specialized organelle of the melanocyte called (logically enough) the melanosome.

There is all sorts of interesting chemistry and physiology involved.  In particular a melanosome protein called Pmel17 adopts an amyloid-like structure (so not all amyloid is bad !) for the construction of melanin.  The crucial enzyme oxidizing tyrosine is tyrosinase, and its activity strongly depends on pH, being most active at pH 7 (neutral pH).

In the melanosome membrane is found TPC2, which helps control ion flow in and out of the melanosome.  Two mutations Methionine #484 –> Leucine (or M484L) and Glycine #734 –> Glutamic acid (G734E) are associated with a shift from brown to blond.  You have blond hair if your melanosomes make less melanin.  Both mutations result in an increase in TPC2 activity resulting in lower pH, lower tyrosinase activity and less melanin in the melanosome — voila — a blond.

So it doesn’t take a big (one amino acid in over 734) change in the huge TCP2 protein for the shift to occur.

A possibly useful computer tip and two social notes

Since the computer was down last week, no science to report, but here’s a possibly useful computer tip and two social notes.

If you’ve been using computers as long as we have (30+ years), you were probably told that it was better to leave the computer on all the time rather than turning the power off and on.   Not so any more — the Apple tech who fixed it told me it should be shut down then rebooted once a week.

Two narratives beloved by the mainstream press since the loss by their candidate  suffered major body blows the past week.

Narrative #1. Trump is a Nazi.  Surely you remember the way a far-Right rally was reported shortly after the election.  Read all about it as reported in the Atlantic — https://www.theatlantic.com/politics/archive/2016/11/richard-spencer-speech-npi/508379/.  It got a lot of press, here and elsewhere.  There may have been all of 300 people there.  Then there were his unfortunate comments after Charlottesville.

Unfortunately for the meme — the following appeared this week in the New York Times  —

WASHINGTON — The Trump administration announced on Thursday that it would withdraw from Unesco, the United Nations cultural organization, after years of the United States distancing itself because of what it called the group’s “anti-Israel bias.”

Here’s the link — https://www.nytimes.com/2017/10/12/us/politics/trump-unesco-withdrawal.html

Narrative #2:  The Russians did everything they could to swing the election to Trump.  Well we finally are finding out just what the Russians actually did — this from Facebook and Cheryl Sandberg (hardly friends of Trump).

The following is from a Wall Street Journal article appearing 13 October 2017.  Here is the link — https://www.wsj.com/articles/facebook-users-were-unwitting-targets-of-russia-backed-scheme-1507918659

“Two accounts that Facebook Inc. FB 0.69% said appear to have ties to Russian operatives amassed more than half a million followers in the past couple of years with posts, ads and events that stoked strong emotions over issues including race and immigration.

Most followers never suspected that people with possible Russian ties were behind the accounts—except for a few users who interacted in real life with the people running the sites.

Some users said the content from these accounts seemed like something their peers would share. “Blacktivist,” an account that supported causes in the black community and used hashtags such as #BlackLivesMatter, frequently posted videos of police allegedly shooting unarmed black men. ”

If the Russians were trying to elect Trump, do you think they would have thought inflaming a group that votes overwhelmingly Democratic was a good idea?.

Basically they were trying to inflame the body politic with divisive material.

The Voice of America had a similar effect behind the Iron Curtain.  The difference, of course, is that our source was quite undisguised.

The Russian government is not our friend.  I’m glad my grandparents got out of the Baltics and Poland in the late 19th century.

Abeta42 at last

It’s easy to see why cryoEM got the latest chemistry Nobel.  It is telling us so much.  Particularly fascinating to me as a retired neurologist is the structure of the Abeta42 fibril reported in last Friday’s Science (vol. 358 pp. 116 – 119 ’17).  

Caveats first.  The materials were prepared using an aqueous solution at low pH containing an organic cosolvent — so how physiologic could the structure actually be?  It probably is physiologic as the neurotoxicity of the fibrils to neurons in culture was the same as fibrils grown at neutral pH.  This still isn’t the same as fibrils grown in the messy concentrated chemical soup known as the cytoplasm.  Tending to confirm their findings is the fact that NMR and Xray diffraction on the crystals produced the same result.

The fibrils were unbranched and microns long (implying at least 2,000 layers of the beta sheets to be described).  The beta sheets stack in parallel and in register giving the classic crossBeta sheet structure.  They were made of two protofilaments winding around each other.  Each protofilament contains all 42 amino acids of Abeta42 and all of them form a completely flat beta sheet structure.

Feast your eyes on figure 2 p. 117.  In addition to showing the two beta sheets of the two protofilaments, it shows how they bind to each other.  Aspartic acid #1 of one sheet binds to lysine #28 of the other.  Otherwise the interface is quite hydrophobic.  Alanine2 of one sheet binds to alanine42 of the other, valine39 of one sheet binds to valine 39 of the other.  Most importantly isoLeucine 41 of one sheet binds to glycine38 of the other.

This is important since the difference between the less toxic Abeta40 and the toxic Abeta 42 are two hydrophobic amino acids Isoleucine 41 and Alanine 42.  This makes for a tighter, longer, more hydrophobic interface between the protofilaments stabilizing them.

That’s just a guess.  I can’t wait for work on Abeta40 to be reported at this resolution.

A few other points.  The beta sheet of each protomer is quite planar, but the planes of the two protomers are tilted by 10 degrees accounting for the helicity of the fibril. The fibril is a rhombus whose longest edge is about 70 Angstroms.

Even better the structure explains a mutation which is protective against Alzheimer’s.  This remains the strongest evidence (to me at least) that Abeta peptides are significantly involved in Alzheimer’s disease, therapeutic failures based on this idea notwithstanding.  The mutation is a change of alanine2 to threonine which can’t possibly snuggle up hydrophobically to isoleucine nearly as well as alanine did. This should significantly weaken the link between the two protofilaments and make fibril formation more difficult.

The Abeta structure of the paper also explains another mutation. This one increases the risk of Alzheimer’s disease (like many others which have been discovered).  It involves the same amino acid (alanine2) but this time it is changed to the more hydrophobic valine, probably resulting in a stronger hydrophobic interaction with isoLeucine41 (assuming that valine’s greater bulk doesn’t get in the way sterically).

Wonderful stuff to think and speculate about, now that we actually have some solid data to chew on.

Who knew Marshall McLuhan was a molecular biologist

Marshall McLuhan famously said “the medium is the message”. Who knew he was talking about molecular biology?  But he was, if you think of the process of transcription of DNA into various forms of RNA as the medium and the products of transcription as the message.  That’s exactly what this paper [ Cell vol. 171 pp. 103 – 119 ’17 ] says.

T cells are a type of immune cell formed in the thymus.  One of the important transcription factors which turns on expression of the genes which make a T cell a Tell is called Bcl11b.  Early in T cell development it is sequestered away near the nuclear membrane in highly compacted DNA. Remember that you must compress your 1 meter of DNA down by 100,000fold to have it fit in the nucleus which is 1/100,000th of a meter (10 microns).

What turns it on?  Transcription of nonCoding (for protein) RNA calledThymoD.  From my reading of the paper, ThymoD doesn’t do anything, but just the act of opening up compacted DNA near the nuclear membrane produced by transcribing ThymoD is enough to cause this part of the genome to move into the center of the nucleus where the gene for Bcl11b can be transcribed into RNA.

There’s a lot more to the paper,  but that’s the message if you will.  It’s the act of transcription rather than what is being transcribed which is important.

The paper doesn’t talk about the structure of ThymoD — how long it is, whether it binds to anything in the nucleus — etc. etc.  Perhaps I’ve missed it.  I’ve written the lead author. Hopefully I won’t be too embarrassed by what he responds.

Here’s more about McLuhan — https://en.wikipedia.org/wiki/Marshall_McLuhan

If some of the terms used here are unfamiliar — look at the following post and follow the links as far as you need to.  https://luysii.wordpress.com/2010/07/07/molecular-biology-survival-guide-for-chemists-i-dna-and-protein-coding-gene-structure/

 

How fast is your biological clock ticking — latest results

Our family breeds like sequoias.  Medicine has improved, but biology hasn’t changed, and problems with fertility and miscarriages have emerged in the generation behind me.   A cousin had a child at 46 who is now in grad school.  My brother had a child at 48, also doing OK. One son, who is north of 50 has an infant and a 3 year old.  That’s why the following paper from Iceland is so relevant.  I’ve posted on this subject before, but the new paper has 10 times the data of the old [ Nature vol. 549 pp. 519 – 522 ’17 ].

The paper is from Iceland, and whether the data can be extrapolated to other populations isn’t clear — but the biology in question is so basic that I think it can. Some 1,548 mother father child trios had their entire genomes (to 35 fold coverage).  In addition, 225 of the children had reproduced, providing a few 2 generation families.  If any position in the 3,200,000,000 bases of the genome differs from that of the mother and the father, than a mutation has taken place.  It isn’t clear how old the children were when sequenced, so possibly some of the mutations arose since birth.

Some 108,778 de novo mutations were found in over 1548 + 225 (at least) individuals — so each individual carried an average of 61 de novo mutations.  When the number of mutations were plotted against the ages of both parents, it was found that each year a father waited to reproduce added 1.51 mutations.  Previous work (with much less data) stated that the age of the mother didn’t matter.  No so, although the mutational burden of an additional year before reproduction in a woman increased the mutations 4 times less (.37 extra mutations/year of maternal life).

The previous paper reported on was somewhat suspect, because the 78 parent child trios had a child with autism.  Not so in this population study.

The numbers were large enough, that the type of mutation could be studied.  Mothers and fathers had different types of mutations in different frequencies.   They found one 20 megaBase region on chromosome #8 with a mutation rate of cytosine to guanosine (C to G) 50 times higher than the rest of the genome.

People use ‘molecular clocks’ to time evolution of species, based on the assumption that the mutation rate is constant.  But it isn’t with age, and a shift in the average age for reproduction could seriously screw up the molecular clock predictions.

An average of 61 de novo mutations per individual sounds pretty horrible, but it isn’t when you consider that 3,200,000,000 – 61 positions were copied faithfully (an error rate of 1 in 50 million).

 

Puerto Rico

Reporting on the recovery efforts in Puerto Rico seems to be more about scoring political points than helping out.   The mainstream press (NYT, CNN, Washington Post) is attempting to paint this as another Katrina, while the conservative side (WSJ, the White House) says that everything is just wonderful.

I don’t like to get into politics, but the following is worth reading.  It is from a good friend who had a long career at Chase Manhattan Bank rising high enough to go on yearly dog and pony shows with the head (David Rockefeller).  It actually has some data.  Unsurprisingly, it has a rather conservative take on things, but it is still interesting.

“The abject irresponsibility of Puerto Rican politicians has been evident for 25+ years. Back some 15 years ago, a  former colleague at Chase Manhattan , Alfredo Salazar,  was for a short period in the Puerto Rican government responsible for finance. He went very publically and very loudly with the  warning to the political establishment that the ongoing fiscal irresponsibility of the PR government was unsustainable. He was purged quickly.

The buying of votes continued to escalate the debt –  reaching a climax of the territorial bankruptcy this year. As usual the politicians get off from, in effect, a crime spree lasting decades without being held accountable. It is one of the weaknesses of our governmental system. There should be no forgiving of debt without a charter change inhibiting the politicians from going back to “business as usual”. Incidentally since 1965 Puerto Rico has only had Democrat Governors.”

 

–       xxxxx

Here’s a link to Wkipedia about Salazar — https://en.wikipedia.org/wiki/Alfredo_Salazar,_Jr. — it doesn’t mention any falling out of Salazar with the government — but these things are edited and re-edited by partisans.

Oct 4, 2017 | 14:29 GMT

Puerto Rico: U.S. President Says Territory’s Massive Debt Will Have To Be Forgiven

 

While on a visit to Puerto Rico to observe recovery efforts following Hurricane Maria, U.S. President Donald Trump said the island’s massive debt will have to be wiped out, Reuters reported Oct. 4. Facing massive debt, Puerto Rico filed for bankruptcy earlier this year and is struggling to regain economic stability.

The worst name for a drug I’ve ever heard of

It is simply impossible for me to think of a worse name for a drug which might help people with Down syndrome than ALGERNON.   The authors can be excused as they’re all from Japan, but the editor of the paper Fred Gage should have known about ‘Flowers for Algernon’– https://en.wikipedia.org/wiki/Flowers_for_Algernon.  Briefly, it’s a story about a drug which tripled the intelligence of Algernon a laboratory mouse which was then given to a retarded individual (Charlie Gordon) whose intelligence similarly tripled, only to decline like Algernon’s.  It was originally a short story, then a book, then a play etc. etc.

The drug is potentially quite exciting — ALGERNON is an acronym forALtered GenERatioN Of Neurons).  It increases the number of neurons form by mice with a model of trisomy 21.  The brain is bigger, and the animals do better on tests.  It is thought to work by inhibiting an enzyme (DYRK1A) which adds phosphate to serine, threonine and tyrosine, making it a dual specificity kinase.  It phosphorylates a variety of proteins known to have significant effects on brain development (tau, cyclin D1, caspase9, Notch, gli1, etc). The net effect of DYRK1A inhibition is to increase neural stem cell proliferation during fetal life.

Chemists will be interested in just how simple the structure of ALGERNON is — it’s an all aromatic compound made of a pyridine linked to a fused 6:5 ring system in which the 5 membered ring contains 2 nitrogens.  That’s it.  No alcohols, methyls, ethyls, ..  amines, amides, ethers etc., etc.

The authors blue-sky a bit at the end.  They note that mice show neural proliferation during adult life (we do as well, but to a much lesser extent).  It might be useful to improve function in living Down syndrome individuals, and just about any other neurological problem in which neural proliferation would be beneficial.  It might also be offered to women carrying a Down fetus who object to abortion on moral grounds.  Exciting stuff, but for god’s sake change the name.

The volcanos did it

Why did the glaciers below the equator retreat 17,700 years ago (17.7 ka)?  A series of volcanic eruptions spanning 192 years down there did it according to Proc. Natl. Acad. Sci. vol. 114 pp. 10035 – 10040 ’17.  No one was driving SUVs then and mankind had barely invented farming in the old world.   Have we had an usual amount of volcanic activity in the past 100 to 1,000 years? Here’s the summary.

“Glacial-state greenhouse gas concentrations and Southern Hemisphere climate conditions persisted until ∼17.7 ka, when a nearly synchronous acceleration in deglaciation was recorded in paleoclimate proxies in large parts of the Southern Hemisphere, with many changes ascribed to a sudden poleward shift in the Southern Hemisphere westerlies and subsequent climate impacts.

We used high-resolution chemical measurements in the West Antarctic Ice Sheet Divide, Byrd, and other ice cores to document a unique, ∼192-y series of halogen-rich volcanic eruptions exactly at the start of accelerated deglaciation, with tephra identifying the nearby Mount Takahe volcano as the source. Extensive fallout from these massive eruptions has been found >2,800 km from Mount Takahe. Sulfur isotope anomalies and marked decreases in ice core bromine consistent with increased surface UV radiation indicate that the eruptions led to stratospheric ozone depletion. Rather than a highly improbable coincidence, circulation and climate changes extending from the Antarctic Peninsula to the subtropics—similar to those associated with modern stratospheric ozone depletion over Antarctica—plausibly link the Mount Takahe eruptions to the onset of accelerated Southern Hemisphere deglaciation ∼17.7 ka.”

DNA solves a 25 year old rape/murder in a new way

It probably won’t make national news, but a 25 year old rape/murder of a 24 year old school teacher was solved with a new way to use DNA.  Yes, the cops had a DNA sample; but no matches were found in the national databases.  Recently they sent some DNA to https://www.parabon-nanolabs.com, a company that claims to produce a descriptive profile of the source of any human DNA sample, including pigmentation, face morphology, and other forensically relevant traits.  Sounds like total BS but it worked.

Law enforcement had worked on the case for 25 years, and the parents never gave up. Over the years they compiled a long list of suspects and persons of interest.  The physical description produced by the company allowed the police to narrow down the list of possible suspects and focus on a smaller group.  Prior to receiving the Parabon information, the DA’s office had begun reexamining all the evidence and reviewing the stories of all the many subjects interviewed over the years, in an attempt to rule out suspects.

In the last few months, the DA’s office went through legal processes to get court orders to compel people of interest to provide DNA samples.  Now that’s fascinating — aren’t you supposed to be protected against self-incrimination — clearly something to ask my nephew — who is an attorney very interested in such matters.  I’ll put in addendum from him.

That was how investigators showed up at the suspect’s residence last week to execute a court order compelling him to give a sample.  He was not home at the time, but investigators left a message explaining why they were there.  The suspect upon learning this, bolted to another state, where he apparently tried to kill himself.  He has apparently confessed.  God only knows what else he’s done in the past 25 years.

Addendum 25 Sep ’17

The following work by Venter is scary with its implications for privacy [ Proc. Natl. Acad. Sci. vol. 114 pp. 10166 -b10171 ’17 ]

Prediction of human physical traits and demographic informa- tion from genomic data challenges privacy and data deidenti- fication in personalized medicine. To explore the current capa- bilities of phenotype-based genomic identification, we applied whole-genome sequencing, detailed phenotyping, and statistical modeling to predict biometric traits in a cohort of 1,061 partici- pants of diverse ancestry. Individually, for a large fraction of the traits, their predictive accuracy beyond ancestry and demographic information is limited. However, we have developed a maximum entropy algorithm that integrates multiple predictions to deter- mine which genomic samples and phenotype measurements origi- nate from the same person. Using this algorithm, we have reiden- tified an average of >8 of 10 held-out individuals in an ethnically mixed cohort and an average of 5 of either 10 African Americans or 10 Europeans. This work challenges current conceptions of personal privacy and may have far-reaching ethical and legal implications.